Psycho-​Oncology
Psycho-​Oncology
FOURTH EDITION
EDITED BY
William S. Breitbart, MD, FAPOS
Phyllis N. Butow, BA(Hons), DipEd, MClinPsych,
MPH, PhD
Paul B. Jacobsen, PhD
Wendy W. T. Lam, RN, PhD, FFPH
Mark Lazenby, APRN, PhD
Matthew J. Loscalzo, MSW, LCSW, FAPOS
1
3
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Library of Congress Cataloging-in-Publication Data
Names: Breitbart, William S., 1951– editor.
Title: Psycho-oncology / [edited by] William S. Breitbart, Phyllis N. Butow, Paul B. Jacobsen, Wendy W. T. Lam,
Mark Lazenby, Matthew J. Loscalzo ; senior editor, William Breitbart.
Other titles: Psycho-Oncology (Holland)
Description: 4th edition. | New York, NY : Oxford University Press, [2021] |
Includes bibliographical references and index.
Identifiers: LCCN 2020029603 (print) | LCCN 2020029604 (ebook) |
ISBN 9780190097653 (hardback) | ISBN 9780190097677 (epub) | ISBN 9780190097684
Subjects: MESH: Neoplasms—psychology | Risk Factors | Neoplasms—prevention & control |
Neoplasms—therapy
Classification: LCC RC262 (print) | LCC RC262 (ebook) | NLM QZ 260 |
DDC 616.99/40019—dc23
LC record available at https://lccn.loc.gov/2020029603
LC ebook record available at https://lccn.loc.gov/2020029604
DOI: 10.1093/​med/​9780190097653.001.0001
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Dedication: Jimmie C. Holland, M.D. (1928–2017)
Psycho-​Oncology, 4th edition is solemnly dedicated to Professor Jimmie C. Holland, MD (1928–​2017), internationally recognized as the founder
of the field of psycho-​oncology. Dr. Holland, who was affectionately known by her first name, “Jimmie,” had a profound global influence on the
fields of psycho-​oncology, oncology, supportive care, psychiatry, behavioral medicine, and psychosomatic medicine. At the time of her passing,
Dr. Holland was the Attending Psychiatrist and Wayne E. Chapman Chair at Memorial Sloan Kettering Cancer Center (MSK) and Professor of
Psychiatry, Weill Medical College of Cornell University in New York.
In 1977, Jimmie was appointed Chief of the Psychiatry Service in the Department of Neurology at MSK, by Jerome Posner, MD, then Chairman of
Neurology at MSK. The Psychiatry Service at MSK was the first such clinical, research, and training service established in any cancer center in the
world. In 1996, Dr. Holland was named the inaugural Chairwoman of the Department of Psychiatry and Behavioral Sciences at MSK—​again,
the first such department created in any cancer center in the U.S. or the world. Dr. Holland had over a 40-​year career at MSK.
Jimmie created and nurtured the field of psycho-​oncology, established its clinical practice, advanced its clinical research agenda, and, through
her pioneering efforts, launched the careers of the leaders of a worldwide field who continue to work in what has become a shared mission to emphasize “care” in cancer care. Dr. Holland founded the International Psycho-​Oncology Society (IPOS) in 1984 and the American Psychosocial
Oncology Society in 1986. Over 25 years ago, Jimmie founded the international journal Psycho-​Oncology and coedited the journal for 30 years.
Dr. Holland received many awards recognizing her achievements over the course of her career. Some of her notable awards include the Medal
of Honor for Clinical Research from the American Cancer Society, the Clinical Research Award from the American Association of Community
Cancer Centers, the American Association for Cancer Research Joseph H. Burchenal Clinical Research Award, the Marie Curie Award from the
Government of France, the Margaret L. Kripke Legend Award for contributions to the advancement of women in cancer medicine and cancer
science from the MD Anderson Cancer Center, the T. J. Martell Foundation 2015 Women of Influence Award, and the Distinguished Alumnus
Award from Baylor College of Medicine in 2016. She served as President of the Academy of Psychosomatic Medicine (APM) in 1996 and was the
recipient of the APM’s Hackett Lifetime Achievement Award in 1994. She was the inaugural recipient of the Arthur Sutherland Award for Lifetime
Achievement from IPOS.
This 4th edition of Psycho-​Oncology is the first edition of this text that has not been edited by Dr. Holland. In 1989, Dr. Holland edited the
Handbook of Psychooncology: Psychological Care of the Patient with Cancer, the first major textbook in our field. This landmark book was notable for several reasons; it established our “new” field, and it was the first use, in a text, of the term “psychooncology” to name our field (thankfully
the hyphen was soon added). Psycho-​oncology was thus born and named with the publication of this textbook. Subsequently, Dr. Holland edited,
with a group of dedicated coeditors, several editions of what became known as the “Bible” of psycho-​oncology or, in many circles, the “Holland
Textbook of Psycho-​oncology.” The textbook Psycho-​Oncology was published in 1998 and represented the most comprehensive, multidisciplinary, and international encyclopedia of a field entering its adolescence. The year 2010 saw the publication of the 2nd edition, followed by the 3rd
edition in 2015, both published by Oxford University Press in collaboration with IPOS and APOS. Every card-​carrying “psycho-​oncologist” in
over 60 countries with national psycho-​oncology societies around the world had to have the latest edition in their library. For many it represented
a valued link to Jimmie Holland. The task of editing this 4th edition of Psycho-​Oncology without Jimmie’s firm guidance and wise counsel was
daunting for all of us, but we were all deeply inspired to do so because of our loving debt to Jimmie. The torch has been passed.
Dedication: Ruth McCorkle, PhD, RN, FAAN (1941–​2019)
In January 1975, a 33-​year-​old Ruth McCorkle, a newly minted PhD from the University of Iowa and a new assistant professor at the University of
Washington, met Jimmie C. Holland at a conference on the behavioral dimensions of cancer that was organized by the National Cancer Institute
in San Antonio, Texas. This meeting began a lifelong friendship and collaboration, not least of which was this book.
Ruth McCorkle died on August 17, 2019, in her home in Hamden, CT, from cancer. At the time of her death, she was the Florence Schorske Wald
Professor of Nursing Emerita at Yale University.
From the earliest days of her career, Ruth was interested in the lived experiences of people diagnosed with cancer, including the effects of touch on
the seriously ill and how the attachments and goals of patients undergoing treatment for lung cancer—​and their families—​changed over time. At
the University of Washington, she and Jeanne Quint-​Benoliel developed the first multidisciplinary cancer unit in which patients and their families
would be seen from the time of diagnosis through the dying experience by an interprofessional team.
It was on this unit, in the mid 1970’s, that she developed the first scale that measured the distress cancer patients experienced, the Symptom
Distress Scale. As a student of history, she learned of how Sir William Osler had taken field notes on his dying experience, in which he wrote that,
because he had “no actual pain,” he felt “singularly free from mental distress” as he was dying. In the early 1970’s, when Ruth had gone to London
to study with Dame Cicely Saunders at St. Christopher’s Hospice, she was introduced to the British psychiatrist J. M. Hinton and his now justly
famous qualitative work on associations between dying patients’ physical and mental distress. From Saunders and Hinton, and from Osler’s field
notes, Ruth began to see that patients’ mental distress could be related to their physical symptoms. She thus became interested in the points at
which a physical symptom becomes emotionally unbearable. Hence, her scale measured the presence of a symptom as well as how distressed a
patient was by it. The development of the Symptom Distress Scale led to her intervention.
She developed and tested in 7 National Institutes of Health-​funded clinical trials the Standardized Nursing Intervention Protocol, an intervention
in which an advanced practice cancer nurse helped patients and families learn to manage distressing symptoms. In a breakthrough, one of those
trials resulted in a 7-​month survival benefit.
We will read much about distress in this 4th edition of Psycho-​Oncology. For the importance of identifying and intervening on the sources of
cancer patients’ distress—​and even for the presence of the word “distress” in the psycho-​oncologic lexicon—​we have Ruth—​and Jimmie—​to thank.
Ruth ended the last article she wrote with this: “. . . patients’ physical needs must be addressed before their psychosocial problems are identified. It
is not just about taking care of their physical needs first. Rather, it is that we may be creating distress by not doing so.” Over the last 6 weeks of her
life, she instructed her hospice care providers on how to manage her physical needs, and her close friends and family provided the physical touch
she knew would comfort her emotionally. In this experience, one can find the truth of Ruth’s entire scientific career.
In this 4th edition of Psycho-​Oncology, you will find this truth woven into the science the book reports on: For Ruth, psycho-​oncology was not
just about how to support patients and families living with cancer. It was also about enabling them to have deaths “singularly free from mental
distress.” It is thus fitting that, along with Jimmie C. Holland, we dedicate this edition to Ruth McCorkle.
Contents
Section editors xiii
Contributors xv
Introduction: Our Past, Our Future—New
Frontiers in Psycho-​Oncology 1
William S. Breitbart (Senior Editor)
SECTION I
Behavioral and Psychological Factors in
Cancer Risk and Prevention
Paul B. Jacobsen (Section Editor)
1 Tobacco Use and Cessation 7
Thomas H. Brandon, Vani N. Simmons, Úrsula Martínez, and
Patricia Calixte-​Civil
8 Cervical Cancer Screening and HPV
Vaccination: Multilevel Challenges to Cervical
Cancer Prevention 61
Richard Fielding, Samara Perez, Zeev Rosberger, Ovidiu Tatar,
and Linda D. L. Wang
9 Breast Cancer Screening 68
Gabriel M. Leung, Irene O. L. Wong, Ava Kwong, and
Joseph T. Wu
10 Prostate Cancer Screening 74
Michael A. Diefenbach, Daniel Nethala, Michael Schwartz, and
Simon J. Hall
11 Lung Cancer Screening 78
Lisa Carter-​Harris and Jamie Ostroff
12 Skin Cancer Screening 87
Jennifer L. Hay and Stephanie N. Christian
2 Diet and Cancer 13
Marian L. Fitzgibbon, Lisa Tussing-​Humphreys, Angela Kong,
and Alexis Bains
3 Physical Activity, Sedentary Behavior, and
Cancer 21
Christine M. Friedenreich, Chelsea R. Stone, and Jessica McNeil
4 Sun Exposure and Cancer Risk 30
Suzanne J. Dobbinson, Afaf Girgis, Bruce K. Armstrong, and
Anne E. Cust
5 Psychosocial Factors 36
Anika von Heymann and Christoffer Johansen
6 Viral Cancers and Behavior 43
Susan T. Vadaparampil, Lindsay N. Fuzzell, Shannon M. Christy,
Monica L. Kasting, Julie Rathwell, and Anna E. Coghill
SECTION III
Screening and Testing for Germ Line and
Somatic Mutations
Paul B. Jacobsen (Section Editor)
13 Psychosocial Issues in Genetic Testing for
Breast/​Ovarian Cancer 95
Mary Jane Esplen, Jonathan Hunter, and Eveline M. A. Bleiker
14 Psychosocial Issues in Genetic Testing for
Hereditary Colorectal Cancer 102
Sukh Makhnoon and Susan K. Peterson
15 Psychosocial Issues in Genomic Testing, Including
Genomic Testing for Targeted Therapies 110
Megan Best
SECTION II
Screening for Cancer in Normal and At-​Risk
Populations
Wendy W. T. Lam (Section Editor)
7 Colorectal Cancer Screening 53
Caitlin C. Murphy and Sally W. Vernon
16 Psychosocial Issues Related to Liquid Biopsy for
ctDNA in Individuals at Normal and Elevated
Risk 116
Jada G. Hamilton, Amanda Watsula-​Morley, and
Alicia Latham
viii
Contents
SECTION IV
Screening and Assessment in Psychosocial
Oncology
Wendy W. T. Lam (Section Editor)
17 Screening and Assessment for Distress 121
Alex J. Mitchell
18 Assessment, Screening, and Case Finding
for Depression and Anxiety in People with
Cancer 130
Kristine A. Donovan and Paul B. Jacobsen
19 Screening for Delirium and Dementia in the
Cancer Patient 137
Christian Bjerre-​Real, James C. Root, Yesne Alici,
Julia A. Kearney, and William S. Breitbart
20 Screening and Assessment for Cognitive
Problems 146
Alexandra M. Gaynor, James C. Root, Elizabeth Ryan, and
Tim A. Ahles
29 Head and Neck Cancer 215
Loreto Fernández González, Jonathan Irish, and Gary Rodin
30 Central Nervous System Tumors 221
Alan D. Valentine
31 HIV Infection and AIDS-​Associated
Neoplasms 226
Joanna S. Dognin and Peter A. Selwyn
SECTION VI
Management of Specific Physical
Symptoms
William S. Breitbart (Section Editor)
32 Cancer-​Related Pain 235
R. Garrett Key, Dustin Liebling, Vivek T. Malhotra,
Steven D. Passik, Natalie Moryl, and William S. Breitbart
33 Nausea and Vomiting 255
Laura J. Lundi and Kavitha Ramchandran
34 Cancer-​Related Fatigue 265
SECTION V
Psychological Issues Related to Site of
Cancer
Mark Lazenby (Section Editor)
21 Melanoma 155
Nadine A. Kasparian and Iris Bartula
22 Lung Cancer 162
Marianne Davies
23 Breast Cancer 169
M. Tish Knobf and Youri Hwang
24 Colorectal Cancer 176
Anne Miles and Claudia Redeker
25 Prostate Cancer and Genitourinary
Malignancies 182
Daniel C. McFarland, Christian Bjerre-​Real, Yesne Alici, and
William S. Breitbart
35 Sexual Problems and Cancer 276
Jeanne Carter, Ashley Arkema, Andrew J. Roth, Sally Saban, and
Christian J. Nelson
36 Neuropsychological Impact of Cancer and Cancer
Treatments 283
Alexandra M. Gaynor, James C. Root, and Tim A. Ahles
37 Sleep and Cancer 291
Amy E. Lowery-​Allison and E. Devon Eldridge-​Smith
38 Weight and Appetite Loss in Cancer 298
Yesne Alici and Victoria Saltz
39 Body Image—​An Important Dimension in Cancer
Care 303
Mary Jane Esplen and Michelle Cororve Fingeret
Andrew J. Roth and Alejandro Gonzalez-​Restrepo
26 Gastrointestinal Cancers 189
Daniel C. McFarland and William S. Breitbart
27 Gynecologic Cancers 196
Heidi S. Donovan and Teresa H. Thomas
28 Hematopoietic Dyscrasias and Stem Cell
Transplantation/​CAR-​T Cell Therapy 203
Jesse R. Fann and Nicole Bates
SECTION VII
Psychiatric Disorders
William S. Breitbart (Section Editor)
40 Adjustment Disorders in Cancer 313
Froukje de Vries, Sarah Hales, Gary Rodin, and Madeline Li
41 Depressive Disorders in Cancer 320
Christian Schulz-​Quach, Madeline Li, Kimberley Miller, and
Gary Rodin
Contents
42 Suicide and Medical Aid in Dying 329
Hayley Pessin, Elie Isenberg-​Grzeda, Reena Jaiswal, and
Monique James
43 Anxiety Disorders 338
Ashley M. Nelson, Chelsea S. Rapoport, Lara Traeger, and
Joseph A. Greer
44 Delirium 345
Yesne Alici and William S. Breitbart
45 Substance Use Disorders 355
Sameer Hassamal, Adam Rzetelny, and Steven D. Passik
46 Posttraumatic Stress Disorder Associated with
Cancer Diagnosis and Treatment 363
Matthew Doolittle and Katherine N. DuHamel
47 Psychiatric Toxicities of Cancer Therapies: Focus
on Immunotherapy and Targeted Therapy 374
Daniel C. McFarland, Mehak Sharma, and Yesne Alici
SECTION VIII
Evidence-​Based Interventions
William S. Breitbart and Phyllis N. Butow (Section Editors)
Models of Care Delivery
48 Delivering Integrated Psychosocial Oncology
Care: The Collaborative Care Model 385
Jesse R. Fann, Julia Ruark, and Michael Sharpe
49 The Engaged Patient: The Cancer Support
Community’s Comprehensive Model of
Psychosocial Programs, Services, and
Research 393
Mitch Golant, Alexandra K. Zaleta, Susan Ash-​Lee,
Joanne S. Buzaglo, Kevin Stein, M. Claire Saxton,
Marcia Donziger, Kim Thiboldeaux, and Linda Bohannon
50 The Role of Implementation Science in
Advancing Psychosocial Cancer Care 400
Paul B. Jacobsen and Wynne E. Norton
Interventions During Active Treatment
51 Supportive Psychotherapy in Cancer 409
Rosangela Caruso, Maria Giulia Nanni, and Luigi Grassi
52 Cognitive and Behavioral Interventions 416
Barbara L. Andersen, Nicole A. Arrato, and Caroline S. Dorfman
53 Metacognitive Approaches 424
Louise Sharpe and Leah Curran
54 Mindfulness-​Based Interventions 429
Linda E. Carlson
55 Acceptance and Commitment Therapy (ACT) for
Cancer Patients 438
Nicholas J. Hulbert-​Williams, Ray Owen, and Christian J. Nelson
56 Supportive-​Expressive and Other Forms of Group
Psychotherapy in Cancer Care 445
David W. Kissane
57 Emotion-​Focused Therapy 452
Sharon Manne
58 Interpersonal Psychotherapy and Cancer 459
Jennifer Sotsky, Hayley Pessin, and John C. Markowitz
59 Integrative Oncology 470
Santhosshi Narayanan, Gabriel Lopez, Jun J. Mao, Wenli Liu,
and Lorenzo Cohen
Interventions for Families and Couples
60 Psychosocial Interventions for Couples and
Families Coping with Cancer 481
Talia I. Zaider and David W. Kissane
Interventions for Advanced Cancer/​End of
Life/​Bereavement
61 Meaning-​Centered Psychotherapy 489
Melissa Masterson Duva, Wendy G. Lichtenthal,
Allison J. Applebaum, and William S. Breitbart
62 Dignity Therapy 495
Harvey Max Chochinov and Maia S. Kredentser
63 Managing Cancer and Living Meaningfully
(CALM) Therapy 502
Sarah Hales and Gary Rodin
64 Bereavement Interventions in the Setting of
Cancer Care 509
Wendy G. Lichtenthal, Kailey E. Roberts, Holly G. Prigerson, and
David W. Kissane
Interventions for Cancer Survivors
65 Meaning-​Centered Group Psychotherapy for
Cancer Survivors 521
Nadia van der Spek, Wendy G. Lichtenthal, Karen Holtmaat,
William S. Breitbart, and Irma M. Verdonck-​de Leeuw
66 Physical Activity and Exercise Interventions in
Cancer Survivors 528
Chloe Grimmett, Rebecca J. Beeken, and Abigail Fisher
ix
x
Contents
Digital Health Interventions
76 Financial Toxicity in Cancer Treatment 616
67 e-Health Interventions for Cancer Prevention
and Control 537
77 The Experience of Cancer as an Immigrant 621
Kelly M. Shaffer, Elliot J. Coups,† and Lee M. Ritterband
68 Digital Health Interventions for Psychosocial
Distress (Anxiety and Depression) in Cancer 543
Lisa Beatty and Haryana Dhillon
69 e-​Health Interventions for Physical Symptom
Control 550
Robert Zachariae
70 e-​Health Interventions for Tobacco
Cessation 561
Chris Kotsen, Jamie Ostroff, and Lisa Carter-​Harris
Victoria Blinder and Francesca M. Gany
Francesca M. Gany and Jennifer Leng
78 Sexual and Gender Minority Health in
Psycho-​Oncology 627
Charles Kamen and Jennifer M. Jabson Tree
SECTION XII
Bio-​Behavioral Psycho-​Oncology
William S. Breitbart and Mark Lazenby (Section Editors)
79 Psycho-​Oncology, Stress Processes, and Cancer
Progression 637
Michael H. Antoni, Jennifer M. Knight, and Susan K. Lutgendorf
SECTION IX
Psychosocial Issues at the Time of Diagnosis
Matthew J. Loscalzo (Section Editor)
71 Treatment Decision Making 573
Allison Marziliano and Michael A. Diefenbach
72 The Family Meeting: Communication across the
Continuum of Cancer Care 578
Stefanie N. Mooney and Marinel Olivares
80 Depression, Inflammation, and Cancer 644
Daniel C. McFarland, Leah E. Walsh, and Andrew H. Miller
81 Biobehavioral Psycho-​Oncology
Interventions 654
Michael A. Hoyt and Frank J. Penedo
SECTION XIII
Geriatric Psycho-​Oncology
Matthew J. Loscalzo (Section Editor)
SECTION X
Palliative and Supportive Care
Mark Lazenby (Section Editor)
73 Psychological and Psychiatric Aspects of Palliative
and End-​of-​Life Care: Synergies between Psycho-​
Oncology and Palliative Care 589
Scott A. Irwin, Nathan Fairman, Chase Samsel, Jeremy M. Hirst,
Jason A. Webb, and Manuel Trachsel
74 Prognostic Understanding in Advanced Cancer
Patients 599
Laura C. Polacek, Leah E. Walsh, Allison J. Applebaum, and
Barry Rosenfeld
SECTION XI
Diversities in the Experience of Cancer
Matthew J. Loscalzo (Section Editor)
75 Cancer, Culture, and Health Disparities 609
Marjorie Kagawa-​Singer and Annalyn Valdez-​Dadia
82 The Older Cancer Patient 663
Barbara A. Given and Charles W. Given
83 Geriatric Psycho-​Oncology Assessment Issues
and Interventions 671
Kelly M. Trevino, Rebecca M. Saracino, Andrew J. Roth,
Yesne Alici, and Christian J. Nelson
84 Communicating with the Older Adult Cancer
Patient 678
Patricia A. Parker, Smita C. Banerjee, and Beatriz Korc-​Grodzicki
SECTION XIV
Pediatric Psycho-​Oncology
William S. Breitbart (Section Editor)
85 Screening and Assessment in Pediatric
Psycho-​Oncology 687
Darcy E. Burgers, Sarah J. Tarquini, Anne E. Kazak, and
Anna C. Muriel
Contents
86 Psychiatric Disorders in Pediatric Psycho-​
Oncology: Diagnosis and Management 696
Julia A. Kearney, Meredith E. MacGregor, and Maryland Pao
87 Evidence-​Based Psychosocial Interventions in
Pediatric Psycho-​Oncology 703
Lori Wiener, Marie Barnett, Stacy Flowers, Cynthia Fair, and
Amanda L. Thompson
88 Adolescent and Young Adult Patients 715
Christabel K. Cheung, Sheila J. Santacroce, and Bradley J. Zebrack
SECTION XV
Psychological Issues for the Family and
Caregivers
Phyllis N. Butow (Section Editor)
89 Including Family Members in Caring for
the Patient with Cancer: A Family-​Centered
Approach 723
Douglas S. Rait
90 Couples Facing Cancer 729
Hoda Badr and Courtney Bitz
SECTION XVII
Building Supportive Care/​Psycho-​Oncology
Teams
Phyllis N. Butow (Section Editor)
Building Supportive Care Teams: Working
Together and Self-​Care
96 Integrating Interdisciplinary Supportive Care
Programs: Transforming the Culture of Cancer
Care 775
Matthew J. Loscalzo, Karen L. Clark, Barry D. Bultz, and
Juee Kotwal
97 Occupational Stress in Oncology Staff: Burnout,
Resilience, and Interventions 782
Fay J. Hlubocky and Daniel C. McFarland
Health Provider/​Patient Communication
98 Principles of Communication Skills Training
in Cancer Care across the Life Span and Illness
Trajectory 791
David W. Kissane and Carma L. Bylund
91 Cancer Caregivers 737
Allison J. Applebaum, Erin Kent, Kristin Litzelman, Betty Ferrell,
J. Nicholas Dionne-​Odom, and Laurel Northouse
92 Addressing the Needs of Children When a Parent
Has Cancer 745
Cynthia W. Moore, Greer J. Dent, and Paula K. Rauch
SECTION XVIII
Psycho-​Oncology in Health Policy
Wendy W. T. Lam (Section Editor)
99 Distress, the Sixth Vital Sign: A Catalyst for
Standardizing Psychosocial Care Globally 801
SECTION XVI
Survivorship
Phyllis N. Butow and Wendy W. T. Lam (Section Editors)
93 Fear of Cancer Recurrence 755
Allan B. Smith, Joanna E. Fardell, and Phyllis N. Butow
94 Implementing the Survivorship Care Plan: A
Strategy for Improving the Quality of Care for
Cancer Survivors 760
Erin E. Hahn and Patricia A. Ganz
95 Adult Survivors of Childhood Cancer 767
Lisa A. Schwartz, Claire E. Wakefield, Jordana K. McLoone,
Branlyn Werba DeRosa, and Anne E. Kazak
Barry D. Bultz, Matthew J. Loscalzo, Alex J. Mitchell, and
Jimmie C. Holland†
100 Implementation of Clinical Practice Guidelines
for Psychosocial Cancer Care 806
Jane Turner and Nicole Rankin
101 Emerging International Directions for
Psychosocial Care: Perspectives from Asia and
Low-​Middle-​Income Countries 813
Jeff Dunn, Melissa Henry, and Maggie Watson
Index 819
xi
Section editors
William S. Breitbart, MD, FAPOS
Wendy W. T. Lam, RN, PhD, FFPH
The Jimmie C. Holland Chair in Psychiatric Oncology
Chairman
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
Professor of Clinical Psychiatry
Vice-Chairman
Department of Psychiatry
Weill Cornell Medical College
President Emeritus, International Psycho-oncology Society
Associate Professor, Head, Division of Behavioural Sciences,
School of Public Health
Director, Jockey Club Institute of Cancer Care, Li Ka Shing
Faculty of Medicine
Director, Centre for Psycho-oncology Research and
Training (CePORT)
The University of Hong Kong
Phyllis N. Butow, BA(Hons), DipEd, MClinPsych, MPH, PhD
Professor of Psychological Medicine
NHMRC Senior Principal Research Fellow
Founding Chair, PoCoG
School of Psychology
University of Sydney
Paul B. Jacobsen, PhD
Associate Director
Healthcare Delivery Research Program
Division of Cancer Control and Population Sciences
National Cancer Institute
Mark Lazenby, APRN, PhD
Associate Dean for Faculty and Student Affairs
Professor of Nursing and Philosophy
University of Connecticut School of Nursing
Matthew J. Loscalzo, MSW, LCSW, FAPOS
Liliane Elkins Professor in Supportive Care Programs
Administrative Director, Sheri and Les Biller Patient and Family
Resource Center
Executive Director, Department of Supportive Care Medicine
Professor, Department of Population Sciences
City of Hope National Medical Center
Contributors
Tim A. Ahles, PhD
Hoda Badr, PhD
Attending Psychologist
Director, Neurocognitive Laboratory
Psychiatry Service
Department of Psychiatry and Behavioral Sciences
Member
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Associate Professor
Department of Medicine
Baylor College of Medicine
Houston, TX, USA
Yesne Alici, MD
Associate Attending Psychiatrist
Clinical Director,
Co-​Director, Bio-​Behavioral Brain Clinic
Psychiatry Service
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Barbara L. Andersen, PhD
Distinguished University Professor
Department of Psychology
Ohio State University
Columbus, OH, USA
Michael H. Antoni, PhD
Professor
Department of Psychology
University of Miami and Sylvester Comprehensive Cancer Center
Miami, FL, USA
Allison J. Applebaum, PhD
Assistant Attending Psychologist
Director, Caregiver’s Clinic
Psychiatry Service
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Ashley Arkema, MS
Nurse Practitioner
Female Sexual Medicine
Brooklyn, NY, USA
Bruce K. Armstrong, BMedSci(Hons), MBBS(Hons), DPhil(Oxon), FRACP, FAFPHM
Retired
School of Population and Global Health
The University of Western Australia
Perth, WA, Australia
Nicole A. Arrato, MA
Graduate Research Assistant
Department of Psychology
Ohio State University
Columbus, OH, USA
Susan Ash-​Lee, MSW, LCSW
Vice President
Clinical Services Program
Cancer Support Community
Denver, CO, USA
Alexis Bains, BSc Nutrition
Research Assistant
Department of Kinesiology and Nutrition
The University of Illinois at Chicago (UIC)
Chicago, IL, USA
Smita C. Banerjee, PhD
Associate Attending Behavioral Scientist
Behavioral Sciences Service
Co-​Director, Comskils Laboratory
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Marie Barnett, PhD
Assistant Attending Psychologist
Psychiatry Service
Department of Psychiatry and Behavioral Sciences &
Department of Pediatrics
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Iris Bartula, DCP
Head of Research Psychology
Melanoma Institute Australia
Senior Lecturer
Northern Sydney Medical School
Faculty of Medicine and Health
University of Sydney
Sydney, NSW, Australia
Nicole Bates, MD
Acting Assistant Professor
Department of Psychiatry and Behavioral Sciences
University of Washington Attending Psychiatrist
Department of Psychosocial Oncology
Seattle Cancer Care Alliance
Seattle, WA, USA
Lisa Beatty, PhD
Senior Research Fellow
College of Medicine and Public Health
Flinders University
Adelaide, SA, Australia
Rebecca J. Beeken, PhD
Associate Professor of Behavioural Medicine
Leeds Institute of Health Sciences
University of Leeds
Leeds, Yorkshire, UK
xvi
Contributors
Megan Best, PhD, MAAE, BMed(Hons), GradDipQHR
Darcy E. Burgers, PhD
Senior Lecturer
Department of Psycho-​Oncology Co-​operative Research Group
University of Sydney
Broadway, NSW, Australia
Psychologist
Division of Pediatric Psychosocial Oncology
Department of Psychosocial Oncology and Palliative Care
Dana-​Farber Cancer Institute
Boston, MA, USA
Courtney Bitz, MSW, LCSW, OSW-​C
Director of Clinical Social Work
Department of Supportive Care Medicine
City of Hope
Duarte, CA, USA
Christian Bjerre-​Real, MD, MMCI
Research Fellow
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Eveline M. A. Bleiker, PhD
Professor
Department of Psychosocial Research and Epidemiology
Netherlands Cancer Institute
Amsterdam, The Netherlands
Victoria Blinder, MD, MSc
Associate Attending Oncologist
Associate Member
Immigrant Health and Cancer Disparities Service
Department of Psychiatry and Behavioral Sciences
Breast Medicine Service
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Phyllis N. Butow, BA(Hons), DipEd, MClinPsych, MPH, PhD
Professor of Psychological Medicine
NHMRC Senior Principal Research Fellow,
Founding Chair, PoCoG
School of Psychology
University of Sydney
Sydney, NSW, Australia
Joanne S. Buzaglo, PhD
Executive Director, PRO Solutions
Outcomes Sciences
ConcertAI
Rydal, PA, USA
Carma L. Bylund, PhD
Professor
College of Journalism and Communications
University of Florida
Newberry, FL, USA
Patricia Calixte-​Civil, MA
Doctoral Student
Department of Psychology
University of South Florida, Moffitt Cancer Center
Tampa, FL, USA
Linda E. Carlson, PhD
President
Global Headquarters
Cancer Support Community
Washington, DC, USA
Professor
Department of Oncology
University of Calgary
Cumming School of Medicine
Calgary, AB, Canada
Thomas H. Brandon, PhD
Jeanne Carter, PhD
Department Chair and Program Leader,
Health Outcomes and Behavior
Moffitt Distinguished Scholar
Director, Tobacco Research and Intervention Program
Moffitt Cancer Center
Professor
Departments of Psychology and Oncologic Sciences
University of South Florida
Tampa, FL, USA
Attending Psychologist
Director, Female Sexual Health Clinic
Gynecology Service
Department of Surgery
Psychiatry Service
Department of Psychiatry and Behavioral Medicine
Memorial Sloan Kettering Cancer Center
New York, NY, USA
William S. Breitbart, MD, FAPOS
Associate Attending Behavioral Scientist
Behavioral Sciences Service
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Linda Bohannon, MSM, BSN, RN
Jimmie C. Holland Chair in Psychiatric Oncology
Chairman
Department of Psychiatry and Behavioral Sciences
Member
Attending Psychiatrist
Supportive Care Service
Department of Medicine
Memorial Sloan Kettering Cancer Center
Vice Chairman and Professor of Clinical Psychiatry
Department of Psychiatry
Weill Cornell Medical College
New York, NY, USA
Barry D. Bultz, AOE, PhD
Professor and Head, Division of Psychosocial Oncology
Daniel Family Leadership Chair in Psychosocial Oncology
Department of Oncology
Cumming School of Medicine
Department of Psychosocial Oncology
Tom Baker Cancer Center
University of Calgary
Calgary, AB, Canada
Lisa Carter-​Harris, PhD, APRN, ANP-​C , FAAN
Rosangela Caruso, MD, PhD
Doctor
Biomedical and Specialty Surgical Sciences
University of Ferrara
Ferrara, Emilia Romagna, Italy
Christabel K. Cheung, PhD, MSW
Assistant Professor
University of Maryland School of Social Work
Member
University of Maryland Greenbaum Comprehensive Cancer Center
Baltimore, MD, USA
Harvey Max Chochinov, OM, OC, PhD, MD, FRCPC, FRSC, FCAHS
Distinguished Professor
Department of Psychiatry
University of Manitoba
Winnipeg, MB, Canada
Contributors
Stephanie N. Christian, MPH
Haryana Dhillon, BSc, MA(Psych), PhD
K. Leroy Irvis Fellow
Department of Behavioral and Community Health Sciences
University of Pittsburgh Graduate School of Public Health
Pittsburgh, PA, USA
Associate Professor
Centre for Medical Psychology and Evidence-​based Decision-​making,
School of Psychology, Faculty of Science
The University of Sydney
Camperdown, NSW, Australia
Shannon M. Christy, PhD
Department of Health Outcomes and Behavior
Division of Population Science H. Lee Moffitt Cancer Center and Research
Institute
Department of Oncologic Sciences
Morsani College of Medicine University of South Florida
Center for Immunization and Infection Research in Cancer
Lee Moffitt Cancer Center and Research Institute
Tampa, FL, USA
Karen L. Clark, MS
Manager of Supportive Care Programs
Department of Supportive Care Medicine
City of Hope National Medical Center
Duarte, CA, USA
Anna E. Coghill, PhD, MPH
Assistant Member
Cancer Epidemiology
Moffitt Cancer Center
Tampa, FL, USA
Lorenzo Cohen, PhD
Professor and Director, Integrative Medicine Program
Department of Palliative, Rehabilitation and Integrative Medicine
The University of Texas MD Anderson Cancer Center
Houston, TX, USA
Elliot J. Coups, PhD†
Member
Rutgers Cancer Institute of New Jersey
Department of Medicine
Rutgers Robert Wood Johnson Medical School
Rutgers, The State University of New Jersey
New Brunswick, NJ, USA
Leah Curran, DCP
Clinical Psychologist
Department of Psychology
The University of Sydney
Camperdown, NSW, Australia
Anne E. Cust, PhD, MPH(Hons), BSc, BA
Professor of Cancer Epidemiology
Sydney School of Public Health
And the Melanoma Institute Australia
The University of Sydney
Camperdown, NSW, Australia
Marianne Davies, DNP, ACNP, AOCNP
Associate Professor Yale School of Nursing
Department of Oncology Nurse Practitioner
Smilow Cancer Hospital
New Haven, CT, USA
Greer J. Dent, BA
Clinical Research Coordinator
Department of Cancer Center
Massachusetts General Hospital
Boston, MA, USA
Branlyn Werba DeRosa, PhD
Research Director
Department of Research and Training Institute
Cancer Support Community
Ardmore, PA, USA
Michael A. Diefenbach, PhD
Professor
Departments of Medicine, Urology and Psychiatry
Northwell Health
Manhasset, NY, USA
J. Nicholas Dionne-​Odom, PhD, RN, ACHPN
Assistant Professor
School of Nursing
University of Alabama at Birmingham
Hoover, AL, USA
Suzanne J. Dobbinson, BSc, MSc, PhD
Senior Research Fellow
Centre for Behavioural Research in Cancer
Cancer Council Victoria
Kensington, VIC, Australia
Joanna S. Dognin, PsyD
Psychologist
Department of Veterans Affairs
NYU Langone Medical Center
White Plains, NY, USA
Heidi S. Donovan, PhD, RN
Professor
Co-​Director National Rehabilitation Research and Training Center
on Family Support
Department of Health and Community Systems
University of Pittsburgh
Pittsburgh, PA, USA
Kristine A. Donovan, PhD, MBA
Associate Member
Department of Supportive Care Medicine
Moffitt Cancer Center
Tampa, FL, USA
Marcia Donziger, BA
Vice President
Digital Strategy and Business Development
Cancer Support Community
Denver, CO, USA
Matthew Doolittle, MD
Assistant Attending Psychiatrist
Psychiatry Service
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Caroline S. Dorfman, PhD
Assistant Professor
Department of Psychiatry and Behavioral Sciences
Duke University Medical Center
Durham, NC, USA
Katherine N. DuHamel, PhD
Director
KND Consulting
New York, NY, USA
Jeff Dunn, PhD, AO
Professor
Department of Research and Innovation
University of Southern Queensland
Toowoomba, Queensland, Australia
xvii
xviii
Contributors
E. Devon Eldridge-​Smith, PhD
Marian L. Fitzgibbon, PhD
Assistant Professor
Department of Medicine
National Jewish Health
Denver, CO, USA
Professor
Department of Pediatrics
University of Illinois
Chicago, IL, USA
Mary Jane Esplen, PhD
Stacy Flowers, PsyD
Professor and Vice-​Chair
Department of Psychiatry
Faculty of Medicine
University of Toronto
Toronto, ON, Canada
Associate Professor
Director of Behavioral Science
Department of Family Medicine
Wright State University
Columbus, OH, USA
Cynthia Fair, LCSW, MPH, DrPH
Christine M. Friedenreich, PhD, FCAHS, FRSC
Professor and Department Chair
Department of Public Health Studies
Elon University
Elon, NC, USA
Scientific Director
Department of Cancer Epidemiology and Prevention Research
Alberta Health Services
Arnie Charbonneau Cancer Institute
Adjunct Professor
The Faculties of Medicine and Kinesiology
University of Calgary
Calgary, AB, Canada
Nathan Fairman, MD, MPH
Associate Clinical Professor
Department of Psychiatry and Behavioral Sciences
UC Davis School of Medicine
Sacramento, CA, USA
Jesse R. Fann, MD, MPH
Professor
Department of Psychiatry and Behavioral Sciences
Adjunct Professor
Departments of Rehabilitation Medicine and Epidemiology
University of Washington
Medical Director
Department of Psychosocial Oncology
Seattle Cancer Care Alliance Clinical Research Division
Fred Hutchinson Cancer Research Center Seattle, Washington
Seattle, WA, USA
Joanna E. Fardell, PhD, MClinNeuropsych, BSc
Research Fellow
Department of Behavioural Sciences Unit, Discipline of Paediatrics,
School of Women’s and Children’s Health, Faculty of Medicine
University of New South Wales
Randwick, NSW, Australia
Loreto Fernández González, BA, BSc, MPH
PhD Student and Connaught Scholar
Social and Behavioural Health Sciences
Dalla Lana School of Public Health
University of Toronto
Toronto, ON, Canada
Betty Ferrell, RN, PhD, FAAN
Professor
Nursing Research
City of Hope National Medical Center
Duarte, CA, USA
Richard Fielding, BA(Hons), CPsychol, PhD, FFPH, FHKPsyS
Lindsay N. Fuzzell, PhD
Applied Research Scientist I
Health Outcomes and Behavior
Moffitt Cancer Center
Tampa, FL, USA
Francesca M. Gany, MD, MS
Attending Physician
Chief, Immigrant Health and Cancer Disparities Service
Department of Psychiatry and Behavioral Sciences
Member
Memorial Sloan Kettering Cancer Center
Professor
Department of Medicine and Department of Healthcare Policy & Research
Weill Cornell Medicine
New York, NY, USA
Patricia A. Ganz, MD
Distinguished Professor
Schools of Medicine and Public Health
University of California, Los Angeles (UCLA)
Los Angeles, CA, USA
Alexandra M. Gaynor, PhD
Post-​Doctoral Neuropsychology Research Fellow
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Afaf Girgis, PhD, BSc(Hons)
Professor
Director, Psycho-​Oncology Research Group
University of New South Wales
Sydney, Australia
Clinical Lead
Jockey Club Institute of Cancer Care, Li Ka Shing Faculty of Medicine
Honorary Professor, School of Public Health
The University of Hong Kong
Hong Kong, China
Barbara A. Given, PhD, RN, FAAN
Michelle Cororve Fingeret, PhD
Charles W. Given, PhD
Fingeret Psychology Services
Houston, TX, USA
Professor Emeritus
College of Nursing
Michigan State University
Okemos, MI, USA
Abigail Fisher, PhD
Associate Professor
Department of Behavioural Science and Health
University College London
Bloomsbury, London, UK
University Distinguished Professor, Associate Dean Emeritus
College of Nursing
Michigan State University
Okemos, MI, USA
Mitch Golant, PhD
Senior Consultant, Strategic Initiatives
Research and Training Institute
Cancer Support Community
Los Angeles, CA, USA
Contributors
Alejandro Gonzalez-​Restrepo, MD
Melissa Henry, PhD
Attending Psychiatrist
Hartford Hospital/​Institute of Living
Hartford Healthcare
Simsbury, CT, USA
Associate Professor
Department of Oncology
Faculty of Medicine
McGill University
Montreal, QC, Canada
Luigi Grassi, MD
Professor and Chair of Psychiatry
University of Ferrara
Chairman of the Department of Biomedical and Specialty Surgical Sciences
University of Ferrara
Ferrara, Italy
Anika von Heymann, MSc, Psych, PhD
Joseph A. Greer, PhD
Jeremy M. Hirst, MD
Associate Professor of Psychology
Department of Psychiatry
Harvard Medical School
Program Director, Center for Psychiatric Oncology &
Behavioral Sciences
Massachusetts General Hospital Cancer Center
Boston, MA, USA
Clinical Professor of Psychiatry; Palliative Care Psychiatry
Department of Psychiatry; Palliative Medicine
UC San Diego School of Medicine
La Jolla, CA, USA
Chloe Grimmett, PhD
Senior Research Fellow
School of Health Sciences
University of Southampton
Hampshire, UK
Erin E. Hahn, PhD, MPH
Research Scientist
Department of Research and Evaluation
Kaiser Permanente Southern California
Pasadena, CA, USA
Sarah Hales, MD, PhD
Assistant Professor
Division of Psychosocial Oncology
Department Supportive Care
Princess Margaret Cancer Centre
Centre for Mental Health
University Health Network
University of Toronto
Toronto, ON, Canada
Simon J. Hall, MD
Zucker Professor of Urologic Oncology
Smith Institute of Urology
Hofstra Northwell School of Medicine
Lake Success, NY, USA
Jada G. Hamilton, PhD, MPH
Assistant Attending Psychologist
Behavioral Sciences Service
Department of Psychiatry and Behavioral Sciences; Department of Medicine
Assistant Member
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Sameer Hassamal, MD
Assistant Professor
Department of Psychiatry
Arrowhead Regional Medical Center
Colton, CA, USA
Jennifer L. Hay, PhD
Attending Psychologist
Behavioral Sciences Service
Department of Psychiatry and Behavioral Sciences
Member
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Postdoctoral Fellow
Department of Oncology
Rigshospitalet
København, Denmark
Fay J. Hlubocky, PhD, MA, CCTP
Clinical Health Psychologist
Research Project Professor
Department of Medicine
University of Chicago Medicine
Chicago, IL, USA
Jimmie C. Holland, MD†
Wayne E. Chapman Chair in Psychiatric Oncology
Attending Psychiatrist
Psychiatry Service
Department of Psychiatry and Behavioral Sciences
Member
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Karen Holtmaat, MSc, MA
Assistant Professor in Psychosocial Oncology
Department of Clinical, Neuro-​and Developmental Psychology
Vrije Universiteit Amsterdam
Amsterdam, NH, The Netherlands
Michael A. Hoyt, PhD
Associate Professor
Chao Cancer Center
UC Irvine
Irvine, CA, USA
Nicholas J. Hulbert-​Williams, BSc, PhD, CPsychol, APBPsS, FHAE
Professor of Behavioural Medicine
School of Psychology
University of Chester
Chester, UK
Jonathan Hunter, BSc, MD, FRCPC
Professor
Department of Psychiatry
University of Toronto
Toronto, ON, Canada
Youri Hwang, MSN, RN, FNP-​C
PhD Student
School of Nursing
Yale University
New Haven, CT, USA
Jonathan Irish, MD, MSc, FRCSC, FACS
Professor and Head
Division of Head and Neck Oncology and Reconstructive Surgery
Department of Otolaryngology-​Head and Neck Surgery
Princess Margaret Cancer Centre, University of Toronto
Toronto, ON, Canada
xix
xx
Contributors
Scott A. Irwin, MD, PhD, FACLP, FAPA
Anne E. Kazak, PhD, ABPP
Professor of Psychiatry and Behavioral Neurosciences
Department of Psychiatry and Behavioral Neurosciences
Director of Patient and Family Support Program
Samuel Oschin Comprehensive Cancer Institute,
Cedars-​Sinai Health System
Los Angeles, CA, US
Editor-​in-​Chief, American Psychologist
Director, Center for Healthcare Delivery Science
Nemours Children’s Health System Co-​Director
Center for Pediatric Traumatic Stress Professor
Department of Pediatrics
Thomas Jefferson University
Wilmington, DE, USA
Elie Isenberg-​Grzeda, MD, CM, FRCPC
Assistant Professor
Department of Psychiatry
University of Toronto
Toronto, ON, Canada
Jennifer M. Jabson Tree, PhD, MPH
Associate Professor
Department of Public Health
University of Tennessee
Knoxville, TN, USA
Paul B. Jacobsen, PhD
Associate Director
Division of Cancer Control and Population Sciences
National Cancer Institute
Bethesda, MD, USA
Reena Jaiswal, MD
Assistant Attending Psychiatrist
Psychiatry Service
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Monique James, MD
Assistant Attending Psychiatrist
Psychiatry Service
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Christoffer Johansen, MD, PhD, Dr. Med. Sci.
Professor
Head, CASTLE—​Cancer Late Effect Research Oncology Clinic
Department of Oncology
Center for Surgery and Cancer
Rigshospitalet
Copenhagen, Denmark
Marjorie Kagawa-​Singer, PhD, MA, MN, RN
Julia A. Kearney, MD
Assistant Attending Psychiatrist
Clinical Director, Pediatric Psycho-​Oncology Program
Department of Psychiatry and Behavioral Sciences &
Department of Pediatrics
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Erin Kent, PhD, MS
Associate Professor
Health Policy and Management
University of North Carolina
Chapel Hill, NC, USA
R. Garrett Key, MD, FAPA, FACLP
Assistant Professor
Psychiatry and Behavioral Sciences
University of Texas at Austin Dell Medical School
Austin, TX, USA
David W. Kissane, AC, MBBS, MPM, MD, FRANZCP, FAChPM, FACLP
UNDA Chair of Palliative Medicine Research
Cunningham Centre for Palliative Care, St Vincent’s Sydney
University of Notre Dame Australia
Head of Szalmuk Family Psycho-​oncology Research Unit
Department of Palliative Care
Cabrini Health, Melbourne, Australia
Head of Psycho-​Oncology Clinic
Monash Medical Centre
Monash University
Clayton, VIC, Australia
Jennifer M. Knight, MD, MS
Associate Professor
Department of Psychiatry, Medicine, and Microbiology and Immunology
Medical College of Wisconsin
Shorewood, WI, USA
M. Tish Knobf, PhD, RN, FAAN
Research Professor
Community Health Sciences
University of California, Los Angeles (UCLA)
Los Angeles, CA, USA
Professor
Department of Nursing
Yale University
New Haven, CT, USA
Charles Kamen, PhD, MPH
Angela Kong, PhD, MPH, RD
Assistant Professor
Department of Surgery
University of Rochester
Rochester, NY, USA
Assistant Professor
Department of Pharmacy Systems, Outcomes, and Policy
University of Illinois Chicago
Chicago, IL, USA
Nadine A. Kasparian, PhD
Beatriz Korc-​Grodzicki, MD, PhD, FAGS
Professor of Pediatrics Director, Cincinnati Children’s Center for Heart Disease
and Mental Health Heart Institute and Division of Behavioral Medicine and
Clinical Psychology
Department of Pediatrics
University of Cincinnati College of Medicine
Cincinnati, OH, USA
Chief, Geriatrics Service
Department of Medicine
Memorial Sloan-​Kettering Cancer Center
Professor of Medicine
Weill Cornell Medical College
New York, NY, USA
Monica L. Kasting, PhD
Chris Kotsen, PsyD, NCTTP
Assistant Professor
Department of Public Health
Purdue University
West Lafayette, IN, USA
Associate Attending Psychologist
Associate Director, Tobacco Treatment Program
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Contributors
Juee Kotwal, MBS, PMP
Kristin Litzelman, PhD
Business Manager
Department of Supportive Care Medicine
City of Hope National Medical Center
Duarte, CA, USA
Assistant Professor
Department of Human Development and Family Studies
University of Wisconsin-​Madison
Madison, WI, USA
Maia S. Kredentser, PhD
Wenli Liu, MD
Research Fellow
Clinical Health Psychology
University of Manitoba
Winnipeg, MB, Canada
Associate Professor
Department of Palliative, Rehabilitation and Integrative Medicine
MD Anderson Cancer Center
Houston, TX, USA
Ava Kwong, MBBS, BSc, PhD, FRCS, FRCS, FHKAM, FCSHK
Gabriel Lopez, MD
Clinical Professor
Division of Breast Surgery, Department of Surgery
The University of Hong Kong Li Ka Shing Faculty of Medicine
Pok Fu Lam, Hong Kong, China
Associate Professor, Center Medical Director
Department of Palliative, Rehabilitation, and Integrative Medicine
University of Texas, MD Anderson Cancer Center
Houston, TX, USA
Wendy W. T. Lam, RN, PhD, FFPH
Matthew J. Loscalzo, MSW, LCSW, FAPOS
Associate Professor, Head, Division of Behavioural Sciences, School of
Public Health
Director, Jockey Club Institute of Cancer Care, Li Ka Shing Faculty of Medicine
Director, Centre for Psycho-​oncology Research and Training (CePORT)
The University of Hong Kong
Hong Kong, China
Alicia Latham, MD
Assistant Attending Physician
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Mark Lazenby, APRN, PhD
Professor of Nursing and Philosophy
Associate Dean for Faculty and Student Affairs
University of Connecticut School of Nursing
Storrs, CT, USA
Jennifer Leng, MD, MPH
Associate Attending Physician
Associate Member
Immigrant Health and Cancer Disparities Service
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Gabriel M. Leung, MD
Dean of Medicine
LKS Faculty of Medicine
The University of Hong Kong
Pok Fu Lam, Hong Kong
Madeline Li, MD, PhD, FRCP(C)
Attending Psychiatrist
Department of Supportive Care
Princess Margaret Cancer Centre
University Health Network
Associate Professor
Department of Psychiatry
Faculty of Medicine
University of Toronto
Toronto, ON, Canada
Wendy G. Lichtenthal, PhD, FT
Associate Attending Psychologist
Director, Bereavement Clinic,
Psychiatry Service
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Dustin Liebling, MD
Clinical Fellow
Anesthesia Pain Management Service
Department of Anesthesiology and Critical Care Medicine
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Liliane Elkins Professor in Supportive Care Programs
Administrative Director, Sheri & Les Biller Patient and Family
Resource Center
Executive Director, Department of Supportive Care Medicine
Professor, Department of Population Sciences
City of Hope National Medical Center
Duarte, CA, USA
Amy E. Lowery-​Allison, PhD
Associate Attending Psychologist
Psychiatry Service
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Laura J. Lundi, BS
Administrative Clinical Research Coordinator
Department of Medicine
Stanford University
Stanford, CA, USA
Susan K. Lutgendorf, PhD
Professor and Starch Faculty Fellow
Departments of Psychological and Brain Sciences, Obstetrics and Gynecology,
and Urology
University of Iowa
Iowa City, IA, USA
Irma M. Verdonck-​de Leeuw, PhD
Full Professor in Psychosocial Oncology
Department of Otolaryngology/​Head and Neck Surgery
Vrije University Medical Center/​Cancer Center Amsterdam
Section of Clinical, Neuro-​and Developmental Psychology
Vrije Universiteit Amsterdam
Amsterdam, The Netherlands
Meredith E. MacGregor, MD
Assistant Attending Psychiatrist
Department of Child and Adolescent Psychiatry and Behavioral Sciences
Children’s Hospital of Philadelphia
Philadelphia, PA, USA
Sukh Makhnoon, PhD, MS
Postdoctoral Fellow
Department of Behavioral Science
University of Texas MD Anderson Cancer Center
Houston, TX, USA
Vivek T. Malhotra, MD, MPH
Chief, Anesthesiology Pain Service
Associate Attending
Department of Anesthesiology and Critical Care Medicine
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Sharon Manne, PhD
Section Chief, Professor of Medicine
Department of CINJ, Behavioral Sciences
Rutgers, The State University of New Jersey
New Brunswick, NJ, USA
xxi
xxii
Contributors
Jun J. Mao, MD, MSCE
Alex J. Mitchell, MBBS, MSc, MD, MRCPsych
Laurance S. Rockefeller Chair in Integrative Medicine
Chief, Integrative Medicine Service
Attending Physician
Department of Medicine
Memorial Sloan Kettering Cancer Center, Bendheim Integrative Medicine Center
New York, NY, USA
Professor
Department of Psycho-​Oncology and Cancer Care
University of Leicester
Leicester, UK
John C. Markowitz, MD
Research Psychiatrist
New York State Psychiatric Institute
Professor of Clinical Psychiatry
Columbia University College of Physicians and Surgeons
New York, NY, USA
Úrsula Martínez, PhD
Applied Research Scientist
Department of Health Outcomes and Behavior
H. Lee Moffitt Cancer Center and Research Institute
Tampa, FL, USA
Allison Marziliano, PhD
Postdoctoral Fellow
Department of Medicine
Northwell Health
Bethpage, NY, USA
Melissa Masterson Duva, PhD
Senior Psychologist
WTC Health Program Clinical Center of Excellence
New York University School of Medicine
New York, NY, USA
Stefanie N. Mooney, MD
Assistant Clinical Professor of Medicine
Division of Supportive Medicine
Department of Supportive Care Medicine
City of Hope National Medical Center
Duarte, CA, USA
Cynthia W. Moore, PhD
Psychologist
Department of Child and Adolescent Psychiatry
Massachusetts General Hospital
Boston, MA, USA
Natalie Moryl, MD
Associate Attending Physician
Supportive Care Service
Department of Medicine
Memorial Sloan Kettering Cancer Center
Associate Professor
Department of Medicine
Weill Cornell Medical College
New York, NY, USA
Anna C. Muriel, MD, MPH
Research Fellow
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Chief, Division of Pediatric Psychosocial Oncology
Associate Psychiatrist
Department of Psychosocial Oncology and Palliative Care
Dana Farber Cancer Institute
Assistant Professor of Psychiatry
Harvard Medical School
Boston, MA, USA
Jordana K. McLoone, PhD
Caitlin C. Murphy, PhD, MPH
Daniel C. McFarland, DO
Post-​Doctoral Research Fellow
Women’s and Children’s Health, Faculty of Medicine
University of New South Wales
NSW, Australia
Jessica McNeil, PhD
Postdoctoral Fellow
Cancer Epidemiology and Prevention Research
Alberta Health Services
Russell, ON, Canada
Anne Miles, BSc, PhD
Reader in Psychology
Department of Psychological Sciences
Birkbeck, University of London
Bloomsbury, London, UK
Andrew H. Miller, MD
William P. Timmie Professor of Psychiatry and Behavioral Sciences
Department of Psychiatry and Behavioral Sciences
Emory University School of Medicine
Atlanta, GA, USA
Kimberley Miller, MD, FRCPC
Attending Psychiatrist
Department of Supportive Care
Princess Margaret Cancer Centre,
University Health Network
Assistant Professor of Psychiatry
Department of Psychiatry
Faculty of Medicine
University of Toronto
Toronto, ON, Canada
Assistant Professor
Department of Population and Data Sciences
UT Southwestern Medical Center
Dallas, TX, USA
Maria Giulia Nanni, MD
Associate Professor
Department of Biomedical and Specialty Surgical Sciences
University of Ferrara
Ferrara, Italy
Santhosshi Narayanan, MD
Assistant Professor
Department of PRIM
MD Anderson Cancer Center
Houston, TX, USA
Ashley M. Nelson, PhD
Postdoctoral Fellow
Department of Psychiatry
Massachusetts General Hospital/​Harvard Medical School
Boston, MA, USA
Christian J. Nelson, PhD
Chief, Psychiatry Service,
Associate Attending Psychologist
Department of Psychiatry and Behavioral Sciences
Associate Member
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Contributors
Daniel Nethala, MD
Hayley Pessin, PhD
Resident
Department of Urology
Smith Institute for Urology at Northwell Health
Lake Success, NY, USA
Psychologist
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Laurel Northouse, PhD
Susan K. Peterson, PhD, MPH
Professor Emerita
School of Nursing
University of Michigan
Ann Arbor, MI, USA
Professor
Department of Behavioral Science
The University of Texas MD Anderson Cancer Center
Houston, TX, USA
Wynne E. Norton, PhD
Laura C. Polacek, MA
Program Director
Division of Cancer Control and Population Sciences
National Cancer Institute
Bethesda, MD, USA
Graduate Student
Department of Psychology
Fordham University
The Bronx, NY, USA
Marinel Olivares, LCSW, ACHP-​SW
Holly G. Prigerson, PhD
Clinical Social Worker
Adult Hematology/​Hematopoietic Cell Transplantation
Director, Family Meeting Program
Department of Supportive Care Medicine
City of Hope National Medical Center
Duarte, CA
Irving Sherwood Wright Professor in Geriatrics
Professor of Sociology in Medicine
Director
Cornell Center for Research on End-​of-​Life Care
New York, NY, USA
Jamie Ostroff, PhD
Clinical Professor of Psychiatry and Behavioral Sciences
Chief, Couples and Family Therapy Clinic
Department of Psychiatry and Behavioral Sciences
Stanford University
Stanford, CA, USA
Chief, Behavioral Sciences Service
Vice Chair for Research
Member and Attending Psychologist
Director, Tobacco Treatment Program
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Ray Owen, DClinPsych, Cpsychol, FHEA
Consultant Clinical Psychologist
Health Psychology Department
Wye Valley NHS Trust
Hereford, UK
Maryland Pao, MD
Clinical and Deputy Scientific Director
Department of NIMH
National Institutes of Health (NIH)
Bethesda, MD, USA
Patricia A. Parker, PhD
Attending Psychologist
Behavioral Sciences Service
Director, Communication Skills Training and Research Program
Department of Psychiatry and Behavioral Sciences
Member, Memorial Hospital
Memorial Sloan-​Kettering Cancer Center
New York, NY, USA
Steven D. Passik, PhD
Vice President,
Scientific Affairs, Education and Policy
Collegium Pharmaceuticals
Stoughton, MA, USA
Frank J. Penedo, PhD
Professor
Department of Psychology and Medicine
University of Miami
Miami, FL, USA
Samara Perez, PhD
Research Associate
Department Lady Davis Institute for Medical Research Jewish
General Hospital
Clinical Psychologist
Psychosocial Oncology Program
McGill University Health Center
Montreal, QC, Canada
Douglas S. Rait, PhD
Kavitha Ramchandran, MD
Clinical Associate Professor
Department of Medicine
Stanford University
Stanford, CA, USA
Nicole Rankin, BA(Hons), MSc, PhD
Senior Research Fellow
Faculty of Medicine and Health
The University of Sydney
Camperdown, NSW, Australia
Chelsea S. Rapoport, BA
Clinical Research Coordinator
Department of Psychiatry
Massachusetts General Hospital
Boston, MA, USA
Julie Rathwell, MPH
Research Project Specialist, Sr.
Department of Cancer Epidemiology
Moffitt Cancer Center
Tampa, FL, USA
Paula K. Rauch, MD
Director, Marjorie E. Korff Parenting at a Challenging Time Program
Department of Psychiatry
Massachusetts General Hospital
Boston, MA, USA
Claudia Redeker, MSc
PhD Student
Department of Psychology
Birkbeck College
Bloomsbury, London, UK
Lee M. Ritterband, PhD
Professor
Department of Psychiatry and Neurobehavioral Sciences
University of Virginia
Charlottesville, VA, USA
xxiii
xxiv
Contributors
Kailey E. Roberts, PhD
Sally Saban, BA
Research Fellow
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Clinic Research Coordinator
Department of Surgery
New York, NY, USA
Gary Rodin, MD
Student
Williams College
New York, NY, USA
Head of Department
Department of Supportive Care
Princess Margaret Cancer Centre
University Health Network
Professor
Department of Psychiatry
Faculty of Medicine
Director
Global Institute of Psychosocial, Palliative and End-​of-​Life Care
University of Toronto
Toronto, ON, Canada
James C. Root, PhD
Associate Attending Neuropsychologist
Psychiatry Service
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Zeev Rosberger, PhD
Senior Investigator and Associate Professor
Departments of Oncology, Psychiatry, and Psychology
Lady Davis Institute for Medical Research
Institute of Community and Family Psychiatry
Jewish General Hospital
Gerald Bronfman Department of Oncology
McGill University
Montréal, QC, Canada
Barry Rosenfeld, PhD
Professor
Chairman
Department of Psychology
Fordham University
Consultant Psychologist
Psychiatry Service
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Andrew J. Roth, MD
Attending Psychiatrist
Psychiatry Service
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
Professor of Clinical Psychiatry
Weill Cornell Medical College
New York, NY, USA
Julia Ruark, MD, MPH
Attending Psychiatrist
Department of Psychosocial Oncology
Seattle Cancer Care Alliance
Seattle, WA, USA
Elizabeth Ryan, PhD, ABPP-​CN
Associate Attending Neuropsychologist
Psychiatry Service
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Adam Rzetelny, PhD
Senior Medical Science Liaison
Department of Medical Affairs
Collegium Pharmaceuticals
Maplewood, NJ, USA
Victoria Saltz
Chase Samsel, MD
Attending Physician
Department of Psychiatry
Boston Children’s Hospital and Dana-​Farber Cancer Institute
Boston, MA, USA
Sheila J. Santacroce, PhD, RN, CPNP, FAANP
Associate Professor
School of Nursing
University of North Carolina
Chapel Hill, NC, USA
Rebecca M. Saracino, PhD
Assistant Attending Psychologist
Psychiatry Service
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
M. Claire Saxton, MBA
Vice President
Department of Education and Outreach
Cancer Support Community
Washington, DC, USA
Christian Schulz-​Quach, MD, MSc, MA
Assistant Professor
Department of Psychiatry
University of Toronto
Toronto, ON, Canada
Lisa A. Schwartz, PhD
Associate Professor
Department of Pediatrics/​Oncology
The Children’s Hospital of Philadelphia
Philadelphia, PA, USA
Michael Schwartz, MD, FACS
Associate Professor
Smith Institute for Urology
Northwell Health
New Hyde Park, NY, USA
Peter A. Selwyn, MD, MPH
Professor and Chair
Department of Family and Social Medicine
Director, Palliative Care Program
Montefiore Medical Center
Albert Einstein College of Medicine
The Bronx, NY, USA
Kelly M. Shaffer, PhD
Assistant Professor
Center for Behavioral Health and Technology, Department of Psychiatry and
Neurobehavioral Sciences
University of Virginia School of Medicine
Charlottesville, VA, USA
Mehak Sharma, MD
Assistant Attending Psychiatrist
Psychiatry Service
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Contributors
Louise Sharpe, BA(Hons), MPsychol, PhD
Manuel Trachsel, MD, PhD
Professor of Clinical Psychology
Department of Psychology
The University of Sydney
Camperdown, NSW, Australia
Head Clinical Ethicist
Clinical Ethics Unit
University Hospital of Basel/​University of Zurich
Zürich, ZH, Switzerland
Michael Sharpe, MA, MD
Lara Traeger, PhD
Professor of Psychological Medicine
Department of Psychiatry
University of Oxford
Oxford, UK
Assistant Professor
Department of Psychiatry
Massachusetts General Hospital/​Harvard Medical School
Boston, MA, USA
Vani N. Simmons, PhD
Kelly M. Trevino, PhD
Senior Member
Department of Health Outcomes and Behavior
Moffitt Cancer Center
Tampa, FL, USA
Associate Attending Psychologist
Psychiatry Service
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Allan B. Smith, PhD
Co-​Deputy Director (Policy and Practice)
Centre for Oncology Education and Research Translation (CONCERT)
Ingham Institute for Applied Medical Research
Liverpool, NSW, Australia
Jennifer Sotsky, MD, MS
Clinical Fellow
Department of Psychiatry
New York State Psychiatric Institute
New York, NY, USA
Nadia van der Spek, PhD
Assistant Professor
Licensed Mental Health Care Psychologist
Department of Clinical Psychology
Vrije Universiteit Amsterdam
Amsterdam, The Netherlands
Kevin Stein, PhD, FAPOS
Associate Professor (Adjunct)
Department of Behavioral Sciences and Health Education
Rollins School of Public Health
Snellville, GA, USA
Chelsea R. Stone, MSc
Research Associate
Department of Cancer Epidemiology and Prevention Research
Alberta Health Services
Calgary, AB, Canada
Sarah J. Tarquini, PhD
Senior Psychologist
Department of Psychosocial Oncology and Palliative Care
Dana-​Farber Boston Children’s Cancer and Blood Disorders Center
Boston, MA, USA
Ovidiu Tatar, MD, MSc
Research Associate
Psychosocial Oncology Lady Davis Institute for Medical Research
Jewish General Hospital Research Center-​Centre Hospitalier
de l'Université de Montréal (CRCHUM)
Montréal, QC, USA
Kim Thiboldeaux, BA Communications
CEO
Cancer Support Community
Washington, DC, USA
Teresa H. Thomas, PhD, RN
Assistant Professor
School of Nursing
University of Pittsburgh
Pittsburgh, PA, USA
Amanda L. Thompson, PhD
Chief, Pediatric Psychology
Department of Life with Cancer
Inova Schar Cancer Institute
Fairfax, VA, USA
Jane Turner, MBBS, PhD, FRANZCP
Professor
Department of Psychiatry
The University of Queensland
Brisbane, Australia
Lisa Tussing-​Humphreys, PhD, MS, RD
Associate Professor
Department of Medicine Co-​leader, Cancer Prevention and Control Program,
Cancer Center
University of Illinois
Chicago, IL, USA
Susan T. Vadaparampil, PhD, MPH
Associate Center Director, Community Outreach, Engagement, and Equity
Department of Health Outcomes and Behavior
Moffitt Cancer Center
Tampa, FL, USA
Annalyn Valdez-​Dadia, DrPH, MPH
Assistant Professor
Department of Human Services
California State University, Dominguez Hills
Carson, CA, USA
Alan D. Valentine, MD
Professor and Chair
Department of Psychiatry
MD Anderson Cancer Center
The University of Texas
Houston, TX, USA
Sally W. Vernon, MA, PhD
Professor
Department of Health Promotion and Behavioral Science
University of Texas School of Public Health
Houston, TX, USA
Froukje de Vries, MD, PhD
Psychiatrist
Department of Supportive Care
Princess Margaret Cancer Centre, University Health Network
Toronto, ON, Canada
Claire E. Wakefield, BPsych(Hons), MPH, PhD
Professor
School of Women’s and Children’s Health and Kids Cancer Centre
UNSW Sydney and Sydney Children’s Hospital
North Willoughby, NSW, Australia
Leah E. Walsh, MS
Doctoral Student
Department of Psychology
Fordham University
The Bronx, NY, USA
xxv
xxvi
Contributors
Linda D. L. Wang, PhD
Joseph T. Wu, PhD, BS
Associate Professor
Department of Clinical Medicine
Medical College of Yangzhou University
Yangzhou, Jiangsu, China
Professor
School of Public Health
The University of Hong Kong
Hong Kong, China
Maggie Watson, BSc, Dip Clin Psych, PhD
Robert Zachariae, DMSc
Honorary Professor
Research Department of Clinical, Educational and Health Psychology
University College London
Institute of Cancer Research
London, UK
Professor
Unit for Psycho-​oncology and Health Psychology
Aarhus University
Aarhus, Denmark
Amanda Watsula-​Morley, MA
Clinical Research Supervisor
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Assistant Attending Psychologist
Psychiatry Service
Department of Psychiatry and Behavioral Sciences
Memorial Sloan Kettering Cancer Center
New York, NY, USA
Jason A. Webb, MD, FAPA, FAAHPM
Alexandra K. Zaleta, PhD
Director of Education, Duke Center for Palliative Care Associate Professor
Department of Medicine, Department of Psychiatry and Behavioral Sciences
Duke University
Durham, NC, USA
Senior Director of Research
Department of Research and Training Institute
Cancer Support Community
Philadelphia, PA, USA
Lori Wiener, PhD, DCSW, FAPOS
Bradley J. Zebrack, MSW, MPH, PhD
Co-​Director, Behavioral Health Care,
Director, Psychosocial Support and Research Program
Department of Pediatric Oncology Branch,
National Cancer Institute, Center for Cancer Research
National Institutes of Health
Bethesda, MD, USA
Professor
School of Social Work
University of Michigan
Ann Arbor, MI, USA
Irene O. L. Wong, BSc, MPhil, MMedSci, PhD
Scientific Officer
School of Public Health
The University of Hong Kong
Hong Kong, China
Talia I. Zaider, PhD
Introduction
Our Past, Our Future—New Frontiers in Psycho-​Oncology
William S. Breitbart (Senior Editor)
Introduction
This textbook, Psycho-​Oncology, 4th edition, is the first edition of this
series of textbooks, which have defined the field of psycho-​oncology,
to be edited without Jimmie C. Holland as the senior editor. Jimmie’s
imprint on these textbooks and on our international field has resulted
in these textbooks often being referred to as the “Holland Textbook
of Psycho-​Oncology”—​that is, when it isn’t, perhaps somewhat sacrilegiously, being referred to as the “Bible of Psycho-​Oncology.” Hence,
those of us who have taken on the both sacred and significant responsibility of editing this 4th edition of Psycho-​Oncology have done so with a
sense of both sadness and honor. The field of psycho-​oncology is truly
interdisciplinary and international, and so it is fitting that the editors
and contributors to this 4th edition are indeed truly international and
represent multiple disciplines. As senior editor, I have been blessed to
have the magnificent talents of the following luminaries in our field
as associate editors: Phyllis N. Butow, BA(Hons), DipEd, MClinPsych,
MPH, PhD, of the University of Sydney; Paul B. Jacobsen, PhD, of the
U.S. National Cancer Institute; Wendy W. T. Lam, RN, PhD, FFPH,
of the University of Hong Kong; Mark Lazenby, APRN, PhD, of the
University of Connecticut School of Nursing; and Matthew J. Loscalzo,
MSW, LCSW, FAPOS, of the City of Hope. Their contributions to the
quality of this textbook will be quite evident to the reader. Each of the
editors of this textbook has had a direct and often life-​changing experience through a long-​standing relationship with Jimmie Holland, and
our dedication to preserving her legacy is on every page of this text.
I do want to take a moment to personally thank Andrea Knobloch,
our editor at Oxford University Press, and her team; the personal assistants of many of the editors and contributors; and most significantly
Laurie Schulman, who served as managing editor of this textbook
and dedicated more than a year of time, energy, and devotion to assisting me in seeing this project through—​even through the interruptions of the coronavirus pandemic. Lastly, our deep appreciation goes
to the International Psycho-​Oncology Society (IPOS), the American
Psychosocial Oncology Society (APOS), and the several hundred authors who contributed more than 100 chapters to this textbook.
Our Past
Jimmie C. Holland, or “Jimmie,” as the world of psycho-​oncology
knew her, is often credited as being the founder or “mother” of
psycho-​
oncology. Interestingly, Jimmie hated being called the
“mother” of psycho-​oncology. It particularly irked her when, as she
got older, this term changed to “grandmother” of psycho-​oncology.
Jimmie much preferred these titles/​roles to be reserved for her personal life—​her family, her beloved children and grandchildren. But
after all, she was a “Cicely Saunders–​type” figure in a new movement
within oncology, and so she was revered and mythologized in ways
that did not make her comfortable. As many who knew Jimmie will
attest, she was in fact somewhat shy and quite humble, quick to give
credit to others, and eager to accelerate the career trajectories of the
next generations of clinicians, scientists, and leaders of our field. That
isn’t to imply that she didn’t have very strong opinions or have enviable political skills, but she clearly used those skills for the benefit of
patients, the field, and the movement. Jimmie and I would often sit
in her office at the end of the day and discuss just about everything
one can imagine related to work, projects, our field, and politics (and
some gossip). There was nothing off limits. Interestingly, we did frequently talk about the origins of psycho-​oncology and individuals
she felt never quite received enough recognition for their roles in the
creation of our field. That is, in part, why she urged the creation of
the IPOS Arthur Sutherland Award. Jimmie always felt that she had
received too much credit for founding the field of psycho-​oncology
and was eager for there to be recognition of such pioneers in our
field as Margit Von Kerekjarto, Robert Zitoun, Hiroomi Kawano,
Steven Greer, Lea Baider, Peter Maguire, Bernard Fox, Juan Ignacio
Romero, Avery Weissman, Edwin Cassem, Noemi Fisman, Maria
Margarida Carvalho, Morton Bard, and Arthur Sutherland himself.
One early pioneer has remained quite obscure and
underrecognized for over 50 years, and Jimmie and I became quite
fascinated with this figure. I became interested because he, like my
parents, was a Holocaust survivor. Jimmie, I believe, became fascinated because he was also someone who had overcome severe physical disabilities (reminding Jimmie of her early days working with
polio patients). Loma Feigenberg was a physician at the Karolinska
Institute in Stockholm. In the 1950s, as an oncologist and radiotherapist, he noted the lack of attention in addressing the psychological
responses of patients with advanced cancer. He later studied psychiatry and began to work with cancer patients at the Karolinska.
He made what he called a “friendship contract” with them in which
he agreed to “confidentiality” of the content of their “sessions” and
made a commitment to ongoing care and support during their cancer
treatment. His book, Terminal Care: A Method for Psychological Care
2
Psycho-Oncology
of Dying Patients, is a landmark text.1 Feigenberg did finally receive
the Distinguished Life Service Award from the IPOS in 1987. He
also founded the International Work Group for Death, Dying and
Bereavement (IWG), an early beginning of thanatology.
However, Dr. Holland’s efforts over the last 43 years, since becoming the founding chief of the Psychiatry Service at Memorial
Sloan Kettering Cancer Center, have indeed brought her well-​
deserved recognition as the founder and past leader of the field of
psycho-​oncology. Having founded the IPOS in 1984 and the APOS in
1986, Dr. Holland went on to edit the first major textbooks of psycho-​
oncology for our field. This textbook, Psycho-​Oncology, 4th edition,
was preceded by four major textbooks that defined our field. In 1989,
Dr. Holland edited the Handbook of Psychooncology: Psychological
Care of the Patient with Cancer, the first major textbook in our field.2
This landmark book (coedited with Julia Rowland, PhD) established
our “new” field and virtually named the field “psycho-​oncology.” The
follow-​up textbook Psycho-​Oncology was published in 1998 and represented the most comprehensive, multidisciplinary, and international encyclopedia of a field entering its adolescence.3 The year 2010
saw the publication of the 2nd edition,4 followed by the 3rd edition5
in 2015, both published by Oxford University Press in collaboration
with the IPOS and APOS. The field of psycho-​oncology was now
mature, rich, and filled with talented, creative, and innovative clinicians, scientists, advocates, and global leaders like Maggie Watson,
Luigi Grassi, Uwe Koch, David Kissane, Christoffer Johansen, Luzia
Travado, Barry Bultz, Maria Die Trill, Gary Rodin, Cristina Bolund,
Bill Redd, Anja Mehnert, Francisco Gil, David Spiegel, Joan Bloom,
Harvey Chochinov, Barbara Andersen, Jamie Ostroff, Phyllis Butow,
Paul Jacobsen, Richard Fielding, Matt Loscalzo, Leslie Fallowfield,
Pierre Gagnon, Jeff Dunn, Mitch Golant, Mary Jane Esplen, Sharon
Manne, Jane Turner, David Cella, Elisabeth Andritsch, Pat Fobair,
Irma Verdonck-​de Leeuw, Michael Antoni, James Zabora, and numerous others (apologies to anyone who deserved mention and was
omitted unintentionally; noninclusion in this list means you’re not
an old-​timer and are part of the new wave, the vital leaders of the
future of our field).
With the publication of this textbook, Psycho-​Oncology, 4th edition, we take this moment to both look to our past and start to examine our future as a field. We have a rich legacy given to us by so
many of the pioneers of psycho-​oncology mentioned earlier. In fact,
this textbook is dedicated to the memory of Jimmie C. Holland and
we honor her and all the past editors and contributors to the prior
editions of this text by moving forward with the creation of what
we hope readers will someday view as a milestone textbook itself.
Of note, two former associate editors of several of the prior editions
of this series of textbooks died in 2019 as this 4th edition was being
prepared. We are indebted to and honor the contributions and lives
of Ruth McCorkle and Marguerite Lederberg—​
two remarkable
women who were cherished by so many of us, worldwide. Ruth was
an editor of several editions of the textbook and so we also dedicate
this textbook in her honor as well as in Jimmie’s.
Our Future
We, the editors of this 4th edition of Psycho-​Oncology, undertook
a careful examination of the content of the 3rd edition of Psycho-​
Oncology, as well as the expert authors who contributed their
expertise. We were particularly interested in two aspects of the
purpose of the Psycho-​Oncology textbook’s purpose: (1) to serve
as the source textbook that provided the broadest and most multidisciplinary and essential science and practice of the field of
psycho-​oncology, and (2) to bring to our field the newest and latest
innovations and cutting-​edge research and clinical practice that
would equip our readers with the knowledge and resources to be
knowledgeable and to participate in the “new frontiers of psycho-​
oncology.” We feel we have accomplished this delicate but critical
balance in the 4th edition of Psycho-​Oncology.
We’ve maintained many of the basic but critical aspects of prevention, screening, assessment, and management of basic common
psychosocial and psychiatric issues in psycho-​oncology, including
cancer site–​specific psychosocial issues and management. As much
as possible, these cancer site–​specific chapters also include some
basic, updated oncological diagnostic and treatment-​related information that is vital for clinicians and clinical researchers in our field.
There are, however, a number of new sections that represent new
developments in basic psycho-​oncology science, breakthroughs in
health care delivery, growth in treating special cancer populations,
and innovative and novel evidence-​based interventions that are
changing the landscape of treatment, and a growing international
perspective that our field has developed over recent years.
Allow me to briefly highlight some of the updates and new sections
in the 4th edition of Psycho-​Oncology that are designed to prepare
psycho-​oncologists for the “new frontiers of psycho-​oncology”:
1. Evidence-​Based Interventions: We have dramatically expanded
this section of the textbook and now include a variety of innovative novel interventions with a significant evidence base for
efficacy. We’ve divided the interventions into models of care
delivery and phases of illness. Models of Care Delivery now includes the following:
(a) Collaborative and Integrated Models of Psychosocial
Oncology
Care,
Community-​
Based
Care,
and
Implementation Science’s Role in Care Delivery
(b) Family and Couples Interventions
(c) Interventions at various stages of illness including Active
Treatment, Advanced Disease, and Survivorship, as well
as novel interventions including Cognitive-​
Behavioral
Interventions, Mindfulness-​Based Interventions, Acceptance
and Commitment Therapy, Interpersonal Therapy,
Supportive-​
Expressive Psychotherapy, and Meaning-​
Centered Psychotherapy for advanced cancer patients, for
bereavement, survivors, and for caregivers, in addition to
CALM Therapy, Dignity Therapy, Emotionally Focused
Therapy, Metacognitive Approaches, Integrative Oncology
Interventions, and Physical Activity Interventions. We had
hoped to include Light Therapy, but that was not possible.
2. Digital Health Interventions: We have an expanded section
on e-​health intervention delivery, which ranges from prevention, smoking cessation, and psychosocial distress to Physical
Symptom Control.
3. Biobehavioral Psycho-​Oncology: We have included the first
ever section on the science of stress and cancer risk and progression. We have wonderful contributions from Mike Antoni
and coauthors of Stress Processes and Cancer Progression;
Depression, Inflammation, and Cancer from Andrew Miller and
Our Past, Our Future
4.
5.
6.
7.
8.
9.
10.
coauthors; and Biobehavioral Psycho-​Oncology Interventions
from Michael Hoyt and Frank Penedo. This somewhat controversial area of psycho-​oncology research has now reached a
level of maturity and there are evidence-​based findings of which
all psycho-​oncologists must be aware.
Geriatric Oncology: This is a growing field in psycho-​oncology.
This section includes chapters on screening, assessment, interventions, and communications issues specific to managing
older cancer patients. Christian Nelson, Andrew Roth, Kelly
Trevino, Patricia Parker, Beatriz Korc-​Grodzicki, and Yesne
Alici were the primary contributors to this section. Their contributions acknowledge the pioneering work of our late friend
and colleague Arti Hurria.
Pediatric Psycho-​Oncology: For the very first time, Pediatric
Psycho-​Oncology is fully included and represented in the
Psycho-​Oncology series of textbooks. This section has chapters on pediatric psycho-​oncology screening and assessment,
management of common psychiatric disorders, evidence-​
based interventions in pediatric psycho-​oncology, and adolescent and young adults with cancer. The contributors to
these sections include the leaders of the field—​Anne Kazak,
Maryland Pao, Julia Kearney, Lori Wiener, Anna Muriel, and
Bradley Zebrack.
Survivorship: This section has been expanded and has interesting new information on approaches to Fear of Recurrence in
Cancer Survivors.
Palliative Care and Advanced Planning: These chapters focus
on the need to focus on treatment decision making; discussion of advance care planning and care goals at the time of
diagnosis—​early in the course of life-​threatening cancer; and
prognostic awareness and the role of the psycho-​oncologist in
palliative care. The interface of psycho-​oncology and palliative
care is a critically important one that needs to be navigated with
a sense of collaboration and integration. Michael Diefenbach,
Stefanie Mooney, Scott Irwin, Barry Rosenfeld, and Allison
Applebaum and their coauthors have contributed outstanding
chapters.
Diversities in the Experience of Cancer: This expanded new
section addresses the important issues of cancer and culture; cancer disparities; access to care and food; financial and
housing insecurities; cancer and sexual minorities; and the experience of cancer as an immigrant. The contributors to this
section include leaders in these areas such as Marjorie Kagawa-​
Singer, Francesca Gany, Victoria Blinder, Jennifer Leng, and
Charles Kamen.
Behavioral and Psychological Factors in Cancer Risk;
Screening for Cancer in Normal and At-​Risk Populations:
These sections have been expanded and include a broad international perspective. Contributors include many luminaries
such as Christoffer Johansen, Jamie Ostroff, Richard Fielding,
Jennifer Hay, Gabriel Leung, and many others.
Screening and Testing for Germ Line and Somatic Mutations:
With the advent of precision oncology and therapies targeted
at actionable tumor mutations, psycho-​oncologists have had
to learn a great deal about genetics, and now we have begun
to explore the various psychosocial sequelae and the need for
counseling presented by this revolution in medical oncology.
This section has chapters on genetic testing in breast and
ovarian cancer, testing in hereditary cancers, genomic testing
for targeted therapies, and psychosocial issues related to large-​
scale liquid biopsy screening for mutations in normal and at-​
risk populations. Mary Jane Esplen, Susan Peterson, Megan
Best, Jada Hamilton, and their coauthors have contributed outstanding chapters.
11. Screening and Assessment in Psychosocial Oncology: We’ve
experienced a revolution in screening and brief assessments
of patients at risk for distress, anxiety, depression, delirium
and cognitive disorders, suicidal ideation, and uncontrolled
symptoms. This section addresses many of these issues. Paul
Jacobsen, Kristine Donovan, Alex Mitchell, Tim Ahles, James
Root, Bill Breitbart, Yesne Alici, and their colleagues have contributed outstanding chapters.
12. Building Supportive Care Teams; Psycho-​Oncology in Health
Policy: These sections are expanded and have a broad international perspective.
Informed by Our Past, Inspired to Create a
Better Future
We have a great legacy. That is the gift our field has received from its
pioneers. We human beings engage in what is termed “cumulative
learning.” We build upon the wisdom and knowledge chronicled by
those who came before us. Einstein’s work on gravity could not have
taken place without building upon our knowledge of the chronicled
work of Newton. We are building upon the knowledge accumulated
and documented by psycho-​oncologists who dedicated their work
to establishing and growing a base of research and clinical innovation over the last 50 years. It is our responsibility to contribute to this
“cumulative” knowledge base and move our field forward to better
“care for the whole person with cancer.” Our hope is that you, the
readers of the 4th edition of Psycho-​Oncology, feel we have made a
valuable contribution to fulfilling the solemn responsibility we have
inherited: to create a better future.
William S. Breitbart, MD, FAPOS
Senior Editor
Psycho-​Oncology, 4th edition
REFERENCES
1. Feigenberg L. Terminal care: Friendship contracts with dying
cancer patients. New York, Brunner/​Mazel, 1980.
2. Holland JC, Rowland J, Eds: Handbook of Psychooncology.
New York, Oxford University Press, 1989.
3. Holland JC, Breitbart WS, Jacobsen PB, Lederberg MS, Loscalzo
M, Massie MJ, McCorkle R, Eds: Psycholo-​Oncology. New York,
Oxford University Press, 1998.
4. Holland JC, Breitbart WS, Jacobsen PB, Lederberg MS, Loscalzo
M, McCorkle R, Eds: Psycho-​Oncology 2nd Edition. New York,
Oxford University Press, 2010.
5. Holland JC, Breitbart WS, Butow PN, Jacobsen PB, Lederberg
MS, Loscalzo M, McCorkle R, Eds: Psycho-​Oncology 3rd Edition.
New York, Oxford University Press, 2015.
3
SECTION I
Behavioral and Psychological
Factors in Cancer Risk and
Prevention
Paul B. Jacobsen (Section Editor)
1
Tobacco Use and Cessation 7
4
Thomas H. Brandon, Vani N. Simmons, Úrsula Martínez, and
Patricia Calixte-Civil
2
Diet and Cancer 13
Marian L. Fitzgibbon, Lisa Tussing-Humphreys, Angela Kong,
and Alexis Bains
3
Physical Activity, Sedentary Behavior,
and Cancer 21
Christine M. Friedenreich, Chelsea R. Stone,
and Jessica McNeil
Sun Exposure and Cancer Risk 30
Suzanne J. Dobbinson, Afaf Girgis, Bruce K. Armstrong,
and Anne E. Cust
5
Psychosocial Factors 36
Anika von Heymann and Christoffer Johansen
6
Viral Cancers and Behavior 43
Susan T. Vadaparampil, Lindsay N. Fuzzell,
Shannon M. Christy, Monica L. Kasting, Julie Rathwell,
and Anna E. Coghill
1
Tobacco Use and Cessation
Thomas H. Brandon, Vani N. Simmons, Úrsula Martínez, and Patricia Calixte-​Civil
Tobacco and Cancer
Each year over 7 million people die worldwide due to tobacco use.1
Smoking is responsible for about 22% of all cancer deaths globally.
It accounts for over two-​thirds of all lung cancer mortalities and
contributes significantly to mortality rates for oral cancer, as well as
bladder, stomach, liver, pancreas, kidney, cervical, and colorectal cancers.2 In addition to cancer, smoking contributes to coronary heart disease, chronic obstructive pulmonary disease, cardiovascular disease,
stroke, and peptic ulcers. Indeed, about 20% of all deaths in the United
States can be attributed to smoking. From the individual perspective,
a given smoker has about a 50% chance of dying from smoking, with
the average smoker living 10 years less than a nonsmoker.3 Although
there are risks associated with noncombustible tobacco use (e.g., chew,
snuff), this chapter focuses on combustible tobacco use (i.e., smoking)
because of its much higher prevalence and relative risk. Nevertheless,
patients should be advised to cease all forms of tobacco use.
Smoking cessation is associated with decreased mortality and
morbidity from cancer and other diseases. Stopping smoking at age
30 restores nine years of life expectancy, whereas stopping at age 60
still restores an expected three years of life, compared to continuing
to smoke.3 Thus, great potential for cancer prevention lies with long-​
term cessation of smoking. In this chapter, we begin by noting the
changing demographic profile of current smokers. We then review
the evidence-​based treatments for tobacco use and dependence, emphasizing primarily qualitative and meta-​analytic reviews. We draw
upon the 2008 update of the U.S. Public Health Service’s Clinical
Practice Guideline, Treating Tobacco Use and Dependence,4 which is
based on a review of 8,700 research articles, with treatment recommendations derived from meta-​analyses of most treatment modalities. We then discuss special issues of relevance for treating cancer
patients. New to this update is a discussion of electronic cigarettes
(e-​cigarettes), the use of which has grown exponentially over the
past decade, including among cancer patients.
Evolving Landscape of Tobacco and Nicotine Use
Changing Demographics of Tobacco Users
Several countries have implemented strategies toward reducing
tobacco burden, such as monitoring tobacco use, offering access
to smoking cessation interventions, increasing tobacco taxes, or
introducing public warnings about the dangers of tobacco use.
Although these actions have led to a global reduction in tobacco use
in most developed countries, these nations still account for half of all
female daily smokers and roughly 75% of male daily smokers. Efforts
to reduce tobacco use have been successful in developed countries,
and they should be bolstered in developing countries (i.e., countries with historically lower education, per capita income, and life
expectancy). Developing countries have shown moderate smoking
prevalence across time, but many of these nations are showing increases in the prevalence of smoking and smoking-​related mortality
that are commensurate with increases in income, decreases in the
cost of tobacco, heavier marketing from the tobacco industry, and
limited tobacco-​related public health policies. As such, developing
countries are vulnerable to assuming the burden of the tobacco
epidemic.1 Moreover, tobacco use burden is disproportionately affecting certain segments of the population worldwide. For example,
tobacco use is rapidly increasing among youth, especially females,
in developing countries, and it is highly prevalent among individuals with low income across nations, regardless of per capita gross
national income.5
In the U.S., since the seminal 1964 U.S. Surgeon General’s report,
the prevalence of smoking among adults has dramatically declined
from nearly half of adults to less than one in five.6 The current demographic profile of smokers is markedly different than decades ago
because the reduction in smoking prevalence has not been consistent across demographic groups. These differences in prevalence
of tobacco use are associated with differential burdens of tobacco-​
related morbidity and mortality. In particular, a substantial body
of evidence demonstrates that lower educational attainment, being
below the poverty level, identifying as American Indian/​Alaska
Native, living in the Midwest or South, working in a blue-​collar or
service industry, having active military or veteran status, having a
disability, having a severe mental illness, and not having health insurance are associated with higher prevalence of smoking in the U.S.
There are also more recent changes in the demographics of tobacco users that coincide with shifts in the racial/​ethnic composition
of the U.S. and/​or more inclusive data collection. That is, subgroups
who identify as more than one race/​ethnicity, as sexual or gender
minorities, or as immigrants report greater tobacco use. Regarding
race/​ethnicity, although Hispanics and non-​Hispanic Asians have
8
SECTION I Factors in Cancer Risk and Prevention
among the lowest smoking prevalence by race/​ethnicity (12.7% and
8%, respectively), there is wide variation in smoking behavior within
the subgroups and across gender. Among foreign-​born men living
in the U.S., 24.8% of Mexicans, 47.7% of Filipinos, and 52.7% of
Chinese people reported being current smokers, which is of particular relevance to healthcare in the United States given that Mexico,
the Philippines, and China represent three of the top five countries
with the largest populations of foreign-​born individuals in the U.S.
In 2010 alone, 29.3% of all immigrants living in the U.S. were from
Mexico. Thus, the distribution of tobacco use and its consequent
health and economic burdens are unequal and shifting, requiring
attention by both researchers and clinicians.
The Emergence of Electronic Cigarettes
E-​cigarette use has grown dramatically in the last 10 years. E-​
cigarettes include a battery and heating element that aerosolizes a
liquid that typically contains nicotine, flavorants, propylene glycol,
and vegetable glycerin. Since their introduction, the available products have expanded and evolved in terms of their ease of use, their
sophistication, and their efficiency of nicotine delivery. The newest
devices deliver a nicotine dose similar to a combustible cigarette,
while also simulating the sensorimotor aspects of smoking (e.g.,
hand and arm movements, puffing and inhalation behavior, and
visible exhalation). Theoretically, these similarities should ease the
transition from combustible cigarettes to e-​cigarettes. Although
there have been regulatory barriers to conducting randomized controlled trials of e-​cigarettes for smoking cessation, evidence of their
efficacy is now emerging.7 However, e-​cigarettes have generated a
magnitude of controversy and division never before seen in the tobacco control and research fields. The current scientific consensus
is that e-​cigarettes are substantially less harmful than combustible
cigarettes,8 and therefore complete switching from smoking to
“vaping” represents significant harm reduction at the individual and
population levels. However, there is growing concern about the recent uptake of vaping by youth and the unknown long-​term health
outcomes of this behavior. The primary public health challenge related to tobacco use is to develop policy that promotes switching by
current smokers while minimizing uptake of vaping by youth who
would not have otherwise used nicotine products.
Treatment of Tobacco Use and Dependence
Tobacco dependence has multiple motivational influences within
and across individual smokers.9 Among these are physical dependence on nicotine, operant and classical conditioning processes, environmental and social factors, cognitive expectancies about the
benefits of smoking, and desire for weight control. Given the complexity of the factors influencing smoking, it is not surprising that
single-​treatment approaches have limited success, with the best
long-​term outcomes obtained from multimodal treatments. In this
section, we review pharmacological interventions, followed by social/​behavioral interventions, broadly defined, and finally discuss
combination treatments.
Pharmacotherapy
Currently, there are seven pharmacotherapies approved by the U.S.
Food and Drug Administration (FDA) for smoking cessation. All of
these medications have been found to approximately double the odds
of long-​term abstinence (with one, varenicline, tripling the odds),
and the Clinical Practice Guideline issued by the U.S. Department of
Health and Human Services recommends that pharmacotherapy be
routinely offered to smokers attempting to quit.4
Nicotine Replacement Therapies
Nicotine replacement therapy (NRT) aids smoking cessation by
partially replacing plasma nicotine levels, thereby reducing symptoms of nicotine withdrawal (e.g., craving, depression, irritability,
difficulty concentrating) and possibly reducing the reinforcement
derived from any cigarettes smoked. Five types of NRT have FDA
approval: chewing gum, transdermal patch, intranasal spray, inhaler device, and lozenge. In general, NRT is used during the first
8–​12 weeks of abstinence, when nicotine withdrawal symptoms are
greatest. Of the five NRT delivery methods, the nicotine nasal spray
reaches its peak concentration most rapidly, whereas the transdermal patch provides the slowest, but most consistent, serum nicotine levels over the course of a day.
Meta-​analyses indicate roughly equivalent efficacies for the five
NRT products, with odds ratios ranging from 1.5 (for nicotine gum)
to 2.3 (for nasal spray) compared to placebo.4 Estimated six-​month
abstinence rates are approximately 20%–​25%. Each product is associated with specific contraindications and cautions, primarily related to its particular mode of drug delivery. Because NRT delivers
nicotine without the harmful byproducts of smoked tobacco, it is
considered a far safer alternative to smoking. The safety of NRT
during pregnancy has not been established.
Bupropion SR (Zyban®)
Bupropion was the first non-​nicotine medication to be approved
by the FDA for treating tobacco dependence. Also marketed as an
atypical antidepressant (Wellbutrin®), bupropion doubles tobacco
abstinence rates compared to placebo, with an average odds ratio
of 2.0, and an abstinence rate of approximately 24%.4 It attenuates nicotine withdrawal and cigarette cravings, and can reduce
postcessation weight gain. Bupropion’s mechanism of action is not
fully understood, but it appears to inhibit the neuronal reuptake
of dopamine and norepinephrine—​key neurotransmitters in the
maintenance of nicotine dependence. It may also have antagonistic
effects on nicotinic receptors, attenuating perceived satisfaction
from smoking.
To reach steady-​state blood levels before quitting smoking, the
smoker should begin using bupropion SR one week before the
target quit date. Contraindications include a history of seizure disorders or factors known to increase the risk of seizures (e.g., bulimia or anorexia nervosa, serious head trauma, alcoholism) and
concomitant use of monoamine oxidase (MAO) inhibitors. Because
of postmarketing reports of neuropsychiatric adverse events, including suicidality, the FDA required “black box” warnings on
both bupropion and varenicline (see later) with respect to possible
neuropsychiatric adverse events, including depression, psychosis,
aggression, agitation, and anxiety, as well as suicidal ideation or behavior. Although the warning remains, the black box was rescinded
in 2016 following additional research that failed to find elevated
neuropsychiatric events for varenicline or bupropion compared to
NRT or placebo. The safety of bupropion during pregnancy has not
been established.
CHAPTER 1 Tobacco Use and Cessation
Varenicline (Chantix®)
Varenicline was the last pharmacotherapy approved for treating
nicotine dependence. It is an orally administered partial agonist of
α4β2 nicotinic acetylcholine receptors (nAChRs). Varenicline appears to reduce nicotine cravings and withdrawal symptoms, and
its agonistic properties appear to attenuate the reinforcing effects
of smoking, including perceived satisfaction.10 Similar to bupropion, varenicline use should be initiated one week before the target
quit date. Evidence suggests that it has outperformed bupropion in
head-​to-​head studies and is the most effective of the smoking cessation medications, with an average odds ratio of 3.1, producing 33%
abstinence.4
The main adverse effect of varenicline is mild to moderate nausea.
However, as with bupropion, warnings of neuropsychiatric adverse
events are also included in labeling. In addition, there is some evidence that varenicline may increase the risk of major cardiovascular
events. Varenicline is not approved for use with pregnant women.
Combination Pharmacotherapies
Recent research has tested the efficacy of combining different forms
of pharmacotherapy. The general model has been to combine a long-​
acting, relatively stable medication, such as the nicotine patch, with
a shorter-​acting medication that can be used ad libitum. In this
manner, both tonic and phasic nicotine cravings and withdrawal
symptoms can be addressed. The combination of nicotine patch with
gum, nasal spray, or inhaler has evidence of significant efficacy, as
does the combination of the patch and bupropion SR.4
Social/​Behavioral Treatments
The nonpharmacological therapies described in this section span a
wide range of intensity and duration, from minimal self-​help interventions to intensive individual counseling. Clinicians should be
aware of the availability of these options and should be willing to
refer patients for services that they are unable to provide themselves.
Self-​help
Self-​help refers to materials that can be provided to smokers, such
as pamphlets, booklets, or audiovisual media. Their primary advantages are low cost and ease of distribution. Unfortunately, the
efficacy of self-​help materials appears to be quite limited, with improved cessation rates of about 1% compared to no-​treatment controls.4 However, a self-​help intervention that extends over time (i.e.,
distribution of sets of materials over 12–​18 months) has recently
demonstrated long-​term efficacy.10
Telephone Quitlines
Smoking cessation quitlines are available throughout the United
States and most of the world. In the United States one number
(1-​800-​QUIT-​NOW) serves as a central access point that automatically routes calls to the appropriate state or federal quitline
service. Approximately 400,000 smokers in the United States are
served annually by state quitlines, with an average utilization rate
of about 1%.11
Quitline services differ in the amount and frequency of counseling offered, the provision of ancillary materials, referrals to local
smoking cessation agencies, the provision of free or subsidized
pharmacotherapies, and whether calls are proactive (call-​out), reactive (call-​in), or both. Quitlines have the advantage of providing
more personal and intensive help than self-​help materials, while also
having greater potential reach than face-​to-​face counseling. Meta-​
analyses show that quitlines are effective, with overall odds ratios of
1.4–​1.6 compared to control conditions, which translates into differential long-​term abstinence rates of at least 3%–​5%.4
Brief Interventions
Healthcare providers have the opportunity to deliver relatively brief
face-​to-​face interventions. The U.S. Public Health Service (PHS)
Clinical Practice Guideline describes an effective brief smoking cessation intervention model most commonly referred to as the “5’A’s.”4
The five key steps include (1) “Asking” every patient about tobacco
use at repeated visits, (2) “Advising” every tobacco user to quit by
providing clear and personalized advice to quit, (3) “Assessing” the
willingness of patients to quit, (4) “Assisting” patients with quitting,
and (5) “Arranging” follow-​up cessation support, ideally within a
few weeks of the quit attempt. Meta-​analyses have indicated that
physician advice alone increases abstinence rates by approximately
2.3%–​2.5%.4 Because 70% of smokers visit their physician each year,
the potential cumulative effect of even this small effect is sizable.
Moreover, there is a dose–​response relationship between contact time
and abstinence outcomes, with minimal counseling (< 3 minutes)
yielding 13.4% abstinence, low-​intensity counseling (3–​10 minutes)
yielding 16.0% abstinence, and higher-​intensity counseling (> 10
minutes) yielding 22.1% abstinence. Abstinence rates also increase
with the number of counseling meetings and/​or the number of clinician types delivering the cessation messages.4 Alternative models
that reduce provider burden include Ask-​Advise-​Refer (AAR) and
Ask-​Advise-​Connect (AAC). In both abbreviated models, patients
are asked about their smoking and are delivered brief advice to quit.
However, in the AAR model, patients are then referred to evidence-​
based cessation programs for assistance in quitting (e.g., a quitline).
Designed to overcome patient barriers that exist with use of a passive referral model, the AAC model directly connects patients to the
smoking cessation resource via an automated connection system
within the electronic health record (EHR). The AAC method has
demonstrated greater impact over the AAR model with respect to a
higher proportion of smokers enrolling in treatment.12
Intensive Interventions
The most intensive interventions tend to be multisession treatments typically offered through smoking cessation clinics, in either
group or individual formats. Of the empirically supported intensive
interventions, the most common approach is cognitive-​behavioral
counseling. Key elements of this approach include patient education
regarding tobacco dependence and withdrawal, advice for coping
with withdrawal symptoms, identifying high-​risk situations (“triggers”) that produce urges to smoke, teaching and practicing cognitive and behavioral responses for coping with urges, discussion of
long-​term risk factors such as depression and weight gain, and discussion of how to respond in the event of an initial “slip” or “lapse.” It
usually involves multiple sessions over several weeks and may begin
before the target quit date. Counseling has been found to be effective, with an odds ratio of 1.5 compared to no counseling and an
average abstinence rate of 16.2% compared to 11.2%.4 In addition
to counseling, the guideline also found evidence for intratreatment
social support, and it therefore recommends providing support and
encouragement as part of treatment.
9
10
SECTION I Factors in Cancer Risk and Prevention
Combining Counseling and Pharmacotherapy
A key conclusion of the most recent guideline is that the combination of counseling and medication is more effective than either alone
in producing long-​term tobacco abstinence. Moreover, as noted
earlier, higher abstinence rates tend to be produced with more intensive counseling. Thus, the guideline meta-​analysis produced an
estimated abstinence rate of approximately 33% when medication
was combined with nine or more sessions of counseling, compared
to 22% when no more than one counseling session was provided.
Conversely, the guideline reported an odds ratio of 1.7 for the combination of medication and counseling, compared to counseling
alone.4 Counseling and medication appear to provide complementary benefits. Whereas medication reduces withdrawal symptoms
and craving, counseling can teach cognitive and behavioral coping
strategies and can provide valuable social support. Therefore, whenever medication is recommended or provided to patients, they
should also be offered counseling.
Special Issues with Cancer Patients
There is a growing body of evidence that smoking following cancer
diagnosis has a negative impact on cancer treatment efficacy,
treatment-​related complications and side effects, cancer recurrence
and second malignancies, and overall survival.13 With advances in
cancer treatments, the number of cancer survivors is significantly
increasing, emphasizing the importance of improving health outcomes and quality of life within this high-​risk population. In this
section, we will describe the benefits of smoking cessation in cancer
patients, review cessation and relapse rates among cancer patients,
and summarize the current knowledge regarding cessation interventions for cancer patients.
Benefits of Quitting Smoking
The last report of the U.S. Surgeon General concluded that continued smoking after cancer diagnosis is causally related to multiple
negative consequences, including increased risk of cancer-​specific
mortality as well as all-​cause mortality. Furthermore, persistent
smoking after a cancer diagnosis has been strongly associated
with cancer recurrence, poor treatment outcomes (e.g., poorer response to treatment, treatment-​related toxicities), and higher risk of
hospitalization.13
Quitting smoking is associated with fewer medical complications,
decreased risk of subsequent malignancies, and increased survival
rate.14 Finally, some research indicates that patients who remain
smoke-​free following cancer treatment report lower levels of depression and fatigue, improving overall quality of life relative to patients
who continue to smoke.15 In summary, evidence is accumulating
that smoking cessation after a cancer diagnosis improves quality of
life, increases survival, and decreases cancer recurrence and psychological distress.
Smoking Cessation and Relapse among Cancer Patients
Despite the benefits of quitting, over 30% of cancer patients continue to smoke after diagnosis. However, cancer patients who smoke
are highly motivated to quit, and many make an attempt to quit at
the time of diagnosis.16 Because most quit attempts appear to occur
at the time of diagnosis and treatment, the period between cancer
diagnosis and end of treatment may represent the optimal window
of opportunity for provision of smoking cessation interventions.
There is less research on long-​term abstinence rates among cancer
patients. Estimates of smoking relapse range from 13% to 60%.
Unlike the general population of smokers for whom relapse most
often occurs within a week after cessation, the majority of relapses
among cancer patients occurs within the first few months following
a quit attempt, again reflecting the initial motivational impact of a
cancer diagnosis. Predictors of both persisting smoking and relapse
have included factors such as longer history of smoking, depression,
lower desire to quit, and alcohol use.17
Interventions for Cancer Patients
Few clinical trials have been conducted on smoking cessation interventions for cancer patients. Interventions tested have included a
variety of formats, such as nurse-​delivered inpatient counseling,
cognitive-​behavioral therapy, motivational interviewing, distribution of educational materials, and follow-​up phone calls. Several
studies have also tested pharmacological cessation treatments (nicotine replacement therapy, varenicline, or bupropion), either alone
or combined with counseling. The overall findings have not demonstrated a significant treatment effect.18
More recently, some innovative interventions are being tested.
System-​
based interventions aim at introducing changes in the
overall organization to change smoking cessation practices (e.g.,
automatic referrals using EHRs). Also, interventions using mobile
technology have been pilot tested. However, evidence on the effectiveness of these new types of interventions is still limited.
Finally, the use of e-​cigarettes has increased among cancer patients, paralleling trends in the general population.19 Overall, it seems
that cancer patients hold generally positive expectancies regarding
e-​cigarettes, as compared to both combustible cigarettes and NRT,
and find them an attractive way to quit smoking.20 The American
Association for Cancer Research (AACR) and the American Society
of Clinical Oncology (ASCO) recommend that healthcare providers
encourage use of FDA-​approved cessation methods, given the lack
of definitive data regarding the safety and efficacy of e-​cigarettes.
However, the American Cancer Society’s 2018 position statement on
e-​cigarettes recommends harm reduction, including e-​cigarettes, for
patients who have not otherwise been able to quit smoking.
When implementing smoking cessation interventions with
cancer patients, clinicians should be mindful of several unique
cancer-​related issues. For instance, the delay in relapse among
cancer patients described earlier may suggest a waning of motivation as patients physically recover and return to their prediagnosis
lifestyles. Thus, smoking relapse prevention interventions may be
particularly important as patients recover. Another issue relates to
potential contraindications with the use of smoking cessation pharmacotherapy. With respect to NRT and e-​cigarettes, for example,
although nicotine is not itself carcinogenic, preclinical research suggests that it can accelerate tumor growth, inhibit apoptosis induced
by several chemotherapy agents, and negatively impact response to
radiotherapy. Nevertheless, there is no evidence to date indicating
that NRT causes adverse events in cancer patients.14 In addition,
NRTs such as nicotine gum, spray, inhaler, or lozenge may not be
appropriate for individuals with oral cancers, whereas bupropion is
contraindicated for patients with a history of central nervous system
(CNS) tumors due to an increased risk of seizures. Hence, clinicians
CHAPTER 1 Tobacco Use and Cessation
must take extra care in selecting appropriate cessation medications
that address cancer patients’ unique needs.
Given the growing body of evidence demonstrating the substantial risks of continued smoking among cancer patients, it is not
surprising that recognition and support of cessation services are
increasing. For example, the ASCO developed updated tobacco
guidelines that include recommendations for health professionals to
assess tobacco use and integrate cessation services in the oncology
setting.21 Similarly, a policy statement by the AACR called for improved documentation of tobacco use among patients, as well as
improvements in evidence-​based cessation assistance provided to
all patients who use tobacco or have recently quit tobacco.22 The
National Comprehensive Cancer Network (NCCN) has also developed clinical practice guidelines for smoking cessation that include a thorough assessment of tobacco use and supports the use
of evidence-​based methods of smoking cessation (i.e., combined
pharmacologic and behavior therapy) for every cancer patient
throughout the continuum of cancer care.23 Finally, the U.S. National
Cancer Institute (NCI), in recognition of the need for system-​level
smoking cessation services, has provided competitive funding to
NCI-​designated cancer centers to develop comprehensive plans to
identify and offer cessation services to every cancer patient who
smokes, via enhanced EHR and other strategies.24
Improved comprehensive documentation of tobacco use would
further clinical support for smoking cessation as well as facilitate
research on the effects of tobacco on cancer-​related outcomes and
its impact on treatment response in clinical trials. With the aim
of improving the assessment of tobacco use in the oncology patient population, the Cancer Patient Tobacco Use Questionnaire
(C-​TUQ) was developed.25 This tool comprises up to 22 items for
standardized assessment of tobacco use among cancer patients. This
is particularly important within clinical trials of cancer therapies,
given that tobacco use is a treatment modifier.
In summary, the importance of quitting smoking for all cancer patients is clear. Clinicians who treat cancer patients must capitalize on
the window of opportunity during cancer diagnosis and treatment
to identify smokers and make cessation interventions readily available to these high-​risk patients. Cancer patients who stop smoking
and remain abstinent after treatment are likely to reap significant
benefits, including improved quality of life and prolonged survival.
Conclusion
Tobacco use by cancer patients appears to be influenced by the
same range of biopsychosocial factors as it is in the general population. However, cancer diagnosis and treatment offer a unique and
potentially powerful opportunity for healthcare providers to intervene by offering cessation advice and assistance. To date, there is
little research to recommend specialized smoking cessation interventions for cancer patients above and beyond the general recommendations of the Clinical Practice Guidelines.7 However, it is likely
that targeted treatments that capitalize on the teachable moment
could be highly effective, and research has been increasing in this
area. Meanwhile, the greatest progress in both cancer prevention
and recovery depends on consistent action by all components of
the healthcare system to promote tobacco cessation. This includes
coverage of smoking cessation interventions by third-​party payers,
establishment of smoke-​free campuses by hospital administrators,
and strong cessation advice and assistance by every healthcare provider. Finally, the changing demographics of tobacco users along
with evolving noncombustible alternatives to smoking require ongoing monitoring and the updating of policies and clinical practices,
as needed.
ACKNOWLEDGMENTS
Preparation of this chapter was supported by National Cancer
Institute grants R01 CA154596, R01 DA037961, R01 CA199143,
and R03 CA227044.
Disclosure: Dr. Brandon has received research support from
Pfizer, Inc., and serves on the advisory board for Hava Health, Inc.
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Sheeran P, Jones K, Avishai A, et al. What works in smoking cessation interventions for cancer survivors? A meta-​analysis. Health
Psychol. 2019;38(10):855–​868.
Sanford NN, Sher DJ, Xu X, Aizer AA, Mahal BA. Trends in
smoking and e-​cigarette use among US patients with cancer, 2014-​
2017. JAMA Oncol. 2019;5(3):426–​428.
Correa JB, Brandon KO, Meltzer LR, et al. Electronic cigarette use among patients with cancer: reasons for use,
21.
22.
23.
24.
25.
beliefs, and patient-​
provider communication. Psychooncology.
2018;27(7):1757–​1764.
Hanna N, Mulshine J, Wollins DS, Tyne C, Dresler C. Tobacco
cessation and control a decade later: American Society of
Clinical Oncology policy statement update. J Oncol Pract.
2013;31(25):3147–​3157.
Toll BA, Brandon TH, Gritz ER, et al. Assessing tobacco use
by cancer patients and facilitating cessation: an American
Association for Cancer Research policy statement. Clin Cancer
Res. 2013;19:1941–​1948.
National Comprehensive Cancer Network. Smoking cessation
guidelines, https://​www.nccn.org/​professionals/​physician_​gls/​
pdf/​smoking.pdf, 2017.
Croyle RT, Morgan GD, Fiore MC. Addressing a core gap in cancer
care—​the NCI Moonshot Program to help oncology patients stop
smoking. N Engl J Med. 2019;380(6):512–​515.
Land SR, Toll BA, Moinpour CM, Mitchell SA, et al. Research
priorities, measures, and recommendations for assessment
of tobacco use in clinical cancer research. Clin Cancer Res.
2016;22(8):1907–​1913.
2
Diet and Cancer
Marian L. Fitzgibbon, Lisa Tussing-​Humphreys, Angela Kong, and Alexis Bains
Overview
Research over the past several decades shows that 95% of cancers
can be attributed to environmental factors,1 including pollution, infections, radiation, and other external factors as well as tobacco use,
alcohol, inactivity, diet, and other lifestyle factors.2 Diet, arguably
among the most modifiable of these factors, likely contributes to the
development of 30% to 35% of cancers.
Substantial shifts in the food landscape in developed countries
have contributed to changes in dietary intake, energy balance, increases in body fat, and the development of obesity. Obesity, defined as a body mass index (BMI) ≥ 30 kg/​m², is associated with
several cancers. Obesity exceeds 30% in both genders and is predicted to reach 51% by 2030 across all adult age groups in the United
States (U.S.). Thus, the World Cancer Research Fund (WCRF), the
American Institute for Cancer Research (AICR), the American
Cancer Society (ACS), and cancer researchers both in the U.S. and
globally are devoting significant time and resources to studying the
relationship between diet, dietary patterns, lifestyle risk factors, obesity, and cancer.3
Advances in research methodology hold promise for reconciling
the complex literature on the role of diet and cancer risk. Prior research focused more often on specific nutrients and foods in isolation rather than examining the effects of dose, timing, exposure, and
overall nutritional status. However, more recent studies demonstrate
that dietary patterns are key to enhancing our knowledge of the relationship between diet and cancer. The consensus across studies suggests that a healthy dietary pattern includes fruits, vegetables, fish,
whole-​grain cereals, nuts, legumes, and intake of healthy fats. This is
presumably due to the value of these foods in providing a combination of important vitamins, minerals, fiber, protein, and antioxidants
associated with reduced cancer risk. An unhealthy dietary pattern,
on the other hand, consists of red meat, processed meat, refined
sugars and sugar-​sweetened beverages, refined flours, alcohol, and
high saturated fat intake.
While diet is often a major contributor to the energy imbalance
that can lead to the development of obesity, physical activity patterns also play a role. Extensive evidence shows increased physical
activity may reduce the incidence of and survival from various cancers and that inactivity is associated with many chronic diseases.
Strong evidence demonstrates that regular physical activity of all
types protects against excessive weight gain and obesity. Thus, the
interaction of energy intake (i.e., diet) and energy expenditure (i.e.,
physical activity) is fundamental to weight management and cancer
risk and control. This chapter (1) summarizes the role of dietary factors and cancer risk, (2) highlights the relationship between dietary
patterns and cancer, (3) summarizes the role of weight management
and energy balance, (4) identifies potential environmental barriers
to diet-​related cancer risk reduction, and (5) offers areas for future
research.
Diet-​, Physical Activity–​, and Body Composition–​
Related Factors and Cancer Risk
This section presents an overview of the best-​established associations (i.e., graded as “strong evidence”) reported by the WCRF and
the AICR between the leading causes of cancer death worldwide and
dietary factors, physical activity, and body fatness4 (summarized in
Table 2.1).
Lung Cancer. Lung cancer is the most common cause of cancer
and cancer death in both sexes combined worldwide. Smoking is the
main cause of lung cancer globally, accounting for an estimated 90%
of lung cancers among men and 80% in women. Arsenic in drinking
water is the most established dietary risk factor for lung cancer.
The World Health Organization (WHO) reports that contaminated
groundwater is the main source of arsenic.5 Beta-​carotene supplements are also associated with increased risk for lung cancer, particularly among smokers. This association was discovered through
two large intervention trials, the Beta-​carotene and Retinol Efficacy
Trial (CARET) and the Alpha-​Tocopherol, Beta-​Carotene (ATBC)
Cancer Prevention Study.6 The CARET study was conducted in the
U.S. with male and female smokers and former smokers, as well as
men with occupational exposure to asbestos. The ATBC Cancer
Prevention Study was conducted in Finland with male smokers.
There is only limited evidence of specific foods decreasing (e.g.,
vegetables, fruits, foods containing carotenoids, etc.) or increasing
(e.g., red meat, processed meat, alcohol) lung cancer risk.
Liver Cancer. Liver cancer is the fourth most common cause of
cancer death worldwide and the fifth most commonly occurring
cancer. Established risk factors of liver cancer include cirrhosis of the
liver, long-​term use of high-​dose estrogen and progesterone, chronic
14
SECTION I Factors in Cancer Risk and Prevention
Table 2.1. Dietary-​, Physical Activity–​, and Weight-​Related Factors Showing Convincing or Probable Evidence of Association with the Top 10
Causes of Cancer Death Worldwide
Cancer
Increases Risk
Decreases Risk
Lung
Arsenic in water**
High-​dose beta-​carotene supplements1**
Liver
Exposure to aflatoxin2**
Alcohol (45 grams or 3 drinks a day)**
Body fatness (based on BMI)**
Coffee*
Stomach
Body fatness (cardia) (based on BMI)*
Alcoholic drinks (45 grams or 3 drinks a day)*
Food preserved by salting3*
Colorectal
Processed meat4**
Alcoholic drinks (30 grams or 2 drinks a day)**
Body fatness5
Adult attained height6**
Red meat (beef, pork, lamb, and goat from domesticated animals)*
Physical activity7**
Whole grains*
Foods containing dietary fiber8*
Dairy products9*
Calcium supplements* (supplemental dose of
200–​1,000 mg/​day) *
Breast
Premenopausal
Adult attained height6**
Alcoholic drinks (no amount/​limit was found)*
Greater birthweight10*
Postmenopausal
Alcoholic drinks (no amount/​limit was found)**
Body fatness5**
Adult weight gain**
Adult attained height6**
Vigorous physical activity*
Body fatness11*
Lactation12*
Physical activity13*
Body fatness in young adulthood11*
Lactation12*
Esophageal
Adenocarcinoma
Body fatness5**
Squamous Cell Carcinoma
Alcoholic drinks**
Mate14*
Pancreatic
Body fatness15**
Adult attained height6*
Prostate
Body fatness (advanced prostate cancer)16*
Adult attained height6*
** Indicates convincing evidence.
* Indicates probable evidence.
Based on the grading criteria reported in the Diet, Nutrition, Physical Activity and Cancer: A Global Perspective, Third Expert Report (2018).
** Convincing (strong evidence): Evidence strong enough to support a judgment of a convincing causal (or protective) relationship, which justifies making
recommendations designed to reduce the risk of cancer. The evidence is robust enough to be unlikely to be modifiable in the foreseeable future as new evidence
accumulates.
* Probable (strong evidence): Evidence strong enough to support a judgment of a probably causal (or protective) relationship, which generally justifies recommendation designed to reduce the
risk of cancer.
1
Based on studies testing high-​dose supplements on smokers and former smokers (beta carotene: 20 mg/​day or retinol: 25,000 IU/​day).
2
Grains (cereals), legumes (pulses), seeds, nuts, and some fruits and vegetables are foods that may be contaminated with aflatoxins.
3
Regarding traditionally prepared in East Asia, high-​salted foods and foods preserved with salt, such as pickled vegetables and salted or dried fish.
4
Regarding meat preserved by smoking, curing, slating, or adding chemical preservatives.
5
Body fatness represents BMI (body mass index), waist circumference, or waist-​hip ratio.
6
Adult attained height is an indicator of genetic, environmental, hormonal, and nutritional growth factors that have an influence on growth from preconception to completion of
linear growth.
7
Includes physical activity of all types: occupational, household, transport, and recreational. The panel judges that the evidence for colon cancer is convincing, but no conclusion was
drawn for rectal cancer.
8
Both foods that naturally have dietary fiber and foods with dietary fiber added.
9
Evidence from dairy, milk, cheese, and dietary calcium supplements.
10
“The Panel’s conclusion relates to the evidence for overall breast cancer (unspecified). The observed association was in estrogen-​receptor-​negative (ER–​) breast cancer only.”
11
Body fatness represents BMI, waist circumference, or waist-​hip ratio. Women 18 to 30 years old included in evidence. For young adults, body fatness represents BMI.
12
“The Panel’s conclusion relates to the evidence for overall breast cancer (unspecified). The evidence for premenopausal and postmenopausal breast cancers separately was less
conclusive, but consistent with the overall finding.”
13
“Physical activity including vigorous, occupational, recreational, walking and household activity.”
14
Beverage is consumed scalding hot and through a metal straw (as traditionally consumed in South America).
15
Body fatness referring to/​interconnected with fat distribution, BMI, abdominal girth, and adult weight gain.
16
Body fatness represents BMI, waist circumference, or waist-​hip ratio. This outcome was seen in advanced cancer only, meaning high-​grade and fatal prostate cancers.
CHAPTER 2 Diet and Cancer
viral hepatitis, and smoking. There is strong evidence that the following diet-​and weight-​related factors increase liver cancer risk: (1)
being overweight or obese (as assessed by BMI), (2) alcoholic drinks
(about 3 drinks/​day), and (3) exposure to aflatoxins. Aflatoxin, a
mold that develops on foods stored in hot, wet conditions, can contaminate foods such as cereals (grains), legumes, seeds, and nuts,
and some fruits and vegetables. Coffee consumption is the only diet-​
related factor that is protective. A dose-​response meta-​analysis of
existing studies conducted by the expert panel suggests that one cup
of coffee per day is associated with a 14% decreased risk.4
Stomach (Gastric) Cancer. Stomach cancer is the fourth most
common cancer worldwide, with the highest incidence noted
among men and in certain regions of Asia, and is the third most
common cause of cancer death. Based on the location of the tumor,
stomach cancer can be classified as cardia (top part and closest to
esophagus) and noncardia (all other regions). Stomach cardia cancers are more common in the U.S. and UK, while noncardia forms
of stomach cancer are more prevalent in Asia. However, incidence
rates of stomach cancer (particularly noncardia) are declining
worldwide due in part to more widespread use of refrigeration to
store foods (rather than salting) and a decrease in Helicobacter pylori
(H. pylori) infections. Smoking and exposure to industrial chemicals are other established contributors to stomach cancer. Diet-​and
body composition–​related factors that increase the risk of stomach
cancer include alcoholic drinks (three drinks/​day), high-​salt foods,
and obesity. Being overweight or obese increases the risk of stomach
cardia cancer in particular.
Colorectal Cancer. Colorectal cancer is the third most commonly
diagnosed cancer and the second most common cause of cancer
deaths worldwide. Diet, physical activity, obesity, and alcohol consumption influence risk. The factors with the strongest evidence for
increasing risk are (1) processed meat intake, (2) alcoholic drinks
(about two drinks/​day), (3) body fatness, (4) adult attained height,
and (5) red meat. Adult attained height is not a direct risk factor,
but rather a marker for factors (e.g., genetic, environmental, hormonal, and nutrition) that could impact growth during the developmental years. Red meat contains the iron-​containing protein heme,
which can facilitate the formation of potentially carcinogenic compounds. Also, red meat cooked at high temperatures can produce
heterocyclic amines and polycyclic aromatic hydrocarbons that may
contribute to colon cancer in people with a genetic predisposition.
Processed meats (e.g., ham, bacon, sausages, canned meats) are preserved by methods other than freezing, such as smoking, salting, air
drying, or heating. Strong evidence of factors decreasing risk include
(1) physical activity, (2) whole grains, (3) dietary fiber, (4) dairy
products, and (5) calcium supplements. Of these factors, the most
convincing evidence is based on studies examining physical activity
(e.g., occupational, household, transport, and recreational) and colorectal cancer. Based on a meta-​analysis of over 30 studies, a reduced risk of about 14% for colon cancer was observed comparing
those in the highest vs. lowest groups for physical activity (risk ratio
[RR] = 0.85; 95% confidence interval [CI]: 0.78–​0.91).4 For whole-​
grain consumption there was a reduced risk of 17% per 90 g/​day
of whole-​grain intake (based on six studies consisting of n = 8,320
cases).4 For fiber-​containing foods, which include fiber that is added
and naturally occurring, there was a reduced risk of 9% per 10 g/​
day (based on 15 studies consisting of n = 14,876 cases).4 Calcium
and dairy products also appear to reduce colorectal cancer risk,
though the effect for milk is, in part, mediated by calcium. Evidence
for calcium’s protective effects is based on studies of supplements at
doses of 200 to 1,000 mg/​day.
Breast Cancer. Breast cancer is the most frequently occurring
cancer and the most common cause of cancer death for women
worldwide. Because it is a hormone-​related cancer, risk is most affected by factors that influence exposure to estrogen, including
menopausal status. In a recent update by the WCRF/​AICR, the
following factors were considered strong evidence (convincing)
for increasing risk of postmenopausal breast cancer: (1) alcoholic
drinks (no amount identified), (2) body fatness, (3) adult weight
gain, and (4) adult attained height.4 Adult attained height (a marker
for factors affecting growth) and alcohol intake also increase risk
for premenopausal breast cancer. Additionally, greater birthweight,
which is an indicator of prenatal growth and fetal nutrition, is also
recognized as a risk factor for premenopausal women. While body
fatness increases breast cancer risk for postmenopausal women, it is
actually protective for premenopausal women. Lactation and physical activity decrease risk for both pre-​and postmenopausal women.
However, evidence is insufficient to confirm protective effects of any
specific dietary factors.
Esophageal Cancer. Cancer of the esophagus is the sixth most
common cause of cancer death and the seventh most common cancer
worldwide. There are two main types of esophageal cancer: squamous cell carcinoma (affects the upper part of the esophagus) and
adenocarcinoma, which occurs in the region between the esophagus
and stomach. Risk factors vary by site. For instance, body fatness
increases the risk for esophageal adenocarcinoma but not squamous
cell. Squamous cell carcinoma can be impacted by diet-​related factors. For instance, intake of alcohol and mate are associated with
increased risk of squamous cell carcinoma rather than adenocarcinoma. Mate is a tea-​like beverage consumed in parts of South
America, usually scalding hot, through a metal straw.
Pancreatic Cancer. Pancreatic cancer is the seventh most
common cause of cancer deaths. Incidence is higher in men than
in women and higher in developed countries. The WCRF/​AICR’s
continuous update project concluded there is convincing evidence
that body fatness and adult attained height increase pancreatic
cancer risk.4 No convincing or probable evidence suggests that any
dietary factors increase risk, though limited data suggests that red
and processed meats, alcohol, high-​fructose foods/​beverages, and
foods containing saturated fatty acids increase risk. Coffee was previously considered a possible risk factor, but the updated report indicates this is unlikely. No food or nutrition factors are identified as
decreasing pancreatic cancer risk.
Prostate Cancer. Prostate cancer is the second most common
cancer and fifth most common cause of cancer death in men.
Incidence is much higher in developed countries. The WCRF/​
AICR’s continuous update project report suggests there is strong
probable evidence that body fatness and adult attained height increase prostate cancer risk. However, insufficient data exists to identify any dietary factor as risk promoting.4
Cervical Cancer. Cervical cancer ranks fourth in both mortality
and incidence for women worldwide. The primary risk factor is infection with human papilloma viruses. Food and nutrition do not play
a significant role in increasing or decreasing cervical cancer risk.4
15
16
SECTION I Factors in Cancer Risk and Prevention
Dietary Patterns and Cancer Risk
Single foods and nutrients are not typically consumed in isolation.
Because dietary nutrients are consumed in combination, synergistic effects between food and nutrients may create a metabolic
milieu that prevents or promotes carcinogenesis. This section presents an overview of dietary patterns and associations with cancer
risk and risk of cancer-​related mortality as indicated by studies
that examined adherence to science-​based public health dietary recommendations such as the U.S. government’s Dietary Guidelines
for Americans (DGAs) and Mediterranean and vegetarian dietary
patterns. The DGAs and a Mediterranean diet (Med Diet) pattern
have corresponding index scores that are used to quantify adherence
using a standardized approach.7
The DGAs are designed to promote good health and reduce the
risk of chronic diseases, including cancer. The guidelines are revised every five years to account for advances in scientific knowledge pertaining to diet and disease relationships (the current
DGAs are presented in Table 2.2). The Healthy Eating Index (HEI)
is a scoring tool that measures adherence to a given set of DGAs;
higher scores are indicative of greater adherence to the guidelines.8
A recent systematic review and meta-​analysis of prospective cohort
studies examining diet quality, using several metrics including
the HEI and various health outcomes, found that individuals consuming the highest-​quality diets compared to lowest-​quality diets
had a 16% reduction in cancer mortality or incidence (RR = 0.84;
95% CI: 0.82–​0.87).9
Ecological studies suggest overall cancer risk is lower in
Mediterranean countries versus northern Europe, the UK, and the
U.S. Many have attributed this distinction to the customary foods
consumed by people residing in this region. A Med Diet pattern
is one in which vegetables and whole grains feature prominently,
fresh fruit is a typical dessert, olive oil is the main fat source,
animal-​based protein intake is limited, and wine is consumed in
moderation, with meals. Mechanistically, it is hypothesized that
certain aspects of the Med Diet, including a healthy fatty acid ratio
and foods rich in antioxidants and anti-​inflammatory nutrients,
work synergistically to promote reduced systemic inflammation
and down-​regulation of pro-​carcinogenic pathways. Several research groups have developed scoring indices to operationalize
and assess adherence to a Med Diet pattern to relate to disease
outcomes. The Alternate Mediterranean Diet (aMED) score is a
Med Diet adherence score developed specifically for U.S. populations.10 The aMED has nine components, with one point awarded
Table 2.2. Dietary and Lifestyle Recommendations for Good Health and Cancer Prevention
2015–​2020 Dietary Guidelines for Americans35
General Mediterranean Diet
Characteristics36
American Cancer Society37
American Institute for Cancer Research38
5 overarching guidelines of a healthy eating
pattern:
• Follow a healthy eating pattern across the
lifespan.
• Focus on variety, nutrient density, and
amount.
• Limit calories from added sugars and
saturated fats and reduce sodium intake.
• Shift to healthier food and beverage choices.
• Support healthy eating patterns for all.
A healthy eating pattern includes:
• A variety of vegetables from all the
subgroups—​dark green, red and orange,
legumes (beans and peas), starchy, and other.
• Fruits, especially whole fruits.
• Grains, at least half of which are whole grains.
• Fat-​free or low-​fat dairy, including milk,
yogurt, cheese, and/​or fortified soy beverage.
• A variety of protein foods, including seafood,
lean meats and poultry, eggs, legumes (beans
and peas), and nuts, seeds, and soy products.
• Oils.
A healthy eating pattern limits:
• Saturated fats (<10% calories per day) and
trans fats, added sugars (<10% of calories per
day), and sodium (<2,300 mg per day).
• If alcohol is consumed, it should be
consumed in moderation—​up to one drink
per day for women, and up to two drinks
per day for men—​and only by adults of legal
drinking age.
Healthy Eating Patterns Dietary Principles:
• An eating pattern represents the totality of all
foods and beverages consumed.
• Nutritional needs should be met primarily
from foods.
• Healthy eating patterns are adaptable.
Meet the Physical Activity Guidelines for
Americans.
• Daily abundance of plant-​
• Achieve and maintain
•
•
•
•
• Be a healthy weight.
• Be physically active.
• Eat a diet rich in whole grains,
•
•
•
•
•
based foods including whole
grains, vegetables, fruits, and
legumes.
Olive oil used daily as the
principal fat source.
Low to moderate daily
consumption of low-​fat
dairy foods.
Animal-​based protein
consumed in low to moderate
amounts weekly or monthly.
Sweets consumed in low
amounts monthly.
Wine in moderation
with meals.
Be physically active.
•
•
•
•
•
a healthy weight
throughout life.
Be physically active.
Limit time spent sitting.
Eat a healthy diet, with an
emphasis on plant foods.
Choose foods and drinks in
amounts that help you get
to and maintain a healthy
weight.
Limit how much processed
meat and red meat you eat.
Eat at least 2½ cups of
vegetables and fruits
each day.
Choose whole grains
instead of refined grain
products.
If you drink alcohol, limit
your intake.
vegetables, fruits, and beans.
• Limit consumption of “fast food” and
•
•
•
•
•
•
other processed foods high in fat,
starches, or sugars.
Limit consumption of red meat and
processed meat.
Limit consumption of sugar-​sweetened
beverages.
Limit alcohol consumption.
Do not use supplements for cancer
prevention.
For mothers: breastfeed your baby if
you can.
After a cancer diagnosis: follow our
recommendations if you can.
CHAPTER 2 Diet and Cancer
for scoring higher than the median intake within a given population/​cohort for whole grains, fruits, vegetables (except potatoes),
nuts, fish, legumes, and monounsaturated versus saturated fat
ratio; one point is awarded for red and processed meat below the
median; and one point is awarded for consuming one alcoholic
beverage daily. In the National Institutes of Health–​American
Association of Retired Persons (NIH-​AARP) Diet and Health
observational cohort study, greater adherence to a Med Diet pattern (aMED scores ranging from six to nine points) was associated with decreased risk of cancer-​related mortality in both men
and women.11 Regarding site-​specific cancers, greater adherence
to a Med Diet, based on aMED, was associated with lower colorectal cancer risk in men in a combined analysis of the Nurses’
Health Study and Health Professionals Follow-​up Study,12 and
decreased risk of lung cancer in both men and women in the
NIH-​AARP cohort, with an even more profound risk reduction
in current and former smokers.13 However, not all studies have
shown a strong association between Med Diet adherence and
decreased cancer risk and mortality. For example, in the French
NutriNet-​Santé cohort study, greater adherence to a Med Diet,
based on the Medi-​Lite score, was not associated with decreased
risk of breast (women), colorectal, or prostate cancer (men).14 In
the Multiethnic Cohort study, greater adherence to a Med Diet,
based on aMED, was associated with lower colorectal cancer mortality among African American cancer survivors but not Native
Hawaiian, Japanese American, Latino, and white survivors.15 An
important issue with the literature examining associations between Med Diet adherence and cancer risk and mortality is the
use of different scoring approaches to assess Med Diet adherence.
However, in the European Prospective Investigation into Cancer
and Nutrition (EPIC) study, researchers investigated three different Med Diet scores (Mediterranean Diet Score [MDS], relative Med Diet Score [rMED], and the Mediterranean Style Dietary
Pattern Score [MSDPS]) and associations with overall cancer
mortality. Comparing the highest versus lower quartile for each
score, higher Med Diet adherence was associated with significantly lower risk of cancer-​related mortality irrespective of the
scoring approach used.16
The association between a vegetarian dietary pattern and reduced cancer risk stems from studies of the Seventh Day Adventist
religious sect whose doctrine advises against eating animal flesh.
Seventh Day Adventists adhering to a vegetarian eating pattern
had lower rates of cancer overall, lower rates at specific sites
such as the prostate and colon, and lower risk of cancer-​related
mortality compared to the general U.S. population.17 However,
Seventh Day Adventists also typically abstain from tobacco and
alcohol, which may contribute to the observed health effect. In
the EPIC cohort, vegetarianism was associated with lower overall
cancer risk and risk for stomach and bladder cancer, but no effect was observed for colorectal and prostate cancer incidence
compared to nonvegetarians.18 Studies of breast cancer incidence
and mortality have not demonstrated differences between vegetarians and nonvegetarians, although there is some evidence that
a vegan diet pattern can reduce breast cancer risk.19 Moreover,
a vegan diet pattern was associated with statistically significant
protection from overall cancer incidence in the Adventist Health
Study-​2.20
Diet and Weight Loss Intervention Trials: Effects
on Cancer-​Related Outcomes
This section presents an overview of several large randomized trials
designed to examine the effects of dietary factors and weight loss
on cancer prevention or control and cancer risk–​related biomarkers.
Increasing Fiber, Fruits, and Vegetables and Decreasing
Total Fat
The Women’s Health Initiative (WHI). The WHI was a study of
over 45,000 postmenopausal women (1993–​2004) that included a
clinical trial with three intervention arms, including two that were
diet and cancer related. The first of these tested a low-​fat eating pattern (less than 20% of total calories; five servings/​day of fruits and
vegetables; six servings/​day of whole grains) on breast cancer and
colorectal cancer. Control participants received information consistent with the U.S. Department of Agriculture DGAs. Follow-​up at
8.1 years showed no significant reduction in the incidence of breast
cancer or colon cancer among women in the intervention group.21
The second arm examined the effects of calcium and vitamin D supplementation on colorectal cancer. Over an average of seven years,
no significant difference was observed in colorectal cancer incidence
between the intervention and control groups.22 The extended period
over which colorectal cancer develops may have led to these null
findings. In recent secondary analyses, vitamin D and calcium supplementation were not associated with reduced invasive cancer risk
or mortality,23 whereas vitamin B6 and riboflavin intake were associated with lower colorectal cancer risk.23
Women’s Intervention Nutrition Study (WINS). This phase III
clinical trial (1994–​2001) was designed to examine the relationship
between dietary fat intake and breast cancer among 2,437 women
with resected, early-​stage breast cancer. Women in the intervention
group were counseled to reduce dietary fat intake to 15% of calories
during a four-​month intervention period. The comparison group received no dietary counseling. Interim results at 60 months showed
dietary fat intake and body weight were significantly lower in the
intervention group compared to the control group.24
Women’s Healthy Eating and Living (WHEL) Study. This randomized trial (1995–​2006) assessed whether a significant increase in
vegetable, fruit, and fiber intake and a decrease in dietary fat intake
could reduce the risk of recurrent and new primary breast cancer
and “all cause” mortality among 3,088 survivors of early-​stage breast
cancer. Women in the intervention were instructed to consume daily
five vegetable servings plus 16 ounces of vegetable juice, three fruit
servings, 30 grams of fiber, and 15% to 20% of energy intake from
fat. Women in the comparison group received written materials consistent with the “5-​a-​Day” fruits and vegetables message. Although
the intervention group did adhere to the prescribed diet, there was
no effect on breast cancer events or mortality among early-​stage
breast cancer survivors.25
Mediterranean Diet
Only two studies have tested the effect of a Med Diet on cancer risk
in the context of a randomized controlled trial.
Lyon Diet and Heart Study. Six hundred and five adult survivors
of a first acute myocardial infarction were randomized to a Med
Diet–​type pattern or control (Step 1 diet of the American Heart
17
18
SECTION I Factors in Cancer Risk and Prevention
Association) over a four-​to five-​year timeframe.26 A secondary
outcome of the study was the occurrence of malignant tumors.
Seventeen cancers developed in the control group and seven in the
Med Diet group (RR = 0.39; 95% CI: 0.15–​1.01; p = 0.05). This study
demonstrated for the first time in a randomized trial the cancer protective effect of a Med Diet in a non-​Mediterranean population.
Prevención con Dieta Mediterránea (PREDIMED) Trial.
Briefly, the PREDIMED study randomized 7,447 participants (4,282
women) to a Med Diet supplemented with extra-​virgin olive oil,
Med Diet supplemented with mixed nuts, or control (low-​fat diet)
intervention with a median follow-​up of 4.8 years.27 A secondary
outcome of the trial was breast cancer incidence for women without
a history of breast cancer (n = 4,152). Breast cancer rates per 1,000
person-​years were 1.1 for the Med Diet plus extra-​virgin olive oil
group, 1.8 for the Med Diet nuts group, and 2.9 for the control group,
respectively. Although the results come from a secondary analysis,
findings suggest a protective effect of a Med Diet supplemented with
olive oil for the primary prevention of breast cancer.
Effect of Diet on Premalignant Lesions and
Cancer-​Related Biomarkers
Polyp Prevention Trial (PPT). The PPT28 was a randomized controlled study of the effects of a low-​fat (20% of total energy intake),
high-​fiber (18 g/​1,000 calories), high-​fruit and -​vegetable (five to
eight daily servings) diet on the recurrence of colorectal adenomas
among individuals who had a polyp removed in the previous six
months. At the four-​year follow-​up, results suggested that adopting a
low-​fat, high-​fiber diet and increasing fruit and vegetable consumption did not affect the risk of recurrence for colorectal adenomas.
Controlled Feeding Studies. In a two-​week strictly controlled
diet exchange study in which native black Africans consumed an
animal-​based diet and African Americans consumed a plant-​based
diet, colonic mucosal proliferation and inflammation were significantly lower in the African Americans and significantly higher
postdiet in the native black Africans.29 The authors attributed the effect in the African Americans to changes in gut microbial metabolic
function (i.e., increased short-​chain fatty acid production and decreases in secondary bile acids) that was related to the diet switch. In
a crossover feeding trial conducted with relatively healthy men and
women, consuming a high (i.e., refined grains and added sugars)
and low (i.e., high in whole grains, legumes, fruits, and vegetables)
glycemic index diet each for 28 days30 resulted in differing expression of plasma proteins related to carcinogenesis that was dependent
on the subject’s baseline body adiposity (high vs. low fat mass).
Specifically, in response to the high-​glycemic-​load diet, those with
high fat mass had increased expression of plasma proteins related to
cell cycle, DNA repair, and DNA replication that if sustained could
lead to carcinogenesis. These findings suggest that obesity’s effect
on cancer development may to some extent be tied to biological response to differing dietary patterns.
Effect of Weight Loss on Cancer-​Related Outcomes
Surgically Induced Weight Loss. There is encouraging albeit
conflicting evidence regarding the effect of surgical weight loss
on cancer risk. In a study of obese patients undergoing laparoscopic gastric banding (n = 327) or medically induced weight loss
(n = 681), gastric banding was associated with significantly lower
incidence of cancer and cancer-​related mortality in the surgical
patients31 over a 23-​year period. In a large population-​based cohort study in the United Kingdom of 8,794 obese patients that
underwent bariatric surgery (gastric banding, sleeve gastrectomy,
and gastric bypass), decreased risk of hormone-​related cancers including breast (odds ratio [OR] = 0.25; 95% CI: 0.19–​0.33), endometrium (OR = 0.21; 95% CI: 0.13–​0.35), and prostate (OR = 0.37;
95% CI: 0.17–​0.76)32 was observed compared to obese patients not
undergoing a bariatric procedure that were propensity matched for
age, sex, comorbidity, and duration of follow-​up. However, in the
same study, there was no effect of gastric banding or sleeve gastrectomy on esophageal or colorectal cancer and an increased risk
of colorectal cancer in patients receiving gastric bypass. Suggested
mechanisms associated with this increase in risk include inflammation and hyperproliferation and gut microbiota changes following
the surgical bypass procedure.
Weight Management Lifestyle Interventions. Several studies
have examined how weight loss through calorie restriction, dietary
changes, and increased physical activity affects biological markers
related to cancer risk. For example, in the Nutrition and Exercise in
Women (NEW) study, 439 overweight and obese postmenopausal
women were randomized to aerobic exercise, dietary weight management, or both versus control for 12 months.33 Compared to
control, exercise plus diet-​induced weight loss was associated with
significantly decreased BMI, insulin resistance, systemic inflammation, sex steroid hormones, and genes related to growth factor
signaling. Nonetheless, few studies have been able to discern the
effect of behavioral weight management interventions on cancer-​
specific outcomes (e.g., cancer risk, disease-​free survival).
Challenges to Healthy Eating and Weight
Management for Cancer Risk Reduction and
Cancer Health Equity
As noted earlier and highlighted in consensus reports from leading
cancer organizations, modifiable lifestyle behavioral risk factors,
including diet and physical inactivity, account for between 30%
and 50% of cancers. Often, the combination of less healthful diets
and physical inactivity leads to excessive weight gain and obesity,
increasing cancer risk. Recent estimates reflect that obesity accounts
for 14% to 20% of the attributable cancer risk for U.S. adults and
as much as 50% of all cancers for individuals under age 65 years.
In the most recent nationally representative survey of adults in the
U.S. (2013–​2014), the age-​adjusted prevalence of obesity was 35.2%
among men and 40.4% among women. There were differences, however, across race/​ethnicity, with prevalence rates of 38.7%, 57.2%,
and 46.6% among non-​Hispanic white, Non-​Hispanic black, and
Hispanic women, respectively.34 The differences in prevalence
rates among men were not as striking, with rates of 35.4%, 38.2%,
and 38.8% among non-​Hispanic white, non-​Hispanic black, and
Hispanic men, respectively.34
Unfortunately, minorities and low-​income individuals are at a
significant disadvantage when it comes to making healthier dietary
choices, driving obesity rates. For example, the main components of
the Med Diet, which is embraced by the scientific community and
associated with an inverse association with total mortality incidence
of coronary heart disease, stroke, and several cancers, are characterized by a high consumption of vegetables, fruits, whole grains,
CHAPTER 2 Diet and Cancer
legumes, olive, and fish and a low intake of saturated fats, red meat,
and dairy products. However, these foods tend to be more costly
than many energy-​dense foods that are discouraged in dietary recommendations for cancer prevention. In addition, urban areas that
are often predominantly minority and/​or low income tend to offer
limited access to the foods recommended for cancer prevention,
and the built environment may offer fewer opportunities for safe
outdoor physical activity and introduce other factors that increase
cancer risk (e.g., higher rates of tobacco or alcohol use, increased
outlets selling alcohol and tobacco, and exposure to manufacturing
chemicals).
Conclusions and Future Research
Primary prevention is possible through changes in modifiable risk
factors, including a healthful diet and regular physical activity,
leading to maintenance of a healthy weight. We have reviewed published guidelines from several agencies that made recommendations that have implications especially for the risk of colon, breast,
and lung cancer. Increasingly, we are understanding that the overall
population’s health is dependent on identifying and intervening on
upstream social determinants of health that address social and environmental contextual factors that can drive unhealthful behavior.
These factors can impede the ability of individuals to make choices
consistent with reduced cancer risk. Further research can provide
a lens for population-​level action that can reduce lifestyle-​related
cancer inequities.
ACKNOWLEDGMENTS
Research reported in this publication was supported, in
part, by the University of Illinois Cancer Center, National
Institutes of Health’s National Cancer Institute, Grant
Numbers U54CA202995, U54CA202997, U54CA203000, and
T32CA057699. The content is solely the responsibility of the authors and does not necessarily represent the official views of the
National Institutes of Health.
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3
Physical Activity, Sedentary Behavior,
and Cancer
Christine M. Friedenreich, Chelsea R. Stone, and Jessica McNeil
Introduction
Physical activity includes elements of planned, intentional activity
such as exercise but also extends further to include domains of
household, occupational, transportation/​
commuting, and recreational/​leisure activities. While the health benefits associated with
regular physical activity for primary prevention of several chronic
diseases have been well established, the benefits for cancer prevention have accumulated mainly in the last 30 years. Nearly 500
observational epidemiologic and randomized controlled exercise
intervention trials have been conducted worldwide that have examined how physical activity is associated with cancer risk and what the
underlying biologic mechanisms are that could explain how physical
activity reduces cancer risk. Given this accumulating evidence base,
several national and international cancer agencies have adapted
physical activity guidelines developed for general health1 to specific
guidelines for cancer prevention.2
Emerging observational epidemiologic evidence also suggests
that high amounts of sedentary time (e.g., too much sitting) increases the risk of developing cancer, independently of physical
activity levels.3 Similar to physical activity, sedentary behavior can
be subdivided into different domains including occupational/​workplace, transportation/​commuting, and recreational/​leisure sedentary activities. Although current recommendations for sedentary
time are generic (e.g., limit total sitting time), the World Health
Organization (WHO) has suggested that the review of the scientific
literature on sedentary behavior contributing to disease risk is a priority area for the development of future physical activity guidelines
amid the growing amount of research being conducted in this area.1
The World Cancer Research Fund (WCRF) and American Institute
for Cancer Research (AICR) also recommend “limiting sedentary
habits/​sitting less” as part of their physical activity recommendations for cancer prevention.2
In this chapter, we review the current observational epidemiologic
evidence on the association between physical activity and sedentary
behavior to cancer incidence. In addition, we review how specific
types of activity (i.e., aerobic and resistance exercise training) and
how cardiorespiratory fitness may play an etiologic role in cancer
incidence. We then describe the hypothesized biologic mechanisms
that appear to explain the association between physical activity, sedentary behavior, and cancer incidence. We also report on the current
burden of cancer that could be attributed to lack of physical activity
and sedentary behavior. Finally, we provide an overview of common
barriers and facilitators to physical activity participation, as well as
recent strategies and recommendations that have been suggested to
promote physical activity participation and decrease sedentary time
for cancer prevention.
Epidemiologic Evidence
Physical Activity and Cancer Incidence
Literature Review Methods
We completed a systematic review of the scientific literature on all
English-​language articles published on PubMed (National Library
of Medicine [NLM], National Institutes of Health [NIH]) through
July 1, 2019. Our search strategy combined terms for physical activity (exercise OR motor activity OR physical activity) as well as
search terms related to cancer (cancer OR tumor OR neoplasm).
All articles were screened via titles and abstracts, with full-​text
screening occurring for articles related to physical activity and
cancer risk/​incidence. In instances where articles reported multiple
domains of physical activity, we extracted the risk estimates for the
most comprehensive domain of physical activity (i.e., total physical
activity or recreational physical activity). Additionally, we preferentially extracted overall estimates over stratified results and estimates
of reported lifetime physical activity. In the event that lifetime physical activity was not reported or assessed, we utilized estimates for
recent physical activity. Physical activity was self-​reported in these
studies and included a wide range of assessment methods that captured either current activity, activity in the past year, or activity over
lifetime with different units of measurement of activity. Since physical activity assessments varied across these studies, the estimates
extracted were those that compared the highest versus the lowest
levels of activity in each study regardless of how these were defined.
Estimates were pooled using DerSimonian-​Laird random effects
22
SECTION I Factors in Cancer Risk and Prevention
models, and for the purpose of this review, we limit the discussion
and presentation of results to cancer sites with 10 or more included
articles.
Overview of the Evidence
Through July 1, 2019, there were over 450 articles published
investigating the association between physical activity and cancer
risk. Of these 450 papers, we found 10 cancer sites for which at least
10 papers had been published. We estimated the summary risk estimates and extracted information on the evidence of dose-​response
effects for bladder, breast, colorectal, endometrial, esophageal,
kidney, lung, ovarian, pancreatic, and prostate cancers as estimated
in the individual studies (Table 3.1). The largest evidence base on
the association between physical activity and cancer risk exists for
breast, colorectal, and prostate cancers with 132, 107, and 67 studies,
respectively, contributing to each estimate. Evidence is also accumulating for associations between physical activity with lung (n = 44
studies), endometrial (n = 31), ovarian (n = 28), and pancreatic cancers (n = 27).
For these 10 cancer sites, there is consistent evidence that physical
activity is associated with decreased cancer risk. The range of the
effect sizes for the associations between physical activity and cancer
risk was from 0.57 to 0.94, with the majority between 0.70 and 0.90.
The strongest effects were found for esophageal cancer, for which
a hazard ratio (HR) of 0.57 (95% confidence interval [CI]: 0.42–​
0.78) was estimated from the 13 studies and 14 estimates that were
combined for this summary effect estimate. There was considerable consistency across these studies, with 12 of the 14 estimates
finding reduced risk of cancer associated with higher levels of physical activity and the two remaining studies finding nonstatistically
significant increased risks with higher levels of physical activity.
Prostate cancer had the smallest protective effect with a hazard ratio
of 0.94 (95% CI: 0.89–​0.99), though the summary estimate remained
statistically significant. Out of the 67 estimates combined, 18 of the
estimates were statistically significant decreased risks (i.e., HR and
95% CI below 1 with increased levels of physical activity). Only
five studies found statistically significant increased risk of prostate
cancer. The remaining 44 studies reported nonstatistically significant results.
Breast cancer had an overall summary estimate of 0.77 (95%
CI: 0.75–​0.80) from 135 contributing estimates. Since there has
been sufficient evidence published on the relation between physical activity and breast cancer incidence, detailed meta-​analyses
have been published on this topic. One such meta-​analysis sought
to investigate the association of moderate-​to vigorous-​intensity recreational physical activity and breast cancer risk, stratified by menopausal status.4 It was determined that estimates were similar for
premenopausal and postmenopausal breast cancer risk, with risk
estimates of 0.80 (95% CI: 0.74–​0.87) and 0.79 (95% CI: 0.74–​0.84),
respectively. Dose-​response analyses were completed for premenopausal and postmenopausal breast cancer risk, for which curvilinear
trends were found, reflecting a point of diminishing returns with
moderate-​to vigorous-​intensity recreational activity beyond 20–​30
metabolic equivalents of task (MET)-​hours/​week.4
There were 107 studies (127 estimates) contributing to the summary risk estimate of 0.75 (95% CI: 0.72–​0.79) between physical
activity and colorectal cancer incidence. Similar to the level of evidence available for breast cancer, there have been targeted systematic reviews and meta-​analyses investigating this association.
More specifically, a review was completed that investigated the
Table 3.1. Summary of Epidemiologic Evidence on the Association between Physical Activity and Cancer Risk through July 1, 2019
Site
Bladder
a
No. of
Studies
No. of
Estimates
Pooled
Estimate
95% CI
I2
Dose-​Response
Effect (%)
WCRF/​AICR
Classificationa
PAGAC Grade
16
19
0.86
0.76–​0.97
76.5%
3 of 11
(27%)
N/​A
Strong
Breast
132
135
0.77
0.75–​0.80
81.4%
58 of 97
(60%)
Convincing decreases
risk/​limited-​suggestive
decreases risk1
Strong
Colorectal
107
127
0.75
0.72–​0.79
70.5%
44 of 67
(66%)
Convincing decreases
risk
Strongb
Endometrial
31
31
0.74
0.68–​0.80
24.4%
15 of 24
(63%)
Probable decreases risk
Strong
Esophageal
13
14
0.57
0.42–​0.78
84.4%
4 of 8
(50%)
Limited-​suggestive
decreases risk
Strong
Kidney
24
30
0.83
0.72–​0.95
70.7%
4 of 20
(20%)
N/​A
Strong
Lung
36
44
0.75
0.69–​0.82
80.3%
10 of 14
(71%)
Limited-​suggestive
decreases risk
Moderate
Ovarian
28
30
0.87
0.77–​0.98
64.7%
10 of 16
(63%)
N/​A
Limited
Pancreatic
27
36
0.83
0.76–​0.91
35.6%
5 of 17
(29%)
N/​A
Limited
Prostate
67
67
0.94
0.89–​0.99
68.0%
18 of 43
(42%)
N/​A
Limited
WCRF/​AICR rates physical activity as convincing decreases risk for premenopausal breast cancer and limited-​suggestive decreases risk for postmenopausal breast cancer. Our
estimate represents an overall breast cancer risk.
b
PAGAC grade based on “colon” cancer specifically.
CHAPTER 3 Physical Activity, Sedentary Behavior, and Cancer
domain-​specific association between physical activity and colon
and rectal cancer incidence.5 Estimates pertaining to recreational
physical activity and cancer risk were 0.80 (95% CI: 0.71–​0.89) and
0.87 (95% CI: 0.75–​1.01) for colon and rectal cancers, respectively.
Occupational physical activity had slightly stronger effects with risk
estimates of 0.74 (95% CI: 0.67–​0.82) and 0.88 (95% CI: 0.79–​0.98)
for colon and rectal cancers, respectively. Statistically significant associations were not found for household physical activity and cancer
risk for either site.5
Within each included study presented in Table 3.1, we examined
whether or not dose-​response associations between increasing physical activity volume and reduced cancer risk have been investigated.
The most evidence of a dose-​response relation between increasing
levels of physical activity and decreasing risks for cancer was found
for lung, colorectal, endometrial, and ovarian cancers, for which
>60% of studies that investigated these trends found statistically significant inverse associations. Evidence of a dose-​response effect for
these cancer sites provides further support for causal associations.
The findings pertaining to physical activity and cancer incidence
from the 2018 update of the WCRF/​AICR2 as well as the 2018
Physical Activity Guidelines Advisory Committee (PAGAC)6 are
also presented in Table 3.1. While our results consistently support
the WCRF/​AICR findings, there were several cancer sites for which
we found considerable evidence for an association between physical activity and cancer risk that were not included in the WCRF/​
AICR 2018 report since that report was focused primarily on the evidence from prospective cohort studies, whereas we included all observational epidemiologic research conducted to July 2019. Prostate
cancer, for example, has nearly 70 studies that have investigated the
association between physical activity and cancer risk; however, it has
not been appraised by the WCRF/​AICR. Given the evidence that we
found in our review, prostate cancer would likely receive a classification of “limited-​suggestive decreased risk” since the effect found
is statistically significant and the overall magnitude of this effect is
small (6% reduction of risk). Other cancers that have yet to be appraised by the WCRF/​AICR include bladder (16 studies), kidney (24
studies), ovarian (28 studies), and pancreatic (27 studies). PAGAC
grades were similar to our summary estimates. The PAGAC concluded that there was “strong” evidence that greater amounts of
physical activity are associated with reduced risks of developing
bladder, breast, colon, endometrial, esophageal, and kidney cancers
and that there was “moderate” evidence for lung cancer and limited
evidence to suggest that increased physical activity was associated
with a decreased risk of ovarian, pancreatic, and prostate cancers.
Heterogeneity
We also examined the level of heterogeneity in the pooled summary
estimates presented (Table 3.1), which were high, suggesting that
the variations in effects between studies are not due to chance. There
are different types of heterogeneity, such as clinical and methodological heterogeneity, that may be contributing to the overall levels
found in the pooled summary estimates. Related to clinical heterogeneity, there may have been differences in populations or outcome
definitions, though these factors were unlikely to be major sources
of heterogeneity given the high degree of certainty in the evidence
regarding most cancer diagnoses. Methodological heterogeneity
was likely the largest contributor, primarily given the differences in
physical activity assessment tools that exist across different studies.
Self-​reported questionnaires were the primary assessment methods
used to capture data on physical activity in these studies; however,
the validity and reliability of these questionnaires vary considerably
across different instruments. For instance, the domains (i.e., occupational, household, recreational, transport), parameters (frequency,
intensity, duration), and time periods (current, past year, lifetime)
for physical activity assessment differ by study. Furthermore, different observational epidemiologic study designs have been used to
capture physical activity either retrospectively (i.e., in case-​control
studies) or prospectively (i.e., cohort studies) in relation to cancer diagnosis with consequent differences in the possibility of recall error
that can influence the magnitude and precision of the estimates.
Sedentary Behavior and Cancer Risk
Sedentary behavior is defined as all waking behaviors with an energy expenditure ≤ 1.5 METs in the sitting, reclining, or lying postures.7 Common sedentary behaviors include watching television
and video game playing (classified as leisure/​recreational sedentary
time), sitting and working at a computer (classified as occupational/​
workplace sedentary time), and sitting in a car (classified as transportation/​commuting sedentary time). Although increases in total
physical activity participation (especially ambulatory, spontaneous
activities) may lead to reductions in sedentary time over a 24-​hour
period, it is important to recognize that sedentary behavior and
physical activity participation are distinct entities.3 Specifically, high
sedentary time is defined as “too much sitting,” whereas physical inactivity is defined as “too little exercise.”3 It is thus possible for an
individual to achieve or exceed physical activity recommendations
but also spend long, uninterrupted amounts of time sitting at work
or at home. Conversely, a person may have a physically demanding
job with little sedentary time (e.g., construction worker, cashier),
but also no or low recreational physical activity participation. The
American Institute of Cancer Research recognized the importance
of considering both the amount of time dedicated to physical activity and time spent in sedentary behavior for cancer prevention
and developed an educational infographic to illustrate these concepts (Figure 3.1). This infographic illustrates the importance of
making time for physical activity and breaking up sedentary time.
A meta-​analysis published in 2014 that included 17 prospective
studies and 18,553 cases reported that the highest levels of sedentary behavior were associated with an increased risk of 1.20 (95%
CI: 1.08–​1.53) in combined cancers compared to the lowest levels
of sedentary behavior.8 Furthermore, a recent narrative review3
summarized the current epidemiologic evidence on the associations between sedentary behavior and the risk of specific cancer
sites. This review suggests that sedentary behavior is most strongly
associated with colon, endometrial, and lung cancers.3 Specifically,
high versus low levels of sedentary time were consistently associated
with a range in effect estimates of 1.28–​1.44 for colon cancer.3 One
meta-​analysis9 also specified that the association between sedentary behavior and colon cancer remained after adjusting for physical
activity (risk ratio [RR] = 1.31; 95% CI: 1.21–​1.42) and stratifying
according to sedentary behavior domains (occupational sedentary
behavior: RR = 1.30; 95% CI: 1.20–​1.40; recreational sedentary behavior: RR = 1.32; 95% CI: 1.17–​1.49). A different meta-​analysis also
conducted a dose-​response analysis and observed a 1.08 increased
risk of colon cancer (95% CI: 1.04–​1.11) for every two-​hour increase
in sitting time per day.10 Similar to colon cancer, a range in the effect
23
24
SECTION I Factors in Cancer Risk and Prevention
Make Time + Break Time = Cancer Protection
Daily
Activity
Cancer
Risk Indicators
Joe
Kim
Mike
Ann
Types of activity:
Moderate/Vigorous
Break
Sedentary
Low
HIGH
Figure 3.1. The American Institute of Cancer Research infographic on making time for physical activity and breaking up sedentary time for cancer
prevention.
Reprinted with permission from the American Institute for Cancer Research, “Make Time + Break Time,” 2019, https://​www.aicr.org/​learn-​more-​about-​cancer/​infographics/​
make-​time-​break-​time.html
estimates for endometrial cancer of 1.28–​1.36 has been previously reported in those with high versus low levels of sedentary time.3 Dose-​
response analysis indicated a 1.10 (95% CI: 1.05–​1.15) increased
risk of endometrial cancer for every two-​hour increment in sitting
time per day; however, the association between sedentary time and
endometrial cancer risk was stronger for recreational sedentary
time (RR = 1.66; 95% CI: 1.21–​1.68) and not statistically significant
for occupational sedentary time (RR = 1.11; 95% CI: 0.88–​1.39).10
Lastly, a range in the effect estimates for lung cancer of 1.21–​1.27
has been observed in those with high versus low levels of sedentary
time,3 with dose-​response analysis indicating a 1.06 (95% CI: 1.00–​
1.11) increased risk of lung cancer for every two-​hour increment in
sitting time per day.10 However, these results should be interpreted
with caution given potential residual confounding by smoking since
smoking has been positively associated with both sedentary behavior and lung cancer risk.3
There has been inconsistent evidence to date regarding the associations between sedentary behavior and rectal, breast, lung,
and ovarian cancers.3 There is an overall 1.02–​1.15 range in effect
estimates for rectal cancer in those with the highest versus lowest
levels of sedentary time, with the majority of studies reporting
nonstatistically significant associations between sedentary time and
rectal cancer.3 Similarly, high levels of sedentary behavior have been
associated with a range in effect estimates of 1.08–​1.17 for breast
cancer, with the majority of studies reporting small effect estimates.3
Conversely, a range in effect estimates of 1.22–​1.26 for ovarian cancer
in individuals with high levels of sedentary time was reported; however, these effect estimates were not statistically significant.3 Lastly,
there is insufficient evidence to currently draw conclusions on the
association between sedentary behavior and cancers of the prostate,
testes, stomach, and kidneys and non-​Hodgkin lymphoma.3
exercise (aerobic versus resistance exercises) influences cancer risk.
In addition to the 150 minutes of moderate-​intensity aerobic physical activity recommended by the WHO for general health, there
are also recommendations to achieve two days or more per week of
muscle-​strengthening activities involving the major muscle groups.1
This type of physical activity is referred to as resistance training,
strength training, weight training, and muscle-​strengthening activities in the scientific literature. Unlike aerobic physical activity, there
is a paucity of evidence to date on the association between resistance
training and cancer risk since few studies have specifically sought to
measure resistance exercise training separately from aerobic exercise training.
A recent publication by Mazzilli and colleagues investigated the
relationship between weight lifting and the risk of 10 common
cancer types.11 Using data from the NIH–​American Association
of Retired Persons (AARP) Diet and Health Study, which included
an analytic sample size of 215,122 individuals, this study reported
that after adjusting for multiple covariates, including moderate-​to
vigorous-​intensity physical activity participation, there was a statistically significant reduced risk of colon cancer for individuals
who weightlifted in the low (5 minutes–​1.5 hours) and high (2–​
10+ hours) categories compared with those in the no weightlifting
category, with hazard ratios of 0.75 (95% CI: 0.66–​0.87) and 0.78
(95% CI: 0.61–​0.98), respectively. Further analyses by sex for colon
cancer indicated that the relation between weightlifting and reduced
cancer risk may be modified by sex, with males experiencing a more
protective effect than females. There was no association found between weightlifting and the other cancer types investigated (kidney,
bladder, breast, lung, non-​Hodgkin lymphoma, pancreas, prostate,
rectum, or melanoma).11
Resistance Training and Cancer Risk
More recently, research has begun to emerge regarding the etiologic role that cardiorespiratory fitness (or physical fitness) has in
cancer incidence. An individual’s cardiorespiratory fitness refers to
Besides examining the association by domain of physical activity,
there is also interest and a need to understand how the type of
Cardiorespiratory Fitness and Cancer Risk
CHAPTER 3 Physical Activity, Sedentary Behavior, and Cancer
the ability of their respiratory and circulatory systems to efficiently
supply oxygen to the skeletal muscles and other organs at rest and
during sustained bouts of aerobic physical activity.12 Hence, cardiorespiratory fitness can serve as a proxy, but objective, measurement
of habitual physical activity, though it is important to recognize that
physical activity participation and cardiorespiratory fitness are distinct entities. Being more physically active is often associated with
higher cardiorespiratory fitness. However, it is possible for physically active individuals to have low levels of cardiorespiratory fitness,
or for individuals with low habitual levels of physical activity to have
high cardiorespiratory fitness. This discrepancy between physical
activity levels and cardiorespiratory fitness may result from underlying health conditions, performing greater amounts of anaerobic
activities (e.g., resistance training), or having a genetic predisposition for high cardiorespiratory fitness/​high trainability in response
to physical activity. Indeed, a systematic review identified 97 genes
that can be used to predict cardiorespiratory fitness trainability,
identifying individuals with a certain genetic makeup (i.e., having
more positive alleles within these genes) to have the potential for
higher increases in cardiorespiratory fitness as a result of physical
activity participation.13
Pozuelo-​Carrascosa and colleagues completed a systematic review
and meta-​analysis that investigated the association between cardiorespiratory fitness and site-​specific cancer risk in men in 2019.14
This review was restricted to men because, as cited by the authors, no
studies retrieved through the literature searches included women.
Ten studies were included for qualitative review, while seven studies
were carried forward for inclusion in the meta-​analysis. Lung (n = 3),
colon/​rectum (n = 3), prostate (n = 3), skin (n = 2), and combined
cancer sites (n = 4) were investigated for cancer risk comparing
moderate versus low cardiorespiratory fitness. From these, there
was a statistically significant reduced risk of lung, colon/​rectum, and
combined cancer sites for moderate versus low cardiorespiratory
fitness, with hazard ratios of 0.53 (95% CI: 0.39–​0.68), 0.74 (95%
CI: 0.55–​0.93), and 0.86 (95% CI: 0.79–​0.93), respectively. Moderate
versus low cardiorespiratory fitness was not associated with prostate
cancer risk (HR 1.07; 95% CI: 0.92–​1.21), and skin cancer did not
have enough contributing studies to warrant meta-​analyses.
In an analysis comparing high versus low cardiorespiratory fitness, the authors investigated lung (n = 4), colon/​rectum (n = 4),
prostate (n = 4), oral and digestive (n = 2), genitourinary (n = 2),
skin (n = 2), and combined cancer sites (n = 5).14 They found a statistically significant reduced risk of lung, colon/​rectum, and combined cancer risk for high versus low cardiorespiratory fitness, with
hazard ratios of 0.52 (95% CI: 0.42–​0.61), 0.77 (95% CI: 0.62–​0.92),
and 0.81 (95% CI: 0.75–​0.87), respectively. There may be an adverse
effect of high cardiorespiratory fitness and prostate cancer risk, with
an increased incidence of 1.15 (95% CI: 1.00–​1.30), and there were
not enough contributing studies to warrant meta-​analyses for oral
and digestive, genitourinary, and skin cancers.
Overall, there appears to be a protective effect of higher versus
lower cardiorespiratory fitness for all cancers combined, as well as
for lung and colon/​rectal cancers. It is important to recognize that
the body of literature examining the association between cardiorespiratory fitness and cancer risk has limitations given that few studies
have been conducted and most of the research has included mainly
Caucasian men with high socioeconomic status, which limits the
generalizability of these findings. This area of research is of high
interest and requires future attention to elucidate the role of cardiorespiratory fitness in cancer etiology.
Population Attributable Risk
Quantifying the burden of cancer incidence that could be avoided if
exposure to a given risk factor was reduced or eliminated can be done
by estimating the population attributable risk (PAR). To estimate the
PAR of a risk factor such as physical inactivity, the prevalence of exposure among cases and estimated risk of exposure is required (such
as those shown in Table 3.1). We recently reported that for Canada
in 2015, the total number of cancer cases attributable to moderate or
low recreational physical activity participation was 9,247, which was
equivalent to 4.9% of all newly diagnosed cancer cases that year (or
10.6% of all cancers associated with physical activity).15 We also estimated that 1.7% of all cancer cases were attributable to leisure-​time
(nonoccupational) sedentary time (or 5.8% of all cancer cases associated with sedentary behavior), accounting for 3,230 cancer cases.16
PAR estimates for physical inactivity and cancer incidence in other
countries have also been provided, including the United States, for
which approximately 46,300 cancer cases were attributed to physical inactivity, which accounted for 2.9% of all newly diagnosed cancers.17 This study was restricted to cancers of the corpus uteri, colon
(excluding rectum), and breast. Hence, if all cancer sites that are now
known to be associated with physical inactivity were included in this
estimate, the number of cancer cases that could be prevented with
adequate levels of physical activity in the United States would be
much higher. Similar analyses have been completed in Australia18
and the United Kingdom,19 with estimates ranging from 1.0–​1.6%
when considering the proportion of newly diagnosed cancers attributable to physical inactivity in these populations. PAR estimates
for sedentary behavior independent of physical inactivity for other
countries besides Canada have not yet been published.
Biologic Mechanisms
Table 3.2 summarizes the biologic mechanisms hypothesized to explain associations of physical activity and sedentary behaviors with
cancer risk. The effects of physical inactivity and sedentary behavior
on carcinogenesis are likely multifactorial and will vary by cancer site
and possibly also by individual factors such as age, gender, ethnicity/​
race, body size, body composition, and cardiorespiratory fitness. In
addition, the domain, type, duration, frequency, and intensity of
physical activity as well as the duration of sedentary behavior are
also key factors that will influence how these behaviors influence
cancer development. Over the past 20 years, several hypothesized
biologic mechanisms that could explain how regular physical activity influences cancer risk have been proposed, and several of these
mechanisms have been examined specifically in randomized controlled exercise intervention trials in cancer-​free populations.20–​22
These trials have targeted biomarkers associated with cancer risk
since trials with cancer incidence endpoints have been infeasible
given the large sample size (estimates of 35,000–​45,000 participants), cost, and long-​term follow-​up required to observe sufficient
numbers of cancer cases. There is now evidence from these trials that
aerobic exercise decreases levels of endogenous sex hormones, insulin resistance, inflammation, and obesity, particularly abdominal
adiposity.20–​22 Higher volumes and more intense levels of aerobic
25
26
SECTION I Factors in Cancer Risk and Prevention
Table 3.2. Possible Effects of Physical Activity and/​or Sedentary Behavior on Proposed Biologic Mechanisms for the Association
with Cancer Risk
Proposed Mechanism
Possible Effects
Strength of Evidence
Cancer Sites
Lower adiposity levels
↓ anti-​inflammatory cytokines (adiponectin)
↓ pro-​inflammatory cytokines (leptin, resistin)
↓ estrogen synthesis in fat
Strong for physical activity
and sedentary behavior
Colorectal, postmenopausal breast,
endometrial, ovarian, bladder, kidney,
pancreatic
Lower chronic inflammation
and better immune response
↓ pro-​inflammatory cytokines (IL-​6, TNF-​α)
↓ reactive oxygen species, nitrogen species
↑ antioxidant and oxidative damage repair capacity
Strong for physical activity
and some/​limited for
sedentary behavior
Colorectal, postmenopausal breast,
endometrial, prostate, ovarian, lung,
esophageal, pancreatic
Higher metabolic function
↑ insulin sensitivity
↑ IGF binding proteins
↓ fasting glucose
Strong for physical activity
and sedentary behavior
Colorectal, breast, endometrial, ovarian,
prostate, bladder, kidney, pancreatic
Lower sex-​steroid hormone
levels
↓ estrone, estradiol, free estradiol
↓ number of ovulatory cycles
↑ sex hormone–​binding globulin
Strong for physical activity
and some/​limited for
sedentary behavior
Breast, endometrial, ovarian, prostate
Lower gastrointestinal
transit time
↓ exposure of colon mucosa and carcinogens
↓ concentrations of bile acids
↓ colon segmentation contractions
Some/​limited evidence for
physical activity. None for
sedentary time
Colorectal
Higher lung function
↓ concentration of carcinogenic material in the lungs
and shorter duration of agent-​airway interaction
↑ pulmonary ventilation and perfusion
Some/​limited evidence for
physical activity. None for
sedentary time
Lung
Higher skeletal muscle
function
↑ GLUT-​4 concentrations
↑ myokine concentrations
↑ mitochondrial function
Some/​limited evidence
for physical activity and
sedentary time
Colorectal, breast, endometrial, prostate
activity have also been shown to be particularly beneficial in reducing some of these biomarkers and adiposity levels.21–​24
As for sedentary behavior, there is some evidence from prospective cohort studies suggesting that higher amounts of sedentary time
are associated with an increased risk of obesity/​weight gain,25–​27 type
2 diabetes,25 and having higher fasting insulin levels.28 A systematic
review of imposed uninterrupted sedentary behavior interventions
lasting ≤7 days reported that these interventions led to decreases in
insulin sensitivity and glucose tolerance, coupled with increases in
triglyceride levels.29 There is also some evidence to suggest that short-​
term (7–​14 days), imposed bed rest leads to a pro-​inflammatory response through increases in C-​reactive protein30 and interleukin-​6
levels.30,31 Based on this evidence, it has been hypothesized that
standing (rather than sitting) increases postural blood flow, energy
expenditure, and muscle contractions, which then improve glucose
regulation through the activation of GLUT-​4 glucose transporters
on skeletal muscles and mitochondrial function to increase energy
production.32 To date, no trials have specifically examined associations between sedentary behavior and biomarkers of cancer risk.
Furthermore, many studies have used self-​reported measurements
of TV viewing time or sedentary time, which is subject to recall and
reporting biases.3 Therefore, additional studies are also needed to
collect both objective and subjective measures of sedentary time to
quantify context-​specific sedentary behaviors more accurately and
to design better randomized controlled trials aimed at reducing
sedentary time.
There are biological mechanisms that support the associations
between cardiorespiratory fitness and cancer risk such as chronic
inflammation, innate immunity, DNA repair ability, apoptosis, and
cell proliferation, as well as regulations to steroid hormone levels.14
Future intervention trials should address the optimal type of
exercise (e.g., aerobic versus resistance exercises) as well as other
novel molecular and genetic pathways that could reduce cancer risk
through physical activity participation and/​or reductions in sedentary time. In addition, mechanisms unique to specific cancer sites
(e.g., colon transit time for colon cancer and improved lung function
for lung cancer) require targeted research studies. Finally, future observational epidemiologic research will help identify tumor characteristics (e.g., tumor subsite, histologic subtype, hormone receptor
status, mutation carrier status) and individual characteristics that
may also modify the causal mechanisms relating physical activity to
cancer prevention.
Barriers and Facilitators to Physical Activity
Although the evidence base on the benefits of physical activity for
reducing cancer risk is becoming well established, large proportions
of the at-​risk population fail to achieve recommended levels of physical activity. A pooled analysis of data from 358 population-​based
surveys done globally with data from 2001 to 2016 revealed that the
prevalence of physically inactive individuals has been increasing,
particularly in high-​income countries.33 More specifically, during
this time frame, the prevalence of physical inactivity increased by
over five percentage points in high-​income Western countries (from
30.9% to 36.8%).33
Understanding the reasons that the general population fails to engage in regular physical activity is challenging since multiple factors
influence achieving recommended levels of physical activity. These
factors can be broadly categorized as either barriers or facilitators to
physical activity participation (Figure 3.2), and extensive research
is focused on identifying, developing, and testing interventions that
address these barriers and facilitators as a means of increasing physical activity levels and reducing sedentary time.34–​37 In general, the
social, economic, and built environments have a major impact on determining if individuals can engage in and sustain physical activity
CHAPTER 3 Physical Activity, Sedentary Behavior, and Cancer
Family
friends
Weather
Lack of
time
Support
Cost
Medical
professionals
External
barriers
Accountability
Access to
facilities
Desire for
health
Prevent
future
illness
Location
Intrinsic
motivation
Knowledge
Facilitators
Barriers
Motivation
Internal
barriers
Enjoyment
Interest
Societal
Health
Income
security
Fear
Education
Comorbid
conditions
Age
Figure 3.2. Model of facilitators and barriers to physical activity.
as a regular component of their lives. For example, individuals with
lower incomes often have more physically demanding jobs, resulting
in higher levels of occupational physical activity, but they may lack
the economic resources or time to invest in recreational physical
activity participation, which has been most commonly associated
with improved health benefits. Typically, those individuals who have
higher education and socioeconomic status understand the benefits
derived from leading active lifestyles and have the means to be able
to engage in such healthy behaviors.
It is often the goal of researchers and public health agencies to
find ways to reduce inequities to allow larger proportions of the population to access resources that may improve health. Actions have
been taken to use publically available educational media campaigns
to promote the health benefits of physical activity, and municipalities have been focused on improving the built environment and
providing resources to encourage active lifestyles in city planning.
Furthermore, employers have been utilizing health benefit plans
to promote physical activity participation by allowing employees
to claim costs for recreational physical activities under health and
wellness spending accounts to provide an incentive to be more physically active. Modifications in workplace designs have also been encouraged to promote physical activity participation (e.g., access to
exercise facilities at work and secure bike storage) and reduce sedentary time (e.g., access to sit-​stand or cycling desks). Lastly, online
platforms, mobile applications, and wearable devices have become
increasingly popular to promote increases in physical activity participation coupled with reductions in sedentary time. These digital
platforms can promote physical activity behavior change by sending
motivational emails or text messages, sharing online educational
modules, and providing readily available information on physical
activity combined with motivational prompts or “nudges.” Indeed, a
systematic review and meta-​analysis reported a mean reduction of
40 minutes/​day of sedentary time in intervention studies that used
technology to promote sedentary behavior change in the workplace,
community, and home settings.38 These examples of primary prevention aim to mitigate some of the barriers and foster factors seen
as facilitators listed in Figure 3.2 in an effort to ultimately prevent
chronic diseases, including cancers, before they ever occur.
Public Health Recommendations
Cancer and public health agencies worldwide have recognized
the benefits of regular physical activity for reducing cancer risk at
the population and individual level. As previously mentioned, the
WCRF/​AICR released its Continuous Update Report 2018, which
included the recommendation that individuals be at least moderately active (defined as raising the heart rate to about 60–​75% of its
maximum) and to follow or exceed national guidelines.2 Specifically,
to achieve benefits for cancer prevention and to have a significant
impact on weight control, they recommend that 45–​60 minutes of
moderate-​intensity physical activity per day is required. The WHO’s
2010 guidelines for physical activity advise adults to be active daily
and to participate in at least 150 minutes of moderate-​intensity aerobic physical activity or at least 75 minutes of vigorous-​intensity aerobic activity or a combination of these intensities.1 These guidelines
are being updated in 2020 and will include specific recommendations for cancer prevention. The recommendations from the WCRF/​
27
28
SECTION I Factors in Cancer Risk and Prevention
AICR are also to limit the amount of sedentary time for extended
time periods given that increased sedentary behavior is also a cause
of weight gain and type 2 diabetes, which are established causes of
several cancers.
In 2018, the U.S. Department of Health and Human Services released the Physical Activity Guidelines for Americans (PAGA) report in which they recommended that adults should undertake at
least 150–​300 minutes per week of moderate-​intensity or 75–​150
minutes per week of vigorous-​intensity activity or an equivalent
combination of both moderate-​and vigorous-​
intensity aerobic
activity.6 In addition, they recommended that adults should also
perform muscle-​strengthening activities on two or more days per
week. For older adults, there were additional recommendations to
undertake multicomponent physical activity that includes balance
training as well as aerobic and muscle-​strengthening activities. The
PAGA 2018 report highlighted that the benefits of increased physical activity included lower risk of several cancers including bladder,
breast, colon, endometrium, esophagus, kidney, lung, and stomach.
While the PAGA 2018 report did not make specific recommendations for physical activity for cancer prevention, it is noteworthy that
the guidelines developed by the WCRF/​AICR and those from the
PAGA committee are both targeting higher levels of activity than
those that were previously developed by the WHO. Hence, with the
increased evidence base and more precision on the amount, type,
and timing of activity required for cancer prevention, it appears that
a minimum level of 150 minutes per week of moderate-​intensity activity is required, with greater benefit being observed with higher
levels of activity (e.g., around 300 minutes weekly).
Conclusion
The evidence base for the etiologic role of physical activity and sedentary behavior associated with cancer incidence has grown rapidly
in the past 30 years, and there is now clear evidence that regular
physical activity and decreased sedentary behavior are associated
with the risk of 10 or more cancer sites. These associations have
been confirmed in nearly 500 studies conducted worldwide using
different study designs, study populations, assessment methods, and
analytic approaches. These consistent risk associations range from
around 10–​45% reductions for the highest levels of physical activity
in these studies compared to the lowest. There is also evidence for
dose-​response effects with increasing activity levels and decreasing
cancer risk. With respect to type of physical activity, evidence is now
emerging that resistance exercise may also be effective in reducing
cancer risk in addition to aerobic exercise, for which the evidence
base is well established. Cardiorespiratory fitness has more recently
been shown in some studies to be an independent risk factor for
cancer risk. Sedentary behavior as an independent risk factor for
cancer risk has recently emerged, and the risks associated with prolonged sitting are now apparent for at least three cancer sites. The biologic mechanisms for these associations are being elucidated with
evidence that physical activity and sedentary behavior influence
cancer risk through multiple pathways that include an effect on adiposity, endogenous sex and metabolic hormones, inflammation, and
possibly also immune and skeletal muscle functions. The burden of
cancer that can be attributed to physical inactivity and sedentary behavior is notable, with up to 10% of all cancers associated with these
risk factors. Multiple barriers and facilitators to regular physical activity participation are also being recognized. Interventions and support networks that address these factors are needed to increase the
levels of physical activity and reduce sedentary time in the general
population since trends of increasing inactivity and sedentary behavior are being reported worldwide.
Public health and cancer agencies have recognized the need for
clear guidelines on physical activity and sedentary behavior for
cancer prevention, and recent updates from these agencies are recommending daily activity with a combination of aerobic and resistance exercises that reaches up to 300 minutes per week of
moderate-​intensity activity. While considerable progress has been
made in elucidating the associations between physical activity, sedentary behavior, and cancer risk, there remain numerous areas that
require future research to address the questions regarding the nature of these associations by domain, type, dose, and timing in relation to cancer risk as well as by population subgroups and by cancer
types. More behavioral interventions specifically targeted at cancer
prevention and focused on reducing sedentary behaviors are also
needed with the objective of increasing the prevalence of physically
active individuals at the population level.
ACKNOWLEDGMENTS
The authors acknowledge the assistance of Rebecca Urbat for
completing literature searches on resistance training and cancer
incidence and also Nathaniel Minichiello for completing literature searches on cardiorespiratory fitness and cancer incidence.
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25. Hu FB, Li TY, Colditz GA, Willett WC, Manson JE. Television
watching and other sedentary behaviors in relation to risk
of obesity and type 2 diabetes mellitus in women. JAMA.
2003;289(14):1785–​1791.
26. Blanck HM, McCullough ML, Patel AV, et al. Sedentary behavior, recreational physical activity, and 7-​
year weight gain
among postmenopausal U.S. women. Obesity (Silver Spring, Md).
2007;15(6):1578–​1588.
27. Mekary RA, Feskanich D, Malspeis S, Hu FB, Willett WC, Field
AE. Physical activity patterns and prevention of weight gain in
premenopausal women. International Journal of Obesity (Lond).
2009;33(9):1039–​1047.
28. Helmerhorst HJ, Wijndaele K, Brage S, Wareham NJ, Ekelund U.
Objectively measured sedentary time may predict insulin resistance independent of moderate-​and vigorous-​intensity physical
activity. Diabetes. 2009;58(8):1776–​1779.
29. Saunders TJ, Larouche R, Colley RC, Tremblay MS. Acute sedentary behaviour and markers of cardiometabolic risk: A systematic review of intervention studies. Journal of Nutrition and
Metabolism. 2012;2012:712435.
30. Bosutti A, Malaponte G, Zanetti M, et al. Calorie restriction modulates inactivity-​induced changes in the inflammatory markers C-​
reactive protein and pentraxin-​3. Journal of Clinical Endocrinology
& Metabolism. 2008;93(8):3226–​3229.
31. Drummond MJ, Timmerman KL, Markofski MM, et al. Short-​
term bed rest increases TLR4 and IL-​6 expression in skeletal
muscle of older adults. American Journal of Physiology-​Regulatory,
Integrative and Comparative Physiology. 2013;305(3):R216–​R223.
32. Kerr J, Anderson C, Lippman SM. Physical activity, sedentary behaviour, diet, and cancer: An update and emerging new evidence.
Lancet Oncology. 2017;18(8):e457–​e471.
33. Guthold R, Stevens GA, Riley LM, Bull FC. Worldwide trends in
insufficient physical activity from 2001 to 2016: A pooled analysis of 358 population-​based surveys with 1.9 million participants.
Lancet Global Health. 2018;6(10):e1077–​e1086.
34. Kuijpers W, Groen WG, Aaronson NK, van Harten WH. A systematic review of web-​based interventions for patient empowerment
and physical activity in chronic diseases: Relevance for cancer survivors. Journal of Medical Internet Research. 2013;15(2):e37.
35. Hadgraft NT, Brakenridge CL, Dunstan DW, Owen N, Healy
GN, Lawler SP. Perceptions of the acceptability and feasibility of
reducing occupational sitting: Review and thematic synthesis.
International Journal of Behavioral Nutrition and Physical Activity.
2018;15(1):90.
36. Kelly S, Martin S, Kuhn I, Cowan A, Brayne C, Lafortune L.
Barriers and facilitators to the uptake and maintenance of healthy
behaviours by people at mid-​life: A rapid systematic review. PloS
One. 2016;11(1):e0145074.
37. Franks H, Hardiker NR, McGrath M, McQuarrie C. Public health
interventions and behaviour change: Reviewing the grey literature. Public Health. 2012;126(1):12–​17.
38. Stephenson A, McDonough SM, Murphy MH, Nugent CD, Mair
JL. Using computer, mobile and wearable technology enhanced
interventions to reduce sedentary behaviour: A systematic review
and meta-​analysis. International Journal of Behavioral Nutrition
and Physical Activity. 2017;14(1):105.
29
4
Sun Exposure and Cancer Risk
Suzanne J. Dobbinson, Afaf Girgis, Bruce K. Armstrong, and Anne E. Cust
Epidemiology
Sun Exposure and Cancer Risk
Skin Cancer
Skin cancers are highly preventable. Exposure to solar ultraviolet
(UV) radiation is responsible for the development of some 50–​90%
of melanomas, 50–​90% of basal cell carcinomas (BCCs), and 50–​70%
of squamous cell carcinomas (SCCs) of skin globally. UV radiation is
also linked with ocular cancers and other eye conditions such as cortical cataract and pterygium (a benign growth of the conjunctiva).
It is widely accepted that UV radiation causes skin cancer.
However, the association of sun exposure with skin cancer appears
complex. Sunburn history and other recalled sun exposure that is
intermittent in nature, and mainly recreational exposure or holiday
exposure, are the UV risk factors most strongly associated with melanoma. More continuous (chronic) sun exposure, typically occupational sun exposure, may not increase melanoma risk. Childhood is
the period of greatest susceptibility to sun exposure effects on later
melanoma risk; however, risk also accumulates with sun exposure
in adulthood.
SCCs are mainly associated with total and occupational sun exposure, and BCCs, like melanoma, with early life sun exposure,
nonoccupational or recreational sun exposure, and history of sunburn. There is also convincing evidence that indoor tanning is associated with melanoma and keratinocyte skin cancers.1,2 For people
who reported ever using indoor tanning devices compared with
those who never used them, the relative risks were 1.20 (95% confidence interval [CI]: 1.08–​1.34) for melanoma, 1.67 (95% CI: 1.29–​
2.17) for SCC, and 1.29 (95% CI: 1.08–​1.53) for BCC; these relative
risks were higher for people who used indoor tanning devices before
the age of 35 years. UV measurements made inside indoor tanning
devices show that mean erythema-​weighted UV irradiances are
higher than those from natural sun, with large variations between
devices, and that UVA exposure is particularly high.3 Importantly
also, Colantonio et al.2 observed that there was no statistically significant difference in this association between exposure before and
after the year 2000, thus suggesting that newer tanning technology is
not safer than older technology.
Incidence rates for melanoma and other skin cancers continue to rise in predominantly fair-​skinned populations in spite of
active promotion of sun protection over the past 50 years. There is,
though, evidence of a plateau and nascent fall in melanoma incidence rates in some such populations (e.g., Australia, New Zealand,
and Denmark), particularly in younger people. These trends could
be due to increasing sun protection in recent cohorts born in these
countries. There is little evidence of similar trends in incidence of
keratinocyte cancers.
Other Cancers
A systematic review of the epidemiological evidence suggests that
there is an inverse association of sun exposure with risk of some internal cancers, namely colorectal, prostate, breast, and non-​Hodgkin
lymphoma (NHL).4 The evidence was considered strongest for an inverse association between sun exposure and colorectal and prostate
cancers; findings were more heterogeneous for the association with
breast cancer and NHL. It is not yet possible to say whether these
observed associations are causal, since confounding with other lifestyle factors such as diet and physical activity cannot be completely
excluded. Paradoxically, a quite strong positive association has been
observed between sun exposure and prostate cancer in Australia,4 a
much higher UV environment than most countries in which an inverse association has been observed.
Possible Cancer Causal or Cancer Protective Mechanisms
Current best evidence indicates that sun exposure causes skin cancer
by way of UV radiation causing damage to cellular DNA and gene
mutation consequent on that damage. Conjunctival melanoma is
probably also caused by UV radiation mutation of conjunctival cells,
but there is little or no evidence of a similar causal path to uveal (internal ocular) melanoma.
Immune-​suppressive effects of sun exposure have been offered as
a possible explanation for an increase in risk of internal cancer, such
as prostate cancer, at higher levels of sun exposure; there is clear evidence that therapeutic immune suppression increases risk of many
cancers. DNA damage in circulating lymphocytes has also been observed in people with higher levels of sun exposure, which raises
the possibility of other mechanisms, although it is yet to be established that the damage observed in lymphocytes also occurs in solid
organs.
Anti-​carcinogenic effects of vitamin D are the most common
mechanism suggested for observed inverse associations between
CHAPTER 4 Sun Exposure and Cancer Risk
sun exposure and internal cancers. Vitamin D is produced in skin
following exposure to solar UVB radiation and is transported
in the bloodstream. Many in vitro studies have shown that high
concentrations of vitamin D compounds can inhibit cancer cell
proliferation and, sometimes, induce differentiation (cell “normalization”).4 A comprehensive review of studies of associations
of vitamin D concentration and cancer incidence and mortality
concluded, “Higher circulating levels of vitamin D (i.e., 25-​
hydroxyvitamin D or 25(OH)D) appear to be associated with reduced risk of colorectal and bladder malignancies, but higher risk
of prostate and possibly pancreatic cancers, with no clear association for most other organ sites examined.”5 There is inconsistent
evidence for a protective effect of vitamin D in the few randomized controlled trials in which the effect on cancer incidence of
vitamin D supplementation, with or without supplementary calcium, has been examined (generally not as the primary objective of
the study).4,5 Similarly, in a more recent review, Zhang et al.6 found
evidence that vitamin D supplementation reduced risk of cancer
death, but not all-​cause mortality. More substantial such studies
are underway (see, e.g., Neale et al.7).
Other Health Effects of Sun Exposure
There is a growing body of evidence for beneficial effects of sun exposure on health, which could be mediated by way of cutaneous production of vitamin D or by other mechanisms. These effects include
reductions in risk of cardiovascular disease, Alzheimer disease or
other dementia, myopia, macular degeneration, diabetes, and multiple sclerosis. While not within the scope of this chapter and not yet
well reviewed, this evidence may have to be taken into consideration
when considering sun protection recommendations and the populations within which they are made.
Evidence That Reducing Sun Exposure Can Reduce Risk
of Cutaneous and Ocular Cancers
There is some evidence of the efficacy or effectiveness of sun exposure reduction in lowering risk of cutaneous or ocular cancer. The
strongest evidence is from a handful of trials of the effects of sun
protection, principally use of sunscreens, in reducing risk of known
skin cancer precursors or skin cancers themselves.
The number of cutaneous pigmented nevi is a very strong predictor of cutaneous melanoma risk and a clear precursor to a proportion of cutaneous melanomas. In an individually controlled trial,
Vancouver schoolchildren 6–​7 or 9–​10 years of age were randomly
assigned to be sent supplies of sun protective factor (SPF) 30 broad-​
spectrum sunscreen at the beginning of three consecutive summer
vacations. Children given sunscreen had significantly smaller increases in number of pigmented nevi than children not given sunscreen.8 This result has been corroborated by a more broadly based,
community intervention trial in Perth, Australia.9 Number of solar
keratoses (SKs) is similarly a very strong predictor of keratinocyte
cancer, and SKs are precursor lesions to cutaneous SCC. In an individually randomized, placebo-​controlled trial of summer use of a
broad-​spectrum SPF 17 sunscreen in Melbourne, Australia, use of
the active sunscreen reduced appearance of new SKs and increased
remissions of existing SKs.10
An individually randomized controlled trial of daily use of an
SPF 15+ sunscreen in southeastern Australia observed a significant,
39% reduction in risk of cutaneous SCC over 4.5 years of follow-​up
in those randomized to sunscreen.11 At approximately 15 years of
follow-​up, the relative risk for melanoma (both in situ and invasive)
was 0.50 (95% CI: 0.24–​1.02); for invasive melanoma alone it was
0.27 (95% CI: 0.08–​0.97).12 Further follow-​up for BCC has not been
reported.
The evidence of a plateau and nascent fall in melanoma incidence
rates, particularly in younger people, in some populations with active and long-​running sun protection programs (e.g., Australia and
New Zealand) suggests that these programs have been effective in
preventing melanoma.
On balance, there is reasonable evidence that effective protection
from exposure to the sun can reduce risk of cutaneous SCC and melanoma. It is also reasonable to conclude that measures demonstrated
to provide that protection can also reduce risk of these cancers.
Sun Protection Measures
Public UV protection messages usually focus on these key points:
• Wear clothing that covers your arms and legs.
• Use sunscreen with an SPF of 30 or higher, and both UVA and
UVB protection.
• Wear a hat with a wide brim to shade your face, head, ears,
and neck.
• Stay in the shade when the UV Index is 3 or more.
• Wear sunglasses that wrap around and block both UVA and
UVB rays.
• Avoid indoor tanning.
In Australia, these messages have been framed in a well-​known
slogan as “Slip” on sun protective clothing; “Slop” on SPF30 or higher
broad-​spectrum, water-​resistant sunscreen 20 minutes before going
outdoors and reapply every two hours afterward; “Slap” on a broad-​
brimmed hat that protects your face, head, neck, and ears; and the
more recent addition of “Seek” shade and “Slide” on sunglasses.
Recommendations for when and where sun protection is required
are complicated by the fact that solar UV radiation varies by latitude,
season of the year, and time of day. UV radiation is strongest at solar
noon and increases closer to summer solstice and with decreasing
latitude. Thick cloud cover can rapidly reduce ambient UV levels;
however, modeling of satellite cloud data and ozone levels enables
accurate UV forecasts. Real-​time UV levels are also available for
most capital cities in Australia.13 Education about the UV Index
is therefore one means of simplifying the sun protection message
for the community. The higher the UV Index value, the greater the
potential for damage to one’s skin. Sun protection is recommended
when the UV Index is 3 or above.14 Internationally, a range of specific
recommendations for sun protection and sun avoidance are made
for skin cancer prevention, with some regions incorporating the UV
Index while for others it is less of a focus. A more rigorous recommendation for sunscreen application, daily application when the UV
Index is 3 or greater, has recently been adopted by skin cancer prevention programs in Australia.15 Sun safety messages in the United
States recommend using sun protection and avoiding prolonged exposure to the sun when possible.16 In the United Kingdom, use of
multiple sun protection behaviors are recommended when the sun
is strong.17
31
32
SECTION I Factors in Cancer Risk and Prevention
Psychosocial and Behavioral Research on Sun
Exposure and Sun Protection
Predictors of Sun Exposure and Sun Protection Behaviors
Like most other health-​related behaviors, changing personal sun
exposure and sun protection behaviors is challenging. Glanz and
Rimer18 highlight some key cognitive-​behavioral concepts that underlie the complexity of changing personal behavior:
• Behavior is mediated by cognitions; that is, what people know and
think affects how they act.
• Knowledge is necessary for, but not sufficient to produce, most
behavior changes.
• Perceptions, motivations, skills, and the social environment are
key influences on behavior.
Knowledge of the dangers of excessive sun exposure and the benefits of sun protection does not necessarily translate into behavior
change; it is clear that practical, social, psychological, and environmental barriers must also be addressed.
A large cross-​sectional online survey conducted by the melanoma
genetics consortium (GenoMEL) of 8,178 individuals across Europe
(73% of respondents), Australia (12%), the United States (7%), and
Israel (2%) found that despite widespread dissemination of sun protection messages, half of all respondents and 27% of those with a
previous melanoma reported at least one severe sunburn during
the previous 12 months.19 They found the strongest predictors of
lack of sun protection behavior were perceived barriers to protection (β = −0.44) and perceiving suntans as “attractive” and “healthy”
(β = −0.16). Perceived vulnerability to melanoma, perceived melanoma severity, and worry about melanoma showed moderate positive correlations with sun protection. Sun protection was also higher
among women, older people, people with high-​risk characteristics
such as fair skin, and people living at lower latitudes. Importantly,
the pattern of results was similar across the different countries, and
the same variables were significant predictors in all regions.19 These
demographic predictors of sun protection are also generally consistent with those identified in nationally representative surveys in
the United States20 and Australia.21
Young people are a particularly challenging group in whom to
motivate risk-​reducing behaviors and their protective behaviors remain low. Among adolescents and young adults, suntanning and
sun exposure behavior is strongly influenced by social norms, body
image concerns, and fashion. Younger people are more likely to perceive a tan as attractive and healthy and to perceive barriers to sun
protection. Despite knowing the risks, many adolescents and young
adults still desire and actively seek a suntan. Frequent users of indoor tanning often display signs and symptoms consistent with an
addictive disorder, suggesting the need to address physiologic effects
of tanning as well as psychosocial factors driving tanning behavior.
In contrast, young children are generally better protected from the
sun than adolescents or adults, while parental attitudes and parental
behavior are strongly associated with children’s sun exposure and
sun protection behavior.
Health Behavior Theories
Skin cancer prevention programs are most likely to be effective
and sustainable when they are based on theoretical models that
underpin a clear understanding of the factors that influence the
target population’s behavior, including their personal beliefs
and attitudes, and social and physical environments. In that regard, application of theory informs the interpretation of research
findings and understanding of the dynamic interactions between behavior and the environmental and social context, hence
increasing the likelihood of effective translation of skin cancer
prevention strategies into public health policy or clinical practice. Theories and their applications at the individual (intrapersonal), interpersonal, and community levels are relevant to skin
cancer prevention.
Individual-​Level (Intrapersonal) Theories
Strategies intended to change people’s behavior can often be derived from individual-​
level theories such as the Health Belief
Model, Stages of Change Model, Theory of Planned Behavior, and
Precaution Adoption Process Model. These theories are important
for skin cancer prevention campaigns as they are related to individuals’ knowledge, perceptions, attitudes, beliefs, intentions, and
decision-​making processes about skin cancer prevention behaviors,
barriers, and benefits. However, on their own, individual-​level theories are usually insufficient to change skin cancer–​related behaviors; to be effective they need to be considered within the social and
environmental context.
Community-​Level Theories
Some population-​based strategies for reducing sun exposure focus
on changing the environment and thus draw on community-​level
theories such as Community Organization, which emphasizes
community-​driven approaches to assessing and solving health and
social problems. An example is the use of shade sails in schools,
whereby the health promotion agency, schools, and students work
together to identify the problem of lack of shade, decide where
best to locate the structures, and raise the funds required for them.
Disparities in provision of shade in public parks may also be addressed in a similar manner through advocacy of community groups
to local governments.22,23 Mass media campaigns that aim to change
social norms, such as tanning desirability, also draw on community-​
level theories. Institutional factors, such as sun protection policies
for outdoor workers and primary school students, have also been
successful for reducing childhood sun exposure, as has advocacy
aimed at legislative changes, which have been shown to be highly
successful in achieving the bans on commercial indoor tanning in
Australia and Brazil.14,24
Interpersonal-​Level Theories
Theories at the interpersonal level, such as Social Cognitive Theory,
explore the reciprocal exchanges between individuals and their social environments including family members, friends, health professionals, and others. Interpersonal theories recognize that the social
environment influences an individual’s feelings and behaviors. They
are particularly useful for examining and understanding behaviors
that relate to skin cancer risk, including sun protective behaviors,
time spent in the sun, and suntanning, as these behaviors have a
strong social influence component. For example, in many societies, having a suntan is seen as being healthy and attractive, and
people do not cover up because of peer pressure and fashion trends.
As such, strategies based on interpersonal-​level theories appear to
CHAPTER 4 Sun Exposure and Cancer Risk
be the most powerful and effective for skin cancer prevention. The
Australian SunSmart program14 is an example of a skin cancer prevention strategy that is based on social cognitive theories of attitudes
and behavior change; it targets knowledge, attitudes, and intentions
of individuals, along with social and cultural norms and environmental change, to promote sun protection behavior.
Interventions and Approaches
Table 4.1 summarizes some of the psychosocial and behavioral
skin cancer prevention interventions and approaches for different target groups: general population, early childhood, adolescence, and other high-​risk groups. This table does not provide
an exhaustive list but gives an indication of the multidisciplinary
and multidimensional approaches that are needed to reduce skin
cancer risk across different community groups. More details of
these and other interventions can be found in systematic reviews
of these topics.25–​31
Given our increasing understanding of the genetic susceptibility
to melanoma, advances in genetic technologies, and the increasing
use of genomic information for health purposes, future interventions should also consider evaluating the effect of interventions that
provide knowledge of personal genetic melanoma risk on motivating risk-​reducing behaviors in the general population. Social and
behavioral theory suggests that the highly personalized nature of
providing results of a genetic risk assessment may increase its motivational potency over standard approaches.
Table 4.1. Summary of Psychosocial and Behavioral Skin Cancer Prevention Interventions and Approaches for Different Target Groups
Target Group
Aims
Types of Interventions and Approaches
Examples
General population
-​ To increase knowledge and awareness
-​ Mass media public education, such as
-​ Slip! Slop! Slap! (Seek! Slide!),
-​
-​
-​
-​
-​
-​
-​
-​
Early childhood
-​ To reduce children’s sun exposure and
-​
-​
-​
-​
-​
Adolescence
of skin cancer and its causes
To improve sun protection behaviors
To reduce excessive sun exposure
To improve early detection of
melanoma
To identify high-​risk individuals who
would benefit from closer follow-​up
and surveillance
To provide information on prevention,
early diagnosis, and treatment of
skin cancer
To reduce the desirability of a tan
To increase knowledge of harmful UV
levels
increase their sun protection behaviors
To improve parents’/​teachers’/​children’s
knowledge and awareness of skin
cancer, risk factors, and sun protection
strategies
To improve parents’ and teachers’ self-​
efficacy, such as confidence in their
ability to increase their child/​children’s
sun protection
To reduce perceived barriers to
sunscreen use and other forms of sun
protection
To change attitudes
To increase sun protection policies at
schools
-​ To change perceptions and attitudes,
such as tanning desirability
-​ To increase awareness that young
people are susceptible to skin cancer
-​ To reduce sun exposure and increase
sun protection intentions and behaviors
-​ To reduce or stop indoor tanning
-​
-​
-​
-​
-​ Targeted interventions that are implemented
in environments such as childcare centers,
preschools, and primary schools, such as
promoting hat wearing, ensuring adequate
shade in the school grounds, and teaching
children about sun protection in school
-​ Protective clothing and swimwear designed
for children
-​ “Toolkits” for policy development, such
as evaluation tools to assess schools’
current sun protection practices and shade
availability, aids for curricula training and
integration into the classroom, and sun
protection policy options
-​ Newsletter information and resources
-​ Mass media campaigns aimed at
-​
-​
-​
-​
-​
Other high-​risk groups -​ To reduce sun exposure and increase
(e.g., genetically
sun protection in people at “high risk” of
susceptible, high
developing skin cancer
occupational
-​ To increase early detection among
sun exposure,
high-​risk groups
immunosuppressed)
-​ To increase knowledge about skin
cancer risk and risk-​reducing behaviors
advertisements on TV, radio, online/​digital
media, newspapers, and billboards
Protective clothing for swimming, golf,
cycling, and gardening and new shade
structures for home and beach use
Free-​of-​charge skin examinations for
the public
Providing shade in public areas1 and at
pools/​beaches
Interventions in recreational or tourism
settings
Tools to assist with and dissemination
of real-​time measures of UV for specific
locations
young adults
Increasing shade cover at high schools
Use methods such as UV photos,
Interventions based on the appearance-​
damaging effects of UV exposure
Policy-​based interventions including
changes to legislation
Coordinated, multi-​level, trans-​disciplinary
approaches to reduce indoor tanning
-​ Genetic screening for people with a strong
family history
-​ Workplace policies for outdoor workers
-​ Providing shade in occupational settings
-​ Family-​based strategies within melanoma-​
prone families
SunSmart, Euromelanoma
prevention campaign, Dear 16-​
YearOld Me; Wes Bonny testimonial,
UV It All Adds Up, Don’t Be A Lobster
-​ Pool Cool, Go SunSmart
-​ Smartphone apps
-​ SunSmart Schools program,
SunWise school campaign, Kidskin
-​ SunSmart primary schools members
program
-​ Tailored mailed newsletters
-​ Wes Bonny testimonial; Dark Side
of Tanning; Tattoo (SunSmart Dear
16YearOld Me
-​ Built shade interventions
-​ Interventions aimed at relatives of
people with melanoma
-​ Go Sun Smart Worksite Health
Communication Campaign,
SUNWISE workplace intervention
33
34
SECTION I Factors in Cancer Risk and Prevention
The Vitamin D Conundrum
In a sun exposure and cancer risk context, there are four main reasons
that vitamin D is important to psycho-​oncology. First, vitamin D
is essential to healthy bone development and to maintaining bone
health. Second, vitamin D is hypothesized to have health benefits
that are independent of these skeletal effects. Although evidence is
mixed and of variable quality, vitamin D possibly protects against
some cancers, infections, autoimmune and cardiovascular diseases,
cognitive dysfunction, and depression,32 while a recent high-​quality
study provides evidence of reduced cancer mortality6. Third, irradiation of skin by solar UVB radiation prompts vitamin D synthesis
and makes an important contribution to serum 25-​hydroxy vitamin
D concentration (the usual measure of vitamin D status) in most
populations, with diet (including vitamin D–​fortified foods and vitamin D supplements) being the alternative source. Fourth, vitamin
D insufficiency (30–​<50 nmol/​L of 25-​hydroxy vitamin D) and frank
deficiency (<30 nmol/​L) are quite common in fair-​skinned as well as
dark-​skinned populations (who generally have lower average serum
25-​hydroxy vitamin D concentrations), even in Australia, where the
potential for exposure of a largely fair-​skinned population to solar
UVB radiation is probably the greatest in the world.
Messages about the health benefits of vitamin D and harmful
effects of sun exposure are therefore in conflict, and health professionals and their clients are easily confused about how much vitamin
D is required, whether it can be safely acquired by prudent sun exposure, and whether more dietary fortification with, or supplemental
intake of, vitamin D is a necessary and safer course or whether some
beneficial effects of sun exposure can only be obtained from sun exposure itself. The issue has been additionally clouded by some scientists’ promotion of a need for particularly high serum 25-​hydoxy
vitamin D concentrations to ensure vitamin D’s hypothesized beneficial effects against nonskeletal conditions.33 Additionally, some
have raised concern that sunscreens inhibit vitamin D production,34
while application of sunscreen is typically inadequate and is still recommended for use when the UV Index is 3 or above.34
Content analysis of news media reports about sun protection issues showed increasing coverage of vitamin D issues from 2001 to
2012.35 Recent quantitative and qualitative surveys in the community have shown low knowledge about vitamin D and lack of understanding of the “balance message”: that is, “some sunlight exposure
each day for adequate vitamin D production, but not so much that
would lead to increased skin cancer risk.”36 Moreover, some people
reported going out into the sun or intentionally tanning to improve
their vitamin D status.37
Publication of findings from vitamin D supplementation trials
and studies of health benefits of UV exposure during this period
appear to have influenced physicians’ practices with respect to
testing of patients’ vitamin D levels and prescribing both sun exposure and vitamin D supplements.38 Physicians surveyed in 2012
also reported a trend toward recommending less sun protection in
the winter and, sometimes, in the summer. It is of concern that some
doctors endorsed sun exposure during peak UV times of the day, in
the summer as well as in the winter, and commonly overestimated
the amount of peak UV exposure in the summer that was needed to
gain or maintain vitamin D sufficiency. Some doctors also expressed
greater concern about vitamin D deficiency than skin cancer in their
patients.
A number of interested agencies, including national public
health agencies, cancer and osteoporosis organizations, and professional organizations of dermatologists, have reviewed the changing evidence about vitamin D and health and considered what, if
any, might be an acceptable balance between sun exposure that is
sufficient to maintain vitamin D sufficiency and protection against
skin cancer due to sun exposure.39 These guidelines inevitably vary
depending on the latitude of the population they address; typically they advise sun protection during the middle of the day in the
summer, when UVB levels are at their highest, and little or no sun
protection at times and in seasons when UVB levels are low (characterized by a UV Index of less than 3). Some, particularly dermatology societies, favor no relaxation in sun protection and increased
dietary intake or supplementation to ensure vitamin D sufficiency,
while others call for more nuanced messaging to account for duration as well as intensity of UV exposure.40 The research on which
these recommendations have been based is very limited, particularly with respect to how much sun exposure will maintain vitamin
D sufficiency, and none of the recommendations have been evaluated for their success in reducing vitamin D insufficiency and not
increasing skin cancer risk.41
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2. Colantonio S, Bracken MB, and Beecker J. The association of indoor tanning and melanoma in adults: systematic review and
meta-​analysis. J Am Acad Dermatol. 2014; 70: 847–​857, e1–​18.
3. Nilsen LT, Hannevik M, and Veierod MB. Ultraviolet exposure
from indoor tanning devices: a systematic review. Br J Dermatol.
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4. Lucas RM, McMichael AJ, Armstrong BK, and Smith WT.
Estimating the global disease burden due to ultraviolet radiation
exposure. Int J Epidemiol. 2008; 37: 654–​667.
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6. Zhang Y, Fang F, Tang J, et al. Association between vitamin D supplementation and mortality: systematic review and meta-​analysis.
BMJ. 2019; 366: 14673.
7. Neale RE, Armstrong BK, Baxter C, et al. The D-​health trial: a randomized trial of vitamin D for prevention of mortality and cancer.
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8. Gallagher RP, Rivers JK, Lee TK, Bajdik CD, McLean DI, and
Coldman AJ. Broad-​spectrum sunscreen use and the development of new nevi in white children: a randomized controlled trial.
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pp. 1061–​1087.
10. Thompson SC, Jolley D, and Marks R. Reduction of solar keratoses
by regular sunscreen use. N Engl J Med. 1993; 329: 1147–​1151.
CHAPTER 4 Sun Exposure and Cancer Risk
11. Green A, Williams G, Neale R, et al. Daily sunscreen application
and betacarotene supplementation in prevention of basal-​cell and
squamous-​cell carcinomas of the skin: a randomised controlled
trial. Lancet. 1999; 354: 723–​729.
12. Green AC, Williams GM, Logan V, and Strutton GM. Reduced
melanoma after regular sunscreen use: randomized trial follow-​
up. J Clin Oncol. 2011; 29: 257–​263.
13. ARPANSA. Ultraviolet radiation index: realtime UV index.
Australian Radiation and Nuclear Safety Protection Agency, 2019,
Realtime UV data for Australian cities [cited 2019 Sep 16]: Available
from
https://​www.arpansa.gov.au/​our-​services/​monitoring/​
ultraviolet-​radiation-​monitoring/​ultraviolet-​radiation-​index
14. Sinclair C and Foley P. Skin cancer prevention in Australia. Br J
Dermatol. 2009; 161 Suppl 3: 116–​123.
15. Whiteman D, Neale RE, Aitken J, et al. When to apply sunscreen: a
consensus statement of Australia and New Zealand. Aust N Z J
Public Health. 2019; 43: 171–​175.
16. Centers for Disease Control and Prevention. Skin Cancer:
SunSafety; 2019 [cited 2019 Sep 30]: Available from https://​www.
cdc.gov/​cancer/​skin/​basic_​info/​sun-​safety.htm
17. Cancer Research UK. Sun, UV and cancer; 2019 [cited 2019 Sep
30]: Available from https://​www.cancerresearchuk.org/​about-​
cancer/​causes-​of-​cancer/​sun-​uv-​and-​cancer
18. Glanz K and Rimer BK. Theory at a Glance: A Guide for Health
Promotion Practice. 2nd ed. US National Cancer Institute, 2005.
Bethesda, Maryland, USA.
19. Branstrom R, Kasparian NA, Chang YM, et al. Predictors of sun
protection behaviors and severe sunburn in an international online
study. Cancer Epidemiol Biomarkers Prev. 2010; 19: 2199–​2210.
20. Buller DB, Cokkinides V, Hall HI, et al. Prevalence of sunburn, sun
protection, and indoor tanning behaviors among Americans: review from national surveys and case studies of 3 states. J Am Acad
Dermatol. 2011; 65: S114–​S123.
21. Dobbinson S, Wakefield M, Hill D, et al. Prevalence and determinants of Australian adolescents’ and adults’ weekend sun protection and sunburn, summer 2003-​2004. J Am Acad Dermatol. 2008;
59: 602–​614.
22. Anderson C, Jackson K, Egger S, Chapman K, and Rock V. Shade
in urban playgrounds in Sydney and inequities in availability
for those living in lower socioeconomic areas. Aust N Z J Public
Health. 2014; 38: 49–​53.
23. Buller DB, English DR, Buller MK, et al. Shade sails and passive
recreation in public parks of Melbourne and Denver: a randomized intervention. Am J Public Health. 2017; 107: 1869–​1875.
24. Gandini S, Sera F, Cattaruzza MS, et al. Meta-​analysis of risk
factors for cutaneous melanoma: II. Sun exposure. Eur J Cancer
(Oxford, Engl. 1990). 2005; 41: 45–​60.
25. Horsham C, Auster J, Sendall MC, et al. Interventions to decrease
skin cancer risk in outdoor workers: update to a 2007 systematic
review. BMC Res Notes. 2014; 7: 10.
26. Saraiya M, Glanz K, Briss P, et al. Interventions to prevent skin
cancer by reducing exposure to ultraviolet radiation: a systematic
review. Am J Prev Med. 2004; 27: 422–​466.
27. Sandhu PK, Elder R, Patel M, et al. Community-​wide interventions to prevent skin cancer: two community guide systematic reviews. Am J Prev Med. 2016; 51: 531–​539.
28. Persson S, Benn Y, Dhingra K, Clark-​Carter D, Owen AL, and
Grogan S. Appearance-​based interventions to reduce UV exposure: a systematic review. Br J Health Psychol. 2018; 23: 334–​351.
29. Stapleton JL, Hillhouse J, Levonyan-​Radloff K, and Manne SL.
Review of interventions to reduce ultraviolet tanning: need for
treatments targeting excessive tanning, an emerging addictive behavior. Psychol Addict Behav. 2017; 31: 962–​978.
30. Williams AL, Grogan S, Clark-​
Carter D, and Buckley E.
Appearance-​based interventions to reduce ultraviolet exposure
and/​or increase sun protection intentions and behaviours: a systematic review and meta-​analyses. Br J Health Psychol. 2013;
18: 182–​217.
31. Holman DM, Fox KA, Glenn JD, et al. Strategies to reduce indoor
tanning: current research gaps and future opportunities for prevention. Am J Prev Med. 2013; 44: 672–​681.
32. Autier P, Mullie P, Macacu A, et al. Effect of vitamin D supplementation on non-​skeletal disorders: a systematic review of meta-​
analyses and randomised trials. Lancet Diabetes Endocrinol. 2017;
5: 986–​1004.
33. Institute of Medicine. Dietary Reference Intakes for Calcium and
Vitamin D. Washington, DC: National Academies Press, 2011.
34. Mancebo SE, Hu JY, and Wang SQ. Sunscreens: a review of health
benefits, regulations, and controversies. Dermatol Clin. 2014;
32: 427–​438.
35. Scully M, Makin J, Maloney S, and Wakefield M. Changes in coverage of sun protection in the news: threats and opportunities
from emerging issues. Health Educ Res. 2014; 29: 378–​387.
36. Bonevski B, Bryant J, Lambert S, Brozek I, and Rock V. The ABC
of vitamin D: a qualitative study of the knowledge and attitudes
regarding vitamin D deficiency amongst selected population
groups. Nutrients. 2013; 5: 915–​927.
37. Youl PH, Janda M, and Kimlin M. Vitamin D and sun protection: the impact of mixed public health messages in Australia. Int J
Cancer. 2009; 124: 1963–​1970.
38. Bonevski B, Girgis A, Magin P, Horton G, Brozek I, and Armstrong
B. Prescribing sunshine: a cross-​sectional survey of 500 Australian
general practitioners’ practices and attitudes about vitamin D. Int
J Cancer. 2012; 130: 2138–​2145.
39. Australian and New Zealand Bone and Mineral Society,
Australasian College of Dermatologists, Cancer Council Australia,
Endocrine Society of Australia, and Osteoporosis Australia.
Position Statement—​Risks and Benefits of Sun Exposure. Sydney,
Australia: Cancer Council Australia, 2016.
40. Lucas RM, Neale RE, Madronich S, and McKenzie RL. Are current
guidelines for sun protection optimal for health? Exploring the evidence. Photochem Photobiol Sci. 2018; 17: 1956–​1963.
41. Khan SR, Whiteman DC, Kimlin MG, et al. Effect of solar ultraviolet radiation exposure on serum 25(OH)D concentration: a
pilot randomised controlled trial. Photochem Photobiol Sci. 2018;
17: 570–​577.
35
5
Psychosocial Factors
Anika von Heymann and Christoffer Johansen
Introduction
This topic covers many risk factors, and the scientific literature on
their role in cancer causation has a long history. Nevertheless, in
scientific studies published during the past 75 years and in reviews
of the literature, little is said about cancer causation as such. It is
important that this subject be raised to emphasize that the criteria
for causation originally stated by Austin Bradford Hill in the early
1960s also apply to psychosocial risk factors. Hill1 suggested that
the following issues be considered to distinguish association from
causation: temporality, coherence, consistency, specificity, biological gradient, strength of the association, analogy, and biological
plausibility. Hill stated, “None of these nine standards can bring indisputable evidence for or against the cause-​and-​effect hypothesis
and none can be required as a sine qua non.”1 This cannot be considered a final list of factors that establish causality, but they must
be taken into account in determining the weight of evidence. Hill
also warned against overemphasis on statistical significance testing,
writing, “The glitter of the t table diverts attention from the inadequacies of the fare.”1 The theory of causality has developed since
Hill’s time, increasing the complexity of establishing causality and
requiring new levels of sophistication in epidemiology.2
The overwhelming body of the scientific literature on psychosocial risk ignores fundamental methodological issues. Taking this
statement further, one can say that psychosocial risk factors can be
addressed only in studies designed for that purpose. Recall bias, lack
of adjustment for disease-​specific factors or comorbidity, use of biased data sources, interviewer bias, and other issues have often been
ignored by researchers working in this area. Today, however, more
studies in this area fully acknowledge the need for such considerations in the search for possible psychosocial risk factors for cancer.
What Is a Risk Factor for Cancer?
Researchers on psychosocial risk factors for cancer should refer to
the guidelines for cancer causation published by the International
Agency for Research in Cancer (IARC). Since 1969, working groups
convened by the IARC have assessed the degree of evidence for the
carcinogenicity to humans of some 800 biological, physical, chemical, and occupational factors and have ranked risk factors for cancer
according to the degree of evidence for causality. Psychological factors have not been reviewed in this context, but a brief review of
psychological factors associated with cancer was included in another IARC publication on cancer prevention and control in 1990.3
No conclusion was reached about the degree of evidence, but it was
stated that future epidemiological studies should include standardized instruments and data on potential confounders to be credible.
The evaluation of psychosocial factors in the causation of cancer
must be addressed in the context of certain methodological problems, which are summarized briefly to follow on the basis of the preamble to the IARC Monographs.3
First, the study population, disease, and exposure should have
been well defined by the authors. Cases of disease in the study population should have been identified in a way that was independent of
the exposure of interest—​in this case, the psychological factor. The
exposure should have been assessed in a way that was not related to
disease status.
Second, the authors should have taken into account other variables that can influence the risk for disease and that might have
been related to the exposure of interest. Potential confounding by
such variables should have been dealt with either in the design of
the study, such as by matching, or in the analysis, by statistical adjustment. In cohort studies, comparisons with local rates of disease
may or may not be more appropriate than those with national rates.
Internal comparisons of frequency of disease among individuals at
different levels of exposure are also desirable in cohort studies, as
they minimize the potential for confounding related to the difference in risk factors between an external reference group and the
study population.
Third, the authors should have reported the basic data on which
the conclusions are founded, even if sophisticated statistical analyses
were employed. At the very least, they should have given the numbers of exposed and unexposed cases and controls in a case–​control
study and the numbers of cases observed and expected in a cohort
study. Further tabulations by time since exposure began and other
temporal factors are also important. In a cohort study, data on all
cancer sites and all causes of death should have been given, to reveal
the possibility of reporting bias. In a case–​control study, the effects of
investigated factors other than the exposure of interest should have
been reported.
CHAPTER 5 Psychosocial Factors
Finally, the statistical methods used to obtain estimates of relative
risk, absolute rates of cancer, confidence intervals, and significance
as well as the methods used to adjust for confounding should have
been clearly stated by the authors.
When an agent is discussed by the independent working groups
convened by the IARC, evidence from studies in humans and experimental animals is evaluated together, and the strength of the mechanistic evidence is also characterized. The groups then decide on the
strength of the association between the exposure under review and
carcinogenicity. An agent is assigned to one of five groups:3
Group 1: The agent is carcinogenic to humans.
Group 2A: The agent is probably carcinogenic to humans.
Group 2B: The agent is possibly carcinogenic to humans.
Group 3: The agent is not classifiable as to its carcinogenicity to
humans.
Group 4: The agent is probably not carcinogenic to humans.
These considerations should be of interest to clinicians and researchers working in the field of psychosocial risk factors for cancer.
They stimulate attention to the design and interpretation of scientific studies and form part of the discussion of the current state of the
art in this intriguing area of research.
Research on Psychosocial Risk Factors for Cancer
The three psychosocial factors that have been most rigorously
studied in investigations of psychosocial cancer risks are major life
events or stress, depression or depressive mood, and personality or
personality traits. The commentary in this chapter does not represent a systematic review; it covers only studies conducted as prospective or retrospective cohort studies and case–​control studies
in which the information on psychosocial variables was collected
independently of the outcome, thereby reducing the possibility of
selection and recall bias. The findings of some of the best-​designed
studies published since 2000 are summarized briefly to follow.
Major Life Events and Stress
Numerous studies have investigated the association between major
life events, stress in daily life, or work-​related stress and the risk for
cancer. Breast cancer has been a focus in this research tradition.
With regard to work-​related stress, a large Finnish prospective cohort study of 10,519 women aged 18 years or more investigated the
relation between stress in daily activities and breast cancer.4 Daily
stress was assessed twice, in 1975 and 1981, by a self-​administered
questionnaire, and study subjects were divided into three groups: no
stress (23% of women), some stress (68%), and severe stress (9%).
The authors identified 205 incident cases of breast cancer by linkage
to the nationwide, population-​based cancer registry and observed
that the hazard ratio for breast cancer in women with “some stress”
was 1.11 (95% confidence interval [CI], 0.78–​1.57) when compared
with women with “no stress.” For women with “severe stress,” the
hazard ratio for breast cancer was 0.96 (95% CI, 0.53–​1.73) when
compared with those with “no stress.” The analysis included detailed
information on reproductive factors, anthropometrics, and lifestyle.
Neither shifting the cutoff point for stress nor restricting the analysis
to women who reported the same level of stress at the two measurements altered the results.4
The same group investigated the same hypothesis in a cohort of
10,808 women sampled in the Finnish Twins Registry and obtained
information on exposure to life events by using a standardized life
event inventory.5 They examined the effect of accumulation of life
events, placing emphasis on events experienced five years before
completion of the questionnaire. They observed that the experience
of divorce or the death of a husband was followed by a significant
twofold increase in the hazard ratio for breast cancer; the death of
a close relative or friend also significantly increased the risk by almost 40%. The analysis included some information on reproductive
factors, anthropometrics, and lifestyle. It is notable that the authors
investigated the effect of cumulative exposure to life events.5
In the Nurses’ Health Study of 69,886 women aged 46–​71 at baseline in the United States, the women answered questions on informal
caregiving.6 The authors hypothesized that hours and self-​reported
levels of stress from informal caregiving would be associated with
breast cancer incidence. A total of 1,700 incident cases of breast
cancer were identified between 1992 and 2000, in which period the
women reported caregiving twice, in 1992 and 1996. The analysis included information on reproductive factors, family history of breast
cancer, psychosocial factors such as depressive symptoms, social
network and self-​reported level of stress, anthropometrics, and lifestyle factors. The authors did not find that stress due to caregiving
increased the risk for breast cancer.6
Two reports based on the Nurses’ Health Study in the United
States and the Danish Nurse Cohort study of job stress and risk for
breast cancer found no increase in the risk of women who reported
high levels of strain in their daily working lives.7,8 Both studies were
conducted as cohort studies, with morbidity from breast cancer as
the outcome and adjustment for a number of factors of relevance for
breast cancer risk. The Danish study also investigated the association
between stress and stage of disease at diagnosis but did not find that
stress affected the prognostic characteristics of disease.
More recent studies that included carefully planned follow-​up
in cohorts with detailed information on other potential risk factors
also do not find that stress causes cancer. In a cohort of 84,334 members of the Women’s Health Initiative in the United States, a total of
2,841 invasive breast cancer cases were observed from an average of
7.6 years of follow-​up. One stressful life event was associated with
breast cancer; however, risk decreased with each additional stressful
life event.9 In a cohort of 11,467 women in the United Kingdom, a
total of 313 cases of incident breast cancer was observed. The authors reported no association with these cases and the reporting of
a summary of social adversities adjusted for well-​known risk factors
for breast cancer.10
Of interest to this discussion is a study that included members
of the Danish resistance movement during the German occupation
of Denmark between April 9, 1940, and May 5, 1945. Their resistance included illegal press activities, intelligence services, collection
of parachuted containers of weapons, sabotage of factories and railways valuable for Germany, and operation of illegal boats to Sweden
(for Danish Jews in October 1943). Between June 1943 and liberation, 1,547 male members of the resistance movement were arrested,
interrogated, exposed to severe mental and physical strain, and deported to German concentration camps as political prisoners. The
survivors continued to have excess somatic and mental morbidity.11
37
38
SECTION I Factors in Cancer Risk and Prevention
Among all male political prisoners (n = 1,547), slightly higher cancer
incidence and mortality than national rates were found, driven
mainly by increased ratios for smoking-​or alcohol-​related cancers.
The study had complete information on exposure status and follow-​
up for cancer incidence and death at the individual level for the entire study period.12
In terms of prognosis, a meta-​analysis found that stressful life
experiences before the diagnosis of cancer were associated with
shorter survival among cancer patients, albeit the effect was small
(hazard ratio [HR] 1.15; 95% CI, 1.06–​1.24).13 After the diagnosis,
stress experienced by cancer patients is influenced by numerous factors, stemming from before the diagnosis, over the diagnostics and
treatment of cancer, to the immediate and late somatic and psychosocial effects of cancer and its treatment. At any given time, there
is likely to be an increased risk for late detection of recurrence and
mortality determined by multiple risk factors, if a patient is stressed
across all meanings of this word. For several cancers, it is known that
clinical depression, which can be detected in almost 20% of cancer
patients within the first 5 years after diagnosis, must be connected to
the exposures provided by stress associated with the cancer trajectory as such. It is quite difficult to disentangle the multiple sources
and determine a causal relationship not confounded residually.
Cancer-​specific, somatic, and social circumstances play a role in this
effect. In light of the results within depression or personality traits as
prognostic factors in cancer, stress may also act as a prognosticator.
However, not many studies have been published in this area.
In summary, very few of the large population-​based studies in
which information on exposure is collected independently of scientific hypotheses found evidence that work-​related stress or major
life events are associated with an increased risk for cancer. Although
a few well-​designed studies have shown an increased risk,5,12,14 the
strong consistency among the presumably unbiased studies indicates that explanations for the elevated risk may include selection
bias, residual confounding, or chance. This conclusion comes close
to the overall conclusion in several reviews.15,16 However, the publication and frequent citation of a review in 2008, which included
some debatable criteria, illustrates how much belief and methodological decisions in reviewing scientific literature also influence
the judgment of the association between stress and cancer risk and
prognosis.13 The review found that stress-​related psychosocial factors, but not stressful life experiences or chronic or daily stress, were
related to cancer incidence. This extensive review and meta-​analysis
has been widely cited despite the inclusion of research that has been
discredited because the data may be flawed, a number of methodological mistakes in the entire construction of the analytical model,
lack of controls in a high number of the studies often underpowered
to detect the association, and the use of quite heterogeneous indicators of stress.17
Depression and Depressive Mood
Another potential psychosocial risk factor that has been widely investigated is depression or depressive mood. In a nationwide Danish
cohort study of the cancer risk of patients hospitalized for depression, all 89,491 adults who had been admitted to a hospital with depression, as defined in the International Classification of Diseases,
Eighth Revision,18 between 1969 and 1993 were identified. A total
of 9,922 cases of cancer were diagnosed in the cohort, with 9,434.6
expected, yielding a standardized incidence ratio of 1.05 (95% CI,
1.03–​1.07). The risk for cancer increased during the first year after
hospital admission, with brain cancer in particular occurring more
frequently than expected. When the first year of follow-​up was excluded, the increase was attributable mainly to an increased risk for
tobacco-​related cancers, with standardized incidence ratios for non-​
tobacco-​related cancers of 1.00 (95% CI, 0.97–​1.03) after 1–​9 years
of follow-​up and 0.99 (95% CI, 0.95–​1.02) after 10 or more years of
follow-​up. These findings provide no support for the hypothesis that
depression independently increases the risk for cancer, but they emphasize the deleterious effect that depression can have on lifestyle.18
In a Dutch prospective follow-​up study of 5,191 women living in
Eindhoven and born in the Netherlands between 1941 and 1947, all
the participants answered a questionnaire about the presence of depressive symptoms measured on the Edinburgh Depression Scale.19
The outcome was morbidity from cancer recorded in the regional
cancer registry, which reported incident breast cancer cases up to
five years after the questionnaire screening. The analyses were adjusted for information on 15 demographic, medical, and lifestyle
factors known to be associated with the risk for breast cancer. Breast
cancer was diagnosed in 58 women during the follow-​up period,
yielding an odds ratio of 0.29 (95% CI, 0.09–​0.92), which suggested
that depressive symptoms may be protective against breast cancer.19
The same design was used in a study in Finland in which 10,892
women aged 48–​50 years at the time of inclusion were followed up
for breast cancer 6–​9 years later.20 The questionnaire included items
on depression, personality traits, attitudes toward illness, life events,
and health history. The incident cancer cases were obtained from
the nationwide Finnish cancer registry, which has almost complete
population-​based coverage. The multivariate analysis controlled for
socioeconomic factors, family history of cancer, parity, and health
behavior, and identified a nonsignificant increased risk of 1.15 (95%
CI, 1.0–​1.28) for breast cancer among women aged 50–​59 when
compared with the general population. There was no evidence that
depression, anxiety, cynical distrust, or coping increased the risk for
cancer.20
A large prospective study was conducted of the association between depressive symptoms as measured by the Mental Health
Index (MHI) and risks for colorectal cancer and colorectal adenomas.21 Women (who were all part of the Nurses’ Health Study) who
scored between 0 and 52 on a 0–​100 scale were defined as having significant depressive symptomatology. A total of 33 of the 400 cases of
colorectal cancer filled this definition, as did 45 of 680 cases of distal
adenoma. The authors created other categories across the range of
MHI scores and reported a nonsignificant elevated risk of 1.43 (95%
CI, 0.97–​2.11) for colorectal cancer in women with the highest score
on the index, with a stronger association in overweight women.
Depressive symptoms did not increase the risk for adenomas.21
A large population-​based record-​linkage study in the Oxford
National Health Service region in the United Kingdom included
people who had been admitted to hospitals for depression or anxiety.22 A reference cohort of 525,436 persons was constructed by
selecting records for admission for various other medical and surgical conditions as “controls.” The outcome was identified as either
death from cancer or hospital care for any cancer. People who had
the cancer at the first recorded admission for the psychiatric disorder
or a comparison condition were excluded to avoid misclassification.
CHAPTER 5 Psychosocial Factors
The authors did not find an overall increase in the risk for cancer
in either the 27,818 persons with depression or the 24,292 persons
with anxiety. When the first year of follow-​up was excluded, the relative risk for lung cancer was significantly increased in both cohorts
(1.30; 95% CI, 1.14–​1.48 in the depression cohort and 1.21; 95% CI,
1.03–​1.36 in the anxiety cohort).22
A study from Taiwan using data from the National Health
Research Institute identified all 8,419 newly diagnosed depression
patients in the period 2000–​2002 and compared the risk for cancer
with all 67,352 (case/​control ratio, 1/​8) other cases claiming insurance but with no diagnosis of depression.23 The authors report no
increased risk for cancer in this study adjusting for gender, age, occupation, urbanization, and comorbidity.
Another study from Taiwan reported an increased risk for cancer
in a cohort of 778 patients hospitalized for depression in the time
period 1998–​2003, together with 3,890 matched persons from the
background population who had undergone minor abdominal
surgery.24 The study found 61 cases of cancer among the severely
depressed cohort members, finding significantly increased hazard
ratios for gastrointestinal, genitourinary, and the group of “other”
cancers. The small numbers and relatively broad categories make inference difficult.
In terms of whether depression affects prognosis, a study including 45,325 Danish women with early breast cancer found that
women who had previously been treated for depression (measured
as antidepressant use) were at significantly greater risk of receiving
nonguideline treatment (odds ratio [OR] 1.14; 95% CI, 1.03–​1.27),
as well as significantly greater risk of mortality (overall HR 1.21; 95%
CI, 1.14–​1.28; breast cancer–​specific HR 1.11; 95% CI, 1.03–​1.2).25
The analyses controlled for sociodemographics and important clinical factors (comorbidity, menopausal status, tumor size, positive
axillary lymph nodes, estrogen receptor status, type of surgery, and
treatment received). This study found that a prior depression may
affect the cancer treatment received.
A meta-​analysis of 76 prospective studies found that depression,
measured as a diagnosis of depression or depressive symptoms assessed in questionnaires, was a significant predictor of cancer mortality, albeit the effect was relatively small (average effect size 1.17;
95% CI, 1.12–​1.22).26
In summary, in most of the studies in which total cancer risk was
assessed, no statistically significant increase related to depression
was seen, or increases were seen in only some strata. Increased risks
were often observed for smoking-​associated cancers such as lung
cancer. Thus, it is the lifestyle of depressed people that is probably
the most straightforward explanation for the positive findings in
some studies, although a depressive component cannot be excluded.
Further, depression may be associated with survival after a cancer
diagnosis.
Personality Traits
A variety of personality traits have been investigated in relation to
cancer incidence and progression. In a large Finnish study based
on the aforementioned Twins Cohort, 12,032 women answered
questions about life satisfaction and neuroticism in 1975 and 1981.
During the 21 years of follow-​up, 238 cases of breast cancer were
identified in the Finnish Cancer Registry. The authors reported no
association between the measures of life satisfaction, neuroticism,
and the risk for breast cancer. Subsequent nested case–​cohort analyses and analyses that included changes in the levels of neuroticism
and life satisfaction at the two times led the authors to conclude that
there was no evidence that breast cancer is more likely to occur in
unhappy, dissatisfied, anxious women.27 This finding was confirmed
in a large study of Swedish and Finnish twin cohorts including close
to 60,000 persons. The authors observed a risk close to unity for any
cancer (HR 0.99; 95% CI, 0.98–​1.01 for extraversion, and HR 1.00;
95% CI, 0.99–​1.02 for neuroticism).28
A smaller prospective cohort study in Germany of 5,114 women
and men aged 40–​65 measured mortality from and incidence of
cancer.29 A number of personality scales were included in a questionnaire, and participants were followed up for a median of 8.5 years.
During this time, 240 persons developed a cancer or died from the
disease. The authors reported no association between the personality measures and cancer occurrence after adjustment for lifestyle,
comorbidity, and family history of cancer.
A large prospective cohort study investigated the Japanese concept of ikigai (something to live for, the joy and goal of living, or the
happiness and benefit of being alive), as well as decisiveness, ease of
anger arousal, and perceived stress. In a cohort of 29,098 Japanese
women aged 40–​79 years, a total of 209 cases of breast cancer were
identified from either mortality records or diagnostic information.
After a mean follow-​up of 12.8 years, none of the traits/​factors were
associated with breast cancer incidence.30
In a cohort of 9,705 women in Nijmegen, the Netherlands, the
authors investigated the association between 10 personality traits as
measured with the Self-​Assessment Questionnaire-​Nijmegen (SAQ-​
N), a questionnaire developed by this group.31 The participation rate
was 34%, which somewhat limits the conclusions. The medical risk
factors included in the analysis were family history of breast cancer,
parity, age at birth of first child, estrogen use, age at menarche, and
body mass index. The authors reported no association between any
of the personality traits and the risk for breast cancer.
Pooling data from a randomized controlled trial nested in the
Whitehall study, with 42 years of follow-​up and 219 cancer deaths,
neither neuroticism nor extroversion were associated with cancer-​
specific mortality.32 Analyses were adjusted for health status, health
behaviors, and socioeconomic factors.
Recently, an individual-​participant meta-​analysis pooled data
from six prospective cohorts of the association between personality
traits in the Five Factor Model (extraversion, neuroticism, agreeableness, conscientiousness, and openness to experience). The study
investigated both the incidence and mortality as outcomes in 42,843
cancer-​free men and women at baseline. A total of 2,156 cancer
cases were diagnosed during a mean follow-​up of 5.4 years and 421
cancer deaths identified in a subcohort with available cause-​specific
mortality information. None of the personality traits were associated with the incidence for cancer overall or for six specific cancers
(lung, colon, prostate, breast, skin, and leukemia/​lymphoma).33
Further, for 21,835 participants with cause-​specific mortality information and 421 cancer deaths, none of the traits were associated
with survival.33
In summary, these studies do not point to an association between personality traits and the risk for cancer, in particular breast
cancer, as well as cancer survival. This statement is based on well-​
designed prospective studies that covered fairly large populations,
39
40
SECTION I Factors in Cancer Risk and Prevention
clear definitions of the “exposure,” an acceptable length of follow-​
up, and adjustment for some factors that might be confounders. The
outcome was based on either information on morbidity or close
follow-​up of mortality to exclude misclassification. Furthermore,
the hypothesis was established independently of the cohort formation, and none of the data sources were biased by interviewers or
information to cohort members. The use of administrative sources
almost completely excludes selection bias.
Socioeconomic Position
When discussing the effects of psychosocial factors on cancer, socioeconomic position should also be mentioned. While this is not a factor
that per se is thought to cause cancer directly, it is a psychosocial factor
that may have substantial indirect effects (e.g., through health-​and
care-​seeking behaviors). In a nationwide register-​based study among
3.22 million Danish residents that used individual-​level data on socioeconomic position, rather than data collected at the local/​area level,
individuals with lower education were found to be at significantly increased risk of a range of cancers, particularly those related to lifestyle
factors, including tobacco.34 Conversely, individuals with higher education were at significantly increased risk of malignant melanoma,
breast, and prostate cancers. However, the same study found that, generally, cancer patients with lower education had lower survival than
cancer patients with higher education. Remarkably, these results stem
from a country with free universal health care, highlighting that the
inequality observed is not based on unequal access to care. A follow-​
up study revealed that the gap in survival between patients in the
lowest compared with the highest income brackets was stable or had
increased for most cancers,35 illustrating that the problem remains despite substantial advances in treatment methods.
Mechanisms
A number of investigations have been conducted of the possible
pathways between mind factors and the risk for cancer. These now
form a complete research area, named psychoneuroimmunology,
which is an important component, with human studies, of a new
field that bridges biology, epidemiology, and cancer risk research.
It has been hypothesized that psychosocial factors act like stress
through the hypothalamic-​pituitary-​adrenal axis in a complex feedback system that adversely affects overall immune function. It has
been further hypothesized that the immune system is involved in
eliminating mutated cells, and it is possible that reduced immunity
could lead to more rapid development of cancer. Furthermore, psychosocial factors may also act as a promoter of faulty DNA repair
and an inhibitor of apoptosis and DNA repair. These systems and
changes in function are suggested to be precursors of certain types
of cancer, such as hormonal and hematological-​lymphatic cancers.
Despite the plausibility of these mechanisms, little or no epidemiological evidence has arisen during the past 50 years of research
on psychosocial risk factors in cancer. The association between
diseases characterized by immune deficiency and breast cancer is
weak, although several studies have demonstrated a reverse causation.36,37 In a large Scandinavian case–​control study, however, a
personal or family history of certain autoimmune conditions was
strongly associated with an increased risk for Hodgkin’s lymphoma.
The association between both personal and family histories of sarcoidosis and a statistically significantly increased risk for Hodgkin’s
lymphoma suggests a shared susceptibility for these conditions.38
This points to the possibility that mechanisms linking psychosocial
factors with cancer differ, depending on the cancer site.
Alternatively, the mechanism may be driven more by changes in
behavior. It is well known that people under severe stress, suffering
from depression, or expressing certain personality traits differ from
others with regard to health behavior. This is true for smoking, alcohol consumption, diet, and physical activity. Some studies have
confirmed this pattern, finding higher risks for cancers associated
with these behaviors.18,39,40 Thus, our understanding of psychosocial
risk factors might have a larger public health impact if we focused
on changes in the lifestyles of people exposed to stress or major life
events who exhibit certain personality traits or experience depression or depressive mood.
Conclusion
During the past 15 years, more than 15 reviews of psychosocial risk
factors for cancer have been published. The conclusions reached go
in two directions: one group of reviewers find small or putative associations, while the other group find no or only a small etiological
fraction reserved for psychosocial risk factors because of methodological limitations in the studies reviewed.
Any conclusion must take into account the quality of the studies,
whether pro or con. From a methodological viewpoint, it is incorrect to use a case–​control design, as such studies have serious problems that are exacerbated in this area of research, such as recall bias.
This design can be used only if information on exposure is obtained
from administrative sources, in which information is collected for
purposes that have nothing to do with the hypothesis of the study, as
illustrated by many of the studies cited earlier.
In terms of prognosis, the evidence is less clear. We have some evidence that personality traits do not contribute to increased risk of
dying from cancer, while depression seems to have some effects on
mortality (much like in the general population). For stress, too few
studies have yet been conducted for any firm conclusions, but the
importance of stress for health behaviors in particular might support the notion that stress during the course of cancer will affect
cancer outcomes. Disentangling the effects of prognosis on stress
and other psychosocial factors will likely prove a substantial challenge to answering this question.
In conclusion, psychosocial factors such as stress, depression, and
personality traits do not appear to play a major role in cancer causation. All the studies published so far have limitations, making it
difficult to reach a definitive decision about causality. However, the
majority of well-​designed studies taking into account methodological issues of relevance for the field do not confirm that the mind
causes cancer.
Future Directions
Among the requirements for future research are prospective data,
clearer definitions of exposure, and repeated measures during
CHAPTER 5 Psychosocial Factors
follow-​up; we also need longer follow-​up to identify more cases and
to investigate psychosocial factors with the same rigorous methods
used in other areas of research. It has also been noted that this field
of research would be more comprehensive if not just one but several
psychosocial factors were included.16 We must include information
on other well-​defined risk factors for the disease under study to find
out how they confound or interact with each other in relation to
the association investigated. This is being recognized in more and
more studies. The socioeconomic aspects of the exposure under
study, comorbidity, and health behavior are new aspects of our understanding of the association between mind and cancer risk. We
must consider carefully whether health behavior is an intermediate
rather than a confounding factor, as this will have profound implications for our understanding of the possible association between
psychological factors and the risk for cancer.
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6
Viral Cancers and Behavior
Susan T. Vadaparampil, Lindsay N. Fuzzell, Shannon M. Christy, Monica L. Kasting,
Julie Rathwell, and Anna E. Coghill
Introduction
The International Agency for Research on Cancer (IARC) currently
classifies seven different viruses as class I carcinogens, defined as
agents with convincing evidence of carcinogenicity in humans. This
includes six viruses that directly cause cancer (Figure 6.1):1 human
papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus
(HCV), Epstein-​Barr virus (EBV), human herpes virus 8 (HHV8),
and human T-​cell lymphotropic virus type 1 (HTLV-​1), and one virus
that indirectly contributes to cancer by impairing the immune system’s
ability to fight infections: human immunodeficiency virus (HIV).
Notably, approximately one in every six cancers that occur globally is
attributable to pathogens, and three of the top four contributors to this
infectious cancer burden are viruses, namely HPV, HBV, and HCV.
These three agents alone play a role in the development of more than
1.2 million new cancers each year and are responsible for nearly 50%
of the infectious cancer burden in the United States (U.S.).
We focus on these three viruses, along with HIV, to illustrate
the intersection between virus-​associated cancers and the field of
psycho-​oncology. They are highlighted in this chapter not only because of their disproportionate cancer burden but also because lifestyle and health-​seeking behaviors are related to both the acquisition
VS
Human Papillomavirus
VT
Hepatitis B
ST
Hepatitis C
Epstein-Barr virus
10
00
00
20
00
00
0
10
00
0
HTLV-1
30
00
00
40
00
00
50
00
00
60
00
00
V: vaccination
S: screening
T: treatment
HHV8
Annual case count (Plummer, Lancet 2016)
Figure 6.1. Global burden of cancers attributable to viruses and
available cancer prevention or treatment options.
Figure 6.1 created based on data presented in Plummer M, de Martel C, Vignat J,
Ferlay J, Bray F, Franceschi S. Global burden of cancers attributable to infections in
2012: A synthetic analysis. Lancet Global Health. 2016;4(9):e609–​e616.
of these viruses and the prevention of their associated cancers. For
example, HPV is sexually transmitted, and persistent infection
status is strongly linked to an individual’s lifetime number of sexual
partners. Likewise, one route of transmission for HBV and HCV is
the exchange of bodily fluids (e.g., blood), such that risk of infection is greatly increased among injection drug users. In addition to
behaviors that can impact rates of viral acquisition, health-​seeking
practices must also be considered since effective prevention strategies exist for cancers attributable to each of these agents, including
(1) primary prevention through vaccination against HBV and HPV,
(2) secondary prevention through screening for evidence of HCV
in blood or presence of high-​risk HPV and related premalignant lesions at the site of infection, and (3) tertiary prevention through appropriate use of anti-​viral medication to control hepatitis. Although
the correlation between certain high-​risk behaviors (e.g., injection
drug use) and a lower likelihood of regular health-​seeking behavior
may complicate cancer prevention efforts, it may also offer opportunities for targeted interventions to impact behavior with the goal
of preventing these virus-​associated cancers.
Each of the virus-​attributable cancers listed in Figure 6.1 occurs
more frequently in HIV-​infected patients because immunosuppression interferes with normal host control of infections. Relevant to
this chapter, the high-​risk lifestyle behaviors that increase the risk of
acquiring HPV, HBV, or HCV, including a high number of lifetime
sexual partners and injection drug use, also markedly increase the
risk of HIV infection. This overlap in risk factors further contributes
to the high rates of hepatitis-​related and HPV-​associated cancers in
the U.S. HIV population, including elevated rates of liver and anal
cancers.
Human Papillomavirus
Epidemiology
HPV is the most common sexually transmitted infection both globally and in the U.S. Most sexually active individuals (80%) will be
infected with at least one HPV strain—​also referred to as HPV
type—​during their lifetime.2 More than 40 HPV types are transmitted through intimate contact (i.e., vaginal, anal, or oral sex or
44
SECTION I Factors in Cancer Risk and Prevention
skin-​to-​skin genital contact).2 Nearly 80 million individuals in the
U.S. have a current HPV infection, with approximately 14 million
individuals newly infected each year.2
Natural History
Most HPV infections are asymptomatic. HPV types are classified as
either low risk or high risk based on their oncogenic potential. Low-​
risk HPV types can cause anogenital warts. Two low-​risk HPV types
can also cause recurrent respiratory papillomatosis. Thirteen high-​
risk HPV types have been identified as carcinogenic to humans;
HPV 16 and HPV 18 cause the majority of HPV-​related cancers.
In the U.S. approximately 34,800 HPV-​attributed cancers are diagnosed annually.2 Although most HPV infections clear on their own
within two years, persistent infections from oncogenic HPV types
over years (and often decades) can progress into oropharyngeal (affecting the throat, tonsils, and/​or base of the tongue), cervical, anal,
penile, vaginal, and vulvar cancers.2 Indeed, nearly all (99%) cervical
cancers, more than 90% of anal, and the majority of oropharyngeal
(~70%), vaginal (75%), vulvar (~70%), and penile cancers (>60%)
are caused by HPV.3
Prevention
The majority of the U.S. HPV-​related cancer cases each year (92%)
are caused by one of the viruses currently included in the HPV vaccine and could be prevented if males and females 9–​26 years old
received the HPV vaccine.4 HPV vaccination has been routinely recommended for U.S. females since 2006 and males since 2011. The
9-​valent vaccine, the only HPV vaccine currently used in the U.S.,
prevents infection from nine HPV types (6, 11, 16, 18, 31, 33, 45, 52,
and 58), seven of which are oncogenic.4
In the U.S., the 9-​valent vaccine is approved for administration
between the ages of 9 and 45; two vaccine doses are recommended
for individuals aged 9–​14, and three for individuals aged 15 and
older or who are immunocompromised.2 The HPV vaccine yields
the strongest immune response when delivered in early adolescence and prior to sexual experience. The Advisory Committee on
Immunization Practices (ACIP) recommends that males and females through age 26 years receive “catch-​up” vaccination if they did
not receive the vaccine during adolescence as they may not have been
previously exposed to all of the HPV types for which the vaccine
offers protection.5 The ACIP recommends that individuals between
ages 27 and 45 not previously vaccinated against HPV discuss with
their health care provider whether they may benefit from vaccination.5 As of 2018, an estimated 68.1% of U.S. adolescents aged 13–​17
had initiated the vaccine series and 51.1% were up-​to-​date with the
vaccine series (either two or three doses completed, depending on
the age at which the series was started).6 These rates fall well below
the Healthy People 2020 goal of 80% vaccination uptake.
Provider recommendation remains the strongest predictor of
HPV vaccine uptake.6 However, providers often fail to utilize strong,
timely, and consistent recommendations. Systems-​wide intervention strategies such as the inclusion of electronic medical prompts to
remind providers to offer the HPV vaccine to patients, as well as automated reminders to parents/​patients to promote next dose receipt,
are strategies used successfully in prior interventions.7 Furthermore,
studies have demonstrated low levels of HPV-​related knowledge in
multiple U.S. subgroup populations, including those diagnosed with
HPV-​related cancers.8–​10 Finally, notable disparities in HPV vaccine
uptake exist based on geographic location and insurance status.6
Thus, multilevel interventions addressing provider, patient, and systems levels will be needed to improve HPV vaccine series completion rates.7
Sexual activity is associated with HPV infection;11 thus, behavioral interventions to support sexual health may reduce some
risk factors associated with HPV infection. In addition, current
smokers are at increased risk for higher HPV viral load, cervical
precancers, active oral HPV infections, and cervical and oropharyngeal cancer incidence, as are individuals exposed to secondhand smoke (including during childhood). Thus, in addition to
vaccination and reducing risk of sexual transmission, reducing
tobacco exposure and treating current tobacco use is another important means of preventing the development of the two most
common HPV-​related cancers. Additional information about tobacco cessation treatment can be found in Section I, Chapter 1,
and additional information about HPV vaccination can be found
in Section II, Chapter 8.
Screening and Early Detection
Currently, cervical cancer screening is the only recommended
screening for HPV-​related cancers. Regardless of HPV vaccination
status, cervical cancer screening is recommended beginning at age
21 and includes Pap testing alone or in combination with HPV-​
DNA testing. In-​home HPV self-​sampling tests may address logistic
(e.g., time, transportation, geographic, cost) and psychosocial (e.g.,
modesty, discomfort) barriers to in-​clinic cervical cancer screening.
Appropriate follow-​up and treatment following an abnormal Pap or
HPV test are critical to cervical cancer prevention or early detection.
See Section II, Chapter 8 for additional information about cervical
cancer screening and Section XI, Chapter 78 for information about
screening for HPV-​related cancers within sexual and gender minority populations.
Treatment
There is currently no treatment to directly combat HPV infection.
However, within two years, 90% of HPV infections resolve on their
own.2 For those that result in cellular changes, such as cervical dysplasia, or anogenital warts, there are several treatments (e.g., loop
electrosurgical excision procedure, topical medications, surgery) to
directly combat abnormal cytology discovered by screening.
Viral Hepatitis
Viral hepatitis includes hepatitis A, B, C, D, and E.12 Although distinct
viruses, each impacts the liver. More than 1 million deaths worldwide are caused by infections from viral hepatitis annually. Chronic
infections with HBV and HCV lead to prolonged inflammation and
cell damage in the liver that increase risk for hepatocellular carcinoma (HCC), a cancer with increasing mortality rates in the U.S.
Hepatitis B Virus
Epidemiology
HBV is a DNA virus that infects an estimated 21,000 people in the
U.S. each year.13 Approximately 3–​5% of HBV-​infected adults and
up to 95% of HBV-​infected infants go on to develop a chronic infection,13 resulting in 850,000 individuals in the U.S. and 257 million
CHAPTER 6 Viral Cancers and Behavior
individuals globally living with HBV. Two out of three individuals
chronically infected with HBV are unaware of their infection status.
Natural History
Infection with HBV is generally asymptomatic. Most infections in
adults are self-​limited and elicit durable immune responses. Acute
infections have an incubation period of 4–​10 weeks, after which
the infection typically resolves with little liver damage. HBV is able
to survive for at least seven days outside of the body, and can be
transmitted in multiple ways, including sexually, through contact
with infected blood (e.g., sharing needles, unsanitary tattooing/​
piercing, needle-​stick injury, use of contaminated razors), and from
mother to child at birth. Although many individuals are asymptomatic, some may experience nausea, vomiting, jaundice, fever, fatigue, loss of appetite, abdominal pain, joint pain, dark urine, and
clay-​colored stool.
Of the less than 5% of adults that develop a chronic infection,
15–​25% of those progress to cirrhosis or HCC. The time between
HBV infection and HCC development varies but is generally between 10 and 40 years. HBV reactivation or HBV-​related disease
progression is related to other hepatotoxic factors including alcohol
consumption, HCV or HIV coinfection, and immunosuppression.
Unfortunately, since 2014, increasing rates of acute HBV infection
have been observed; in the U.S. these rates are attributed to increased
rates of injection drug use associated with the opioid epidemic. An
estimated 14,000 deaths each year in the U.S. are due to chronic HBV
infection.13 Worldwide deaths from HBV and subsequent cirrhosis
and HCC in 2015 totaled 887,000.14
Prevention and Screening
Vaccination remains the best method for preventing HBV infection
and the effective, three-​dose vaccination schedule for HBV is recommended by the U.S. Centers for Disease Control and Prevention
(CDC) for all children beginning at birth.13 In 2018, 92.1% of adolescents between the ages of 13 and 17 in the U.S. had received all
three doses.6 Other important prevention methods include use of
universal precautions in health care settings, screening of donated
blood, screening pregnant women for HBV infection (as children
born to infected mothers are at increased risk), consistent condom
use, and educating infected individuals on how to prevent HBV
transmission to others. HBV screening in the clinic is conducted
through a blood test to detect HBV antibodies.
Treatment
There is currently no effective medication to help resolve acute HBV
infection, and treatment involves only supportive care. For those
chronically infected, the majority require long-​term antiviral treatment to reduce the risk of liver disease and prevent transmission
to others. The preferred course of treatment varies by patient; the
American Association for the Study of Liver Diseases (AASLD) recommends antiviral therapy for immune-​active chronic HBV infection to reduce the risk of liver-​related complications.15 However,
the AASLD recommends against antiviral therapies for patients
with immune-​tolerant chronic HBV infection. Although side effects of antiviral therapy vary by medication and dose, they include
headaches, fatigue, fever, depression, and, rarely, lactic acidosis and
nephropathy.15 Patients who decline antiviral therapies are required
to complete regular bloodwork to monitor liver function and disease
progression. HBV can reactivate spontaneously and immunosuppressed individuals (e.g., cancer patients receiving chemotherapy
or other immunosuppressive therapies, individuals receiving organ
and/​or bone marrow transplantations, and those with HIV and/​or
HCV) are at increased risk for HBV infection reactivation.
Hepatitis C Virus
Epidemiology
HCV infects approximately 1.75 million people globally, with
41,000 new infections in the U.S. each year. Unlike HBV, up to 85%
of HCV infections become chronic. Approximately 2.4 million
people are currently chronically infected in the U.S., 50% of whom
are unaware of their infection status. Recent data show that 75% of
people infected were born between the years 1945 and 1965 (baby
boomers). Chronic infection with HCV results in an increased risk
of cirrhosis and HCC. Chronic HCV infection has also been associated with non-​Hodgkin lymphoma; however, those cases are rarer
manifestations of HCV infection and will not be discussed in this
chapter.
Natural History of Infection
HCV is primarily transmitted through contact with infected blood,
although there is a small risk of acquiring an infection through
sexual contact. While acute HCV infections are typically asymptomatic, some experience symptoms such as fever, abdominal pain,
and jaundice. An infection is considered chronic if a person has
detectable HCV RNA at least six months after an acute infection.
Chronic infections can persist for approximately 20 years without
causing any clinical symptoms, with serious health sequelae developing after approximately 30 years. Among the chronically infected, 10–​20% develop cirrhosis, which confers a 1–​5% annual risk
of developing HCC. Overall, HCV prevalence is higher in males
compared to females, and in people born between 1945 and 1965
as compared to other birth cohorts in the U.S. Within the baby
boomer cohort, non-​Hispanic black males have the highest prevalence. Factors associated with more rapid HCV-​related disease progression include older age, male sex, obesity, coinfection with HIV
and/​or HBV, and alcohol use. Targeted testing and treatment are
necessary to reduce the increasing rates of HCV-​related morbidity
and mortality.
Prevention and Screening
Prior to 2012, HCV testing was recommended for groups in the
U.S. considered high risk, such as persons living with HIV, those
who had ever injected illegal drugs, or individuals that had been
incarcerated. Other people at risk are those who received clotting
factor concentrates produced before 1987 or a blood transfusion
or organ transplant prior to 1992 (i.e., before blood products were
regularly screened for the virus), healthcare workers exposed to
infected blood (e.g., through a needle stick), and children born to
HCV-​infected mothers. In the U.S. in 2012, testing recommendations were augmented to also include one-​time testing for all people
born from 1945 to 1965, as baby boomers account for 75% of prevalent HCV cases. Unfortunately, testing rates are low, and a significant proportion of the baby boomer birth cohort remains unaware
of their HCV infection status, making it likely that the HCC burden
in the U.S. will continue to rise.
45
46
SECTION I Factors in Cancer Risk and Prevention
To achieve the World Health Organization goal of eliminating
viral hepatitis,12 there needs to be a significant focus on testing and
treatment of high-​risk populations as recommended by medical and
public health organizations. Such strategies include treating persons
who inject drugs, as well as implementing harm reduction interventions (e.g., needle and syringe exchange) to halt the spread of the
virus. Persons who inject drugs (PWID) are the group most likely to
acquire new HCV infections, and this is an ever-​growing population,
due in large part to the U.S. opioid epidemic. Up to 50% of PWID
have been exposed to HCV. This results in a bimodal age distribution of HCV cases, with one peak among people in their mid-​20s
(PWID) and a second peak among aging adults (baby boomer birth
cohort). Other populations with higher-​than-​average rates of HCV
prevalence are incarcerated and unsheltered homeless persons.
Despite available screening tests and treatment options, barriers
include cost and routine access to health care; this is particularly
challenging among patients at highest risk of infection (e.g., homeless, incarcerated, PWID). High-​risk persons may not disclose risk
behaviors for fear of stigma, and patients who have not engaged in
high-​risk behavior for decades may not identify themselves as being
at risk. Patients often rely on providers to recommend appropriate
tests, but providers may not be familiar with the screening guidelines. Finally, HCV testing is a two-​step process beginning with an
antibody screening, followed by an HCV RNA diagnostic test. Not
all patients who receive a positive antibody test return for confirmatory RNA testing. Depending on the population, 50–​60% of HCV
antibody–​positive individuals return for the confirmatory testing.
This problem could be ameliorated if health care systems implemented an automatic RNA reflex test if someone screens positive for
HCV antibody, but this has not been adopted in all practice settings.
Treatment
Unlike HBV, there is no vaccine to prevent HCV infection. However,
with the development of direct-​acting antivirals (DAAs) in recent
years, 97–​99% of HCV infections can now be cured. Cure is defined as sustained virologic response (SVR). DAAs have fewer side
effects than prior interferon-​based treatment regimens and can result in SVR with only 8–​12 weeks of treatment. However, SVR does
not confer protective immunity; thus, there is a risk for reinfection.
Reinfection rates are higher among PWID and those with HIV infection. One of the primary barriers to treatment among all populations is the cost of the medications, and policy-​level solutions are
needed to enable all HCV-​infected persons to be treated. Those who
have chronic HCV may need support for adherence to treatment regimens and ongoing surveillance.
Patients should be tested 12 weeks after completing therapy to determine whether they have achieved SVR. SVR is associated with reduced liver-​related morbidity and mortality. Patients with advanced
fibrosis require additional surveillance, with screening every six
months, as they are at a persistently higher risk for HCC.
HIV
Epidemiology
Approximately 1.1 million individuals in the U.S. are infected with
HIV. Unfortunately, this includes a notable percentage (~14%)
who are currently undiagnosed. Approximately 38,000 new HIV
infections still occur each year in the U.S., even in the era when effective HIV therapy is widely available. These infections are not equitably distributed in the population, with more than 50% of new
infections occurring in African Americans and two-​thirds in men
who have sex with men (MSM).
Access to HIV therapy has been remarkably effective at increasing
the life expectancy of the U.S. HIV population, with mortality rates
falling to less than 5 per 105 patients in the most recent CDC assessment. HIV-​associated deaths have dropped sharply since 1995.16
Current variation in HIV mortality patterns is likely a reflection of
health care access, with the proportion of U.S. HIV deaths in the
South increasing from less than 30% of the national total in the early
stages of the HIV epidemic to 53% more recently, in sharp contrast
to decreases in mortality rates in the West and Northeast regions of
the U.S.17
Natural History
HIV does not survive long outside of the body and requires human
T-​cells to replicate. The virus also can only be transmitted when
certain bodily fluids (e.g., blood, breast milk, fluids associated with
sexual intercourse) interact with mucous membranes. However, the
infection does not spontaneously clear once acquired, persisting for
the life of the host in CD4+ T-​cells. The most common modes of
transmission in the U.S. include receptive anal intercourse and injection drug use, although the likelihood of HIV transmission through
these routes is still highly dependent on an individual’s viral load.
The risk of HIV transmission is high during the acute phase (i.e.,
within 2–​4 weeks of infection), which is often accompanied by
spikes in viral load and flu-​like symptoms. Of note, the U.S. HIV
epidemic continues to accumulate new diagnoses because those
who are infected often are not aware of their HIV status. One
French study estimated that enrolling 75% of yet untreated people
living with HIV (PLWH) into highly active antiretroviral therapy
(HAART) to control viral load would decrease new diagnoses 10-​
fold.18 After the acute phase, patients persist (even untreated) for
an average of 10 years before signs of severe immunosuppression
indicative of acquired immunodeficiency syndrome (AIDS) manifest, including opportunistic infections and AIDS-​associated malignancies. However, if consistently treated with modern antiretroviral
therapy, patients are far more likely to survive without manifestations of AIDS for decades.
Infection with HIV increases the risk of cancer. HIV-​infected individuals develop AIDS-​defining cancers (ADCs) such as Kaposi
sarcoma (KS) and non-​Hodgkin lymphoma (NHL) at substantially higher rates than HIV-​uninfected individuals. Risk is also elevated for several non-​AIDS-​defining cancers (NADCs) including
Hodgkin lymphoma (HL), anal cancer, and lung cancer. The link
between HIV and cancer is largely attributable to the effects of immunosuppression. Since antiretroviral therapy to combat HIV and
restore patient immunity became widely available in the U.S. (1996),
not only has there been a marked decrease in AIDS-​related mortality,
but also rates of AIDS-​associated cancers have decreased sharply.
However, even in the HAART era, immunosuppression remains an
important risk factor for both ADCs and NADCs. In the most recent
(1996–​2012) assessment from the HIV/​AIDS Cancer Match Study, a
national linkage of state HIV and cancer registries, PLWH remained
at a higher risk of a range of cancers caused by infections when compared to the general U.S. population.19 This included approximately
CHAPTER 6 Viral Cancers and Behavior
3-​fold higher rates of liver cancer (associated with HBV and HCV)
and up to 19-​fold higher rates of anal cancer (associated with HPV).
Although the authors of the study acknowledge that risks for these
cancers have declined over time in PLWH, likely due to expansion
of effective HIV therapy, they also note that the persistence of elevated cancer risk warrants additional efforts at cancer prevention
and screening in this high-​risk population.19
Prevention
The risk of HIV infection is strongly linked to several behavior and/​
or lifestyle factors. The most effective way to eliminate risk of HIV is
to practice safe sexual behaviors. For example, correct and consistent
condom use can result in a 20-​fold decrease in HIV infection and
is 90–​95% effective for preventing transmission of the virus. HIV
transmission can also be reduced through avoidance of drug use
that involves needle sharing. Cities that have implemented syringe
service or needle exchange programs have decreased incidence of
HIV annually by 11%. In an occupational context, accidental needle
sticks or exposure to blood or other bodily fluids is associated with
a low risk of HIV transmission of 0.09–​0.30% on average. With
proper preventive health care procedures (e.g., personal protective
equipment, administrative and work practice controls) and treatment after possible exposure (postexposure prophylaxis [PeP] or
HAART), this risk can be effectively managed. Transmission from
mother to baby can also occur, but this can be prevented by ensuring
the mother’s awareness of her HIV status, having a cesarean rather
than vaginal birth, avoidance of breastfeeding, and HAART for the
mother and child.
For individuals at higher risk of HIV exposure, often in cases
where sexual partners are known or suspected to be HIV positive
or in PWID, a few treatments can be utilized for prevention. Pre-​
exposure prophylaxis (PrEP) involves daily medication to prevent
HIV in those at high risk of infection. Consistent, daily PrEP use
reduces the risk of HIV transmission through sexual contact by 99%
and reduces the risk of transmission from injection drug use by 74%.
Similarly, PeP can also be used preventively when an individual believes they have recently been exposed to HIV. PeP includes a daily,
28-​day course of HAART, begun within 72 hours of potential exposure to HIV. PeP use after occupational exposure to HIV has been
associated with an 81% reduction in HIV infection. Effectiveness
of PeP after nonoccupational exposure varies by study and is dependent upon factors such as timing of PeP initiation, medication
adherence, and continued exposure to HIV through ongoing risk
behaviors. For those already infected with HIV, HAART can lower
the viral load to undetectable levels and is regarded as a method of
preventing HIV transmission to others.
Early Detection and Screening
Awareness of HIV status can be increased through screening in clinical and nonclinical settings. HIV screening can be performed in
a lab via blood test, with rapid testing at home, or in a clinical or
nonclinical site via finger prick or oral fluid. Awareness of status can
reduce risky HIV sexual transmission behaviors by approximately
68%. The CDC recommends voluntary HIV screening for all adults
and adolescents (ages 13–​64) as a normal part of medical care.20
Guidelines specific to MSM suggest that those who are sexually active undergo annual screening.21 Other high-​risk groups for whom
annual screening is recommended include sexual partners of those
who are diagnosed with HIV, PWID and their sexual partners, and
those who exchange sex for money or drugs. Opt-​out testing should
be conducted for all pregnant women as part of their routine prenatal care, and repeat screening should be conducted for pregnant
women in certain areas.
Screening in nonclinical settings may be helpful for those who
do not routinely participate in medical care. Common nonclinical
settings include mobile testing units, churches, parks, community
centers, or syringe service programs. Testing in community settings
has successfully increased uptake of screening, is cost effective, and
is viewed positively by clients and providers.22 Couples interested in
“testing together” may also take advantage of screening in nonclinical or community settings.
Treatment
Antiretroviral therapy for HIV involves a combination of medications to slow the progression of the virus. HAART should be started
immediately upon HIV diagnosis and taken correctly and consistently (daily). Although HAART does not cure HIV, it can reduce
the viral load of HIV in the body to undetectable amounts. HAART
helps to preserve immune function and can keep patients healthy for
many years. However, if HAART treatment is not effectively maintained, viral suppression may not be achieved and progression to
AIDS becomes more likely, increasing the likelihood of opportunistic infections and HIV-​associated cancers. Medication adherence
is a major concern for many PLWH. Barriers include patient beliefs, psychosocial and mental health issues, cognitive barriers and
burden in understanding and adhering to complicated treatment
regimens, structural barriers (e.g., transportation, insurance, childcare, housing), side effects, and comorbid conditions. In addition to
consistent HAART use, HIV treatment includes regular viral load
monitoring, regular follow-​up care with a provider, and monitoring
of potential coinfections. Quality of life while living with HIV is relatively high with correct and consistent HAART use and continued
follow-​up care.
An estimated 22% of patients with a newly diagnosed HIV infection do not receive HIV-​specific medical care within at least a
month of their diagnosis. This, as well as incomplete retention in
medical care for patients who do initiate therapy, contributes to
the fact that only 62% of HIV-​infected patients achieve viral suppression, which is crucial to reducing the spread of the infection
and maintaining adequate levels of immunocompetence in people
living with HIV.
Implications for Psycho-​Oncology
Virus-​associated cancers may have different considerations with
respect to prevention, early detection, treatment, and survivorship
compared to other malignancies. For most viruses described in this
chapter, transmission is largely attributable to high-​risk sexual or
drug use–​related behaviors. The populations at greatest risk for infection (and subsequent health issues, including cancer) are often
from marginalized populations including racial and ethnic minority
groups, sexual and gender minority groups, and rural populations.
Additionally, there may be stigma associated with reporting risk behaviors to alert providers about possible exposure to a virus that is
associated with cancer risk.
47
48
SECTION I Factors in Cancer Risk and Prevention
Diagnosis with HPV, HBV, HCV, or HIV may invoke many emotions, often due to feared stigma or social consequence. For example,
receipt of a positive HPV-​DNA test and/​or an abnormal Pap test result
can result in distress, anxiety, and fear,23,24 as well as stigma, shame,
and self-​blame.25 Women with normal Pap test results who tested
HPV positive were more anxious than those who tested HPV negative.26 Distress levels may be highest at or near the time of initial diagnosis, and may decrease over time.24,27 Among individuals diagnosed
with an HPV-​related cancer, the concerns expressed are generally focused on the cancer itself rather than HPV as a cause of the cancer.
Because chronic HBV infection requires life-​long follow-​up, and
there is not an available curative treatment, there are significant implications for psychosocial outcomes. Even in the absence of cirrhosis or HCC, patients with chronic HBV infection report various
negative psychosocial symptoms related to their condition including
feelings of HBV-​related isolation, sadness, anger, higher fear and
anxiety, and lower vitality.28 While there are few studies on HBV-​
related stigma, particularly in the U.S., research shows HBV patients
frequently report internalized and social stigma.29 Specifically, a
systematic review from 2018 found that up to 20% of patients reported believing they were denied health care due to their diagnosis
and 30% indicated they faced workplace discrimination due to their
HBV diagnosis.29 However, more research is needed to assess the effects of stigma on diverse populations of patients with HBV.
Similar to HBV, patients with HCV may be blamed for acquiring
the disease due to a history of intravenous drug use, leading to social isolation.30 Patients with HCV can experience decreased muscle
strength (asthenia), moderate to severe fatigue, cognitive deficits,
depression, and anxiety.30,31 Achieving HCV cure has been shown to
improve patients’ quality of life, although the extent of improvement
that can be expected is not well established.31 The improvements
may depend on the length of time a patient was infected, as well as
any underlying psychological issues that the patient had before acquiring the infection.
Those living with HIV may feel isolation and depression32 and
face perceived or actual discrimination and stigma.33 Isolation and
loneliness are common because of the need to disclose HIV status
to obtain treatment and social support, and disclosure may come
with consequences like judgment, rejection, or discrimination.33
Depression in PLWH negatively impacts treatment outcomes and
quality of life, but psychological and antidepressant interventions
show promise for addressing these issues.32 Because of increased
awareness of certain cancers associated with HIV (e.g., anal cancer
in MSM), screening may be more regularly accessed; there may be
psychological consequences that accompany more awareness and
screening though. For instance, those with HIV who were screened
for anal cancer report more anal cancer worry, worse self-​rated anal
health, and less optimism about the future.34,35
Thus, behavioral interventions to reduce risk or promote prevention and early detection behaviors must consider the unique characteristics, preferences, and values of the target populations. This
process may include using formative research methods to develop
new, or adapt existing, behavioral interventions. For those already
affected with a virus-​associated cancer, psychosocial providers and
researchers must consider the balance between positive implications
for treatment based on infection status (e.g., HPV-​positive oropharyngeal cancers have higher disease-​free survival), with possible
feelings of stigma associated with having a viral cancer diagnosis.
Chapters 17 and 18 (Section IV) provide extensive information on
techniques to screen for distress, anxiety, and depression. In addition, further information about the psychological needs of gynecological cancer patients and head and neck cancer patients can be
found in Section V, Chapters 27 and 29, respectively.
Future Directions
The field of psycho-​oncology is in a unique position to contribute
to the prevention of virus-​associated cancers. While there are challenges associated with virus-​associated cancers, the opportunities
for prevention of future cancers are promising. Unlike other tumors
for which there is no single direct causal factor for the majority of
cases, preventing acquisition of the virus can prevent a majority
of these virus-​associated cancers. Given the importance of provider and systems/​policy-​level factors in reducing virus-​associated
cancers, future behavioral interventions at the patient/​client level
should also consider addressing issues at the provider, health care
system, and/​or policy level. For example, health care provider recommendation is a critical factor in promoting uptake of a variety
of screening and testing behaviors. However, these recommendations must be made using evidence-​based strategies. For health care
systems, many prevention and early detection strategies are recommended routinely for a large age group (e.g., HBV vaccination for all
infants, routine HPV vaccination for all adolescents ages 11–​12, universal screening of baby boomers for HCV infection). As such, it will
be important to consider normalizing these recommendations by
integrating them into electronic health record reminders, standing
orders, or other system-​wide approaches to increase uptake. Finally,
at the policy level, it will be critical to support local, state, or national
policies to facilitate access to screening and treatment (both medical
and psychosocial) for those at risk for or affected by virus-​associated
cancers.
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15. Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention,
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49
SECTION II
Screening for Cancer in Normal
and At-​Risk Populations
Wendy W. T. Lam (Section Editor)
7
Colorectal Cancer Screening 53
Caitlin C. Murphy and Sally W. Vernon
8
Cervical Cancer Screening and HPV
Vaccination: Multilevel Challenges to Cervical
Cancer Prevention 61
Richard Fielding, Samara Perez, Zeev Rosberger, Ovidiu Tatar,
and Linda D. L. Wang
9
Breast Cancer Screening 68
Gabriel M. Leung, Irene O. L. Wong, Ava Kwong, and
Joseph T. Wu
10 Prostate Cancer Screening 74
Michael A. Diefenbach, Daniel Nethala, Michael Schwartz,
and Simon J. Hall
11 Lung Cancer Screening 78
Lisa Carter-​Harris and Jamie Ostroff
12 Skin Cancer Screening 87
Jennifer L. Hay and Stephanie N. Christian
7
Colorectal Cancer Screening
Caitlin C. Murphy and Sally W. Vernon
The overall goal of colorectal cancer (CRC) screening is to reduce
morbidity and mortality from CRC. CRC is the second leading cause
of cancer death in the United States, with estimates of 145,600 new
cases and 51,020 deaths in 2019.1 Incidence and mortality rates have
declined dramatically in the U.S. since the early 1990s, particularly
among older adults. For example, incidence in the 65–​69 age group
decreased from 210.3 per 100,000 in 1992 to 108.5 per 100,000 in
2016—​a 50% decrease. Mortality rates decreased similarly during
that period. Improvements in CRC incidence and mortality rates
are often attributed to increased uptake of screening.2 Regular
screening with guaiac-​based fecal occult blood test (gFOBT), fecal
immunochemical test (FIT), or sigmoidoscopy facilitates earlier detection of CRC and lowers mortality.2 Screening colonoscopy may
also decrease CRC incidence through early detection and removal
of precancerous polyps.
Most professional organizations agree that CRC screening should
begin at age 50 years for those at average risk. In their 2016 update
to CRC screening guidelines, the U.S. Preventive Services Task Force
recommended screening with colonoscopy every 10 years, annual
FIT or high-​sensitivity gFOBT, FIT-​DNA every 1 or 3 years, sigmoidoscopy every 10 years with annual FIT, flexible sigmoidoscopy
every 5 years, or computed tomographic colonography/​virtual colonoscopy every 5 years for average-​risk, asymptomatic adults aged
50–​75 years.3 However, the American Cancer Society issued a new
guideline in May 2018 recommending CRC screening begin at age 45
(vs. 50) years for average-​risk adults.4 This new guideline was commissioned in response to increasing rates of CRC incidence among
younger (age <50 years) adults and is based primarily on simulation modeling. As such, the recommendation to initiate screening at
age 45 years is qualified, with some uncertainty about the balance of
screening benefits and harms in this age group.
Two national sources of prevalence data on CRC screening in
the United States are the National Health Interview Survey (NHIS)
and the Behavioral Risk Factor Surveillance System (BRFSS).
Differences in the methods of data collection have resulted in
slightly different estimates of screening prevalence; however, both
sources show a gradual increase in overall test use, with some suggestion that use started to plateau after 2010. NHIS data show an
increase from 42.5% in 2000 to 58.3% in 2010 for any recent CRC
screening (e.g., stool blood test in last year or colonoscopy in last
10 years).5,6 Prevalence slightly increased in 2015 to 62.4%. Most of
the increase in screening has been due to increased use of colonoscopy (Figure 7.1). Despite overall improvements in screening uptake, the prevalence of CRC screening in the United States is lower
than breast or cervical cancer screening. Moreover, there are disparities in screening prevalence by race/​ethnicity and socioeconomic
status. For example, NHIS data from 2015 showed that, compared
to non-​Hispanic whites (63.7%), Hispanics and American Indian/​
Alaska Natives had the lowest screening uptake (47.4% and 48.4%,
respectively), followed by Asians (52.1%). Screening uptake was also
low among adults with less than a high school education (46.7%)
and without insurance (25.1%).5 These estimates fall short of the targets set by Healthy People 2020 (70% screened) and the National
Colorectal Cancer Roundtable (80% screened).
The purpose of this chapter is to review behavioral research on
CRC screening in the United States and to identify directions for
future research based on this evidence.
60
50
% Screened
Introduction
40
30
20
10
0
2000
2003
2005
2010
Any recent CRC test
COL past 10 years
SIG past 5 years
FOBT past year
Figure 7.1. Recent colorectal cancer screening test use among
respondents age 50 years and older.
National Health Interview Survey, 2000, 2003, 2005, 2010, and 2015, National
Center for Health Statistics, Centers for Disease Control and Prevention.
2015
54
SECTION II Cancer Screening in Normal and At-Risk
CRC Screening Correlates and Predictors
Studies of factors associated with CRC screening are used to inform the selection of target populations for intervention and the
content of interventions. For example, demographic variables are
useful for identifying population subgroups to target interventions.
They are less amenable to change and are, therefore, not as useful
for informing the content of interventions designed to motivate
and enable screening test use. The major categories of factors that
have been studied in relation to CRC screening behaviors include
sociodemographics, healthcare access, health status, health behavior,
and cognitive, psychosocial, and environmental factors. Because
CRC screening is unique in that multiple test options are available,
the role of test preferences and informed decision-​making in CRC
screening test use has also been examined. Although numerous
studies have identified factors associated with CRC screening, there
have been only a few attempts to review this literature.5,6 Most of this
literature is based on cross-​sectional study designs that can only establish associations. Too few studies have used prospective designs
or tested hypotheses about causal pathways of factors influencing
CRC screening by examining mediators and moderators.
Sociodemographics, Healthcare Access, Health Status,
and Health Behavior Factors
Studies of sociodemographics, access to healthcare, health status,
and health behavior have often used data from national surveys.
Although CRC screening rates have increased over time, rates have
remained lower among nonwhites, those with less education, those
living in rural versus urban areas, and those without a regular source
of healthcare or medical insurance.3 CRC screening is the only type
of cancer screening that is recommended for both males and females,
but few studies have examined whether correlates differ by gender.7
Such differences may inform the use of gender-​specific messages or
intervention strategies to increase CRC screening test use.
The most common reasons for not having a CRC test include lack
of awareness or no physician recommendation.7,8 Cross-​sectional
studies report that a physician’s recommendation for CRC screening
is important for patient adherence, but prospective studies suggest
that a recommendation may not be sufficient for increasing CRC
screening uptake to desired levels.9 Engaging in other preventive
health behaviors, such as other cancer screening tests, has been
positively associated with CRC screening. Health status has been
measured in multiple ways (e.g., self-​reported health, comorbidity,
functional status), which may explain why the patterns of association with cancer screening behaviors have varied.10 Compared with
stool blood tests, the likelihood of completing an endoscopic test is
greater among people with a family history of CRC, access to regular healthcare and health insurance, fewer concerns about cost, and
higher perceived CRC risk.8
Cognitive and Psychosocial Factors
Health behavior theories are used to identify cognitive and psychosocial variables that may influence behavior. In cross-​sectional
studies, consistent correlates of CRC screening include preventive health orientation, physician recommendation, knowledge of
cancer risk factors, perceived benefits (pros) and barriers (cons) to
screening, and self-​efficacy.6 Most, but not all, studies of perceived
risk and severity report a positive association with CRC screening.
Fear and worry about CRC or the screening test itself have small, if
any, direct effects on CRC screening behavior, possibly due to low
levels of worry even among high-​risk populations. Specifying the
source of worry has shown that worries about cancer are positively
associated with screening, whereas worries about the test may act as
a barrier to screening. Hypotheses of a curvilinear effect of worry or
anxiety have not been supported.11
Relatively few psychosocial constructs have been examined in prospective studies, and fewer have been examined across studies.6 Even
when the same constructs were used, they were often defined and operationalized differently, and few measures of psychosocial constructs
have been validated. Nevertheless, cumulative evidence based on prospective study designs and multivariable analyses suggest consistent
independent associations between CRC screening and perceived
benefits and barriers, self-​efficacy, and intention. Preferences for specific CRC screening tests vary by screening goals, test characteristics,
and patient-​level variables. In one prospective study, only about half of
the sample received the CRC screening test they preferred.12
Future research should confirm the predictive utility of CRC
screening correlates and explore their interrelations in theory-​based
causal models. Some individual-​level variables that warrant examination as predictors in future research include affect, social influence, trait-​level personality characteristics such as dispositional
optimism or conscientiousness, patient and provider CRC screening
test preferences (and their potential mismatch), low perceived need
or value for screening, and avoidant or self-​exemption tendencies.
Conceptual Models
Basic causal models are formed when intermediate behavioral outcomes are examined as mediators. Variables that have been examined as intermediate outcomes of intervention efforts to increase
CRC screening behavior include intention, awareness, knowledge,
risk perceptions, and physician-​
patient discussion about CRC
screening. Intention is a frequently studied intermediate outcome
because it is a strong predictor of behavior. Different intervention
strategies may be needed to increase CRC screening, depending on
individuals’ behavioral intentions. Understanding how to effectively
tailor intervention messages or strategies is informed by process
evaluation; however, few studies have reported thorough evaluations
of participants’ appraisal of CRC screening informational materials
or intervention components. Similarly, not all CRC screening discussions lead to CRC screening adherence; therefore, we need to
better understand which components of these discussions or which
informed decision-​making criteria are important for increasing
CRC screening uptake.
Very few studies have tested hypothesized causal pathways of
multiple predictors of CRC screening. Health behavior models that
posit only direct effects between predictors and intention and behavior may underestimate the total effects of CRC screening determinants through other mediating and moderating pathways. One study
used longitudinal data to examine competing conceptual models
of the role of perceived susceptibility on CRC screening intention
and behavior.13 That study found that the influence of perceived
susceptibility on screening behavior was independent of perceived
barriers, moderated changes in perceived benefits and self-​efficacy,
and was mediated by social influence. Other studies that have examined mediators or moderators generally have focused on evaluating
CHAPTER 7 Colorectal Cancer Screening
intervention effects rather than testing conceptual models that explain health behaviors. Future studies need to examine different
causal models of mediators and moderators to provide new ways to
think about the underlying mechanisms relating cognitions and behaviors in order to improve the effectiveness of interventions.
Multilevel models can examine the independent and interactive effects of individual-​and environmental-​level variables on
CRC screening. Examining environmental-​
level variables could
potentially identify screening disparities across health systems or
geographic areas that could be targeted for interventions or CRC
screening programs. An emerging literature has identified multiple environmental-​level factors associated with CRC screening,
including, among others, several indicators of area socioeconomic
status, availability, density, capacity, or features of local healthcare resources, and managed care penetration.14 Future research is
needed to further elucidate the mechanisms of influence between
environment-​level factors and CRC screening.
Interventions to Promote CRC Screening
Efforts to promote the uptake of CRC screening began in the 1980s
and accelerated in 1997 upon publication of consensus screening
guidelines. An increasing number of reviews have evaluated the effectiveness of interventions to increase CRC screening. Arguably,
the most widely used recommendations for selecting interventions
to promote CRC screening are those of the Community Preventive
Services Task Force (see more at https://​www.thecommunityguide.
org/​topic/​cancer). The Community Guide recommendations were
updated in 2016 based on an expanded literature review of studies
published through November 2013. The review included 56 intervention studies, and the cumulative evidence demonstrated that
multicomponent interventions increase CRC screening by a median
of 15%. Multicomponent interventions include approaches within
the strategies of increasing community demand (e.g., reminders),
increasing community access (e.g., reducing structural barriers), or
increasing provider delivery of screening (e.g., provider assessment
and feedback), and these interventions may also address needs at the
individual, provider, community, and system levels (Table 7.1). The
largest effect on screening uptake was observed in multicomponent
interventions that combined approaches from each of these three
strategies, and those with five or more intervention approaches
showed a larger median increase. There was limited evidence on the
effect of specific combinations of intervention approaches, as well as
the efficacy of interventions among population subgroups (e.g., low
health literacy, low income).
Recent reviews of the CRC screening intervention literature have
focused on mailed outreach, patient navigation, and interventions
offering a choice of screening test.7 The field has moved away from
patient-​level interventions to intervening at the provider or healthcare system levels, and many recent studies were conducted in large,
integrated healthcare systems or federally qualified health centers.
In these settings, mailed outreach and patient navigation, particularly in the context of multicomponent interventions, are associated
with increased CRC screening. Offering patients a choice between
a stool blood test and colonoscopy appears to increase screening
initiation compared to offering only colonoscopy; some data also
suggest better completion with a two-​sample FIT compared to a
three-​sample gFOBT. We highlight briefly some of the key findings
from these reviews and selected studies.
Interventions Using Mailed Outreach
Several studies tested interventions of mailed outreach, or distributing
stool blood test kits by mail with postage-​paid return envelopes to
patients who are not up-​to-​date with CRC screening.8 Mailed outreach includes two intervention components recommended by the
Community Preventive Services Task Force: (1) increasing community demand via client reminders and written education materials
and (2) increasing community access by reducing structural barriers
through the delivery of a mailed (often free) test kit, eliminating
the need for patients to attend a clinic visit to complete screening.
Some also consist of telephone or written reminders to complete
screening. Importantly, many trials of mailed outreach have been
conducted in low-​income, uninsured, or minority populations—​
groups with historically low screening. Mailed outreach in these
settings is associated with statistically significant improvements in
screening uptake, ranging from 18% to 36% across studies.8 Even
in studies not designed to test directly the effect of mailed outreach,
Table 7.1. Multicomponent Interventions Include Approaches within the Strategies of Increasing Community Demand, Increasing
Community Access, and Increasing Provider Delivery
Intervention Strategy
Intervention
approach
Increase Community Demand
Increase Community Access
Increase Provider Delivery
Group education
Reduce client out-​of-​pocket costs
Provider reminders
One-​on-​one education
Reduce structural barriers
Provider incentives
Client reminders
• Reduce administrative barriers
Provider assessment and feedback
Client incentives
• Provide appointment scheduling assistance
Mass media
• Use alternative screening sites
Small media
• Use alternative screening hours
• Provide transportation
• Provide translation
• Provide childcare
Adapted from Community Preventive Services Task Force, Increasing Colorectal Cancer Screening: Multicomponent Interventions, Finding and Rationale Statement, August 2016 (see
more at https://​www.thecommunityguide.org/​topic/​cancer).
55
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SECTION II Cancer Screening in Normal and At-Risk
this intervention strategy appears to drive screening uptake. For example, tailored telephone counseling increased screening compared
to a web-​only intervention,9 largely driven by the telephone group’s
participants’ ability to request a FIT kit by mail.
A systematic review and meta-​analysis by Jager et al.8 of seven
randomized trials shows a 28% absolute increase in screening when
comparing mailed outreach to usual care. Results were consistent
in subgroup analyses by test type (FIT vs. gFOBT), setting (underserved/​minority vs. all else), and inclusion of telephone reminders
(with vs. without). Among studies included in the review were a
cluster randomized trial10 at federally qualified health centers in
Oregon and California (13.9% mailed outreach vs. 10.4% usual
care); comparative effectiveness trial11 in a rural safety-​net hospital (40.7% mailed outreach vs. 12.1% usual care); and randomized trial in a community health center network in Chicago (36.7%
mailed outreach vs. 14.8% usual care). The 28% absolute increase
in screening across these trials compares favorably to or exceeds
interventions offering stool blood tests at the time of annual flu
vaccination, patient reminders, and educational campaigns. Taken
together, the Jager et al. review supports mailed outreach offering
either FIT or gFOBT as an effective, evidence-​based strategy for
increasing CRC screening, particularly in low-​income or underserved populations.
Observational studies similarly support the efficacy of mailed outreach. For example, in a large, integrated healthcare system, an organized CRC screening program with mailed outreach doubled the
proportion of adults up-​to-​date with screening (from 40% to over
80%).12 The increase in screening was associated with a substantial
decrease in CRC incidence and mortality of 26% and 52%, respectively. In the Veteran’s Health Administration (VHA), the largest
healthcare provider in the U.S., screening has increased dramatically
over time, largely driven by increases in gFOBT13 offered through
organized programs. The majority of patients in the VHA who
complete CRC screening do so by gFOBT. Finally, many European
studies report success with mailed outreach as part of nationwide
programs implementing organized screening,14 with up to 60% of
participants returning a test kit by mail. These findings suggest that
organized screening programs with mailed outreach have the potential to both achieve national screening goals and reduce cancer
mortality in the population.
Interventions Using Patient Navigation
Patient navigation is a barriers-​focused intervention, whereby a
trained healthcare professional (e.g., nurse, lay health worker) guides
a patient through a complex healthcare system and addresses sociocultural, educational, and logistical barriers to screening. A number
of CRC screening intervention trials have compared patient navigation of varying levels of intensity to usual care, and with or without
mailed outreach. Tested strategies include (1) standard navigation
vs. usual care, (2) standard navigation vs. enhanced navigation, and
(3) navigation with mailed outreach vs. mailed outreach alone.
Ritvo et al.15 conducted a pragmatic trial comparing patient navigation to usual care among more than 5,000 patients in primary care
clinics. Patients randomized to patient navigation were contacted by
a trained nurse navigator to discuss CRC screening by telephone;
interested patients then met with the navigator, who helped them
identify and arrange a screening test based on their preferences.
Screening was higher in the intervention group (35%) compared
to usual care (20%). Green et al.16 evaluated a stepped intervention
approach in a large managed care network of primary care clinics,
building from an existing system in which usual care involved promotion of preventive services, including CRC screening. Usual care
was compared with interventions of increasing intensity, including
(1) automatically generated letter and informational pamphlet
indicating that patients were due for CRC screening (automated
group), (2) telephone assistance from a medical assistant (assisted
group), or (3) navigation from a registered nurse who assessed the
patient’s CRC and procedural risks; provided motivational counseling to help patients define their intent, select a test, and develop
an action plan; assisted with referrals, appointments, and test preparation; and tracked test completion (navigation group). Screening
was highest among those randomized to navigation, and there was
a stepped increase in screening as the intensity of the interventions
increased: 26%, 51%, 58%, and 65% for usual care, automated, assisted, and navigation groups, respectively. Five-​year follow-​up of
this study shows patients assigned to any intervention continued to
adhere to screening recommendations.17
Other studies comparing standard navigation to enhanced or
culturally tailored navigation show no difference in CRC screening
uptake between the two types of navigation (pooled odds ratio
[OR]: 1.04; 95% CI: 0.98–​1.11).7 Enhanced navigation often included a range of activities, from more frequent contact with patients to address screening barriers to motivational interviewing to
language concordance between the patient and navigator.
Importantly, many patient navigation interventions also included
mail outreach. For example, Myers et al.18 evaluated tailored navigation (i.e., mailed FIT kit and instructions plus a telephone call from a
patient navigator) versus standard intervention (mailed FIT kit and
instructions) versus usual care. There was no significant difference
in screening between the two intervention groups (45% vs. 37%),
raising questions about the incremental benefit of patient navigation
compared to mailed outreach. However, other studies directly comparing navigation plus mailed outreach to mailed outreach alone
demonstrated a small, but statistically significant, benefit of adding
navigation.7,19 Indeed, a more recent trial20 compared a decision
support and navigation intervention to standard of care, and despite both groups receiving a mailed FIT kit and instructions, those
randomized to decision support and navigation were more likely to
complete FIT (57%) compared to those randomized to a standard
intervention (37%).
A challenge in the patient navigation literature has been inconsistent names or labels used to describe similar intervention
strategies—​ranging from patient management to targeted telephone
education. In addition, there are differences across navigation
studies in delivery mode (e.g., telephone vs. in-​person), dose (e.g.,
brief telephone call vs. 30-​minute educational session), and frequency of contact. Navigation likely involves increasing behavioral
capacity and self-​efficacy by addressing patient and system barriers
to accessing screening. Of the few studies that explicitly state they
used theory to inform intervention development, facilitation, cues
to action, and tailored messaging are the most common behavior
change methods. Patient navigation interventions can be strengthened by a more systematic use of behavioral theory to guide development and implementation.
CHAPTER 7 Colorectal Cancer Screening
Interventions Offering Choice
Several intervention studies have examined the effect of providing
patients with a choice of screening test. This approach is consistent with literature on patient preferences for CRC screening,
demonstrating that patients often prefer the test they feel most confident in completing. Specifically, patients less interested in getting
screened are more likely to choose stool blood tests, which require
less planning and preparation and are more convenient and less invasive than colonoscopy; patients exhibiting more readiness to complete screening tend to prefer colonoscopy.21 Incorporating patient
preferences in interventions may increase the likelihood that patients initiate screening. For example, Inadomi et al.22 randomized
patients to recommendation for screening by FOBT, colonoscopy,
or their choice between the two. Participants randomized to colonoscopy were less likely to complete screening (38%) compared to
those randomized to FOBT (67%) or a choice (69%). Of the latter
group, 31% completed colonoscopy, suggesting that offering only
colonoscopy would decrease screening participation. In the 3-​year
follow-​up of this trial, patients offered a choice between FOBT and
colonoscopy (42%) continued to have high adherence to screening,
but adherence in the FOBT group (14%) fell below the choice and
colonoscopy (38%) groups.23
Post hoc analyses of randomized intervention trials have generated
compelling evidence supporting the importance of incorporating
patient preference in intervention strategies. In a pragmatic trial of
mailed outreach, 20% of patients mailed invitations to complete colonoscopy “crossed over” to complete FIT instead (vs. 3% crossover
to colonoscopy among those mailed invitations for FIT).24 Similarly,
in an intervention trial of patient navigation and mailed outreach,
patients were more likely to complete the test they preferred, and the
effect was even stronger when combined with navigation.25 Other
trials of decision aids26,27 (i.e., structured tool for offering choice to
patients) suggest that patients who are able to weigh the pros and
cons of CRC screening tests are more likely to complete screening
with a test of their choice.
We still know relatively little about the importance of patient preference and screening choice in relation to other factors, such as access and navigation that may be more important to test completion.
Myers et al. studied 764 African Americans and found that, in an
intervention that included a navigation component, patients who
expressed a preference for stool testing were much more likely to
obtain a stool test than a colonoscopy (41.1% vs. 7.1%).19 In the comparison group without navigation, fewer patients who expressed a
preference for stool testing completed the test (12.1% vs. 7.6%), even
though a stool kit had been mailed to them.
Timely Follow-​Up of Abnormal Screening Tests
Timely follow-​up of abnormal or inconclusive test results achieves
maximum benefits from cancer screening because delays in follow-​
up may contribute to advanced cancers. For example, among patients with a positive FIT, follow-​up colonoscopy at or after 7 months
is associated with an increased risk of advanced adenoma, any
CRC, and advanced-​stage disease.28 Yet, as few as 50% of patients
with abnormal test results complete colonoscopy within 6 months,
compared to the 90% in randomized trials of screening efficacy.
Selby et al.29 conducted a systematic review of 23 randomized and
nonrandomized studies of interventions to improve follow-​up of
positive fecal tests, and moderate evidence supported only patient
navigation as an effective intervention. Instead, much of the literature is descriptive and focuses on patient characteristics associated
with timely follow-​up. Evidence concerning provider-​and system-​
level strategies, such as identification, reporting, and resolution of
abnormal findings, is scant and insufficient. For example, administrative databases and algorithms that identify the appropriate
follow-​up needs of individual patients, based on test results, could
be linked to communication interventions of increasing intensity,
starting with tailored mailed letters or automated phone calls and
progressing to personal phone calls and navigation, as was done in
one study.16 Implementing standard tracking and reporting procedures in clinical practice may also improve completion of diagnostic
colonoscopy, and more intensive outreach may be needed to reduce
disparities in follow-​up among underserved patients.
Longitudinal Adherence to Screening
Repeat FOBT
Because most studies report one-​
time use rather than repeat
screening outcomes, we know little about interventions designed to
promote regular FIT or gFOBT. On-​schedule screening is particularly important for these stool-​based tests because of the relatively
frequent interval over which they need to be performed, and because effectiveness may be reduced when patients do not adhere to
a regular schedule. Most European countries, Canada, and Australia
recommend stool-​
based screening every 2 years, while annual
screening is recommended in the U.S. and Asian countries.14
Observational studies show a wide range of repeat screening.
Prevalence of repeat FIT or gFOBT in community settings varies from
25% to 90% among persons who have previously completed a negative test,30–​32 and prevalence generally decreases across screening
rounds. Connection to primary care, comorbidity, and self-​efficacy
appear to be important determinants of repeat screening.30,32–​34
Routine screening is most likely to be accomplished in healthcare
settings that have systems in place that can monitor patients’ status
and can generate automatic reminders, as is the case, for example,
in some managed care organizations.20 As healthcare systems adopt
a “FIT First” approach to CRC screening,35 data concerning adherence to repeated rounds of screening and over longer time periods
will become increasingly relevant.
Although few studies have explicitly tested the effects of an intervention to increase repeat or longitudinal adherence to screening,
some have examined patient adherence to repeat stool blood tests by
extending an intervention trial over at least two rounds of screening.
For example, Baker et al.36 examined adherence to repeat FOBT
among patients who completed an index test during an intervention
trial of mailed outreach; 89% of patients completed repeat screening
within 6 months of their second outreach. Long-​term follow-​up of
the Systems of Support to Increase Colorectal Cancer Screening
(SOS) Trial shows intervention participants had over 30% more time
adherent to screening compared to usual care over a 5-​year period,
and stool tests accounted for almost all of the difference in covered
time between the two groups.17
57
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SECTION II Cancer Screening in Normal and At-Risk
Notably, a recent pragmatic trial conducted by Singal et al.37 suggests that more patients offered mailed outreach for colonoscopy
(vs. FIT or gFOBT) complete screening when followed for a longer
duration. This trial compared two mailed outreach strategies to
usual care in a safety-​net hospital over a 3-​year period. Patients were
randomized to receive a mailed invitation to complete a FIT with
a home test kit and postage-​paid return envelope; a mailed invitation to schedule a colonoscopy and, if scheduled, a bowel preparation kit and preprocedure instructions; or opportunistic, visit-​based
screening through usual care. Both outreach groups received telephone reminders from research staff. An important feature of this
study was the primary outcome—​screening process completion—​
defined as adherence to colonoscopy, annual testing for a normal
FIT, diagnostic colonoscopy after abnormal FIT, or treatment evaluation if CRC was detected. Prior studies of mailed outreach have
been limited to 1-​year outcomes. During the first year of the trial,
screening with FIT was nearly doubled among patients randomized to mailed outreach (58.8%) compared to usual care (29.6%).
However, by the end of the 3-​year trial period, screening process
completion was highest among those randomized to colonoscopy
outreach. Notably, screening completion was higher in both outreach groups compared to usual care (38.4% colonoscopy outreach
vs. 28.0% FIT outreach vs. 10.7% usual care). FIT may have fewer
barriers to one-​time completion, but it requires annual screening
and diagnostic evaluation of abnormal results. In contrast, colonoscopy is both a screening and diagnostic test, and a single examination can satisfy screening completion for up to 10 years.
Under-​and Overuse of Colonoscopy
Adherence to repeat colonoscopy may be less of a concern because
when no polyps are found, the next colonoscopy is not recommended for another 10 years. However, it is important to monitor
repeat colonoscopy, particularly in the setting of surveillance colonoscopy administered at more frequent intervals. Deviations from
guideline recommendations for follow-​up and surveillance colonoscopy include both under-​and overuse of colonoscopy.
Screening overuse has been identified as a potential risk for
overtreatment of benign disease, and overuse of colonoscopy may
additionally increase risk of adverse events (e.g., bleeding), increase
healthcare costs, and reduce endoscopic capacity in underscreened
populations. Among Medicare patients with a negative screening
colonoscopy, nearly half underwent a repeat colonoscopy in fewer
than 7 years.27 Similarly, a mail survey of gastroenterologists and
surgeons performing colonoscopy found that 24% of gastroenterologists and 54% of surgeons recommended repeat colonoscopy at
intervals not concordant with guidelines.28 Follow-​up of this survey
study showed that a nonconcordant recommendation from physicians was associated with screening overuse.38
On the other hand, underuse of colonoscopy remains an ongoing
concern, particularly for those at higher risk of CRC (e.g., due to
personal history of adenomas). About one-​quarter of patients who
undergo screening colonoscopy will have adenomas that require
removal and a follow-​up colonoscopy in 3–​5 years. Several recent
studies have examined patterns of and factors associated with surveillance colonoscopy, and many of these were conducted in large,
integrated healthcare systems. For example, in a multisite study of
patients with advanced adenomas, receipt of surveillance colonoscopy at 3 years ranged from 18% to 60% across healthcare systems.39
A study in the VHA found that the majority of patients with advanced adenomas did not receive a follow-​up colonoscopy, or received it after the recommended interval.38 Correlates or predictors
of adherence to surveillance colonoscopy include perceived barriers,
perceived benefits, social deprivation, and cancer worry.40
These observational studies highlight the need for system-​level
improvements that may facilitate appropriate delivery of repeat colonoscopy. Enhancing existing information systems to systematically
track patients by CRC risk could identify patients eligible for surveillance colonoscopy when testing is due. Reminder and recall systems
can be set to guideline-​recommended intervals that alert both physicians and patients to schedule colonoscopy. Other changes include
computer prompts or lock-​outs, which prohibit physicians from ordering inappropriate procedures without override.
Future Directions
Substantial progress has been made in decreasing incidence and mortality from CRC, and this progress is often attributed to increasing
use of CRC screening. However, the approximately 65% of adults
up-​to-​date with screening indicates that there is still room for improvement. Moreover, there are important disparities in screening
prevalence by race/​ethnicity and socioeconomic status. Several systematic reviews focus specifically on interventions in racial/​ethnic
groups in the United States,16–​18 and many of the intervention trials
reviewed in this chapter (e.g., mailed outreach, patient navigation)
were conducted in low-​income or underserved populations.
Several points that we raised in an earlier chapter on this topic
remain to be addressed.
Comparative Effectiveness Research
No head-​to-​head trial has as yet compared screening strategies to
determine whether or not some strategies have a greater net benefit than others. In the absence of empirical evidence, the U.S.
Preventive Services Task Forces recommends that clinicians engage
patients in informed decision-​making about the screening strategy
that the patient is mostly likely to complete and that reflects the
patient’s preferences and local availability.3 An ongoing trial in the
VHA will directly address this gap in evidence by comparing colonoscopy versus FIT screening strategies, with a primary outcome
of CRC mortality after 10 years of follow-​up. The CONFIRM trial
(clinicaltrials.gov, NCT01239082) has randomized nearly 50,000
patients to complete annual FITs or to receive colonoscopy consistent with current standards of care. Three ongoing trials in Europe
address similar questions.
Impact of Healthcare Policy
Health insurance is a consistent and strong predictor of CRC
screening, and uninsured populations are far less likely to engage
in screening. The Affordable Care Act (ACA) has improved insurance coverage and preventive healthcare visits, including uptake of
CRC screening, in states expanding Medicaid. Indeed, prevalence
of CRC screening among low-​income adults increased in Medicaid
expansion states, and increases in screening were even higher in
states earliest to expand Medicaid.41 Other research suggests that
screening has increased among Medicare beneficiaries, driven by the
ACA’s mandate to eliminate cost sharing for preventive services.42
CHAPTER 7 Colorectal Cancer Screening
As the healthcare landscape continues to evolve in the U.S., it will be
important to monitor the impact of policy on screening.
Dissemination and Implementation
For CRC screening programs to be successful, they must involve
more than one-​time screening but a series of coordinated steps, from
initial screening to diagnostic evaluation to treatment of any detected
lesions.43 Patient navigation and mailed outreach have been the most
extensively tested interventions and have the strongest evidence
base for increasing screening. As noted by Selby et al.,29 patient navigation and clinician reminders have a similar impact on follow-​up
of abnormal test results, although the strength of evidence is lower
by comparison. Broad implementation of either of these strategies,
as well as others involving multiple components (see Table 7.1), may
bring the current screening prevalence of 65% closer to the national
goal of 80%. An important next step is to focus on implementing
these approaches in large healthcare systems—​or population health
management programs—​where there can be follow-​up to determine
effectiveness over the long term, as well as sustainability.44 Future
research should move away from efficacy trials and toward a better
understanding of how best to implement and scale these strategies.
Dissemination and implementation science is a quickly developing
field devoted to understanding factors in the adoption of evidence-​
based interventions and testing different strategies for improving integration of these interventions into practice.
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health insurance coverage. Preventive Medicine. 2018;112:199–​206.
7. Dougherty MK, Brenner AT, Crockett SD, et al. Evaluation of interventions intended to increase colorectal cancer screening rates in
the United States: a systematic review and meta-​analysis. JAMA
Internal Medicine. 2018;178(12):1645–​1658.
8. Jager M, Demb J, Asghar A, et al. Mailed outreach is superior to
usual care alone for colorectal cancer screening in the USA: a systematic review and meta-​analysis. Digestive Diseases and Sciences.
2019;64(9):2489–​2496.
9. Champion VL, Christy SM, Rakowski W, et al. A randomized trial
to compare a tailored web-​based intervention and tailored phone
counseling to usual care for increasing colorectal cancer screening.
Cancer Epidemiology, Biomarkers & Prevention: A Publication of
the American Association for Cancer Research, cosponsored by the
American Society of Preventive Oncology. 2018;27(12):1433–​1441.
10. Coronado GD, Golovaty I, Longton G, Levy L, Jimenez R.
Effectiveness of a clinic-​
based colorectal cancer screening
promotion program for underserved Hispanics. Cancer.
2011;117(8):1745–​1754.
11. Gupta S, Halm EA, Rockey DC, et al. Comparative effectiveness
of fecal immunochemical test outreach, colonoscopy outreach,
and usual care for boosting colorectal cancer screening among the
underserved: a randomized clinical trial. JAMA Internal Medicine.
2013;173(18):1725–​1732.
12. Levin TR, Corley DA, Jensen CD, et al. Effects of organized colorectal cancer screening on cancer incidence and mortality
in a large community-​
based population. Gastroenterology.
2018;155(5):1383–​1391.e1385.
13. El-​Serag HB, Petersen L, Hampel H, Richardson P, Cooper G.
The use of screening colonoscopy for patients cared for by the
Department of Veterans Affairs. Archives of Internal Medicine.
2006;166(20):2202–​2208.
14. Schreuders EH, Ruco A, Rabeneck L, et al. Colorectal cancer
screening: a global overview of existing programmes. Gut.
2015;64(10):1637–​1649.
15. Ritvo PG, Myers RE, Paszat LF, et al. Personal navigation increases colorectal cancer screening uptake. Cancer Epidemiology,
Biomarkers & Prevention: A Publication of the American
Association for Cancer Research, cosponsored by the American
Society of Preventive Oncology. 2015;24(3):506–​511.
16. Green BB, Wang CY, Anderson ML, et al. An automated intervention with stepped increases in support to increase uptake of
colorectal cancer screening: a randomized trial. Annals of Internal
Medicine. 2013;158(5 Pt 1):301–​311.
17. Green BB, Anderson ML, Cook AJ, et al. A centralized mailed
program with stepped increases of support increases time in compliance with colorectal cancer screening guidelines over 5 years: a
randomized trial. Cancer. 2017;123(22):4472–​4480.
18. Myers RE, Bittner-​Fagan H, Daskalakis C, et al. A randomized controlled trial of a tailored navigation and a standard intervention in
colorectal cancer screening. Cancer Epidemiology, Biomarkers &
Prevention: A Publication of the American Association for Cancer
Research, cosponsored by the American Society of Preventive
Oncology. 2013;22(1):109–​117.
19. Myers RE, Sifri R, Daskalakis C, et al. Increasing colon cancer
screening in primary care among African Americans. Journal of
the National Cancer Institute. 2014;106(12):dju344.
20. Myers RE, Stello B, Daskalakis C, et al. Decision support and navigation to increase colorectal cancer screening among Hispanic
patients. Cancer Epidemiology, Biomarkers & Prevention: A
Publication of the American Association for Cancer Research,
cosponsored by the American Society of Preventive Oncology.
2019;28(2):384–​391.
21. Hawley ST, McQueen A, Bartholomew LK, et al. Preferences
for colorectal cancer screening tests and screening test use
in a large multispecialty primary care practice. Cancer.
2012;118(10):2726–​2734.
22. Inadomi JM, Vijan S, Janz NK, et al. Adherence to colorectal
cancer screening: a randomized clinical trial of competing strategies. Arch Intern Med. 2012;172(7):575–​582.
23. Liang PS, Wheat CL, Abhat A, et al. Adherence to competing
strategies for colorectal cancer screening over 3 years. American
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24. Murphy CC, Ahn C, Pruitt SL, et al. Screening initiation with FIT
or colonoscopy: post-​hoc analysis of a pragmatic, randomized
trial. Preventive Medicine. 2019;118:332–​335.
25. Daskalakis C, Vernon SW, Sifri R, et al. The effects of test preference, test access, and navigation on colorectal cancer screening.
Cancer Epidemiology, Biomarkers & Prevention: A Publication of
the American Association for Cancer Research, cosponsored by the
American Society of Preventive Oncology. 2014;23(8):1521–​1528.
26. Mehta SJ, Khan T, Guerra C, et al. A randomized controlled trial
of opt-​in versus opt-​out colorectal cancer screening outreach.
American Journal of Gastroenterology. 2018;113(12):1848–​1854.
27. Reuland DS, Brenner AT, Hoffman R, et al. Effect of combined patient decision aid and patient navigation vs usual care for colorectal
cancer screening in a vulnerable patient population: a randomized
clinical trial. JAMA Internal Medicine. 2017;177(7):967–​974.
28. Corley DA, Jensen CD, Quinn VP, et al. Association between time
to colonoscopy after a positive fecal test result and risk of colorectal cancer and cancer stage at diagnosis. JAMA: The Journal of
the American Medical Association. 2017;317(16):1631–​1641.
29. Selby K, Baumgartner C, Levin TR, et al. Interventions to improve
follow-​up of positive results on fecal blood tests: a systematic review. Annals of Internal Medicine. 2017;167(8):565–​575.
30. Liss DT, Petit-​Homme A, Feinglass J, Buchanan DR, Baker DW.
Adherence to repeat fecal occult blood testing in an urban community health center network. Journal of Community Health.
2013;38(5):829–​833.
31. Gellad ZF, Stechuchak KM, Fisher DA, et al. Longitudinal adherence to fecal occult blood testing impacts colorectal cancer screening
quality. American Journal of Gastroenterology. 2011;106(6):1125–​1134.
32. Fenton JJ, Elmore JG, Buist DS, Reid RJ, Tancredi DJ, Baldwin
LM. Longitudinal adherence with fecal occult blood test
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Green BB. Longitudinal predictors of colorectal cancer screening
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35. Jensen CD, Corley DA, Quinn VP, et al. Fecal immunochemical
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effectiveness of a multifaceted intervention to improve adherence
to annual colorectal cancer screening in community health centers. Cancer Causes & Control: CCC. 2015;26(11):1685–​1690.
Singal AG, Gupta S, Skinner CS, et al. Effect of colonoscopy
outreach vs fecal immunochemical test outreach on colorectal cancer screening completion: a randomized clinical
trial. JAMA: The Journal of the American Medical Association.
2017;318(9):806–​815.
Murphy CC, Sandler RS, Grubber JM, Johnson MR, Fisher DA.
Underuse and overuse of colonoscopy for repeat screening and
surveillance in the Veterans Health Administration. Clinical
Gastroenterology and Hepatology: The Official Clinical Practice
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2016;14(3):436–​444.e1.
Chubak J, McLerran D, Zheng Y, et al. Receipt of colonoscopy
following diagnosis of advanced adenomas: an analysis within
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Society of Preventive Oncology. 2019;28(1):91–​98.
Murphy CC, Lewis CL, Golin CE, Sandler RS. Underuse of surveillance colonoscopy in patients at increased risk of colorectal cancer.
American Journal of Gastroenterology. 2015;110(5):633–​641.
Fedewa SA, Yabroff KR, Smith RA, Goding Sauer A, Han X,
Jemal A. Changes in breast and colorectal cancer screening after
Medicaid expansion under the Affordable Care Act. American
Journal of Preventive Medicine. 2019;57(1):3–​12.
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cancer screening in the era of the Affordable Care Act. Journal of
General Internal Medicine. 2016;31(3):315–​320.
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screening process in community settings: a conceptual model for
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Oncology. 2014;23(7):1147–​1158.
Green BB. Colorectal cancer control: where have we been
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2018;178(12):1658–​1660.
8
Cervical Cancer Screening and
HPV Vaccination
Multilevel Challenges to Cervical Cancer Prevention
Richard Fielding, Samara Perez, Zeev Rosberger, Ovidiu Tatar, and Linda D. L. Wang
Introduction
Although largely preventable, cervical cancer is a disease that affects
over half a million women each year. Despite a safe and effective vaccine having been available for 13 years, cervical cancer still causes
over 300,000 deaths per year, 90% of which are in low-​income (LICs)
and lower-​middle-​income countries (LMICs). Despite monumental
advances in prevention, screening, diagnosis, and treatment over the
past decade, substantial regional and global disparities in cervical
cancer outcomes remain and cervical cancer continues to be a major
worldwide health challenge.
Epidemiology of Cervical Cancer
Cervical cancer ranks as the 10th most prevalent cancer overall
and the fourth for both incidence and mortality among females1.
Cervical cancer is second only to breast cancer in terms of cumulative risk from birth to age 74 in LICs and LMICs.1 Cervical cancer
is often referred to as the “disease of disparity” as age-​standardized
rates (ASRs) for cervical cancer are highest in the LMICs of Africa
and Melanesia. For example, Swaziland ranks #1 with an ASR of 75.3
and Kenya ranks #20 with an ASR of 33.8 cases per 100,000 of the
population. The only non-​African country in the top 20 is Bolivia,
which ranks 16, with an ASR of 38.5. Countries in Southeast Asia,
Eastern Europe, the Caribbean, and South America have the next
highest rates.2
In contrast, rates are 7–​10 times lower in high-​income countries
(HICs: e.g., US, Canada, New Zealand/​Australia, and West Asia).1
Importantly, even in developed countries, disparities remain and
disproportionately impact certain women compared to others. For
example, in the US, Hispanic and Black American women historically have faced a higher incidence of cervical cancer than other
ethnicities, attributable to lower screening rates, lower adherence to
medical follow-​up recommendations after abnormal screening results, and poorer-​quality medical treatment.
Most cases of cervical cancer are caused by human papilloma virus
(HPV) subtypes. Of the hundreds of types, 12 have been identified
as Class 1 carcinogens by the International Agency for Research
on Cancer (IARC).1 Despite HPV being the most prevalent sexually transmitted disease, the vast majority of women infected do not
develop cancer. Transient infections may cause low-​grade cervical
lesions, but 90% of HPV infections clear naturally within several
months. Other environmental cofactors include (1) early onset of
sexual activity and (2) higher number of sexual partners, both of
which increase HPV exposure frequency and duration, thereby indirectly affecting risk;2 (3) being overweight;2 (4) smoking, which
accounts for around 2% of cervical cancer cases;1,2 and (5) immunosuppression conditions, such as human immunodeficiency virus
(HIV).1 Persistent HPV infection is therefore the main risk factor
for cervical cancer.
Public Health Burden from Cervical Cancers
Rates of cervical cancer have declined globally over the past few
decades, in part due to increasing socioeconomic development,
as well as reduced persistence of HPV infection arising from general improvements in hygiene, reductions in parity (number of
births), and declining sexually transmitted disease incidence.1 In
virtually all HICs, including the US, Canada, Australia, Germany,
the Netherlands, Italy, and Sweden, cervical cytology has played
a crucial role in substantially bringing down deaths from cervical
cancers. In the absence of effective cervical screening, the reverse
trend is found, with premature mortality rates from cervical cancer
increasing.
In May 2018, the World Health Organization (WHO) declared
cervical cancer as “one of the world’s deadliest, but the most easily
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preventable forms of cancer for women.”3 The director-​general of
the WHO called for “coordinated action globally to eliminate cervical cancer,” with the plan to submit a resolution of a global cervical cancer elimination strategy at the World Health Assembly in
May 2020.3
The implementation of both cervical cancer screening and HPV
vaccination programs faces multiple challenges, particularly in the
developing world. Common established barriers include high vaccine prices in countries where no funded vaccination programs
exist, poor heath infrastructure, low health literacy, lack of political
will, vaccine hesitancy, evolving shifts in screening technologies,
and competing public health priorities in countries with limited
resources. A further complicating factor is that cervical cancer is
exclusively a disease that affects females, and in many countries, patriarchal values place a lower priority on girls and women and their
health, limiting arguments for extending preventive care to women’s
sexual health. Most recently, the growing anti-​vaccine movement
has emerged, which adds major challenges to cervical cancer prevention. In Japan and India, for example, unrelated deaths of recently vaccinated young girls were cited as sufficient rationale to
lead to a suspension of the national HPV vaccination program in
Japan and the continued blockage of HPV vaccine inclusion in the
Universal Vaccination Program in India.
HPV Vaccines
The primary prevention strategy for cervical cancer is HPV vaccination. There are three HPV vaccines available: the bivalent vaccine
Cervarix®, the quadrivalent vaccine Gardasil®, and the nonavalent
vaccine Gardasil® 9. The primary target of publicly funded HPV
vaccination programs is girls aged 9–​14 years old with a two-​dose
schedule. Girls and women over 15 are recommended to receive
a three-​dose schedule. All three vaccines protect against types 16
and 18, which are the oncogenic high-​risk types, and are responsible for about 70% of all cervical cancers. Gardasil® 9 offers protection against five additional high-​risk HPV types and can prevent
up to 90% of cervical cancers. The HPV vaccines have proven to be
safe and highly immunogenic and to induce strong direct and indirect (cross-​immunity) protection against HPV. With the development of these vaccines, there is the likelihood of almost completely
eliminating cervical cancer among vaccinated women, particularly
in the context of continued cervical cancer screening programs and
wide population vaccine coverage.
HPV Vaccine Availability and Accessibility: Successes
and Challenges
Over the last 13 years, the HPV vaccine has been approved in 129
countries, and over 270 million doses of the vaccine have been distributed worldwide.4 The proportion of countries that have introduced
HPV vaccine by WHO regions are Africa—​17%, Americas—​69%,
Eastern Mediterranean—​5%, Europe—​64%, Southeast Asia—​27%,
and Western Pacific—​48%.5 These percentages reflect why the title
of “disease of disparity” has far from faded. Worldwide, only one-​
quarter of girls aged 9–​14 years live in a country with a national
HPV program (~90 programs and 38 pilot programs), with the vast
majority of national programs in upper-​middle-​income countries
(UMICs) and HICs and most pilot programs in LICs and LMICs.5,6
The proportion of countries that have introduced HPV vaccination
by World Bank categories are LICs—​13%, LMICs—​20%, UMICs—​
42%, and HICs—​82%, with 43% globally. Unfortunately, those most
at risk of cervical cancer are the least likely to have access to the vaccine, with only 13 LICs having HPV programs.5
The most extensive estimates report a worldwide HPV vaccine
coverage of 6.1% (95% confidence interval [CI]: 4.9–​7.1) among females aged 10–​20 years, with a 33.6% coverage (95% CI: 25.9–​41.7)
in more developed regions and a mere 2.7% coverage (95% CI: 1.8–​
3.6) in less developed regions.5 High, successful coverage (i.e.,
reaching targets of >80–​90%) among the target population has been
achieved in 18 countries, for example, Australia, Bhutan, Iceland,
Malaysia, Mexico, Rwanda, and Seychelles, typically through
school-​based programs, complemented and supported by health facility outreach.5
The GAVI Alliance, a public-​private partnership working to improve vaccine coverage worldwide, has launched demonstration
programs in Ghana, Kenya, Laos, Madagascar, Malawi, Niger, Sierra
Leone, and Tanzania providing HPV vaccines to girls 9–​13 years
old through schools and community health programs since 2013.
Through these demonstration programs, an estimated 180,000 or
more girls have been protected from HPV. GAVI expects to have
more than 30 million girls vaccinated in over 40 countries by 2020.6
However, many LICs do not offer regular health services for girls
aged 9–​13 and it is difficult to ensure that these programs will reach
those at highest risk. Civil unrest in many countries compounds
these difficulties.
The two countries with the largest populations globally, India
and China, currently lack population-​based programs for HPV
vaccination.
India
According to data compiled by the HPV Information Center, a collaboration of the Catalan Institute of Oncology and the IARC, India
has one of the world’s highest burdens of HPV-​related cancer. More
than 122,000 Indian women are diagnosed with cervical cancer and
around 67,000 die from this disease each year, which is greater than
the country’s maternal mortality burden of 45,000.7 Estimates have
been made of the cost-​effectiveness of various cervical cancer control strategies, namely vaccination prior to 12 years of age and cancer
screening among women above 30 years of age living in India. If
a bivalent vaccine coverage of 70% was assumed, there would be a
44% mean reduction in the lifetime risk of cervical cancer.7 If HPV
testing twice in one’s lifetime was added in the analysis, mean risk
reduction increased to 63%.7 The combination of HPV vaccine and
screening (either using visual inspection with acetic acid [VIA] or
HPV DNA testing) was reported as cost-​effective for India if the cost
per vaccinated girl was $10 USD (653 INR). Recommendations for a
combined vaccination/​screening program have been made by medical bodies7 and the Indian Council of Medical Research, which advises government about inclusions into the Universal Vaccination
Program. Unfortunately, aggressive objections from nationalist
groups, some arising from an earlier failed clinical trial and accusations of associated deaths that on closer investigation proved
to be due to unrelated snakebites, drowning, or suicides, have so far
blocked the implementation of a national program in India.
CHAPTER 8 Cervical Cancer Screening and HPV Vaccination
China
In July 2016, China’s Food and Health Administration approved
the bivalent vaccine, a decade after the first HPV vaccine’s licensing
in the US. This delay resulted from no priority-​setting system in a
lengthy trial registration and almost 8-​year-​long clinical trials done
in the domestic population. The approval lag in mainland China for
HPV vaccines prompted thousands of women and girls to seek vaccination in Hong Kong, where HPV vaccines have been available
since 2006. The quadrivalent and nonavalent HPV vaccines were
recently approved for future use in mainland China. While there is
no publicly funded vaccination program, nor even official publicity
regarding HPV vaccination, potential vaccine recipients must register for HPV vaccination at their local community health centers.
Waiting times for the first vaccination vary from a few months to
more than one year. On September 23, 2019, China’s central government released Healthy China Action—​Implementation Program
for Cancer Prevention and Control (2019–​2022). This document
presents plans for a strengthened scientific campaign of HPV vaccination and promotion of HPV vaccination uptake among the
age-​appropriate population; acceleration of the approval process for
domestic HPV vaccine production, thereby improving vaccine accessibility; and mechanisms to impel vaccine suppliers to set reasonable prices through price negotiation and centralized purchasing,
and it suggests exploring various channels to ensure effective population coverage in poor areas of China. Given the important role of
social influence in Chinese vaccination decision-​making,8 the central government action plan should help to substantially increase the
uptake rate of HPV vaccination and further reduce cervical cancer
incidence in this enormous population.
High-​Income Countries
In contrast to India and China and many other LICs and LMICs,
HPV vaccination programs are more widely established in UMICs
and HICs, yet uptake rates vary considerably—​
not only from
country to country, but also within the same country or jurisdictions, evidencing state/​provincial, regional, local, and territorial
differences.4 Australia was the first country globally to introduce
a nationwide HPV vaccination program for girls in 2007, followed
by vaccination for boys in 2013, and by 2017 it had successfully
achieved national coverage rates of 80% for females and 76% for
males. The UK reports stable and consistent uptake rates of 80–​90%
in their 2017/​2018 school-​based HPV vaccination programs for
girls, and young boys are now included as of the 2019 academic year.
The Netherlands achieves HPV vaccination coverage among girls of
~65% and recently agreed to include boys, along with lowering vaccination age to 9 years. In the US, the HPV vaccine is funded and
included nationally by the Vaccines for Children Program and by
private insurance, and coverage is mandated by the Affordable Care
Act. Importantly, substantial variation has been reported by state,
with HPV vaccine coverage as high as 87.5% in Massachusetts and
as low as 52.2% in Kentucky in 2018. In Canada, all 10 provinces
and three territories have publicly funded school-​based HPV vaccination programs for females and males in place. Canadian rates as
high as 90% in Newfoundland and Labrador and as low as 40% in the
Northwest Territories have been reported.4
From an accessibility standpoint, the HPV vaccine supply is insufficient to meet demand. There are challenges with price and
affordability, including high price per vaccine dose; highly variable
pricing, with some HICs paying less than the average LMIC prices;
and additional delivery operation costs. From an acceptability standpoint, many countries continue to face numerous challenges related to population fears of adverse side effects4 and concerns about
safety and growing reactionary attitudes toward vaccination in general. These have significantly impacted and lowered the coverage
rate in numerous countries that previously had high levels of vaccine uptake—​for example, Japan (1%), Denmark (54%), Columbia
(14%), and Ireland (50%), to name a few.
These challenges sometimes overshadow the successes of HPV
vaccination.4 A recent meta-​analysis9 of 65 studies from 14 HICs
using pooled follow-​up data collected over 9 years on 60 million
people found that there have been declines in HPV 16 and 18 infections of 83% (relative risk [RR] 0.17; 95% CI: 0.11–​0.25) among
vaccinated girls and young women aged 13 to 19 years and 66% (RR
0.34; 95% CI: 0.23–​0.49) among women aged 20–​24 years, while
there was a significant decrease in the prevalence of HPV 31, 33,
and 45 infections in 13–​19-​year-​old girls and women (RR 0.46; 95%
CI: 0.33–​0.66). Taken together, these five HPV strains account for
90% of all cervical cancer cases. Moreover, nonvaccinated populations such as older women, boys, and men have also benefited from
vaccination of young girls through reduced rates of infection.9 Thus,
the impact of HPV vaccination transcends beyond cervical cancer
and also helps prevent other HPV-​related cancers such as anal, penile, and head and neck cancers.
However, vaccination alone, even if widely implemented, will not
eradicate cervical cancer for several reasons. First, over 100 HPV
serotypes have been identified, and while the seven most oncogenic
strains are covered by existing HPV vaccines, other less oncogenic
strains do remain. With the existing HPV vaccines, 70–​75% of all
cervical cancer cases are preventable given 80–​100% population
coverage, though such coverage relies on vaccination rates currently
underachieved in many parts of the world and assumes a world
where people do not travel easily and often. Therefore, it is necessary
to retain and more effectively implement cervical cancer screening
as a core element of cervical cancer prevention and control.
Strong evidence has emerged that high-​risk HPV testing has
greater sensitivity for cervical cancer risk than does cytology in
detecting cervical intraepithelial neoplasia (CIN) in primary cervical cancer screening and is less prone to misinterpretation due
to human error. Cost issues, however, may limit uptake LICs and
LMICs. Taken together with HPV vaccination, there is a major opportunity for improved screening to drive down long-​term rates
of advanced disease leading to the virtual elimination of cervical
cancer.
Cervical Cancer Screening
The goal of cervical cancer screening is to identify those at high risk
of developing the disease, in this case women having an immediate
precursor lesion (CIN). The effective prevention of progression to
cervical cancer depends on this early detection. Screening requires
three related approaches to be successful: an effective testing protocol
associated with a continuous case-​finding policy, the willingness of
susceptible individuals to attend screening, and affordable and effective follow-​up and treatment in those who screened positive.
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SECTION II Cancer Screening in Normal and At-Risk
Screening Protocols in High-​and
Low-​Resource Settings
Screening may involve a multistep process involving cervical cytology, for example, Papanicolaou (“Pap”) test/​smear or liquid
cytology, and/​or HPV testing, with colposcopy/​biopsy where dysplasia is suspected. Cytology requires a sample of cells scraped
from the cervix that are later manually or, increasingly, automatically (liquid cytology) scanned for abnormal cells. Generally, cytology is recommended every 3 years, cotesting (cytology + HPV
testing) every 5 years, and HPV testing alone every 5 years. Pap
smears alone, though, have low sensitivities of around 53–​55%,
compared to HPV DNA testing, which has sensitivities of ~95%,
while both combined give a sensitivity of 100% with 92% specificity.10 However, this approach is both expensive and cumbersome,
and unsuitable for most LICs where cervical cancer incidence remains high. Moreover, HPV testing before 25 years old is not indicated as the incidence of HPV infections is high and very rarely
associated with dysplasia, and testing has unnecessary financial and
psychological costs. In LICs, visual inspection of the cervix (VIC)
after application of 3–​5% acetic acid or Lugol’s iodine is often used
and can achieve sensitivities of 73–​85% with 85% specificity.10 This
approach has been shown to reduce lifetime risk to women from
cervical cancer by around 40%. However, performance remains dependent on the skill of the observer. To avoid this, countries are increasingly moving and progressing toward a single screening HPV
test that offers greater sensitivity. There is controversy as to which
approach is optimal, and cost-​effectiveness is a key issue. Table 8.1
describes programs in a selection of countries, highlighting policy
variations (organized vs. opportunistic) and implementation decision strategies. To help decision makers, in 2014, the WHO3
published a manual entitled the Comprehensive Cervical Cancer
Control: A Guide to Essential Practice, which offers expert panel
guidelines on screening and treatment protocols. As mentioned
earlier, with the WHO director-​general’s 2018 call to action for the
elimination of cervical cancer, many individuals including seven
working groups are trying to accelerate the dissemination of up-​
to-​date cervical cancer screening recommendations based on the
evolving scientific evidence.
Table 8.1. Examples of Routine HPV Vaccination Policy and Primary Cervical Cancer Screening Protocols
Country
Routine HPV Vaccination Policy
Primary Screening for Cervical Cancer
a
Australia
Organized, school-​based HPV vaccination program at age 12–​13
for girls and boys. Girls and boys up to age 19 can receive HPV
vaccine for free.
Organized HPV-​based testing program from ages 25 to 74 at 5-​year intervals
Canada*b
Organized, school-​based HPV vaccination program given at ages
9–​15*
Organized cytology program in 9 out 13 provinces/​territories at 2-​or 3-​year
intervals starting at age 21 or 25 until 65 or 70*
UKc
Organized, school-​based HPV vaccination programs at ages 12–​13
for girls
Organized HPV-​based testing program (with cytology) from ages 25 to 49 at
3-​year intervals, or at 5-​year intervals for women aged 50–​64 years
Netherlandsd
Organized, school-​based HPV vaccination program at ages 12–​13
for girls only
Organized HPV-​based testing program from ages 30 to 60 at 5-​year intervals
USe
Opportunistic HPV vaccination
Opportunistic screening with cytology for ages 21–​29 at 3-​year intervals;
opportunistic screening with cytology at 3-​year intervals or HPV testing at
5-​year intervals or cotesting at 5-​year intervals from ages 30 to 65. Women
aged 30–​65 should discuss with their HCP which of the 3 recommended
screening strategies work best for them.
No organized HPV vaccination program available
Organized HPV-​based testing program at ages 30–​65 at 5-​year intervals
India
No organized HPV vaccination program. The Indian Academy of
Pediatrics Committee on Immunization recommends offering HPV
vaccine to all females who can afford the vaccine.
No cervical cancer screening program. Screen-​and-​treat approach using
visual inspection with acetic acid, consistent with WHO guidelines for
countries that do not have cervical cancer screening programs
Chinag
No established HPV vaccination program
Organized cytology screening program for rural women aged 35–​59 years.
Opportunistic screening and regular cervical screening benefits offered by
urban employers for married female employees
Turkeyf
g
*Variations in grade given dependent on province/​territory.
European guidelines recommend implementation of HPV-​based screening starting at 30–​35 years at >5-​year intervals up to 60–​69 years. WHO guidelines recommendation: HPV
screening age 30 and older, every 3–​5 years; Cytology acceptable if HPV unavailable and cytology of good quality; visual inspection after application of acetic acid as alternative in
low-​resource settings. 7
a
Australian Government Department of Health. 2018. National Cervical Screening Program. http://​www.cancerscreening.gov.au/​internet/​screening/​publishing.nsf/​Content/​
cervical-​screening-​1
b
Canadian Partnership Against Cancer. 2018. Cervical cancer screening in Canada: Environmental scan. https://​www.partnershipagainstcancer.ca/​topics/​
cervical-​cancer-​screening-​environmental-​scan-​2018/​
c
Cancer Research UK. 2019. Cervical cancer screening. https://​www.cancerresearchuk.org/​about-​cancer/​cervical-​cancer/​getting-​diagnosed/​screening/​about
d
National Institute for Public Health and the Environment. 2019. Cervical cancer screening programme. https://​www.rivm.nl/​en/​cervical-​cancer-​screening-​programme
e
U.S. Preventive Task Force. 2019. Final Recommendation Statement, Cervical Cancer: Screening. https://​www.uspreventiveservicestaskforce.org/​Page/​Document/​
RecommendationStatementFinal/​cervical-​cancer-​screening2
f
Turkey Public Health Institution Cancer Control Department. 2016. Turkey Cancer Control Programme. https://​www.iccp-​portal.org/​system/​files/​plans/​Turkiye_​Kanser_​Kontrol_​
Program_​English.pdf
g
Geneva Foundation for Medical Education and Research, Obstetrics and Gynecology Guidelines. Cervical cancer screening, prevention. Accessed on December 13, 2019, from
https://​www.gfmer.ch/​Guidelines/​Female_​genital_​neoplasms/​Cervical_​cancer_​screening.htm
CHAPTER 8 Cervical Cancer Screening and HPV Vaccination
Changes in Screening Recommendations and
Programs Worldwide
New recommendations in the US, Europe, and Australia incorporate
HPV testing as a primary screen for cervical cancer in women aged
between 30 and 65 years, either as a stand-​alone test11–​13 or with cytology (cotesting).13 Globally, population-​based HPV test screening
programs that replace Pap testing (cytology) are being implemented
in Australia, the Netherlands, Sweden, and Italy, while the UK and
Norway started in 2019.14 Other HICs considering such a shift include Canada, France, and Finland.14 Of the existing organized HPV
test-​based screening programs, there are noted variations, including
age of starting (e.g., 25–​35 years old) and ending screening (e.g., 60–​
74 years old), triage of HPV-​positive women (e.g., cytology, colposcopy, repeat HPV testing in 1 year), and longer screening intervals
(e.g., 3–​5 and possibly up to 10 years).14 As an increasing number of
vaccinated females move into the screening target population, ensuring the most appropriate screening protocol to maximize benefits
and minimize potential harms for both vaccinated and unvaccinated
women becomes even more pressing.
Barriers and Facilitators to HPV: Vaccination, Screening,
and Testing
Central to cervical cancer prevention is the recipient’s or recipient’s
parent’s knowledge, beliefs, understanding, and ultimately acceptance of HPV vaccination and/​or screening. While HPV vaccination
is currently widely and unequivocally backed by the scientific and
medical communities, sociocultural and behavioral challenges remain at the individual level,4 as well as accessibility, availability, and
cost at the country level, particularly in LICs and LMICs.
At the individual level, vaccination decision-​making is complex
and multifaceted. Currently, parental unwillingness to have their
young children vaccinated has led to both lower vaccination coverage and the resurgence of several vaccine-​preventable infections,
notably measles and pertussis. Novel, nonmandated vaccines particularly generate concerns about safety, “newness” (though HPV vaccines have now been available for over 13 years), and side effects.4
Vaccination hesitancy and general anti-​vaccine attitudes are cited as
barriers to HPV vaccination for certain subpopulations. Moreover,
there are differences in sociocultural characteristics: for example,
some studies15 indicate Chinese groups have lower HPV vaccination coverage in the US, while elsewhere lower income, having fewer
children, religiosity, and suspicion about physicians’ motivation are
associated with higher belief that such vaccination was unnecessary,
despite considering vaccination generally to be effective and beneficial. One particular variable that has consistently emerged from
studies of Chinese parents is that anticipated affective consequences
(asking parents to think about how they might feel if their daughter
developed cervical cancer) and social influences (knowing other
parents were vaccinating their daughters) influence parents’ plans to
vaccinate their daughters. These factors may have wider relevance in
other Asian communities.
There is also discussion about where and who is best positioned
to give the HPV vaccine. In middle-​income countries and HICs, the
health care provider (HCP), be they doctor, nurse, or pharmacist,
can provide key information to motivate an individual to receive the
HPV vaccine. Moreover, organized, government-​funded programs
administered at school are likely to be the most cost-​effective and
optimal approach, though children not attending school would be
missed.7 However, as is the case in India, where it has led to prolonged deferral of program implementation, reactive patriarchal attitudes are often evoked in response, reflecting the wider issue of
women’s rights.
Barriers to Pap screening uptake include availability, accessibility,
affordability, and the lack of women physicians or health workers.
However, a self-​administered cervical swab can now be used to provide cytology samples for HPV DNA testing, where this is available,
removing some of the privacy issues that can discourage women
from undergoing vaginal inspection. Self-​sampling “represents a
new advance in cancer control that is unequivocally empowering
to women” and can effectively reach underscreened (and often marginalized) women in which about half of all invasive cervical cancers are diagnosed.16 Overcoming women’s lack of knowledge and
anxieties surrounding cervical screening requires both wider education, particularly among older women, those of low socioeconomic
status, and those from diverse ethnicities, and interventions aimed
to encourage health workers to ask and prompt female clients about
cervical screening.
HPV and Cervical Cancer Screening Messaging
Safe and effective public health programs can fail because of lack
of effective communication. The development of the internet and
the rise of social media make it clear that a new public health program must be introduced carefully so that the target population’s
unique needs are considered in order to increase uptake. This requires the effective education and mobilization of key stakeholders,
including not only the young women and girls themselves but also
parents, health practitioners/​providers, community leaders, religious leaders, teachers, and journalists.
With respect to HPV vaccine messaging, high levels of HPV vaccine acceptance are most likely a result of the extensive educational
work done in the communities prior to vaccine introduction, a key
point described in the PATH HPV Vaccine Lessons Learnt Project,
which is part of a comprehensive review of HPV vaccine delivery experiences across 46 low-​and middle-​income countries.17 Emphasis
on the protection against cancer has been critical in many communities that don’t necessarily understand that HPV is the cause of the
cancer itself. As such, a key and clear message is that the HPV vaccine prevents cervical cancer, is safe, will not harm future fertility,
and is endorsed as safe and effective by public health and other medical professionals, the government, and the WHO.
Women’s negative attitudes related to deferring the start of
screening using HPV testing to 25 or 30 years and/​or increasing the
screening interval to 5 years or more, and women’s negative emotions and perceptions related to HPV testing (since it detects a sexually transmitted infection) represent important barriers toward
implementation of HPV testing in primary screening.18 Addressing
these barriers in a timely manner underscores the importance of effective communication about forthcoming HPV test-​based national
screening programs.
Adequate stakeholder engagement in policy setting appears to be
crucial. For example, in Australia, following inadequate community
engagement prior to government announcing changes to screening
protocols, women’s collective anxiety fueled an organized, grassroots
online petition titled “Stop May 1st Changes to Pap Smears—​Save
Women’s Lives” signed by more than 70,000 women, which forced
65
66
SECTION II Cancer Screening in Normal and At-Risk
the Australian Ministry of Health into a 6-​month delay of the implementation date to December 2017. Nevertheless, the only informational response to women was a one-​paragraph letter from the
Ministry of Health summarizing the major points of the change with
no apparent input from women. Preliminary reports indicated that,
subsequently, initial uptake of HPV testing is suboptimal.
Similarly, in the UK, where the new screening program started
in 2019, to the best of our knowledge, little information has been
disseminated thus far. In the Netherlands, women over age 40 have
been expressing concerns about a proposed 10-​year screening interval after a negative HPV test.
In countries without a national HPV test-​based cervical screening
program, HCPs’ recommendation for the HPV test is critical.19 In
the context of multiple updates of specialty organizations’ guidelines
for HPV testing over the last decade and inconsistencies in these
guidelines, a recent review has shown that HCPs’ recommendations
for HPV testing are suboptimal.19 Improving consistency across
guidelines and educational interventions for HCPs is needed to increase HPV test uptake.
Psychological Impact of a Positive HPV Test Result
after Cervical Cancer Screening
Women’s reactions to testing positive for HPV reflects a complex interaction between emotions (feelings), cognitions (thoughts, beliefs,
attitudes), and behaviors (actions).20 Receiving a positive HPV test
result is associated with elevated state anxiety that declines if women
subsequently search for HPV-​related information and adopt open
and communication-​rich interactions with HCPs. Similarly, testing
positive for HPV may elicit significant levels of nonspecific or sexual
distress around, for example, impact of the result on close relationships or fertility concerns, which persists for at least 6 months. Being
diagnosed with high-​risk HPV types 16 and 18 can trigger feelings
of fear, compounded by the necessity to attend frequent follow-​ups
after testing positive, that fuel women’s thoughts about the probability of developing cervical cancer at some point.20 Not surprisingly,
considering that HPV is a sexually transmitted infection, a positive
HPV test result can evoke feelings of shame and disgust in affected
women that persist for at least 6 months after diagnosis, along with
worries about being sexually rejected by prospective partners. Long-​
time monogamous relationships can fuel a false sense of security
related to sexually transmitted diseases and explain women’s initial emotional reaction of surprise when testing HPV positive and
confusion that can be explained by their lack of knowledge related
to the asymptomatic nature of HPV infection.20 In some societies
a positive test result may even precipitate incorrect accusations of
primarily female infidelity and, in extreme cases, marital breakup.
Further, testing positive for HPV can be associated with sadness or
feelings of depression. Facilitators of coping favorably with a positive
HPV test result include acceptance that HPV infections are inevitable when having an active sexual life, receiving reassuring information from HCPs about the natural course of HPV infection and
treatment options for precancerous lesions, and their resilience in
dealing with health issues. Taken together, HCPs should be aware
that HPV-​positive test results can have a significant psychological
impact on women and should be prepared to address their needs in
an open and reassuring way and offer and encourage psychological
counseling with knowledgeable professionals.
Future Directions and Challenges
In contrast with almost all other cancers, we have the tools to eliminate and eradicate this disease. This in itself is likely why cervical
cancer is one of the WHO’s top 10 global health priorities for 2020–​
2030.3 The WHO’s proposed target is that 90% of girls receive the
HPV vaccine by 15 years old, that 70% of women are screened with
an HPV test at 35 and 45 years of age, and that 90% of women identified with cervical cancer receive treatment and care;3 these goals are
intensive but are within our reach. Studies are underway to confirm
if using a single dose of the HPV vaccine offers adequate protection
against cervical cancer. A one-​dose HPV vaccination schedule would
decrease vaccination costs and increase vaccination coverage globally. This possibility, combined with a focus on school settings for
optimal delivery as well as government funding, augurs well for high
levels of HPV vaccine coverage globally. Moreover, both enhancing
demand and simplifying the protocol and implementation of organized HPV testing are key to reaching the WHO goals. However, the
policy landscape internationally is vulnerable to cosmic shifts. For
example, at the time of completing this chapter, the WHO Strategic
Advisory Group of Experts (SAGE) on immunization, in response
to a worldwide unexpected shortage of vaccine production capacity
to meet demand, has recommended that “all countries should temporarily pause implementation of gender neutral, older age group,
and multi-​age cohort HPV vaccination strategies until supply allows
equitable access by all countries,” until the supply shortfall is met
by 2024. While the immediate justification is that available vaccines
should be delivered to women most at risk in LMICs, for example,
there may be unintended consequences in countries that have already implemented gender-​neutral programs. Stopping or delaying
gender-​neutral programs could provoke a backlash among parents
of eligible boys and could inadvertently provide more fodder for
the anti-​vaxxer movement by suggesting that males are not as “at
risk” as has been previously advocated. A better recommendation
might have been to invest in screening programs more rapidly in
LMICs in the interim, programs that will be critical, in addition to
vaccines to ensure effective prevention in the future.21 Differences in
infrastructure, cultural barriers, technology, and ability to feasibly
address prevention and treatment strategies are key reasons that
the epithet “disease of disparity” cannot yet be shed. By using clear
policy protocols coupled with appropriate use of vaccines and effective, well-​established screening strategies, morbidity from cervical
cancers can be drastically reduced and hopefully eliminated in the
foreseeable future.
REFERENCES
1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A.
Global cancer statistics 2018: GLOBOCAN estimates of incidence
and mortality worldwide for 36 cancers in 185 countries. CA: Can J
Clinicians. 2018; 68: 394–​424.
2. Continuous Update Project. 2018. https://​www.wcrf.org/​
dietandcancer/​cancer-​trends/​cervical-​cancer-​statistics.
3. World Health Organization. Global Strategy Towards the
Elimination of Cervical Cancer as a Public Health Problem.
[Internet]. 2019. https://​www.who.int/​docs/​default-​source/​documents/​cervical-​cancer-​elimination-​draft-​strategy.pdf. Accessed
June 3, 2019.
CHAPTER 8 Cervical Cancer Screening and HPV Vaccination
4. Perez S, Zimet GD, Tatar O, Stupiansky NW, Fisher WA, Rosberger
Z. Human papillomavirus vaccines: successes and future challenges. Drugs. 2018; 78: 1385–​1396.
5. Bruni L, Diaz M, Barrionuevo-​Rosas L, et al. Global estimates of
human papillomavirus vaccination coverage by region and income
level: a pooled analysis. Lancet Glob Health. 2016; 4: e453–​463.
6. Gallagher KE, LaMontagne DS, Watson-​Jones D. Status of HPV
vaccine introduction and barriers to country uptake. Vaccine.
2018; 36: 4761–​4767.
7. Kaur P, Mehrotra R, Rengaswamy S, et al. Human papillomavirus
vaccine for cancer cervix prevention: rationale & recommendations for implementation in India. Ind J Med Res. 2017; 146: 153.
8. Wang LD-​L, Lam WWT, Fielding R. Determinants of human papillomavirus vaccination uptake among adolescent girls: a theory-​
based longitudinal study among Hong Kong Chinese parents.
Prevent Med. 2017; 102: 24–​30.
9. Drolet M, Bénard É, Pérez N, et al. Population-​level impact and
herd effects following the introduction of human papillomavirus
vaccination programmes: updated systematic review and meta-​
analysis. Lancet. 2019; 394: 497–​509.
10. Brown AJ, Trimble CL. New technologies for cervical
cancer screening. Best Pract Res Clin Obstet Gynaecol.
2012;26(2):233–​242.
11. von Karsa L, Arbyn M, De Vuyst H, et al. European guidelines
for quality assurance in cervical cancer screening. Summary of the
supplements on HPV screening and vaccination. Papillomavirus
Res. 2015; 1: 22–​31.
12. Huh WK, Ault KA, Chelmow D, et al. Use of primary high-​risk
human papillomavirus testing for cervical cancer screening: interim clinical guidance. Gynecol Oncol. 2015; 136: 178–​182.
13. U.S. Preventive Services Task Force. Screening for cervical
cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018; 320: 674–​686.
14. Wentzensen N, Arbyn M, Berkhof J, et al. Eurogin 2016
roadmap: how HPV knowledge is changing screening practice. Int
J Cancer. 2017; 140: 2192–​2200.
15. Wang LD-​L, Lam WWT, Fielding R. Hong Kong Chinese parental
attitudes towards vaccination and associated socio-​demographic
disparities. Vaccine. 2016; 34: 1426–​1429.
16. Franco EL. Self-​sampling for cervical cancer screening: empowering
women to lead a paradigm change in cancer control. Curr Oncol.
2018; 25: e1–​e3.
17. London School of Hygiene & Tropical Medicine & Path. HPV
Vaccine Lessons Learnt Project overview. PATH. 2016. https://​
www.path.org/​resources/​hpv-​vaccines-​lessons-​learnt/​
18. Tatar O, Thompson E, Naz A, et al. Factors associated with human
papillomavirus (HPV) test acceptability in primary screening for
cervical cancer: a mixed methods research synthesis. Prevent Med.
2018; 116: 40–​50.
19. Tatar O, Wade K, McBride E, et al. Are health care professionals
prepared to implement human papillomavirus testing? A review
of psychosocial determinants of human papillomavirus test acceptability in primary cervical cancer screening. J Wom Health.
2019. Epub ahead of print doi.org/​10.1089/​jwh.2019.7678
20. Bennett KF, Waller J, Ryan M, Bailey JV, Marlow LAV. The psychosexual impact of testing positive for high-​risk cervical human
papillomavirus (HPV): a systematic review. Psycho-​Oncol. 2019;
28: 1959–​1970.
21. Arie, S. HPV: WHO calls for countries to suspend vaccination of
boys. BMJ. 2019; 367: l6765 doi:10.1136/​bmj.l6765
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9
Breast Cancer Screening
Gabriel M. Leung, Irene O. L. Wong, Ava Kwong, and Joseph T. Wu
Introduction
Globally breast cancer is the most common cancer in women, accounting for an estimated one-​quarter of all malignancies.1 While
the disease is now very treatable, there remains subgroups of patients who experience dire outcomes, for instance, those with triple-​
negative disease. Many survivors report significant disability, both
physical and psychosocial. Therefore, any effort to ideally prevent
incident disease or at least reduce cancer-​related morbidity and
mortality would be of enormous benefit to the individual patient as
well as whole populations at large.
While primary prevention by lifestyle modification and environmental improvements are the ultimate determinants of disease in
the long run,2 they are not easily amenable to rapid modification
given the long latency period and life-​course nature of cancer risks.
Screening thus represents the direct, expeditious intervention of
choice for many women and policymakers.
In this chapter, by screening, we mean mass or population-​based
screening of well women at average risk of disease unless otherwise specified. One should also take care to distinguish between
using the same test modality for screening as opposed to diagnosis
or postcancer surveillance. Our scope does not include high-​risk
groups, who may qualify for enhanced screening, intensive lifestyle
modification, and/​or even primary chemoprevention.
Breast Cancer Biology Determines
the Comparative Inefficiency of Screening
Unlike two other common cancers (i.e., colorectal and cervical) with
unequivocally accepted screening protocols, invasive breast malignancies do not exhibit an obligate precursor stage to allow for precancerous detection and thus intervention. The long-​held Wilson
and Junger screening criteria require that, among other attributes,
“the natural history of the condition, including development from latent to declared disease, should be adequately understood.”3 Modern
updates additionally stipulate that there should be a detectable preclinical state.3 Specifically applied to the case of breast cancer, over
80% of women with a previous diagnosis of carcinoma in situ (CIS),
whether of the ductal (DCIS) or lobular (LCIS) variety, remain free
of invasive breast cancer 20 years later.4 Nevertheless, those who
have been diagnosed with in situ conditions indeed demonstrate a
two-​to threefold elevated risk of developing breast cancer.4
Therefore, regardless of the screening modality deployed or design of the screening program, any preventive attempt to reduce
breast cancer–​related deaths would be handicapped by the biology
of the disease per se. Additionally, both cervical and colorectal cancers have precursor lesions, metaplastic intraepithelial lesions and
hyperplastic polyps, respectively, with a sufficiently long sojourn
time that are amenable to complete excision and thus primary prevention of invasive disease. In contrast, in situ neoplastic lesions of
the breast are nonobligate precursors only occasionally, whereas
true obligate precursor states remain to be identified.
Efficacy and Effectiveness of Screening
Mammography
Mammography basically refers to an x-​ray examination of the breast.
It has been the most intensively scrutinized and the only screening
modality shown to reduce breast cancer–​related deaths.
Since the eight original mammography screening trials involving
about half a million mostly Caucasian women in the developed
West, there have been many systematic reviews of these data (some
with longer-​term follow-​up) as well as observational effectiveness
studies of routine screening programs. They consistently converge
on a roughly 20% risk reduction of breast cancer–​related mortality
in women who start biennial screening from age 50 years.
Myers et al.,5 in the most comprehensive and most recent systematic review, reported that three major meta-​analyses of the trial
data, by the UK independent panel (“Marmot review”6), Canadian
task force,7 and Cochrane Collaboration8, have yielded almost
identical estimates at 18–​20% that reach the 0.05 alpha threshold.
Observational cohorts tended toward a larger effect size at 25%, as
would be anticipated given the uncontrolled or uncontrollable bias
inherent in the noninterventional study design. Figure 9.1 presents
summary estimates of the pooled effect sizes by study type and
age group.
CHAPTER 9 Breast Cancer Screening
Study
4 systematic reviews (UK Independent Panel,
Canadian Task Force, Cochrane, USPSTF) of 8 RCTs
Overall (UK Independent Panel)
Overall (Canadian Task Force)
Overall (Cochrane)
Design
Age 40–49
Age ≥50
Age 60–69
Age 70–74
1 systematic review including
Meta-analysis of 7 cohort studies
95% CI
0.80
0.82
0.81
0.85
0.86
0.69
1.12
(0.73, 0.89)
(0.74, 0.94)
(0.74, 0.87)
(0.75, 0.96)
(0.75, 0.99)
(0.54, 0.87)
(0.73, 1.72)
0.75
0.62
(0.69, 0.81)
(0.56, 0.69)
0.52
(0.42, 0.65)
Meta-analysis of
Cohort studies
Age ≥50 (Invited to screen)
Age ≥50 (Accepting screening)
1 systematic review including
Meta-analysis of 7 studies
RR
Systematic review and
Meta-analysis of RCTs
Meta-analysis of
Case-control studies
Age 50–70
0.25
0.5
0.75
1
1.25
1.5
1.75
Figure 9.1. Summary estimates of pooled effect sizes of mammography screening on breast cancer mortality, by study type and by age group.
Data from Myers et al.5
Other Screening Modalities
One major caveat concerning the original randomized controlled
trials is that mammographic technology has substantially improved
since, and thus the protective benefit of regular mammography has
been underestimated. The then-​prevailing two-​dimensional (2D)
analog technique has evolved to full-​field digital mammography,
with some evidence of lower false positivity and greater sensitivity.9
Further, digital breast tomosynthesis or three-​dimensional (3D)
mammography has been built on digital mammography to provide 3D reconstruction of breast anatomy in thin image slices. It can
be deployed alone or in combination with full-​field digital mammography, although the latter would necessarily increase radiation
dose exposure. Given the recency of these new technologies, there
is not yet definitive evidence to directly show substantive patient
outcome–​relevant improvements.9
In addition to, or more appropriately in conjunction with, mammography, there are other radiologic techniques commonly deployed to screen for breast cancer—​namely ultrasound and magnetic
resonance imaging (MRI). However, neither modality has been assessed in randomized trials with hard clinical endpoints, and given
widespread organized or haphazard screening practices worldwide,
the key question of whether either or both modalities can reduce
breast cancer–​associated mortality will likely remain unanswered.
In women with elevated cancer risk and/​or those with dense breasts,
the latter being particularly prevalent in East Asian women, ultrasonography can be a useful adjunct to mammography.10 Similarly,
MRI as a supplemental screening tool could potentially reveal lesions that are otherwise occult to mammography and ultrasonography. It is usually reserved for women with at least a 1 in 5 lifetime
risk for invasive disease, who are typically BrCA1/​2 susceptibility
gene carriers, but does not include those with an otherwise strong
family history.11 It should be noted that with the higher sensitivity
that ultrasound or MRI examination usually confers, especially for
smaller or more hidden lesions, false positivity necessarily increases
with the attendant adverse effects (see “Overdiagnosis and Potential
Harms of Screening” later).
Finally, there are two other nonradiologic strategies that are commonly used—​clinical breast examination (CBE) by a trained health
care professional and breast self-​
examination (BSE). The large
Shanghai BSE trial conclusively demonstrated no breast cancer–​
related survival benefit,12 as did a smaller, earlier Russian trial.13
Inferences based on observational data have nevertheless provided
tentative evidence of benefit.10
Whereas there has not been a head-​to-​head trial comparing CBE
vs. no CBE, the Canadian National Breast Screening Study showed
that breast cancer–​related mortality and nodal involvement were
similar among those who received CBE alone and those who underwent both CBE and mammography.14 Thus, this suggests good efficacy of CBE, or looked at another way, it infers little added clinical
value of routine mammograms. Of note, however, the very high sensitivity achieved under those trial conditions was double that usually
achievable in practice.15
Evidence Gap for the Majority of Women Globally
The evidence base for or against screening to reduce breast cancer disease and associated mortality is generally weak for non-​Caucasian
women outside of North America and Western Europe, who form
the vast majority of the world’s female population.
For instance, although it is the top female cancer among Chinese
populations and the incidence has been increasing,16 the lifetime
risk of developing breast cancer in Hong Kong, Shanghai, Singapore,
Taiwan, and elsewhere in mainland China remains 32–​82% lower
than that in Western populations.16–​18 The epidemiology (e.g., age
distribution) is different between Chinese and Western women,
thus exposing the potential frailties of wholesale adoption of
69
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SECTION II Cancer Screening in Normal and At-Risk
inferences drawn from the latter group that have so far dominated
the literature.19 Therefore, secondary prevention by mass screening
mammography in East Asian women remains controversial with
limited direct evidence of benefit supporting its population-​based
deployment.16,20
Despite such an empirical vacuum, several East Asian governments have begun, since the early 2000s, to offer organized population screening (Table 9.1). Additionally, haphazard opportunistic
screening in women at average risk has substantially increased
in mainland China, which has sustained the fastest growth of
mammographic equipment acquisition in the world over the last
decade.21
Nevertheless, at the individual level, it is important to offer
women an informed choice, especially in places where the private
sector thrives, including the newly developed, prosperous Chinese
coastal cities. Individual variation in risk is substantial within any
given population. For example, although the average lifetime risk
of developing invasive cancer was 4.5% for women in Shanghai, the
lifetime risk for women at the 90th risk percentile was 9.5%, which
was comparable to the population average in the UK and US.22,23
As such, compared to universal screening conventionally adopted in
Western populations, risk-​based screening that aims to stratify the
female population by their remaining lifetime risk and targets only
high-​risk women for organized screening would be more in keeping
Table 9.1. Breast Cancer Screening Practices in Western and East Asian Settings
Country
Launch Year
Screen Age (Years)
Frequency
Screening
Modality
Funding
Support
Notes
UKa
1988
50–​70
Every 3 years
MM
NHS
Ongoing randomized trial to evaluate
whether extend eligible age range to
47–​73 years.
USb
Since early 1980s USPSTF: 50–​74
ACS: 40 and older
USPSTF: Every 2 years
ACS: Every 1 year for
ages 40–​54 years;
every 1–​2 years for
55 years or older
MM
Individual
insurance plans
ACS recommends that women
continue screening if general health is
good with remaining life expectancy of
10 years or longer.
Greater Chinac
Beijing: 2009
Beijing: 35–​59
Shanghai: 2008–​ Shanghai: 35–​74
2012
Beijing: Every 2 years
Shanghai: Every
2 years
Beijing: CBE,
US, (MM for
suspected
positive)
Shanghai: MM
Social insurance
Shanghai: Only lasted 5 years to
2013. Only women with household
registered in Minhang district could
join.
Hong Kong:
—​
—​
—​
—​
CEWG advises that all women at
average risk or high risk of breast
cancer should be aware of early
symptoms of breast cancer and should
visit doctors promptly if symptoms
appear.
Taiwan: 1999
45–​69;
40–​44 (with second-​
degree relatives ever
diagnosed with breast
cancer)
Every 2 years
MM
Social insurance
—​
South Koread
2002
40 and older
Every 2 years
MM
Social insurance
—​
Japane
2000
40 and older
Every 2 years
MM, CBE
Social insurance
—​
2002
40–​69
50–​69 years: Every
2 years
40–​49 years: Every
1 year
MM
Medisave
—​
f
Singapore
MM = mammography; CBE = clinical breast examination; US = ultrasound; ACS = American Cancer Society; USPSTF = US Preventive Services Task Force; NHS = UK National Health
Service; CEWG = Cancer Expert Working Group on Cancer Prevention and Screening, the Government of Hong Kong SAR
* Websites were accessed in October 2019.
Data sources:
a
UK NHS: https://​www.nhs.uk/​conditions/​breast-​cancer-​screening/​when-​its-​offered/​
b
US Preventive Services Task Force: https://​www.uspreventiveservicestaskforce.org/​Page/​Document/​RecommendationStatementFinal/​breast-​cancer-​screening1
American Cancer Society: https://​www.cancer.org/​health-​care-​professionals/​american-​cancer-​society-​prevention-​early-​detection-​guidelines/​breast-​cancer-​screening-​guidelines.html
c
Beijing: http://​www.bjwch.cn/​zt/​lasc/​20120815/​19537.shtml
Shanghai: https://​link.springer.com/​article/​10.1186/​2193-​1801-​2-​276
Hong Kong: https://​www.chp.gov.hk/​files/​pdf/​breast_​ca_​en.pdf
Taiwan: https://​www.hpa.gov.tw/​EngPages/​Detail.aspx?nodeid=1051&pid=5957
d
South Korea: https://​ncc.re.kr/​main.ncc?uri=english/​sub04_​ControlPrograms03
e
Japan: https://​www.mhlw.go.jp/​stf/​seisakunitsuite/​bunya/​0000059490.html
Hamashima C. Cancer screening guidelines and policy making: 15 years of experience in cancer screening guideline development in Japan. Japanese Journal of Clinical Oncology.
2018;48(3):278–​286.
f
Singapore: https://​www.moh.gov.sg/​docs/​librariesprovider5/​licensing-​terms-​and-​conditions/​moh-​cir-​no-​08_​2019_​6mar19_​screening.pdf
CHAPTER 9 Breast Cancer Screening
with precision preventive care. Indeed, some Western countries
have already begun to assess the potential benefits of switching from
universal to risk-​based screening.24 Recent studies in the UK and US
have suggested that personalized screening tailored to individuals’
risks and preferences could improve the efficiency and effectiveness
of breast cancer screening.25,26
In East Asia, we were only able to identify one study by Sun et al.,23
who evaluated the cost-​effectiveness of risk-​based screening conducted based on aggregate data of breast cancer epidemiology in
mainland China. Their risk stratification model, however, lacked
calibration and validation. Another recent cohort study of more
than 1.4 million Taiwanese women27 reported that compared with
annual clinical breast examination, risk-​based biennial mammography screening only provided a modest reduction in breast cancer
mortality (hazard ratio [HR] 0.89, 0.75–​1.06) compared to its universal counterpart (HR 0.62, 0.50–​0.76). This should be interpreted
in the context where 45–​49% of women enrolled in their risk-​based
screening were assessed as high risk and referred for mammography
and the proportion adherent to these referrals was 58–​62%. That is,
26% of the women enrolled in their risk-​based screening underwent mammography. Because they used the initial number of enrolled women (i.e., before risk assessment) as the denominator for
calculating HR, the HR reduction in risk-​based screening (0.11) was
approximately 0.26 times that in universal screening (0.38). Of additional note, we recommend caution in understanding their propensity score–​based findings, which concluded a relative risk reduction
of 38% for universal biennial screening contrasted with virtually
the entire corpus of past work consisting of both randomized controlled trials and empirical evidence5 suggesting about only half that
quantum at around 20%.
Our own model, trained on Hong Kong data and validated on
a Shanghai sample, showed that risk-​based and conventional universal mammography screening of women aged 44–​69 years biennially would provide similar relative reduction in breast cancer–​related
mortality among screenees, but the former would be far more cost-​
effective at half the cost per quality-​adjusted life-​year (QALY) saved,
that is US$18,151 vs. $34,953 per QALY, respectively, compared
to no screening.28 In fact, most of the difference was driven by the
QALY loss due to false-​positive mammograms, arising from complications of consequential confirmatory testing as well as psychosocial
implications (see next section). Fundamentally, risk-​based strategies
optimize screening by reducing unnecessary mammography and
tissue biopsy among well women. Therefore, one must consider the
undesirable adverse effects induced by screening and avoid as far as
possible associated iatrogenic harm imposed on otherwise healthy
persons.
Overdiagnosis and Potential Harms of Screening
Overdiagnosis is defined as the “detection of cancers that would
never have been found were it not for the screening test.”29 The
Independent UK Panel on Breast Cancer Screening30 surveyed the
literature for evidence of overdiagnosis and concluded that 11% of
cancers identified through population screening would not otherwise be detected, because those lesions would not have progressed to
the symptomatic stage or the affected women would have died from
another cause. Presented another way, from an individual screenee’s
perspective, the likelihood of overdiagnosis if a woman were to receive a breast cancer diagnosis during the screening period is 19%.
The foregoing concerns invasive disease, although carcinoma in
situ, particularly DCIS, incidence has increased disproportionately
in all populations that have implemented organized screening, and
is thus strongly suggestive of overdiagnosis. However, because some
DCIS indeed progresses to invasive cancer and can affect prognosis,
not all such diagnoses should be similarly classified as overdiagnosis.
Findings from the ongoing LORIS trial comparing expectant management with annual mammogram vs. immediate surgery for low-​
grade DCIS may shed new light on this vexed issue.31
Each overdiagnosed invasive or in situ cancer carries with it the
attendant risks, cost, and burden of surgery and possible adjuvant
therapies and their impact on personal and professional lives.6,32–​34
A large part of the harm associated with screening relates to the
need for confirmatory testing subsequent to a positive screen. The
10-​year cumulative risk of at least one false-​positive result with biennial screening has been estimated to be 42%.35 Associated harm
would include fine-​needle, core, or infrequently excisional biopsy,
with or without radiologic guidance or general anaesthesia, and any
complications of wound hematoma or infection.36 The probability
of a biopsy arising from an initial false-​positive screen over 10 years
of biennial mammography was 6–​10% in the US and breast biopsy
had a complication rate of 8–​15%.20,37 Taken together, 1.5–​4.5% of
low-​and average-​risk women who undergo biennial screening over
a lifetime of routine screening would experience at least one episode
of complications due to unnecessary biopsy. There is also considerable psychological harm generated by the large number of false
positives and their sequelae,35 as well as misplaced reassurance and
delayed treatment of the much smaller number of false negatives.38
Future Directions: Precision Screening and
Emerging Modalities
Given that the benefit-​to-​harm tradeoff and cost-​effectiveness of
screening strongly depend on the QALY loss brought about by unnecessary biopsies and potential complications, future efforts should
focus on reducing the need to proceed to tissue biopsy for confirmatory workup. For instance, novel noninvasive diagnostics could
become the reflex test after a positive mammogram. The prebiopsy
odds of disease for those who would subsequently require the invasive procedure could be improved. For instance, recently developed
liquid biopsy modalities may hold such promise.39,40 Liquid biopsy
harnesses cancer signals embedded in circulating DNA and protein
biomarkers for cancer detection.28,41,42
Working further upstream, moving toward risk-​based screening
with precise stratification before undergoing mammography would
better target those more likely to benefit from screening while minimizing overdiagnosis and potential iatrogenic harm for those at
lower risk. To this end, improving the predictive power of the risk
stratification algorithm would be important. While the conventional risk factors are well rehearsed, single nucleotide polymorphism (SNP)-​based polygenic risk scores have already been shown
to improve predictive performance.28 Next-​generation programs,
with increasing affordability and popularity of genetic risk profiling technology, should routinely include such scores into risk
assessment tools.
71
72
SECTION II Cancer Screening in Normal and At-Risk
Finally, based on the ethos of patient-​centered choice and precision preventive care, women’s own risk preferences43 should be explicitly incorporated into algorithms that inform whether a woman
would be recommended to undergo screening. This would further
modify the usual universally imposed age thresholds for the general
population such that each individual woman could input her own
risk tolerance into the decision tool.44
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3. Dobrow MJ, Hagens V, Chafe R, et al: Consolidated principles for
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19. Wong IOL, Schooling CM, Cowling BJ, et al: Breast cancer incidence and mortality in a transitioning Chinese population: current
and future trends. British Journal of Cancer 112:167–​170, 2015.
20. Leung GM, Lam TH, Thach TQ, et al: Will screening mammography in the East do more harm than good? American Journal of
Public Health 92:1841–​1846, 2002.
21. Grand View Research: Breast Imaging Market Size, Share & Trend
Analysis Report by Technology (Ionizing Technology, Non-​
Ionizing Technology), and Segment Forecasts, 2018—​2024, 2018.
22. Zheng W, Wen W, Gao Y-​T, et al: Genetic and clinical predictors
for breast cancer risk assessment and stratification among Chinese
women. Journal of the National Cancer Institute 102:972–​981, 2010.
23. Sun L, Legood R, Sadique Z, et al: Cost-​effectiveness of risk-​based
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Health Organization 96:568–​577, 2018.
24. Onega T, Beaber EF, Sprague BL, et al: Breast cancer screening in
an era of personalized regimens: a conceptual model and National
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25. Pashayan N, Morris S, Gilbert FJ, et al: Cost-​effectiveness and
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to-​
harm ratio of risk-​
stratified screening for breast
cancer: a life-​table model. JAMA Oncology 4:1504–​1510, 2018.
26. Ayer T, Alagoz O, Stout NK: OR Forum—​a POMDP approach
to personalize mammography screening decisions. Operations
Research 60:1019–​1034, 2012.
27. Yen AM-​F, Tsau H-​S, Fann JC-​Y, et al: Population-​based breast
cancer screening with risk-​based and universal mammography
screening compared with clinical breast examination: a propensity
score analysis of 1 429 890 Taiwanese women risk-​based and universal mammography vs clinical breast examination risk-​based
and universal mammography vs clinical breast examination.
JAMA Oncology 2:915–​921, 2016.
28. Leung K, Wu JT, Wong IOL, et al: Characterizing the epidemiology
of breast cancer in Chinese women and using risk stratification to
optimize personalized mammography screening (Unpublished
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29. International Agency for Research on Cancer: IARC handbooks of cancer prevention (volume 7): breast cancer screening.
Lyon: IARC, 2002.
30. Independent UK Panel on Breast Cancer Screening: The benefits
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31. Cancer Research UK: A trial comparing surgery with active monitoring for low risk DCIS (LORIS). https://​www.cancerresearchuk.
org/ ​ a bout- ​ c ancer/ ​ f ind- ​ a - ​ c linical- ​ t rial/ ​ a - ​ t rial- ​ c omparing-​
surgery-​with-​active-​monitoring-​for-​low-​risk-​dcis-​loris
32. Assad H, Badhwar G, Bhama S, et al: Impact of breast cancer diagnosis and treatment on sexual dysfunction. Journal of Clinical
Oncology 32:125–​125, 2017.
33. Stanton AL, Wiley JF, Krull JL, et al: Depressive episodes, symptoms, and trajectories in women recently diagnosed with breast
cancer. Breast Cancer Research and Treatment 154:105–​115, 2015.
34. Ekenga CC, Perez M, Margenthaler JA, et al: Early-​stage breast cancer
and employment participation after 2 years of follow-​up: a comparison with age-​matched controls. Cancer 124:2026–​2035, 2018.
CHAPTER 9 Breast Cancer Screening
35. Nelson HD, Pappas M, Cantor A, et al: Harms of breast cancer
screening: systematic review to update the 2009 U.S. Preventive
Services Task Force Recommendation. Annals of Internal
Medicine 164:256–​267, 2016.
36. Le MT, Mothersill CE, Seymour CB, et al: Is the false-​positive rate
in mammography in North America too high? British Journal of
Radiology 89:20160045, 2016.
37. Hofvind S, Ponti A, Patnick J, et al: False-​positive results in
mammographic screening for breast cancer in Europe: a literature
review and survey of service screening programmes. Journal of
Medical Screening 19:57–​66, 2012.
38. de Gelder R, van As E, Tilanus-​Linthorst MM, et al: Breast cancer
screening: evidence for false reassurance? International Journal of
Cancer 123:680–​686, 2008.
39. Cristiano S, Leal A, Phallen J, et al: Genome-​
wide cell-​
free DNA fragmentation in patients with cancer. Nature
570:385–​389, 2019.
40. Coy JF: EDIM-​
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system based liquid biopsy for the early detection, characterization and targeted treatment of cancer. International Journal of
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41. Page K, Shaw JA, Guttery DS: The liquid biopsy: towards
standardisation in preparation for prime time. Lancet Oncology
20:758–​760, 2019.
42. Heitzer E, Haque IS, Roberts CES, et al: Current and future perspectives of liquid biopsies in genomics-​driven oncology. Nature
Reviews Genetics 20:71–​88, 2019.
43. Cohen JD, Li L, Wang Y, et al: Detection and localization of surgically resectable cancers with a multi-​analyte blood test. Science
359:926–​930, 2018.
44. Puzhko S, Gagnon J, Simard J, et al: Health professionals’ perspectives on breast cancer risk stratification: understanding evaluation of risk versus screening for disease. Public Health Reviews
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73
10
Prostate Cancer Screening
Michael A. Diefenbach, Daniel Nethala, Michael Schwartz, and Simon J. Hall
Introduction
It is commonly accepted that cancer morbidity and mortality are
lessened or avoided through regular screening programs. Clear epidemiological evidence supports the utility of cancer screening for
skin, cervical, colon, and breast cancer on the population level. The
recommendations for population-​level screenings of other cancers,
such as lung or prostate cancer, are less clearly defined. The current
chapter describes the rapid and widespread adoption of the prostate-​
specific antigen, once discovered, as a biomarker for prostate cancer;
its impact on prostate cancer detection and treatment rates; the subsequent revision of population-​based screening practices; and finally refined screening recommendations, based on the analyses of
several large-​scale trials. The example of prostate cancer screening
can be seen as a case study of how well-​intentioned actions have
unintended consequences that go beyond the immediate patient-​
physician encounter and influence how screening recommendations for the public are formulated, evaluated, and communicated.
Prostate Cancer Incidence and Risk Factors
Prostate cancer is the most frequently diagnosed and second most
lethal cancer in men in the United States (US), with an estimated
174,650 new cases detected and 31,620 cancer-​related deaths predicted in 2019.1 Approximately one in nine men in the US will be
diagnosed with prostate cancer within their lifetime.
The risk factors associated with developing prostate cancer include
age, being of African American (AA) descent, and having a family
history of the disease. Study of age-​specific incidence curves show
that the risk of developing prostate cancer begins to rise abruptly
after the age of 55 and peaks between 70 and 74, with the median
age at diagnosis currently being 66.2,3 AA men are at a higher risk
of developing and dying from prostate cancer than their Caucasian
counterparts. Studies are not clear as to whether this difference in
incidence and mortality is explained entirely by socioeconomic limitations and stage at diagnosis or whether an inherent difference
exists in the underlying biology of the cancer in these populations.
The hereditary risk of developing prostate cancer was delineated
originally by extensive cancer pedigrees showing that individuals
with first-​degree relatives (father or brothers) with prostate cancer
carried a two to three times increased risk of developing the disease
over families with no history of the disease.4,5 With the advent of
sophisticated sequencing technology, numerous single gene alterations have been identified and confirmed that increase the risk of
prostate cancer including BRCA1/​2, CHEK2, and ATM.6
Controversies in Prostate Cancer Screening
The history of prostate cancer screening is storied and centers
around one of the most controversial and the most utilized biomarker for the diagnosis and follow-​up of any cancer in clinical
medicine—​the prostate-​specific antigen (PSA).7 Prior to the discovery of the PSA in 1979 and US Food and Drug Administration
(FDA) approval for its use in the screening of asymptomatic men in
1994, prostate cancer was only detected by digital rectal examination (DRE). Given that the cancer had to be palpable as a nodule or
an irregularity of the prostate to be diagnosed, treatment for prostate cancer resulted in a stagnated cancer-​related death rate from
about 1950 to 1994, likely due to the advanced stage at time of diagnosis.1 In 1987, Stamey et al. launched the PSA as the primary biomarker for screening prostate cancer in men by demonstrating that
serum PSA correlated with advancing stages of prostate cancer, was
proportional to the estimated volume of tumor, and reached undetectable levels after complete removal of the prostate.8 As a result of
numerous studies and the FDA approval, the PSA and DRE became
the standard screening protocol for prostate cancer in primary care
for asymptomatic men with threshold levels of PSA warranting a
biopsy. This protocol led to a staggering increase in prostate cancer
incidence and a significant reduction in cancer-​related death rates
likely due to the increased detection of nonpalpable, clinically localized cancers.
The unrestricted usage of the PSA to screen asymptomatic men
for prostate cancer was not without harm. Controversy emerged as
the widespread screening practices resulted in overdiagnosing clinically insignificant cancers and subsequent treatment of such cancers.
Unrestricted screening led to false-​positive biopsies; biopsy-​related
morbidity including pain, bleeding, and infections; psychological
harms for the patient undergoing the biopsy; and treatment-​related
side effects including erectile dysfunction, urinary incontinence,
and possible androgen deprivation.
CHAPTER 10 Prostate Cancer Screening
Three large randomized controlled clinical trials conducted in the
US and in Europe were designed to answer the question of whether
screening for prostate cancer with PSA truly saved lives. The results published in 2009–​2010 showed that in the US, prostate cancer
screening did not save lives,9 while data from the European trials
showed that screening produced a 27–​40% reduction in prostate
cancer–​specific mortality.10,11 However, all three trials concluded
that screening of asymptomatic men with PSA resulted in substantial overdiagnosis and produced unnecessarily high diagnostic and
treatment-​related morbidity.
As a result of these trials, in 2012 the US Preventative Services Task
Force (USPSTF) took the position that prostate cancer screening
with PSA should not be recommended routinely by providers, giving
it a Grade D recommendation. They stated, “Physicians should not
offer or order PSA screening unless they are prepared to engage in
shared decision making that enables an informed choice by the patients” and that “there is moderate or high certainty that the service
has no benefit or that the harms outweigh the benefits.”12 The Grade
D recommendation was based on the conclusion that the data for
screening with PSA only affected the prostate cancer–​specific mortality of patients and not their overall mortality. The scales balancing
the risks of screening with the burdens of overdiagnosis and treatment were tipped in the aftermath of this statement, leading to an
immediate 12% decline in the incidence of prostate cancer detected
in the year following, a durable 28% decline after 1 year, and ultimately a reverse stage migration with an increased incidence of
high-​risk disease in the years to follow.13 Factoring this data and the
further analysis of the original trials, in 2018 the USPSTF amended
their 2012 recommendation of not screening asymptomatic men
for prostate cancer to a Grade C recommendation for selectively offering screening for men between the ages of 55 and 69 years. Table
10.1 lists the current guidelines for prostate cancer screening.14–​16
The Complexity of Prostate Cancer Screening
The changing recommendations of the USPSTF and by professional
organizations over the past years about prostate cancer screening has
been amplified by reports in the popular press. This led to increased
confusion among men who are at normal risk (i.e., without any of
the traditional risk factors, such as a family history of prostate cancer
or being of AA decent). The overall message about prostate cancer
screening is made more difficult as scientists and organizations
compare different outcomes that are hard to compare. For example,
should one focus on preventable cancer deaths, the prevention of
metastatic disease, frequent and common side effects of treatment
of consequential and nonconsequential cancers, or quality-​of-​life
outcomes of the patient and the impacted family? Given that prostate cancer is a slow-​growing tumor, which affects older men who
often suffer from other comorbidities, the decision to be screened
is now one to be made by the patient with the help of the health
care professional within a shared decision-​making paradigm. Due to
the complexity of the issue, high levels of uncertainty and dependence on patient preferences make it a perfect example of a shared
decision-​making approach, but the same complexity is a significant
barrier for physicians and patients to engage in such an approach, as
it takes time and many providers are not adequately trained in this
approach.
Factors Influencing Screening Decision Making
There are a number of factors that influence patients’ decision to obtain prostate cancer screening. Chief among those factors are physician recommendations. A recent study on providers’ attitudes about
recommendations for prostate and colon cancer screening indicated
Table 10.1. Current Guidelines for Prostate Cancer Screening
Source and Year
Recommendation for Prostate Cancer Screening
Population
Guidelines
American Cancer
Society (ACS)
2019
Asymptomatic AND life expectancy greater than 10 years
No PSA screening
Average risk AND life expectancy at least 10 years
PSA screening starting at 50 years
High risk (African American with first-​degree relative diagnosed
younger than 65 years old)
PSA screening starting at 45 years
For all patients
The ACS recommends patients to make an informed decision with
their physician based on their risk level. Yearly PSA testing should be
done for men with a PSA level 2.5 ng/​mL or greater. Men with a PSA
level less 2.5 ng/​mL should be tested every 2 years.
40 years of age or younger
No PSA screening
40–​54 years of age AND average risk
No routine PSA screening
55 years of age or younger AND higher risk (i.e., African American,
multiple first-​degree relatives diagnosed at a younger age)
Individualized screening based on the man’s preference and informed
discussion with physician
55–​69 years of age
Shared decision making coinciding with the man’s preference.
Routine screening should be every 2 years, but tailored depending on
baseline PSA results.
70 years of age or older (or life expectancy less than 10–​15 years)
No PSA screening, unless in good health
40–​54 years of age
Not enough evidence on the benefit of screening in this age group
55–​69 years of age
Shared decision making coinciding with the man’s preference
70 years of age or older
No PSA screening
American
Urological
Association
(AUA) 2018
US Preventative
Services Task
Force (USPSTF)
2018
75
76
SECTION II Cancer Screening in Normal and At-Risk
that men often receive cancer screenings even if they are of low value
to the patient (i.e., when the net harms clearly outweigh the benefits,
as is the case for patients older than 70 years of age, according to
the USPSTF recommendation). Factors associated with low-​value
screening behavior are patient requests for screening and, on the
provider side, clinical reminders to perform screening, anticipated
regret of a later cancer diagnosis and not recommending screening,
and worry about lawsuits.
Factors that influence patients’ desire to be screened or not to be
screened are a family history of prostate cancer, associated higher
levels of anxiety, and cognitive factors such as personal experience
and anecdotal evidence. Oftentimes men default to an attitude of
“it’s cancer, what do I have to lose?”—​an attitude that is also reinforced by providers’ attitude of “better safe than sorry.”17
Screening Disparities among High-​Risk Groups
The evidence is indisputable that AA/​Black men are at a higher risk
of developing prostate cancer, present with more aggressive disease,
and are 2.5 times more likely to die from prostate cancer than White
men. AA men are less likely to be screened, although initial efforts
from the Affordable Care Act have narrowed the gap in screening
rates between AA and White men.18 Because of the higher-​risk
status of AA men, screening among this population is recommended under the revised USPSTF guidelines. This is supported by
an analysis of Surveillance, Epidemiology, and End Results (SEER)
data that supported the notion that screening among AA men is associated with a mortality benefit.18 Yet, despite recommendations
for a shared decision-​making approach, AA men often lack basic
knowledge of prostate cancer screening and its pros and cons, and
are often unsure about their preferences about screening.17 A recent
study underscored this point: in a sample of 414 AA men, prostate
cancer screening was discussed by less than 50% (i.e., 45.2%) of men
with their physicians, and overall knowledge about prostate cancer
was low, but increased with higher education and income,18 but not
with more frequent physician contact. Thus, patients cannot rely on
health care providers to be the sole source of health information.
Having recognized this, researchers, community organizations, and
activists have started to find other ways of informing at-​risk populations, such as AA men. A promising avenue is the involvement of
faith-​based organizations and/​or places frequented by AA men, such
as barbershops, to educate men about recommended screenings and
other lifestyle choices.18
Future Directions
Prostate cancer screening recommendations have changed radically
over the past two decades. The discovery of the PSA and its strong
predictive correlate to prostate cancer led to a paradigm change in
prostate cancer screening. Routine screening using the PSA test
was quickly adopted by physicians and urologists who welcomed
a clinical marker to detect early disease. After a few years of routine screening, mounting clinical and epidemiological evidence
pointed to the fact that many small and insignificant cancers were
detected and treated, which were unlikely to cause harm to the patient. Physicians were urged to involve patients in the screening
and subsequent treatment choice decisions. However, as described
in this and the shared decision-​making chapter, many barriers to
shared decision making still exist and this approach is not universally employed.
As a consequence, the onus is on the patient and his family to be
informed and to ask the “right” questions to the provider about the
pros and cons of a screening decision. But how does a patient know
which questions to ask and, more importantly, how to explore his
preferences regarding screening and subsequent possible follow-​up
care? Researchers have attempted to answer this challenge by developing various screening decision aids, either in paper or electronic
format. A systematic review and meta-​analysis of decision aids on
screening choice presented mixed evidence of their utility. Although
decision aids are possibly associated with improved screening and
disease knowledge, and somewhat of a reduction of decisional conflict, they were not found to be associated with an increased discussion of screening in the first place or an increased uptake of
screening.17 A second recent systematic review and meta-​analysis,
in contrast, reported that the use of decision aids was associated
with a decrease in screening choice.18 These seemingly contradicting
results point to the need for subgroup analyses as other research,
discussed earlier, identified disparities in screening knowledge and
utilization of at-​risk populations. Future efforts need to focus on the
development and implementation of targeted and tailored decision
aids that meet the needs of at-​risk populations.
As clinicians struggle with the optimal way of implementing
screening in real-​world settings, researchers attempt to develop new
models to inform and to reach men. These may include targeting
individual groups, such as first-​degree relatives of affected men or
spouses of at-​risk men, with the goal to disseminate information and
to identify the pros and cons of screening. Other approaches focus
on communities and organizations to educate men and their families. Detailed assessments of these resource-​intensive approaches
need to be performed to assess their long-​term utility.
Software-​and Internet-​based solutions to inform patients about
screening options have also been developed, yet they face similar
problems than more conventional approaches, such as identifying
the desired target audience, as well as technology-​specific problems,
such as access through a still existing “digital divide,” and mistrust of
Internet-​based information.
The issue of screening for prostate cancer has been instructive on
many levels. On a public health level, it demonstrated the perils of
adopting a screening tool without long-​term data; on a communications level, the revisions of screening recommendations affected
and complicated health communications to the public. Overall,
the experience surrounding the prostate cancer screening recommendations and resulting controversy is a worthwhile case study to
improve future public health and communication efforts.
REFERENCES
1. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2019. CA
Cancer J Clin, 2019. 69(1): p. 7–​34.
2. Gann, P.H., Risk factors for prostate cancer. Rev Urol, 2002. 4 Suppl
5: p. S3–​S10.
3. NCI, SEER Cancer Stat Facts: Prostate Cancer. 2019.
4. Steinberg, G.D., et al., Family history and the risk of prostate cancer.
Prostate, 1990. 17(4): p. 337–​347.
CHAPTER 10 Prostate Cancer Screening
5. Spitz, M.R., et al., Familial patterns of prostate cancer: a case-​control
analysis. J Urol, 1991. 146(5): p. 1305–​1307.
6. Zhen, J.T., et al., Genetic testing for hereditary prostate cancer: current status and limitations. Cancer, 2018. 124(15): p. 3105–​3117.
7. Hernandez, J., and I.M. Thompson, Prostate-​specific antigen: a review of the validation of the most commonly used cancer biomarker.
Cancer, 2004. 101(5): p. 894–​904.
8. Stamey, T.A., et al., Prostate-​specific antigen as a serum marker for
adenocarcinoma of the prostate. N Engl J Med, 1987. 317(15): p.
909–​916.
9. Andriole, G.L., et al., Mortality results from a randomized prostate-​
cancer screening trial. N Engl J Med, 2009. 360(13): p. 1310–​1319.
10. de Koning, H.J., et al., Prostate cancer mortality reduction by
screening: power and time frame with complete enrollment in the
European Randomised Screening for Prostate Cancer (ERSPC) trial.
Int J Cancer, 2002. 98(2): p. 268–​273.
11. Hugosson, J., et al., Mortality results from the Goteborg randomised
population-​based prostate-​cancer screening trial. Lancet Oncol,
2010. 11(8): p. 725–​732.
12. Moyer, V.A., and U.S.P.S.T. Force, Screening for prostate cancer: U.S.
Preventive Services Task Force recommendation statement. Ann
Intern Med, 2012. 157(2): p. 120–​134.
13. Barocas, D.A., et al., Effect of the USPSTF Grade D
Recommendation against Screening for Prostate Cancer on
Incident Prostate Cancer Diagnoses in the United States. J Urol,
2015. 194(6): p. 1587–​1593.
14. American Cancer Society, American Cancer Society recommendations for prostate cancer early detection, 2019. Retrieved
from: https://​www.cancer.org/​cancer/​prostate-​cancer/​detection-​
diagnosis-​staging/​acs-​recommendations.html
15. Ballentine Carter, H., et al., Early detection of prostate cancer: AUA
guideline. American Urological Association Guideline,
2018. Retrieved from: https://​www.auanet.org/​guidelines/​
prostate-​cancer-​early-​detection-​guideline
16. U.S. Preventative Services Task Force, Final recommendation
statement: prostate cancer: screening, 2018. Retrieved from:
https://​www.uspreventiveservicestaskforce.org/​Page/​Document/​
RecommendationStatementFinal/​prostate-​cancer-​screening1
17. Riikonen, J.M. et al., Decision aids for prostate cancer screening
choice: a systematic review and meta-​analysis. JAMA Intern Med,
2019. 179(8): p. 1072–​1082.
18. Ivlev, I., Jerabkova, S., Mishra, M., Cook, L.A., and K.B. Eden,
Prostate cancer screening patient decision aids: a systematic review
and meta-​analysis. Am J Pre Med, 2018. 55(6): p. 896–​907.
77
11
Lung Cancer Screening
Lisa Carter-​Harris and Jamie Ostroff
Introduction
Lung cancer kills more people worldwide than breast, colorectal,
and prostate cancers combined.1,2 Lung cancer screening is intended
to identify earlier, more treatable cases of lung cancer—​the leading
cause of cancer-​related deaths, regardless of gender or ethnicity.
More than 1.8 million people are expected to die this year from lung
cancer.1,2 Most die because they are diagnosed at an advanced stage
with limited treatment options and a 1% 5-​year relative survival
rate.1 Until 2013, an effective screening test to identify lung cancer
at an earlier stage did not exist.3 In the United States, the National
Lung Screening Trial (NLST) compared screening long-​term, heavy
smokers with either low-​dose computed tomography (LDCT) of the
chest or chest radiography. The NLST randomized 53,454 long-​term
heavy smokers to a series of annual chest LDCT versus chest radiography, finding a significant life-​saving benefit for annual chest LDCT
with an approximate 20% relative reduction in lung cancer–​related
mortality and 6.7% relative reduction in all-​cause mortality.3 In response to mounting scientific evidence, including the NLST, the U.S.
Preventive Services Task Force (USPSTF) issued a Grade B recommendation for annual lung cancer screening for individuals aged 55
to 80 years who are current smokers or former smokers who have
quit within the past 15 years.4 Subsequent research has supported the
benefit of lung cancer screening with LDCT of the chest including
the Dutch-​Belgian Lung Cancer Screening trial (commonly known
as the NELSON trial), Danish Lung Cancer Screening trial, and UK
Lung Cancer Screening trial.5–​7 Although screening programs have
been implemented in the U.S. over the past 5 years and offer the potential to detect deadly tumors at an earlier stage, resulting in better
outcomes, lung cancer screening uptake remains abysmally low in
the U.S. Approximately 9 million Americans qualify for lung cancer
screening, but less than 4% have been screened annually.8 Despite
the fact that lung cancer screening is a covered preventive service
benefit for Medicare beneficiaries and those of many other insurers
for long-​term smokers who meet eligibility requirements, screening
uptake is low. Canada is the only other country that currently recommends lung cancer screening with LDCT of the chest.9
This chapter focuses on lung cancer screening and describes risk
factors for the development of lung cancer; reviews the lung cancer
screening guidelines as well as factors associated with screening
uptake, including psychosocial factors and stigma; and discusses
shared decision-​making, smoking cessation, clinical implications,
and suggestions for future work.
Risk Factors
While a number of factors influence an individual’s risk for developing lung cancer, the two most common risk factors are cumulative exposure to tobacco smoke and increasing age, respectively.10
The incidence of lung cancer increases with age and occurs most
commonly in older individuals aged 55 years and older. While it is
important to note that the majority of lung cancers are linked to primary tobacco use and secondhand smoke exposure, approximately
15% of patients are never smokers and the second leading cause of
lung cancer is exposure to radon followed by exposure to other environmental toxins as well as a genetic predisposition. The greatest
risk factor—​tobacco smoking—​is a modifiable risk factor on which
there is opportunity to intervene, which is why lung cancer screening
has the potential to capitalize on a potentially teachable moment for
smoking cessation interventions among current smokers who present for screening.
Controversy and Consensus
Lung cancer screening has experienced a complex journey toward
implementation in the U.S. since the issuance of the USPSTF’s Grade
B recommendation. This is primarily attributed to the fact that lung
cancer screening produces potential risks such as false-​positive results, overdiagnosis, radiation exposure, and psychological distress
in the presence of frequently noted indeterminate results that require a “wait and watch” approach.3 The following section will review the USPSTF recommendation and discuss eligibility criteria,
integration of tobacco treatment into lung cancer screening, and
the importance of adherence to an annual screening program for
screening eligible persons.
USPSTF Recommendation
In December 2013, the USPSTF issued the first official guidelines for lung cancer screening (Grade B) in response to the findings of the NLST.4 Prior to this recommendation, there were no
CHAPTER 11 Lung Cancer Screening
Table 11.1. Differences between Lung Cancer Screening
Recommendations
Organization
Age Parameters
Minimum Pack-​Year History
U.S. Preventive Services
Task Force4
55–​80 years
30
American Cancer Society1 55–​74 years
30
National Comprehensive
Cancer Network
(Group 1)81
55–​77 years
30
National Comprehensive
Cancer Network
(Group 2)81
50 years or older 20 + one other risk factor
Centers for Medicare &
Medicaid Services11
55–​77 years
30
Canadian Task Force on
Preventive Health Care9
55–​74 years
30
official recommendations for lung cancer screening. The guidelines
target the population of asymptomatic adults with a long history
of smoking.4 The population targeted for lung cancer screening is
based primarily on the strong evidence from the NLST finding that
age, total cumulative exposure to tobacco smoke, and years since
quitting smoking are the most important risk factors for the development of lung cancer. LDCT of the chest has high sensitivity and
acceptable specificity for detecting lung cancer in high-​risk individuals and is the only recommended screening test for lung cancer. In
addition to the parameters of age and smoking history, the USPSTF
lung cancer screening guidelines also include recommendations on
counseling and interventions for tobacco cessation among current
smokers. In 2015, the Centers for Medicare and Medicaid Services
(CMS) went further by mandating a shared decision-​making and
counseling visit as a requirement for reimbursement of lung cancer
screening in their National Coverage Determination.11 While the
USPSTF has issued an official recommendation, there are additional
organizations that have issued guidelines that slightly differ, primarily with regard to the upper age limit of who is eligible for screening.
These differences as well as the guidelines issued by the Canadian
Task Force are summarized in Table 11.1.
Eligibility
Although the upper age limit varies across professional organization
recommendations, based on the USPSTF criteria, individuals are eligible for lung cancer screening if they are aged 55 to 80 years, have a
30 pack-​year smoking history, and are a current smoker or a former
smoker who quit within the past 15 years.4 Pack-​year is calculated
by multiplication of the total number of packs of cigarettes smoked
per days by the total number of years smoked. This population is
recommended to screen annually with LDCT of the chest and to
discontinue screening when the individual has either not smoked
for 15 years or passes the age threshold.
Psychosocial Influences on Lung Cancer
Screening Behavior
Psychosocial factors can influence lung cancer screening behavior.
Unlike other types of cancer screening, having a smoking history
adds a layer of psychosocial complexity to the decision-​making
process for lung cancer screening not present in other types of
screening.12 Smoking is a unique health status characteristic that
has the potential to negatively impact health behavior primarily due
to perceived stigma.13 However, other psychosocial factors such as
medical mistrust, lung cancer fatalism, lung cancer worry, and lung
cancer fear are also important barriers to screening. To date, the
Conceptual Model for Lung Cancer Screening Participation is the
only conceptual model specific to lung cancer screening from the
perspective of the individual making the decision to screen, or not,
for lung cancer.12 See Figure 11.1.
Lung Cancer Screening Health Beliefs
Health beliefs are concepts that have been used widely to explain the
etiology of individual preventive actions, efforts for early detection
through screening for certain illnesses including cancer, and individual actions to minimize illness.14 Health beliefs have been documented in lung and other types of cancer screening as potentially
modifiable intervention targets on which efforts to increase cancer
screening participation may be successful; a subset of health beliefs
have been found to mediate the relationship between key antecedent
variables and the decision to screen, or not, for lung cancer in preliminary research.
Perceived risk, perceived benefits, perceived barriers, and self-​
efficacy are health beliefs that reflect individual beliefs about lung
and other cancer screening behaviors.15,16 Health Belief Model constructs have been reported as important in qualitative research exploring lung cancer screening participation13,15,17,18 and predictive
in one study thus far.12
In the context of lung cancer, perceived risk is conceptually defined as individuals’ belief in the likelihood they will develop lung
cancer and has been shown to predict intention to screen for lung
cancer.17 However, early evidence does not support that perceived
risk is correlated with screening behavior,19 which is consistent
with research in other areas noting that intention does not necessarily equate to behavior. Perceived benefit is conceptually defined
as the belief in the efficacy of an advised course of action to reduce
risk through early detection.14 In the context of lung cancer, perceived benefits are individuals’ beliefs about the positive outcomes
associated with lung cancer screening participation and potential
outcomes from early detection. Higher perceived benefits of lung
cancer screening have been associated with increased willingness to
participate in lung cancer screening with 209 military veterans.17 In
addition, focus group participants (N = 26) reported finding lung
cancer early, giving peace of mind, and providing a motivation to
quit smoking as three perceived benefits of lung cancer screening.13
Conceptually, perceived barriers are an individual’s belief about the
costs (both tangible and psychological) of an advised course of action
such as cancer screening.14 In the context of lung cancer, perceived
barriers are a person’s estimation of the level of challenge associated
with lung cancer screening participation. In lung cancer screening,
there are multiple notable perceived barriers to screening such as
fear, age, inconvenience, mistrust, and stigma. Fear and the belief
that one is too old to benefit from screening as well as inconvenience have been identified as barriers to lung cancer screening participation among eligible individuals.13 Stigma and mistrust will be
discussed in more detail in the following section. Self-​efficacy is the
confidence individuals have in their ability to take action.14 In the
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80
SECTION II Cancer Screening in Normal and At-Risk
Mediators
Proximal Outcome
Lung Cancer Screening
Health Beliefs
(perceived risk, perceived
benefits, perceived
barriers, self-efficacy)
Shared DecisionMaking Outcomes
Antecedents
Psychological Variables
(perceived smoking-related
stigma, medical mistrust,
cancer fatalism, lung cancer
worry, lung cancer fear)
Demographic and Health
Status Characteristics
(age, gender, race/ethnicity,
income, insurance status,
education, smoking status,
family history of lung
cancer)
Cognitive Variables
(knowledge: lung cancer
and lung cancer screening)
Healthcare Provider
Recommendation
Social and Environmental
Variables (social influence,
media exposure)
Distal Outcome
Lung Cancer
Screening
Participation
Stage of Adoption
(unaware, unengaged,
undecided, decided not
to act, decided to act,
action, maintenance)
Preference-Concordant
Decision Reached
(to be screened,
not to be screened,
undecided/delayed
decision)
Shared Decision-Making
Process (patient-provider
discussion including
healthcare provider
recommendation, quality of
communication, time,
discussion of risks vs
benefits, and quality of the
patient-provider relationship)
Figure 11.1. Conceptual model for lung cancer screening participation.
Copyright 2016. Dr. Lisa Carter-​Harris. Reprinted with Permission.
context of lung cancer, self-​efficacy is the confidence that one has the
ability to perform all tasks related to arranging and completing lung
cancer screening. Self-​efficacy has a positive association with lung
cancer screening behavior,20 with higher levels of self-​efficacy correlated with positive screening follow-​through. Further, the link between screening behavior and self-​efficacy for lung cancer screening
appeared to be fully mediated by cancer fatalism, lung cancer fear,
positive family history of lung cancer, knowledge of lung cancer risk
and screening, higher annual income, receiving a healthcare clinician recommendation to screen, and social influence (p < 0.05).18
Finally, it should be noted that perceived severity was not included
in the Conceptual Model for Lung Cancer Screening Participation
secondary to numerous studies reporting that perceived severity is
not useful in explaining cancer screening behavior because cancer
is universally perceived to be severe, and studies have found ceiling
effects when examining this construct in this context.
Stigma
The reality of lung cancer stigma is tangible and has a profound
impact on people living with this disease.21 Similarly, lung cancer
stigma has the potential to negatively impact individuals at risk for
lung cancer who are considering the option of screening. The stigma
of lung cancer is perpetuated by the public’s perception that this is
a “smoker’s only” disease when in fact 20% to 30% of individuals
diagnosed with lung cancer have never smoked. The prevailing perspective is one of blame and highlighting a lifestyle choice fueled
by addiction (i.e., smoking). A recent study conducted by the Lung
Cancer Alliance in 2018 to examine the prevalence of lung cancer
stigma 10 years after the original study found increased levels of
perceived stigma among individuals at risk for the development of
lung cancer. Despite best efforts, lung cancer–​related stigma has actually increased.22 Ten years ago, there were no approved methods
to screen for lung cancer. Now that annual LDCT of the chest is an
official recommendation for lung cancer screening by the USPSTF,
it is concerning that lung cancer–​related stigma is trending upward.
Stigma has been noted to be a barrier among individuals at risk for
the development of lung cancer. If individuals feel stigmatized, they
are less likely to engage in a conversation about the potential for
screening as well as actually screening. In a recent study exploring
the decision to opt out of screening among screening-​eligible patients who had recently received a recommendation to screen for
lung cancer from their primary care clinician, some reported they
would agree to screening just to conclude the conversation with
the clinician as quickly as possible, fearing shame and blame from
continued discussion, only to cancel or not show to the scheduled
screening.23
Mistrust
Medical mistrust is the belief that the healthcare system itself and/​
or those working within it are untrustworthy. Medical mistrust has
been identified as a barrier to lung cancer screening. Individuals
have described mistrust of the healthcare system, tobacco industry,
CHAPTER 11 Lung Cancer Screening
and government overall as linked with their uncertainty of the value
of screening, comparing “new machines to screen to a scam.”13
Because medical mistrust has been associated with late-​stage lung
cancer presentation among minorities,18 an individual’s mistrust of
the healthcare system and/​or those working within it is concerning
in its potential to impede lung cancer screening participation.
Lung Cancer Fatalism
Lung cancer fatalism is the belief that being diagnosed with lung
cancer will result in death.18 Fatalism is significantly associated with
avoidance of lung cancer screening.24 Building upon prior research
in colorectal and breast cancer screening that found an association between fatalism and lack of screening,25 early qualitative research suggested a similar relationship in lung cancer screening.18
In a population-​based survey of 1,007 adults in Wales, Smits et al.
found that low perceived effectiveness of lung cancer screening was
significantly associated with cancer fatalism (adjusted odds ratio
[aOR] = 6.4; 95% CI = 3.5–​11.7; p ≤ 0.001).24 Fatalism often reflects
individuals’ desire to not know if they have lung cancer and may be
reflective of their fear of treatment or death.
Psychological Distress, Anxiety, and Health-​Related
Quality of Life
Given that LDCT of the chest is very sensitive to detecting abnormalities and identifies both cancerous and benign noncalcified
nodules, Bach and colleagues26 have cautioned about the potential
harms of lung cancer screening including false-​positive findings,
overdiagnosis, complications of diagnostic procedures, and radiation exposure. In addition to the potential physical risks, these potential harms also include psychological risks such as lung cancer
worry, anxiety, and fear, particularly for those with true-​positive
(lung cancer diagnosis) and false-​positive findings.
Using NLST data from a large ancillary study, Black and colleagues27 examined the psychosocial impact of undergoing lung
cancer screening by examining health-​related quality of life (HQOL)
and anxious mood (state anxiety). Data were collected at 1 month
and 6 months following receipt of screening results using psychometrically sound, patient-​
reported measurement tools. Global
HQOL and anxiety outcomes were compared for individuals receiving one of four screening results: true positives (lung cancer
diagnosis), false positives (benign noncancerous nodule), significant incidental findings (e.g., emphysema), and negative screening
results. They found no significant differences in HQOL or state
anxiety at 1 and 6 months post–​lung cancer screening result disclosure between participants with negative screening findings (normal
scans) compared to those who either received false-​positive or had
significant incidental findings. Not surprisingly, those who were
found to have lung cancer (true positives) reported lower HQOL
and higher state anxiety at both follow-​up time points. Clark and
colleagues conducted a parallel study in the UK and also found no
statistically significant differences in lung cancer worry and health
anxiety regardless of LDCT scan results.28 Similarly, no adverse psychological consequences were observed in the Pan-​Canadian Early
Detection of Lung Cancer. A multicenter Veteran’s Administration
(VA) study reported that 25% of patients with incidental pulmonary
nodules experienced clinically significant distress.29,30 However, no
baseline (prescan) data were collected, thereby limiting the ability
to determine whether certain individuals may be more or less prone
to postscreening emotional distress because of pre-​existing anxiety.29,30 These limitations underscore the importance of examining
demographic and psychosocial history factors that may moderate
the psychological impact of lung cancer screening. Overall, these
findings provide evidence that undergoing lung cancer screening in
the context of a high-​quality screening and follow-​up protocol poses
little or no psychosocial harm to screening participants, regardless
of scan result.
Concern about the emotional impact of undergoing cancer
screening, particularly for those who receive abnormal or false-​
positive results, is neither new nor specific to lung cancer screening.31
The findings reported on the psychosocial impact of undergoing
lung cancer screening are generally consistent with the existing literature that has examined the psychological consequences of other
types of cancer screening.32 For instance, HQOL and cancer-​specific
distress outcomes were assessed in the Prostate, Lung, Colorectal
and Ovarian Screening Trial.33 No short-​or intermediate-​term differences by screening results on global HQOL were found; however,
participants with abnormal findings reported higher short-​term
cancer-​specific distress than those who received normal results.
The overwhelming majority of published studies and systematic
reviews have focused on the psychological impact of undergoing
routine breast cancer screening and the effect of false-​positive mammograms.34,35 Similar results have been observed in the context of
colorectal cancer screening.36 Overall, the relevant breast cancer
and colon cancer screening literature supports the notion that, beyond the transient anxiety and cancer-​specific worry experienced by
those with abnormal (including false-​positive) findings needing further work-​up, undergoing cancer screening per se does not generally
result in adverse psychosocial outcomes. It is expected that individuals will experience short-​term worry and cancer-​specific anxiety
when there is a suspicion of lung cancer and they are waiting and
hoping for reassurance that they do not have cancer.5
Consistent with recommendations for informing individuals
about the risks and benefits of undergoing cancer screening, individuals seeking lung cancer screening should be informed about
the sensitivity of LDCT of the chest and the likelihood of needing
further work-​up because of this test’s high sensitivity. A pilot study
reported a promising video intervention to reduce screening anxiety and promote preparedness for lung cancer screening. Screening
programs need to be aware of the potential for increased short-​term,
lung cancer–​specific anxiety and worry and provide timely disclosure of results, education, and support, as needed.37
Decision Support and Screening
Considering the multiple potential benefits and harms associated
with lung cancer screening, multiple professional organizations advocate for shared decision-​making in lung cancer screening. In an
unprecedented move, the CMS mandated shared decision-​making
documentation for screening reimbursement. Lung cancer screening
is the first cancer screening modality to have shared decision-​
making mandated by the CMS for reimbursement. Among other
components, the specific language of the national coverage determination notes that “shared decision-​making, including the use of one
or more decision aids, to include benefits and harms of screening,
follow-​up diagnostic testing, over-​diagnosis, false positive rate, and
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SECTION II Cancer Screening in Normal and At-Risk
total radiation exposure,”11 is required for reimbursement. As a result, a number of decision support tools including patient decision
aids, risk prediction tools, and patient education materials have been
developed. The next section will discuss shared decision-​making
specific to lung cancer screening.
Shared Decision-​Making in the Context of Lung
Cancer Screening
Shared decision-​making is viewed as the pinnacle of patient-​centered
care and resonates with the ethical imperative of respect for patient
autonomy and engagement.38 Epstein and Street’s summary of the
evidence on patient-​centered communication posits that clinical encounters between a patient and clinician should be based on collaboration and deliberation.39 Shared decision-​making first appeared in
the literature in 1982.40 Over the past three decades, shared decision-​
making has become somewhat synonymous with patient decision
aids. The prevailing belief that information exchange via patient decision aids would enhance the patient-​clinician collaborative process
has resulted in a proliferation of studies that target the effects of decision aids. The decision to screen for lung cancer is not straightforward and is the epitome of a preference-​sensitive cancer screening
decision best made in the context of shared decision-​making. The
National Academy of Medicine identified patient-​centered care as
a critical component of healthcare quality.38 Patient-​centered care
is defined as “respectful of and responsive to individual preferences,
needs, and values, and [ensures] that patient values guide all clinical
decisions.”38 This principle emphasizes shared decision-​making and
enabling patients to become active participants in making healthcare decisions when there is no clear, evidence-​based “right” choice.
Shared decision-​making involves weighing benefits against harms
with the premise that shared decision-​making can result in a more
informed decision and better quality of care.41 Shared decision-​
making is now considered a critical component of patient-​centered
care, which has contributed to the recent paradigm shift in health
communication from a paternalistic authority toward a communication process shared between the clinician and the patient with an
emphasis on decision support to promote good medical decision
making.”38,41 Many investigators have attempted to enhance shared
decision-​making by developing and implementing patient decision
aids in clinical care without truly understanding the components
that lead to positive patient decisional outcomes (i.e., high decision
quality) or behavioral outcomes. This has led to inconsistencies reported in the literature such as variable decision aid effects,42 lack of
evidence of associations between shared decision-​making empirical
measures and patient behavioral and health outcomes,43 and lack
of knowledge regarding the relationship between communication
quality and cancer screening.44 Two studies noted that the decision
to screen, or not, for lung cancer was not associated with knowledge
or values clarification; rather, it was associated with patient-​clinician
communication quality.23,45 To date, psychosocial factors that influence the shared decision-​making process in lung cancer screening
has not been explored. For patients who chose not to screen, most
(72%) described a short or limited discussion with their clinician
that, from their perspective, focused on the fact that they were eligible and did not include any shared discussion.23 In addition to
low knowledge levels about screening benefits and potential harms,
patients reported encounters with clinicians where opportunities
to fully consider the benefits versus risks of lung cancer screening
were not provided nor did they perceive they had made an informed
decision. For patients who chose to be screened, knowledge levels
also were low, and while participants perceived benefits to detecting
lung cancer early, they reported having no discussion about potential screening harms. Both studies highlight the importance
of the patient-​
clinician discussion and communication quality
in shared decision-​making, and the current knowledge gap about
which shared decision-​making components lead to positive patient
decisional and behavioral outcomes.
Integration of Tobacco Treatment in Lung
Cancer Screening
Widely regarded as a potential teachable moment for tobacco cessation
advice and treatment, lung cancer screening offers a critical opportunity to promote smoking cessation and reduce further lung cancer
morbidity and mortality46 and the cost-​effectiveness of lung cancer
screening.27 Despite the potential for reaching high-​risk, vulnerable
populations, there is strong consensus from systematic reviews and
meta-​analysis that merely undergoing lung cancer screening itself in
the absence of delivery of evidence-​based tobacco treatment has limited sustained effect on smoking cessation.47 Quit rates from several
international lung cancer screening trials have shown mixed results
with regard to the impact of undergoing screening on smoking behavior. Data from the Dutch-​Belgian Lung Cancer Screening trial
(commonly known as the NELSON trial) suggested a possible negative impact on smoking as screening was associated with a lower
prolonged abstinence rate compared to the control group (14.5% vs.
19.1%; odds ratio [OR] = 1.40; 95% CI = 1.01–​1.92; p < 0.05).48 The
VA Demonstration Project49 and the Danish Lung Cancer Screening
trial showed no significant impact of screening on smoking cessation,6 whereas data from the UK Lung Cancer Screening trial demonstrated a positive impact of screening with quit rates of 14% vs. 8%
observed at 1 year and 24% vs. 21% at 2 years in the screening vs. control arms.7 The impact was especially strong among those with a positive LDCT result. An ancillary study of the NLST reported that 37%
of smokers had quit at their last follow-​up assessment and that likelihood of quitting was greater among participants reporting higher
perceived severity of smoking-​related diseases, greater self-​efficacy
for quitting, and fewer perceived barriers to quitting.50
In the U.S., the CMS requires that smoking cessation is offered to
all current smokers seeking lung cancer screening and virtually all
professional health organizations and societies recommend smoking
cessation services as an essential aspect of high-​quality lung cancer
screening.51 Despite the strong endorsement that high-​quality lung
cancer screening should include integration of evidence-​based tobacco treatment, the optimal approach for delivering feasible, cost-​
effective, and sustainable cessation interventions in the context of lung
cancer screening remains largely unknown.52 There is considerable interest in developing and testing the effectiveness of various types and
doses of tobacco treatment delivery,53 such as telephone or in-​person
counseling, pharmacotherapy, and other cessation support strategies. The U.S. National Cancer Institute has established the Smoking
Cessation at Lung Examination (SCALE) collaboration,54 a network
of randomized clinical trials testing the cost-​effectiveness of various
tobacco treatment models in the context of lung cancer screening, and
several SCALE and other study protocols have been published.55,56
Results from systematic reviews of prior studies examining the
effectiveness of integrating smoking cessation within the context of
CHAPTER 11 Lung Cancer Screening
lung cancer screening have yielded mixed yet promising findings.57–​
60 One pilot study showed promise in offering screening participants
telephone counseling;60 however, a larger trial did not demonstrate that an opt-​out offer of telephone counseling for all smokers
seeking LDCT was superior to a mailed brochure containing contact information for cessation services at increasing cessation rates
at 12 months.61 Brief cessation counseling delivered on the day of
LDCT screening may be feasible but not adequately intensive for
long-​term smoking abstinence.59 Two small studies of intensive cessation support found favorable cessation rates.62,63 A recently published systematic review and meta-​analysis64 of the effectiveness of
smoking cessation in the context of lung cancer screening identified 83 relevant trials and categorized their tobacco treatments as
electronic/​
web-​
based intervention, in-​
person counseling, pharmacotherapy, and telephone counseling. At 6-​month follow-​up,
electronic/​web-​based (OR = 1.14; 95% CI = 1.00–​1.25), in-​person
counseling (OR = 1.46; 95% CI = 1.25–​1.70), and pharmacotherapy
(OR = 1.53; 95% CI = 1.33–​1.77) interventions significantly increased the odds of smoking abstinence. Telephone counseling increased the odds of quitting but did not reach statistical significance.
At 12-​month follow-​up, in-​person counseling and pharmacotherapy
remained efficacious.
The potential benefits for lung cancer screening to accelerate
smoking cessation may go unrealized in the absence of access to
evidence-​based tobacco treatments. In an ancillary NLST study,
clinician-​delivered 5As (the five major steps to tobacco cessation intervention: Ask, Advise, Assess, Assist, and Arrange), particularly
offering assistance and arranging follow-​up, was associated with
smoking cessation after lung cancer screening; however, delivery of
cessation assistance was relatively low and arranging follow-​up cessation counseling was very low.65 Screening sites vary in their readiness
and capacity for delivering high-​quality tobacco treatment. In a national survey of smoking cessation practices at lung cancer screening
sites, most sites reported assessing patients’ smoking status (99%)
and advising to quit (91%), but fewer provided cessation coaching
or referral (60%) or recommended cessation medications (33%).66
Patient-​, clinician-​, and system-​level barriers exist and await further
needed research on implementation processes and outcome.
Engagement of smokers seeking lung cancer screening in tobacco
treatment services can also be challenging. Individuals seeking lung
cancer screening present with variable levels of cessation motivation67 and are likely different in many ways from volunteers who participated in the initial screening trials.7,68 Some screening-​seeking
smokers report low quitting readiness,46,69 whereas others are highly
motivated to quit and may have actively sought out screening because of concerns about their lung health.54 Given the older age and
heavy smoking history of screening eligible smokers, it is important
to address smokers’ nihilism (“why bother”?) and acknowledge that
there is compelling evidence that cessation among older, long-​term
smokers will prevent deaths from lung cancer and other tobacco-​
related diseases.70 It is apparent that simply understanding the elevated risk of lung cancer and other diseases associated with smoking
does not necessarily lead to smoking cessation.71 Overestimation of
the benefit of cancer screening alone and the minimization of harm
reduction that can be achieved through smoking behavior change
may contribute to low uptake of tobacco treatment services.72 A recent qualitative study involving a small sample (N = 45) of NLST participants showed that while most patients reported that screening led
to increased reflection on the harms and long-​term consequences
of smoking, as many as half of the patients reported avoidance of
thinking about perceived lung cancer risk.71 There is a misperception among some patients that “undergoing screening yields the
same benefits as smoking cessation” and “everyone who undergoes
screening will benefit.”73 In a larger subsample of smokers (N = 430)
from the NLST assessed 1 year following their initial LDCT, patients
showed no significant changes in risk perceptions from baseline as
a function of screening results, nor was risk perception associated
with quitting, which occurred in only 10% of the patients.74
Many critics of lung cancer screening have cautioned that negative screening results may mitigate current smokers’ concerns about
the health consequences of smoking, thereby reducing motivation
to quit. There remain concerns about whether those who receive
a negative screening scan result will perceive a “license to smoke,”
also referred to as a “health certificate” effect,52,73,75 and false reassurance resulting in reduced quitting motivation.73 To date, findings examining whether lung cancer screening results (normal,
incidental, or suspicious) influence cessation outcomes have been
mixed. It is encouraging that consistently negative scans have not
been associated with greater relapse among long-​
term former
smokers or among baseline smokers. In a substudy69 of smokers
who participated in the NLST, a false-​positive screen was associated
with increased smoking cessation among current smokers and less
relapse among recent quitters. Fortunately, consistently negative
screens were not associated with greater relapse among long-​term
former smokers.
Adherence to Annual Repeat Screening, Follow-​Up, and
Treatment Recommendations
Promoting adherence to annual repeat screening guidelines as well
as follow-​up and treatment recommendations for screening abnormalities are all necessary for ensuring that lung cancer screening
achieves its full benefit in reducing lung cancer morbidity and mortality. Although identifying and addressing barriers for adherence is
a common behavioral issue for all cancer screening guidelines, the
research literature focusing on understanding the extent and drivers
of adherence in the context of lung cancer screening is nascent and is
currently informed by findings from relevant studies examining adherence to older, well-​established cancer screening guidelines such
as breast and colorectal cancer.
To date, older lung cancer screening studies examining chest
radiography have found wide variation in repeat screening
nonadherence with rates ranging from 10% to 45%.76,77 Within
the Prostate, Lung, Colorectal, and Ovarian screening trial, 14% of
screening enrollees were nonadherent to one or more annual, repeat screenings using chest radiography.78 Among individuals with
a false-​positive screening result, nonadherence was 17.2% compared
to 10.3% among those with negative screening results. Montes and
colleagues found that 45% of smokers did not return for annual repeat lung cancer screening with LDCT.79
Future Directions
Given expertise in the psychological and behavioral aspects of
cancer prevention and control, there are critical research needs
and clinical roles for psycho-​oncologists to play in realizing the full
83
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SECTION II Cancer Screening in Normal and At-Risk
public health benefit of lung cancer screening. There are also several
high-​priority research needs that will benefit from continued input
from investigators with relevant expertise. As lung cancer screening
programs are more widely implemented, it is critical to identify the
most salient factors associated with lung cancer screening participation. Early research has supported that lung cancer screening participation is influenced by multilevel factors at the individual, provider,
and healthcare system levels. There is value in understanding all
variables at all levels that have the potential to influence clinical
outcomes. However, for lung cancer screening to be effective, addressing the critical psychosocial factors and their key relationships
associated with screening behavior in this population at the individual level is vital. The current state of the science has provided
researchers with relevant psychosocial factors and informed a theoretical foundation on which to develop tailored interventions for
those most at risk for lung cancer.
To better understand the psychological harms of lung cancer
screening, it is also recommended that lung cancer screening registries capture follow-​up data on clinically meaningful psychological
distress and lung cancer–​specific anxiety. It is important to consider
interventions such as the addition of nurse navigators to assist patients toward scheduling and completion of the initial lung scan as
well as to promote adherence to follow-​up. This may serve as a layer
of psychosocial support for the patient as well as individuals newly
diagnosed with lung cancer as they navigate the healthcare system.
As the science moves forward, it is essential that multilevel interventions be developed to address the individual psychosocial variables
that have the potential to negatively influence lung cancer screening
participation, to support both patients and providers in the shared
decision-​making process specific to a complex cancer screening decision like lung cancer, and to increase awareness of the need for
greater access to psychosocial support services for the individual.80
Specifically, deconstructing the components of patient-​clinician discussions that lead to positive decision and behavioral outcomes is
critical to inform the development of the next generation of decision
support tools and alternative communication strategies, and to shift
the paradigm further in health communication beyond increasing
patient knowledge.
Future research is also needed to better understand the role of
lung cancer screening results and associated risk perceptions on
smoking cessation. Future research is needed to identify effective
ways of communicating lung cancer screening results so as to optimize comprehension, motivate health behavior change (i.e., quitting
smoking), promote adherence to repeat annual screening/​follow-​up
recommendations, and minimize transient anxiety.
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12
Skin Cancer Screening
Jennifer L. Hay and Stephanie N. Christian
Introduction
Skin cancers are the most commonly diagnosed cancer in the United
States (US), and they can very often be efficiently detected on the
skin surface, as they usually arise as a skin change or growth on
the skin.1 Melanoma, the most deadly form of skin cancer, is the
fifth most common cancer in the US, with about 96,500 persons expected to develop melanoma in 2019.1 Unfortunately, the incidence
of melanoma has tripled in the last four decades, and the incidence
and mortality are highest among adults over 55,2 yet there is also
a rising prominence of this potentially fatal skin cancer in young
adults. Over 4.3 million adults are treated for keratinocyte cancers,
including squamous cell carcinoma (SCC) and basal cell carcinoma
(BCC), annually in the US, and population-​based studies show these
cancers are increasing steadily. Although keratinocyte cancers, in
particular BCC, impart low risk of death, they are common and expensive to treat. Most melanomas are caused by ultraviolet radiation
(UVR), predominately from sun exposure and indoor tanning beds.
Keratinocyte cancers share UVR exposure as a major risk factor.
Outside of the US, skin cancer is most prevalent in regions with
large fair-​skinned populations such as Europe, North America, and
Australia. Between the years of 1953 and 2008, numerous studies
have reported that skin cancer rates stabilized or decreased for
populations in many of these regions.3 Despite the overall decline,
as of 2018, the highest rates of keratinocyte cancers worldwide have
been found in New Zealand, Australia, and North America.4
Skin cancer screening involves the process of having either the
whole or partial sections of the skin visually examined for any
changes in appearance to detect suspicious lesions for potential biopsy. This can be conducted by a trained health care professional,
such as a dermatologist or primary care physician, or conducted by
the patient, as a skin self-​examination. Skin self-​examination is arguably an important strategy for screening, given that most melanomas
are detected by patients and their family members.5 An easy-​to-​
remember rubric has been developed to guide patients in remembering the factors that may prompt further skin self-​examinations
by the general public.6 Such visual inspection would seem to be an
intuitive strategy to increase earlier detection of malignancies of the
skin. Indeed, if caught early, all forms of skin cancer are curable.
However, at the current time, there is no national recommendation
for skin cancer screening in the US7 and thus physicians and patients
are often confronted with the decision about whether to conduct or
recommend such screenings in the absence of firm guidance. In
this chapter, we will first review the current evidence and recommendations for skin cancer screening in the US. Second, we will review the current rates of screening, both overall and in higher-​risk
subgroups. Third, we will review the recent evidence for the use of
interventions to enhance skin cancer screening. Fourth, we will present some innovative use of new technology to increase skin cancer
screening. Finally, we will present future directions for this research.
Current Evidence and Recommendations
In 2016, the United States Preventive Services Task Force (USPSTF),
which makes evidence-​based recommendations about clinical preventive services, released a statement that the current evidence
available did not warrant recommendation for the use of skin cancer
screening.7 The report states, “At present, there is insufficient evidence for any population that regular visual skin examination by a
clinician can reduce skin cancer–​related morbidity and mortality.”
The USPSTF was guided by the lack of evidence from a randomized
controlled trial confirming the benefit of screening in reducing morbidity and mortality related to skin cancer, as well as the potential
risks that could be associated with routine skin cancer screening in
the general population. These risks were specified as the anticipated
increase in detection and treatment of skin cancers, such as basal cell
cancers, that do not impact life expectancy; the high number of biopsies and excisions that may be generated by screening to treat small
numbers of skin cancers and melanoma; and the complications and
potential poor cosmetic outcomes that can result from such excisions. For instance, Wernli and colleagues argued from the USPSTF
perspective that, although rates of skin cancer have increased since
1986, mortality rates have remained stable, indicating the potential
that increased screening may be leading to the finding of clinically
less significant cases of skin cancer instead of more harmful invasive
tumors.8
Numerous medical and public health organizations have followed
suit with the USPSTF by not issuing official guidelines, yet have
tried to provide some guidance for the general public with information and resources on how to advocate for themselves regarding
follow-​up of any noticed changes with their skin, particularly among
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subpopulations with skin cancer risk factors. Skin cancer risk factors
can include light skin, hair, and eyes; multiple moles; and a family or
personal history of skin cancer. Current recommendations and resources for the general public from major medical and public health
organizations can be found in Table 12.1. The general theme across
organizations is that while there is no consensus on standard guidelines for the public, those who are at higher risk for skin cancer are
encouraged to consult with their clinicians regarding personalized
treatment plans for physician and self-​screening. For instance, the
American Academy of Dermatology recommends that those with
a history of melanoma should have a full body exam at least once
annually in addition to regular self-​screenings,9 and the Skin Cancer
Foundation recommends a full body exam more often than annually if at higher risk.10 Similar to the US, there is currently no formal
population-​based screening program in New Zealand, Australia, or
the UK. However, Cancer Council Australia recommends that those
at higher risk for developing skin cancer, such as those with fair skin,
a tendency to burn or tan easily, light eyes and hair color, increased
number of moles, or a family and/​or personal history of skin cancer,
undergo physician skin examinations every 6 months, and to conduct self-​examinations regularly.11 Additionally, the Cancer Society
of New Zealand has recommended that those at higher risk for the
onset of skin cancer develop evidence-​based management strategies
for early detection with their clinicians.12 Guidelines for screening
by the British Association of Dermatologists are that those at moderately increased risk, defined as patients with a previous history
of melanoma or a large number of moles, some of which may be
atypical, should be referred to a specialist and counseled on how
to conduct a self-​examination; those at a “greatly increased risk of
melanoma,” including those with “giant congenital” nevi, should be
monitored for life by a specialist; and those with a family history of
melanoma or pancreatic cancer in three or more members should be
referred to a specialist.13
A seminal observational study of systematic skin cancer screening
was recently mounted in Germany, which highlights some of
the challenges inherent in interpreting nonrandomized studies.
This important example of the widespread implementation of
population-​based, one-​time screening was conducted in the region of Schleswig-​Holstein, Germany, in the north of Germany,
starting in 2008, where a 1-​year skin cancer screening program
was integrated into routine primary care. This SCREEN program
(Skin Cancer Research to Provide Evidence for Effectiveness of
Screening in Northern Germany) was initiated by the Association
of Dermatological Prevention in 2003 to establish the efficacy of
population-​based screening. Initial promising evidence found that
offering community screening over 5 years saw an increase in incidence rates of skin cancer diagnoses and, importantly, a 48% decrease in melanoma mortality, yet subsequent analyses found that
over time the initial decrease in mortality was transient and returned
to levels observed before screening initiation within the next 5 years.
Given that this study was an observational study and not a randomized controlled trial, there are many factors that may have accounted
for these findings, the most important of which were differences in
physician reporting of cause for death in this area.14
Since these results have come out, other groups around the world
have continued to deliberate as to whether a well-​designed randomized controlled trial could confirm whether the value of skin cancer
screening is possible or worthwhile. For instance, a group in Norway
concluded that given the risks to overdiagnosis and treatment, the
rarity of melanoma detracts from mounting a trial. In contrast, Cust
and colleagues15 responded that the number needed to invite for
screening to prevent one melanoma death is inversely proportional
to the mortality rate in the cohort, making it potentially worthwhile
to conduct such a trial in a part of the world with very high melanoma incidence. Further, these authors note that the integration of
new technologies such as total body photography, dermoscopy, and
artificial intelligence would not make a trial obsolete, but could be
incorporated into the trial design and lead to improvements in sensitivity and specificity, increasing cost-​effectiveness.
A multidisciplinary US group including expertise from dermatology; dermatopathology; cutaneous, surgical, and medical oncology; clinical research; epidemiology; and social psychology have
recently responded to the USPSTF 2016 recommendations with a
set of well-​justified skin cancer screening recommendations. These
risk-​based, data-​driven guidelines for skin cancer screening are
modeled based on USPSTF guidelines for other cancers.16 These
guidelines highlight the remarkable safety, ease, and low-​cost nature
of total body skin examination (TBSE), compared to screening for
other cancers such as breast and colorectal cancer, which is defined
as evaluation of the entire skin surface, including scalp, face, ears,
neck, chest, abdomen, back, buttocks, genitals, upper and lower extremities, hands, feet, eyes (iris and sclera), oral mucosa, hair, and
Table 12.1. Guidelines for Early Detection of Skin Cancer for General Public from Public Health Organizations in the United States
Organization
Official Guidelines for General Public
Resources for General Public
1
Division of Cancer Prevention and
Control, Centers for Disease Control and
Prevention (CDC)37
No official guidelines for general public
Provide information through their website and recommend the
public report any noted changes in the skin to a clinician for
further review
2
United States Preventive Services Task
Force (USPSTF)38
No official guidelines for general public
Provides facts about skin cancer and recommendations to speak
with a clinician38
3
American Academy of Dermatology
(AAD)9
No official guidelines for general public
Encourages all people to conduct self-​examinations regularly and
provides services through their SPOTme program39
4
American Cancer Society (ACS)40
No official guidelines for general public
Provides extensive details and information on how to conduct
skin examinations through their website and prevention report
5
National Council on Skin Cancer
Prevention (NCSCP)41
Self-​examination once a month
Provides prevention behavioral recommendations for public
6
Skin Cancer Foundation10
Yearly screening with physician; monthly
self-​exam
Provides information regarding self-​exam, tips for what to do for
the yearly screening, and resources to find a physician
CHAPTER 12 Skin Cancer Screening
nails. Based on international recommendations from countries with
similar levels of elevated risk, these authors recommend a target
age range of 35 to 75 years for at least annual TBSE, and targeting
risk groups such as those with a personal or family history of melanoma or a hereditary predisposition to melanoma based on a developing number of melanoma susceptibility genes; phenotypic factors
indicating higher risk, such as blonde or red hair; or a history of
overexposure to ultraviolet radiation, such as a history of blistering
or peeling sunburns. They also note that detection of keratinocyte
cancers cannot be considered only a harm of screening, as it adds to
the costs and workload, but also a benefit of screening, given that important elements of quality of life are gained from their improved diagnosis and early excision. As such, these authors strongly argue that
risk-​based skin cancer screening is justifiable and warranted and
could reduce morbidity and mortality associated with melanoma.
Current Rates of Screening in General Population
and High-​Risk Subgroups
Completion of skin cancer screening is low in the US, with about 1
in 5 adults reporting having ever received a TBSE from a clinician.
Multiple national probability surveys have included assessment of
skin cancer screening that have allowed for estimates of prevalence
of skin cancer screening in large population subgroups. In general,
results show an increased prevalence of screening over time, with
higher rates among those with skin cancer risk factors. The National
Health Interview Survey (NHIS), a nationally representative survey
sponsored by the Centers for Disease Control and Prevention’s
(CDC) National Center for Health Statistics, shows that as of 2015,
about 21% of US adults reported ever having had a TBSE to check
for cancer by a dermatologist or other physician (N = 33,672), and
about 45% of those had one within the past year. Of these, two-​
thirds (66%) reported having a skin check as part of a routine exam,
while 27% had one because of a skin problem.17 We are not aware
of studies specifying population-​level rates of skin self-​examination,
but reviews examining rates of skin self-​examination across smaller
studies range extremely widely.18
Fortunately, screening rates are higher among those with skin
cancer risk factors. A study incorporating NHIS data from 201019
indicated that rates of screening among high-​risk individuals differ
modestly from those classified as medium-​risk or low-​risk groups.
Among those in the high-​risk group, including those who identify as
non-​Hispanic, White, or older than 65 years old and with a history
of sunburns and a family history of skin cancer, it is estimated that
24% had ever received at least one TBSE, and about 11% had done
so in the past year. These lower rates of recent screening in those
at higher risk may indicate that they may have adopted screening
over time, rather than more recently, as might be the case with those
in the general population. Among those in the medium-​risk group,
rates of screening are comparable. This group is defined as the remainder of the White non-​Hispanic population, where 24% are
estimated to have ever had a TBSE, and 10% within the past year.
Indeed, for those who engage in indoor tanning, screening may be
more important than for those who do not due to their increased
risk of developing skin cancer. In a study utilizing 2015 NHIS data,
it was found that about 30% of those who have ever indoor tanned
report ever having a TBSE by a physician; further, indoor tanners
had been screened for skin cancer at younger ages than those who
had never tanned.20
The highest rates of screening are likely concentrated in the melanoma survivorship population. As such, a small 2014 study analyzing health behaviors of melanoma survivors within a US cancer
center from 1995 to 2011 found that 94% of melanoma survivors
reported routinely receiving clinical skin examinations since their
diagnoses.21 In addition to clinical examinations, studies have shown
that about half of recurrent melanomas have been identified first by
the patient or loved one before being officially diagnosed by a health
care provider, indirectly indicating enhanced self-​screening in the
survivorship population.5 Internationally, a study examining the role
of various factors in determining both skin cancer self-​examinations
and clinical examinations between 2007 and 2008 (N = 8,178) in
Australia, the US, and Europe found that those with a history of melanoma had much higher rates of both types of screening compared
to those without a history of melanoma; further, rates of both types
of screening were higher among those living in Australia and the US
compared to Europe.22
Interventions to Improve Skin Cancer Screening
Interventions to improve skin cancer screening have targeted medical providers, including physicians and medical students, with the
aim to improve rates of completion of screening among medical professionals such as primary care physicians who see patients regularly
and have a focus on preventive care. Some of these efforts have taken
an opportunistic approach whereby physicians are trained to distinguish benign versus suspicious lesions on areas of the body that
are exposed during their typical primary care examination, such as
the chest and back, that would reduce the need for a special visit for
clinical skin examination. Interventions have also been developed to
encourage patients to conduct regular skin self-​examinations. In the
following section, we present some recent examples of this research.
Many of the efforts targeted to medical providers have focused on
nondermatologically trained clinicians. Such efforts have included
training for physicians to identify benign versus suspicious lesions,
to conduct clinical skin examinations, and to use novel strategies to
aid in detection such as dermatoscopes. One promising example includes the INFORMED (Internet Curriculum for Melanoma Early
Detection) program, which was developed to provide a web-​based
early detection training program that includes a large image database
for imaging. This program involves 1–​2 hours of training that can
be delivered via traditional textbook format or case-​based format,
which includes nine case vignettes illustrating teaching points with
quizzes and feedback. The course improved primary care physicians’
ability to manage skin lesions without increasing dermatologist referrals, and improvement was still evident at 6 months.23 Of note,
INFORMED was focused largely on improving physicians’ ability to
diagnose and manage skin lesions correctly rather than on general
knowledge about skin cancer risks per se, so that they may not necessarily be better prepared to offer skin cancer prevention advice to
patients. Further work with INFORMED moved this training to a
large, observational, year-​long study in a large health care system
at the University of Pittsburgh and a relatively higher-​risk sample
of older individuals than previous skin cancer screening programs
have targeted. Of note, physicians did not receive compensation for
89
90
SECTION II Cancer Screening in Normal and At-Risk
conducting the screenings, increasing the generalizability of the
study findings. This study focused on increasing use of full-​body
skin examination (FBSE) by primary care physicians and included
promotion of the program to physicians as well as patients, and finally adjustment of the electronic medical record to include FBSE as
a recommended preventive service for individuals over age 35. This
large study included over 300,000 patients seen in an office visit by a
primary care physician in 2014; about 53,000 patients were included
in the screened cohort. Findings indicated a higher likelihood of
melanoma diagnoses in those who were screened compared to those
who were unscreened; melanomas in screened patients were thinner
than those in unscreened patients. The incidence of thicker melanomas (1 mm or thicker) was the same in screened and unscreened
groups, however. Importantly, these findings are observational, not
the result of a randomized trial, so there may be confounding factors
that may have influenced screening as well as data quality. Medical
students have also been a focus of training to encourage skin cancer
examination, including, for example, the development of a film,
The Integrated Skin Exam, to increase medical students’ knowledge,
identification of higher-​risk groups, the characteristics of suspicious
nevi, and intentions to conduct skin examinations, which showed
promising effects in second-​year medical students recruited across
the US.24 The film is available through the American Academy of
Dermatology Medical Student Core Curriculum.
Another important effort to enhance skin cancer screening in
primary care providers has focused on opportunistic screening, or
the ability of physicians to identify suspicious lesions when they
are conducting standard primary care examinations. As such, the
focus here is not on thorough or comprehensive examinations per
se. These authors conducted a randomized trial (N = 89 primary
care physicians) to examine a mastery learning course that included
training in use of dermoscopy, which is a noninvasive in vivo technique commonly used by dermatologists to visualize lesions, as well
as deliberate practice and feedback to reach a standard. In the intervention group, fewer benign lesions were referred for additional
follow-​up within 3 months of the training and physicians referred
significantly more melanomas in that time period. Most of the melanomas were located on the head and neck, which is consistent with
the opportunistic, rather than comprehensive, nature of these examinations.25 Importantly, a reduction in referrals for benign lesions
is quite important given that this can potentially reduce health care
costs, decrease patient anxiety, and reduce office visit burden.
Additional efforts have been mounted to encourage skin self-​
examination, both in the general population and in community
settings, and also among patients at higher risk of developing skin
cancers. One important and successful effort to increase skin cancer
screening rates in primary care patients included the Check-​It-​
Out intervention that promoted thorough skin self-​examination.
Importantly, physicians did not participate in the intervention
and in fact were blinded to the group assignment.26 The study
randomized primary care patients to intervention or control condition (dietary improvement). Results found that thorough skin
self-​examination increased in the intervention group at 2, 6, and
12 months, and although skin surgeries increased initially, there
were no differences in surgery rates at 6 and 12 months between intervention and control groups.26 Additional analyses looking at the
most important components of the intervention arm found that the
video that was developed for the study, the hand mirror, a brochure
developed by the American Cancer Society, and sample photos led
to higher rates of skin self-​examination. Importantly, the clinicians
who agreed to have their patients participate in the Check-​It-​Out
study may be more prevention focused than the general community
of primary care physicians. An important community-​wide effort to
improve skin self-​examination, the SkinWatch study, included skin
self-​examination self-​help guides, skin cancer seminars, skin cancer
education to local medical practitioners, and free, open-​access skin
screenings in Queensland, Australia, and found promising effects
on screening rates, which were attenuated after the open-​access skin
screenings were eliminated.27
There has been a focus, as well, on higher-​risk patients. For example, patients who attend pigmented lesion clinics undergo enhanced dermatologist surveillance given their very high-​
risk
phenotypes, but also can benefit from skin self-​examinations conducted between office visits. Marek and colleagues conducted a trial
examining the use of a smartphone mobile application (app) that included a set of total body photographs that were taken professionally
in their dermatologists’ office to document skin lesions.28 A trial including 69 patients randomized them evenly across four arms: either
use of the mobile app alone or use of the mobile app along with either skin exam reminders, sending monthly performance reports to
an accountability partner identified by the patient such as a spouse,
or use of both the reminders and accountability partner. Outcomes
were evaluated at 6 months. In all arms, skin self-​examination increased from 58% at baseline to 83% at 6-​month follow-​up; there
were no differences by intervention group. The study was shown to
be efficacious, and this seemed especially true for hard-​to-​examine
areas such as the lower back and back of legs. Participants found the
reminders to be especially useful.
Other efforts have focused on encouraging skin self-​examination
in specific circumstances where patients may be especially receptive.
For instance, Robinson and colleagues developed an interesting intervention targeting women undergoing mammography screening
who reported melanoma risk factors such as a history of sunburn,
indoor tanning, or personal or family history of melanoma. In the
changing room while waiting for their mammogram, they were
exposed to an informational poster and brochure promoting risk-​
targeted skin self-​examination advice. The authors argue that mammography is a great way to target higher-​risk patients, given that
most melanomas occur in those over age 40, making this a feasible
approach to getting women to focus on skin self-​examination. Half
the group also received a reminder to complete skin self-​examination
at 1 week. At 1 month, 80% of those who had completed the follow-​
up survey had performed skin self-​examination,25 which was a great
improvement over baseline skin self-​examination assessment (30%
reported ever having done a skin self-​examination). Further, anxiety was not increased in the intervention as associated with skin
self-​examination.
Other efforts have included combined interventions to encourage
skin cancer prevention as well as early detection strategies, especially in higher-​risk individuals. For example, Bowen and colleagues focused on increasing both physician screening and skin
self-​examination in family units as well as sun protection, where
at least one family member had a history of melanoma, one was
a first-​degree family member of the patient, and one was a parent
of a young child, with very promising indicators for both types of
screening.29 The PennSCAPE trial recently examined the use of
CHAPTER 12 Skin Cancer Screening
mailed tailored print materials compared to generic print materials
in primary care patients to encourage both sun protection and skin
self-​examination behaviors. Materials were tailored to patient risk
level and found promising outcomes.30 In addition to promising increases in sun protection, the intervention also increased use of skin
self-​examination and skin examinations by a health care provider.
Recent Use of Innovative Technology
Innovation strategies to motivate screening, as well as ways to
improve the accuracy of screening, have been evolving quickly.
Strategies that serve as a cue to action, or enhance screening motivation, have been developed. For example, electronic reminders have
been used to facilitate completion of skin cancer screening, as well
as the use of digital interventions, using tablets and mobile phones
to prompt and support total skin self-​examinations. These online,
interactive interventions can be targeted to family members who
can aid patients in conducting skin examinations. Further, the provision of photographs of patients’ entire skin surface31 has also provided promising prompts to perform skin self-​examination. More
recently, the use of mobile teledermoscopy has been examined as a
way for patients to conduct skin self-​examination and then to use
their mobile telephone to photograph and send in the photographs
for dermatologist assessment; results have shown patient acceptance
of this technology, yet with some important caveats regarding patient trust, and mixed findings on clinical accuracy of the photographs sent in by patients for examination,32 supporting the use
of teledermoscopy as a complement rather than a replacement for
clinical skin examination. Motivation to increase screening might
be galvanized by personalized information, such as genetic information.33 Other strategies are focused more specifically on accuracy,
or improving the sensitivity and specificity of the screening, which
can reduce unnecessary biopsies and corresponding screening costs.
Such emerging technology includes dermoscopy, confocal microscopy, and digital photographic imaging, including artificial intelligence,34 which have the potential to improve screening efforts among
the wider population of health care providers as well as for patient-​
initiated examination. However, use of dermoscopy is relatively low
among US nondermatologist physicians, but higher in those who
graduated from medical school more recently and those who see
more skin cancer patients.35 Barriers to use in primary care include
the time and resources to adequately train nondermatologists. Of
note, an innovative intervention has been developed for individuals
who received radiation as children for their malignancies and who
are at significantly increased risk for skin cancer. It uses patient-​
driven innovative health technology—​teledermoscopy—​whereby
patients take photographs of concerning moles and then transfer
them electronically for dermatological assessment; this was combined with web and print materials encouraging the patients to conduct skin self-​examinations and request physician examinations.36
Future Directions
There are a number of barriers that stand in the way of increasing
skin cancer screening in the US and around the world that require
work to surmount them. First, the lack of USPSTF recommendations
limits physician reimbursement for screening and may detract from
the devotion of time and effort for physicians to complete screening
or encourage self-​screening in their patient populations. As of 2019,
Illinois has provided reimbursement for screening, which will present an important opportunity to examine effects of these changes
in reimbursement over time. Important, well-​justified efforts to justify more uniform and intensive screening for higher-​risk groups
may change physician practice over time. Second, preferences
among patients for physicians and health care providers to conduct
exams—​rather than to learn and consistently practice skin self-​
examinations—​may continue to limit skin self-​examination uptake,
even in higher-​risk populations, and requires further study. Third,
given limitations in the dermatology workforce in the US and other
countries, there is a need for continued efforts to extend the capacity
to conduct thorough screenings by primary care physicians, as well
as physician assistants and nurses, which will be important as interest
and demand for health care–​provided screenings increases. Efforts
to test the delivery of education to primary care providers over broad
geographical areas via video technology may enhance knowledge
acquisition and practice change in primary care. Finally, the use of
new technology, such as artificial intelligence and other technology,
may substantially improve diagnostic accuracy and reach across
dermatologists and other physicians who may start to practice more
regular screening in their higher-​risk patients. Overall, while current rates of screening are low in the general population, risk-​based
screening seems justified enough to continue robust efforts to train a
broad range of physicians and health care providers to conduct skin
cancer screening and to encourage skin self-​examination. Given the
associated morbidity and dramatically increasing cost to treat advanced melanomas, such efforts are strongly warranted from both a
patient well-​being and a cost perspective.
ACKNOWLEDGMENTS
We acknowledge with thanks the technical assistance of Liliane
Sar-​Graycar and Teddy Smith in the completion of this chapter.
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SECTION III
Screening and Testing for Germ
Line and Somatic Mutations
Paul B. Jacobsen (Section Editor)
13 Psychosocial Issues in Genetic Testing for Breast/​
Ovarian Cancer 95
Mary Jane Esplen, Jonathan Hunter, and
Eveline M. A. Bleiker
14 Psychosocial Issues in Genetic Testing for
Hereditary Colorectal Cancer 102
Sukh Makhnoon and Susan K. Peterson
15 Psychosocial Issues in Genomic Testing, Including
Genomic Testing for Targeted Therapies 110
Megan Best
16 Psychosocial Issues Related to Liquid Biopsy for
ctDNA in Individuals at Normal and Elevated
Risk 116
Jada G. Hamilton, Amanda Watsula-​Morley, and
Alicia Latham
13
Psychosocial Issues in Genetic Testing
for Breast/​Ovarian Cancer
Mary Jane Esplen, Jonathan Hunter, and Eveline M. A. Bleiker
Background
Approximately 10% of all breast cancers are due to hereditary factors, with the majority caused by mutations in two autosomal dominant breast cancer genes, BRCA1 and BRCA2. Therefore, identifying
mutation carriers means that genetic counseling and testing of individuals, with or without cancer, can occur to inform health-​related
decision-​making. For instance, mutations in these genes confer
cumulative risks of breast cancer of 72% in BRCA1 mutation carriers and 69% in BRCA2 mutation carriers by age 80.1 Women with
BRCA1/​2 mutations who develop breast cancer also have a 20-​year
cumulative incidence of contralateral breast cancer estimated at 26%
to 40%. In addition, BRCA1/​2 mutations place women at risk for
ovarian cancer with a cumulative risk of 44% by age 80 in BRCA1
carriers and 17% in BRCA2 carriers.1 An increased risk for prostate and pancreas cancer has also been reported.1 This knowledge of
being at high risk of developing cancer offers opportunities for prevention. However, a number of psychological and social challenges
have been identified with cancer genetic counseling; these will be
discussed in this chapter.
Outline of Genetic Counseling
Individuals with characteristics suggestive of a hereditary cancer
gene may be referred to specialty genetic clinics to see a genetic
counselor and/​or geneticist. These characteristics include having
multiple cases of cancer in more than one generation, a young age of
onset, bilateral breast cancer, breast and ovarian cancer, and triple-​
negative breast tumor at a young age. Genetic counseling aims to
help counselees comprehend and adapt to the medical, psychological, and familial implications of having genetic contribution to
disease. In BRCA counseling, individuals are educated about their
breast and ovarian cancer risk, including risk of prostate cancer for
men. This usually takes place across two consultations, at least one
of which is performed before a genetic test, typically face to face
with a trained genetics professional. More recently, to meet growing
demand, alternative models of genetic service delivery using telephone or group counseling are underway.2
Outcomes of Genetic Testing for Breast Cancer
The genetic test may result in a number of different outcomes: (1) a
counselee is determined to have a pathogenic BRCA1 or BRCA2 mutation known in his or her family, defined as being a “carrier”; (2) a
counselee is not a carrier of a pathogenic BRCA1 or BRCA2 mutation,
a “noncarrier”; (3) no known BRCA1 or BRCA2 mutation is detected
in the family or the counselee, despite a strong family history of breast/​
ovarian cancer, an “inconclusive” result; or (4) an unclassified variant/​
variant of uncertain clinical significance (UV) is found, so contribution of this BRCA1 or BRCA2 variant to cancer risk is “undefined.” As
a result of this genetic screening, individuals can make individualized
decisions. Proven carriers of a BRCA1/​2 mutation have a substantially increased risk of breast or ovarian cancer, so periodic surveillance (mammography and/​or breast magnetic resonance imaging)
or preventive mastectomy and/​or oophorectomy are recommended.3
Women who are proven to be noncarriers have no increased risk and
are advised to participate in population-​based breast cancer screening.
For those individuals receiving an inconclusive test result, evidence-​
based guidelines are lacking; however, routine screening options are
recommended and preventive surgery may also be considered.
Treatment-​Focused Genetic Testing
Previously, breast cancer patients at increased genetic risk were
offered genetic counseling and testing following completion of oncology treatment. However, a new model of “rapid” genetic testing
in which testing happens before their primary surgery is now available.4 This process allows women to receive information on their
carrier status close to their breast cancer diagnosis so that they can
incorporate this knowledge into treatment decisions. These women
may, for example, opt for mastectomy instead of lumpectomy, or
for an immediate contralateral prophylactic mastectomy to prevent
breast cancer in the unaffected breast.
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Section III Screening and Testing for Germ Line and Somatic Mutations
Initially, concerns were raised about the possibility that providing
genetic testing at the time of diagnosis could result in both an informational and emotional overload at a stressful time. However, a recent study showed that, despite the additional distress burden, 73%
percent of patients who received the results of genetic testing before surgery recommended genetic testing to other high-​risk breast
cancer patients, and 88% believed that the best timing of genetic
testing was between breast cancer diagnosis and surgery.4 A recent
randomized trial of rapid DNA testing before surgery among newly
diagnosed breast cancer patients also showed no significant differences between study groups in psychosocial outcomes.4
The Possible Burden of Intense Surveillance and
Prophylactic Surgery
Following confirmation of a BRCA mutation, women are faced
with difficult choices around how best to manage their risk of developing breast or ovarian cancer. Options to consider are enhanced
surveillance with magnetic resonance imaging (MRI), mammography, transvaginal ultrasound scan of ovaries and fallopian tubes,
risk-​reducing surgery to their breast tissue, removal of their ovaries
and/​or fallopian tubes, chemoprevention, and lifestyle interventions. While prophylactic surgeries offer the best chance for reduced
risk, such surgeries impact quality of life, body image, and sexuality.
We will review each option with respect to its psychological consequences and benefits.
Breast Cancer Surveillance
Carriers of a BRCA1/​2 mutation, as well as women who receive an
inconclusive genetic test result, are all offered an intensive surveillance program, including mammography, MRI, and a clinical breast
examination by a physician. In two reviews of women with a family
history of breast cancer or with BRCA1/​2 mutations undergoing
intensive surveillance, normal levels of distress and better general
health compared to the general population were found.5 However,
if recall tests or false positives for a mammographic finding occur,
anxiety inevitably elevates.5
Prophylactic Mastectomy
By having a risk-​reducing mastectomy, a woman with BRCA1/​2
lowers her risk by about 90%. Furthermore, female breast cancer
patients who carry a BRCA1/​2 mutation have an increased risk of
developing a second primary breast cancer.6 Contralateral prophylactic mastectomy (CPM) has been reported to lead to a reduction of
up to 95% in the risk of contralateral breast cancer. However, there
is still some debate on the effect on both overall and breast cancer–​
specific survival.7
Studies on the long-​term satisfaction and psychosocial impact
of risk-​reducing surgery in breast cancer patients, or women at
increased risk with a positive family history, report both positive and negative consequences. There is an overall high level of
satisfaction, favorable effects on emotional stability and stress,8
and lower level of breast cancer concerns compared to women
who have not had prophylactic mastectomy.9 Negative effects include a compromised body appearance and a reduced sense of
femininity.8,9
In newly diagnosed breast cancer patients who have contralateral prophylactic mastectomy, no differences have been found in the
first year after surgery in quality of life and distress, as compared to
women who opt for breast conservation or unilateral mastectomy.10
Despite the potential negative impact of contralateral mastectomy,
such as an adverse impact on body appearance, sense of femininity,
sexual relationships, and unanticipated reoperations due to complications with reconstruction, the large majority of women report
being satisfied with their decision to undergo prophylactic contralateral mastectomy.11
Recent research suggests that particular psychosocial factors are
associated with pursuing prophylactic surgery. The age of the woman,
her status as a parent, the gender of her children, and guilt about
passing on a mutation to a child can all play a role.8,12 Psychological
factors related to the BRCA experience, such as distress prior to surgery or uncertainty about familial support and medical options, also
contribute to the decision to have prophylactic surgery. One study
found that the more distress a woman experiences related to testing
positive for BRCA, the less likely she is to have surgery and to continue with surveillance.12
Individuals who report practitioner-​initiated discussions about
undergoing bilateral risk-​reducing mastectomy may be more prone
to having regret. An approach focused exclusively on statistical risk
reduction, without taking into account potential consequences of
surgery and opportunity for reflection on other management options, may result in increased psychological issues postoperatively.
Exploring motivational factors and assessing psychosocial functioning are critical. It has been recommended that women considering prophylactic mastectomy be referred to a psychosocial
clinician to discuss options and to ensure that the woman is making
an informed decision not driven by fear or based on perceived bias
of one health professional—​or other individuals, such as anecdotal
advice from well-​meaning friends or family.13
Studies of partners indicate that they are focused most on supporting the preservation of overall health of their partner with
BRCA1/​2;14 however, they too can experience difficulties related to
the woman’s altered body image and sexual functioning, and should
be offered psychosocial support.14
Ovarian Cancer Surveillance and Risk-​Reducing
Salpingo-​Oophorectomy
Until recently, ovarian cancer screening with a CA-​125 test every
4 months and annual ultrasound was recommended as one of the “preventative” options for women at increased risk. Although final results
of large trials are yet to be reported, initial studies suggest that gynecological screening has not led to decreased ovarian cancer mortality.15
Therefore, screening for ovarian cancer in asymptomatic women is
no longer a standard recommendation. However, for women with a
BRCA1/​2 mutation, risk-​reducing bilateral salpingo-​oophorectomy is
recommended, as it is believed to reduce the risk of ovarian cancer by
80%–​96%. Furthermore, salpingo-​oophorectomy contributes to a reduced breast cancer risk by 50% when performed prior to menopause.
Madalinska et al.16 found favorable effects of prophylactic oophorectomy in terms of reduced cancer worries and low perceived cancer
risk. However, as the surgery results in the onset of menopause, the
observed benefits need to be weighed against impacts on body image
and an increase in endocrine and sexual symptoms.
CHAPTER 13 Psychosocial Issues in Genetic Testing for Breast/Ovarian Cancer
Psychosocial Issues Encountered by Individuals
Undergoing Genetic Counseling and Testing
While it is generally recognized that many individuals will benefit
from genetic testing and counseling for breast cancer, genetic testing
may induce serious psychosocial problems.
Testing Positive for a Genetic Mutation
Reviews and a meta-​analysis indicate that the majority of counselees
informed of carrier status do not exhibit heightened or clinically relevant levels of depression, anxiety, and/​or distress, at least beyond
the short term, as assessed by standardized questionnaires with
established score thresholds for clinical relevance.17,18 However,
depending on the type and timing of the assessment, a subset of
approximately 25% of counselees demonstrate high levels of psychological morbidity, sufficient to merit interventions.18 It has become increasingly clear that the historical context of the individual
coming forward for testing, such as that related to the prior experience of cancer in the family, cancer-​related deaths, the genetic test
result of a sibling, and having children or not, play an increasing role
in understanding who may require added psychological support.
Risk Factors for Increased Psychosocial Distress
A listing of risk factors for increased emotional distress appears in
Box 13.1. A robust predictor of post–​genetic testing distress is the
pretest emotional state or distress level.17,18 Among the risk factors
for high distress is the experience of parental cancer in childhood.19
Specifically, women who have lost their mothers to cancer report
more cancer-​specific distress.20,21 Similarly, individuals who have
cared for and/​or lost a parent during adolescence are more vulnerable to psychological distress and may request additional psychosocial support during the genetic counseling process.22,23 Related risk
factors for distress are the recent loss of a close relative to cancer, the
recent diagnosis of cancer in the counselee,18,22 and problems encountered communicating with family members.24
Recognition and support of the counselee who is the “family messenger,” typically the first utilizer of predictive testing and preventive surgery in the family, are important—​especially when they feel
that they must provide a “good example” for the rest of the family.
Furthermore, special caution is needed in those families in which
clear expectations exist about carrier status. If the test outcome differs from what is anticipated, families often have more difficulty
adapting.22,23 Finally, psychosocial support is frequently needed by
those who are confronted with the decision to undergo risk-​reducing
surgery. Pre-​as well as postsurgery support can help individuals in
making a well-​balanced decision about undergoing surgery and facilitate the adaptation to the operation.25
Identification of Psychosocial Problems
Specific brief screening instruments have been developed to identify
increased psychosocial risk at the beginning of genetic counseling.
The Genetic Psychosocial Risk Instrument (GPRI) identifies individuals at risk for psychological distress.22 Another brief instrument,
the Psychosocial Aspects of Hereditary Cancer (PAHC) questionnaire, detects individuals experiencing current psychosocial problems.23 Additional instruments assess psychological response after
genetic testing. Examples include the Psychological Adaptation to
Genetic Information Scale (PAGIS)26 and the Multidimensional
Impact of Cancer Risk Assessment (MICRA).27
Receiving a Negative Test Result
Some individuals will receive the good news that they do not carry a
genetic mutation. This is typically associated with relief and reductions in both general and breast cancer–​specific anxiety. Surprisingly,
however, testing negatively can cause struggles adjusting to a new
sense of personal risk. Frequently, individuals with a strong family
history of cancer have integrated a sense of being at increased risk to
cancer and feel a strong identification with the relative(s) affected by
the disease. A negative test is therefore unexpected, and individuals
have the task of integrating this incongruent information into their
sense of self. This task is complicated by the feeling that one is giving
up being a member of a group, which can be felt as a distressing separation from loved ones. Other feelings that can emerge for those
Box 13.1. Factors Associated with Psychological Risk or
Adjustment Difficulties
Sociodemographic
♦ Younger age
♦ Female sex
♦ Being unmarried
♦ Lower socioeconomic status
♦ Having children
Cancer and symptom related
♦ Recent diagnosis
♦ Recent history of breast symptoms
♦ Past experience of cancer and its impact on the family
Psychosocial
♦ Increased risk perception
♦ Appraisal of high relevance and threat
♦ Loss of close relative to cancer, especially loss of mother at
young age
♦ Caregiving of family member with cancer
♦ Prior history of additional life losses/​trauma
♦ Premorbid psychological condition
♦ Current level of psychological functioning (e.g., presence of depression, anxiety, disease-​specific worry)
♦ Low self-​esteem
♦ Feeling stigmatized by BRCA1/​2 status
♦ Expectation of receiving a negative test result
♦ Coping style (e.g., avoidant coping, anxious preoccupied, health
monitoring, using suppression as emotional regulation strategy,
pessimistic)
♦ Low level of social support
Family
♦ Being first in family tested
♦ Low level of family cohesion
♦ Knowledge of siblings’ positive result
♦ Anticipated or actual changes in relationships as a result of testing
♦ Anxious partner
♦ Frequent concern for children; guilt of passing on mutation
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Section III Screening and Testing for Germ Line and Somatic Mutations
testing negative include feelings of guilt about being unjustly spared
the legacy of the familial disease, a form of “survivor guilt.”24
Inconclusive Test Results
Even if an individual receives an “inconclusive” result, it is still possible for the individual to carry a gene mutation that is rare, or not
yet determined to be significant. Such a result causes clinicians concern, as they worry that the individual could feel reassured but in
fact be at some elevated risk. The individual’s comprehension of an
inconclusive test result must be reviewed during follow-​up, particularly in relation to adherence with surveillance and preventive options.28 There is some evidence that those who receive inconclusive
results experience higher levels of distress compared to carriers and
noncarriers,28 so follow-​up of both comprehension of cancer risk
and coping with uncertainty is necessary.
Family Communication Issues
Genetic testing results have implications for family members beyond the consultee. It can be difficult to notify family members who
may have never been met or who do not live close by about a genetic
test result, for fear of causing emotional upset.29 In addition, individuals with genetic knowledge may also feel pressure to encourage
family members to be tested. When these individuals are not interested, conflict can follow.
Women with a BRCA1/​2 gene mutation and their partners can
find it particularly challenging to inform their offspring of a mutation.30 Studies have shown that parents have a strong interest
in notifying underage and adult offspring,31 although sex of the
child can make a difference, with informing daughters of greater
concern.32 Mothers can be conflicted in that they wish to ensure
their adult daughters are enrolled in the appropriate surveillance
programs and adopt healthy lifestyle behaviors, yet can simultaneously feel a need to not disclose the mutation to protect the child
from psychological burden.
Parents with younger children have an additional challenge of explaining absences or changes due to medical appointments or procedures and communicating complex genetic information, while
striving to reinforce a current state of good health.
Studies on offspring show that children demonstrate a range of
responses to the initial disclosure and are more likely to recall favorable and/​or neutral responses.33 Although some children have
sufficient literacy around genetic information, others demonstrate misinformation about cancer risk, similar to that of adults.33
Adolescents and young adult children do demonstrate psychological hardiness around the potential threat and may focus on healthy
ways to control cancer via lifestyle choices, seeing the positive side of
the situation. A parent’s style and perception can play a pivotal role,
as children often take behavioral cues from their parents.33 Overall,
early studies show adjustment and resilience in the short term, but
there can be adverse impacts, such as concern around cancer risk
or challenges in coping with information. Less is known about the
long-​term impact of genetic knowledge on offspring.
Family communication challenges can be helped by healthcare
professionals. Decisional aids and guides offer a developmental
framework to guide discussions in communication with offspring.
They are being tested to help guide when and how to disclose,
recognizing that most parents plan on having the discussion in the
near future, regardless of the age of the child,31,34 Family-​oriented
interventions that guide the sharing of sensitive information are also
helpful29 as how individuals perceive a relative’s opinion of genetic
testing, or sense of control, can influence whether or not individuals share genetic information.29 As well, given that individuals with
greater depression or inconclusive results may be less likely to disclose genetic test results,29 targeted psychosocial support to address
these specific barriers are indicated.
BRCA1 and BRCA2 Carriers and Assisted
Reproduction
Individuals carrying a BRCA1/​2 mutation are frequently concerned
about passing their predisposition to their children even to the
point of foregoing childbearing.35 Healthcare professionals will be
increasingly involved in discussions and decisional counseling regarding reproductive options in families with a known mutation. In
recent decades, genetic testing for hereditary cancers before birth
has become available through prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD). PND is performed during
early pregnancy at 10–​20 weeks. If the fetus is found to be a BRCA1/​
2 carrier, the pregnancy can be terminated. PGD, also called embryo selection, is a technique that involves in vitro fertilization with
a biopsy at the six-​to eight-​cell stage of the embryo, 3 days after insemination. Only noncarrier embryos are transferred to the uterus.
PGD has been used to avoid the potential risk of a miscarriage and
decisions about pregnancy termination, both associated with PND.
PND and PGD have first been applied to prevention of births of children with cancer predisposition syndromes that have early ages of
onset, but PGD has been advocated for by members of families affected by hereditary breast/​ovarian cancer.
Potential reasons for not utilizing PGD include psychological, economic, and ethical considerations. A major factor is patient lack of
awareness about applicable reproductive technologies. For example,
in studies of acceptance of PGD among hereditary cancer family
members, 50%–​60% of those surveyed had not heard of PGD until
the survey.36 Cost, restriction of services to major medical centers,
lack of contact with reproductive specialists, and hesitancy among
oncologists to bring up PGD as an option have been discussed as
other limiting factors.36 Another potential factor is the negative
judgment that such a step may imply about the value of a life lived
with a cancer-​predisposing hereditary syndrome. Personal and familial cancer experience may also influence such decisions. The use
of decision aids and/​or decisional counseling can be helpful in assisting individuals to make a balanced decision.
Psychological Approaches That Support
Genetic Testing
Having well-​
designed genetic counseling to provide information and strategies for direct family communication reduces psychosocial distress.17 Studies have focused on psychoeducational
approaches, added counseling sessions with an educator or psychologist, or using decisional aids (DAs) in counseling to facilitate
decision-​making concerning risk management options.
CHAPTER 13 Psychosocial Issues in Genetic Testing for Breast/Ovarian Cancer
DAs are available to support the decision to have genetic testing,37
or to undergo risk-​reducing surgery versus surveillance,25 and are
found to reduce decisional conflict, facilitate adjustment, and improve patient satisfaction.25 For example, a computerized decision
aid (tailored to age, menopausal status, and breast cancer history)
was found, in a randomized controlled trial, to be effective among
carriers who were initially undecided about managing their breast
cancer risk. It facilitated decision-​making, decreased decisional
conflict, and increased satisfaction.25 Similar decisional aids (both
web and paper based) show reductions in decisional conflict, clarification of personal values and preferences, and improvements in
satisfaction.25,27,37
Psychosocial support provided in one-​on-​one sessions or via telephone have also demonstrated benefit.38 For example, five weekly
telephone sessions of psychosocial support following standardized
genetic counseling for BRCA1/​2 reduced cancer-​related distress, anxiety, and depressive symptoms in the short term.38 While differences
were not maintained at 1 year, the authors suggest that the alleviation
of distress in the short term is especially important, given that it is
the time when important risk management decisions are being made.
For individuals with higher levels of cancer worry or with communication challenges that interrupt sleep or interfere with optimal
coping and decision-​making, additional follow-​up is recommended.
Enhanced genetic counseling guided by the Cognitive-​Social Health
Information Processing (C-​SHIP) model39 adds a session with a
health educator who uses the contemplation of possible genetic
testing scenarios to elicit relevant cognitive and affective reactions.
This helps women prepare and plan for using specific coping strategies
to manage these reactions. The enhanced counseling group demonstrated greater knowledge compared to controls postintervention.39
Behavioral interventions, such as relaxation, mindfulness-​based
stress reduction, or distraction techniques, can assist in addressing
anxiety and the lifelong stress associated with repeated medical and
screening appointments. Cognitively oriented strategies typical of
cognitive behavioral therapy used to manage anxiety or to facilitate medical decision-​making are helpful and can be employed in
individual or group formats to learn about the connections among
thoughts, moods, and behaviors. Mental exercises such as thought
records assist individuals in gaining insight on specific self-​beliefs
and catastrophic or rigid thinking habits. A counselor can help to
identify inaccurate cognitions and to encourage more realistic interpretations of the circumstances.
Psychodynamic therapies may be suitable but have yet to be
tested. Because psychodynamic therapies focus on how previous relationships and bereavements relate to current distress, they may be
well suited to helping people appreciate how previous losses related
to cancer impact on current medical decision-​making. Wellisch
and Lindberg20 have highlighted the unique issues that are highly
relevant in young women who lost a mother to cancer, particularly
during their adolescence. These women can develop a sense that it
is inevitable that they will suffer and die from cancer, just as their
mothers did. In a psychodynamic framework this self-​belief can be
explored and eventually challenged within the safety of the therapeutic relationship.
There is also evidence showing benefit through professionally led
support groups that provide direct social support and incorporate
therapeutic factors such as the vicarious learning that occurs among
peers.40 Groups have shown benefit by decreasing cancer worry
or general anxiety and may be particularly helpful to individuals
who have endured prior loss to cancer.40 For example, principles of
supportive-​expressive group therapy (SEGT) have been applied to
the genetic counseling context.40 The SEGT model focuses on the existential impact on one’s life of the genetic risk, and through the here
and now of the group encourages individuals to live fully authentically.40 Sessions focus on explorations of past familial experiences
of cancer and their influence on evaluation of risk, as well as their
impact on current medical decision-​making. The model also creates
a forum for the processing of unresolved grief and the exploration
of adjustment challenges. This occurs via an emphasis on the legitimacy of a full range of emotion and the centrality of relationships in
giving value to life, a tenet taken from existential psychotherapy.40
There is further need for randomized controlled trials to address
the psychosocial needs of the BRCA1/​2 population. A number of
interventions are currently being evaluated, including strategies to
address the psychosexual and psychological impacts following risk-​
reducing surgery and lifestyle-​behavioral interventions (e.g., physical fitness).
Future Directions
Information around BRCA1/​2 testing has the potential to provide
many benefits; however, genetic information can also result in emotional distress or decisional conflict around preventative options.
Psychosocial, emotional, personal historical, cultural, and familial
contextual factors play an important role in how an individual
adapts to, and utilizes, genetic information. For those found to be at
risk of maladaptive coping, standardized instruments can assist in
identifying them and offering tailored interventions known to facilitate accurate knowledge and adjustment.
During the coming years we will be faced with a number of additional challenges. These include the implementation of screening
questionnaires for psychosocial issues as part of standard care, and
the trend to offer fewer counseling sessions. The more recent availability of genetic knowledge of single nucleotide polymorphisms
(SNPs) related to breast cancer risk and how best to convey the
modest increased risk of these gene variants will require further
study. There are also populations not yet included in research, such
as various cultural minorities, who have less frequently taken up
genetic counseling for cancer, whose specific issues need to be addressed. Further, direct-​to-​consumer testing, for example, through
mail-​order applications, requires further study to assess the impact
of receiving genetic knowledge in the absence of genetic counseling.
In this evolving field of genetics, it is of great importance that psychosocial researchers and clinical workers such as psychologists and
social workers remain closely involved to ensure the best quality of
care for this unique group of high-​risk individuals and families.
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25. Schwartz MD, Valdimarsdottir HB, DeMarco TA, et al.
Randomized trial of a decision aid for BRCA1/​BRCA2 mutation
carriers: impact on measures of decision making and satisfaction.
Health Psychol. 2009;28(1):11–​19.
26. Read CY, Perry DJ, Duffy ME. Design and psychometric evaluation of the Psychological Adaptation to Genetic Information
Scale. J Nurs Scholarsh. 2005;37(3):203–​208.
27. Cella D, Hughes C, Peterman A, et al. A brief assessment
of concerns associated with genetic testing for cancer: the
Multidimensional Impact of Cancer Risk Assessment (MICRA)
questionnaire. Health Psychol. 2002;21(6):564–​572.
28. Maheu C, Thorne S. Receiving inconclusive genetic test results: an
interpretive description of the BRCA1/​2 experience. Res Nurs
Health. 2008;31(6):553–​562.
29. Montgomery SV, Barsevick AM, Egleston BL, et al. Preparing individuals to communicate genetic test results to their relatives: report
of a randomized control trial. Fam Cancer. 2013;12(3):537–​546.
30. Tercyak KP, Mays D, DeMarco TA, et al. Decisional outcomes of
maternal disclosure of BRCA1/​2 genetic test results to children.
Cancer Epidemiol Biomarkers Prev. 2013;22(7):1260–​1266.
31. Santerre-​Theil A, Bouchard K, St-​Pierre D, Drolet AM, Chiquette
J, Dorval M. Development of a tool to guide parents carrying a
BRCA1/​2 mutation share genetic results with underage children. J
Cancer Educ. 2018;33(3):569–​575.
32. Peshkin BN, Demarco TA, Tercyak KP. On the development of
a decision support intervention for mothers undergoing BRCA1/​
2 cancer genetic testing regarding communicating test results to
their children. Fam Cancer. 2010;9(1):89–​97.
33. Tercyak KP, Bronheim SM, Kahn N, et al. Cancer genetic health
communication in families tested for hereditary breast/​ovarian
cancer risk: a qualitative investigation of impact on children’s genetic health literacy and psychosocial adjustment. Transl Behav
Med. 2019;9(3):493–​503.
34. Werner-​
Lin A, Merrill SL, Brandt AC, Barnett RE, Matloff
ET. Talking with children about adult-​onset hereditary cancer
risk: a developmental approach for parents. J Genet Couns.
2018;27(3):533–​548.
35. Chan JL, Johnson LNC, Sammel MD, et al. Reproductive decision-​
making in women with BRCA1/​2 mutations. J Genet Couns.
2017;26(3):594–​603.
36. Vadaparampil ST, Quinn GP, Knapp C, Malo TL, Friedman S.
Factors associated with preimplantation genetic diagnosis acceptance among women concerned about hereditary breast and
ovarian cancer. Genet Med. 2009;11(10):757–​765.
37. Grimmett C, Pickett K, Shepherd J, et al. Systematic review of the
empirical investigation of resources to support decision-​making
regarding BRCA1 and BRCA2 genetic testing in women with
breast cancer. Patient Educ Couns. 2018;101(5):779–​788.
CHAPTER 13 Psychosocial Issues in Genetic Testing for Breast/Ovarian Cancer
38. Graves KD, Wenzel L, Schwartz MD, et al. Randomized controlled trial of a psychosocial telephone counseling intervention in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol
Biomarkers Prev. 2010;19(3):648–​654.
39. Roussi P, Sherman KA, Miller S, et al. Enhanced counselling for
women undergoing BRCA1/​2 testing: impact on knowledge and
psychological distress-​results from a randomised clinical trial.
Psychol Health. 2010;25(4):401–​415.
40. Esplen MJ, Hunter J, Leszcz M, et al. A multicenter study of
supportive-​expressive group therapy for women with BRCA1/​
BRCA2 mutations. Cancer. 2004;101(10):2327–​2340.
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14
Psychosocial Issues in Genetic Testing
for Hereditary Colorectal Cancer
Sukh Makhnoon and Susan K. Peterson
Introduction
Genetic testing for hereditary colorectal cancer (CRC) syndromes is
increasingly used in clinical practice to ascertain inherited disease
susceptibility or genetic etiology. A primary benefit of genetic testing
is the resulting ability to provide targeted prevention strategies and
surveillance for the proband as well as their family. Psychosocial
research on hereditary CRC has focused on understanding individuals’ motivations and decisions regarding genetic testing, the
psychological impact of genetic risk notification, the effects on
family and interpersonal relationships, and factors influencing the
uptake of risk reduction options (e.g., screening, risk-​reducing surgery, or chemoprevention). We review the literature on the impact
of genetic counseling (GC) and genetic testing on individuals at risk
for two common hereditary CRC syndromes, Lynch syndrome and
familial adenomatous polyposis. Findings from these studies can
guide clinicians in understanding why people seek GC and genetic
testing, how they cope with the results of testing, and how they subsequently integrate that information into cancer prevention and
treatment decisions.
Hereditary Colorectal Cancer
An estimated 30% of all CRCs involve a hereditary component, approximately 5% of which are caused by highly penetrant inherited
Mendelian pathogenic variants. The most common Mendelian risk
of CRC (2–​4% of all CRCs) is due to Lynch syndrome (LS), also
known as hereditary nonpolyposis colon cancer (HNPCC). LS is an
autosomal dominant condition conferred by inherited mutations
in mismatch repair (MMR) genes including MLH1, MSH2, MSH6,
and PMS2 and deletions in EPCAM.1 LS is characterized by a 70–​
80% lifetime risk of CRC and 50–​60% risk of endometrial cancer,
with increased lifetime risks for ovarian, stomach, small bowel,
hepatobiliary tract, pancreatic, urinary tract, brain, and skin cancers.2 Identification of these genetic mutations allows for targeted
risk reduction in mutation carriers and for notification of risk to relatives who may also be carriers.
Familial adenomatous polyposis (FAP) is the second most
common inherited CRC syndrome with a prevalence of 1 in 10,000
individuals. FAP is an autosomal dominant condition that results
from germline mutations in the APC gene with a penetrance of
100%, meaning that cancer develops universally in mutation carriers. FAP is characterized by the development of hundreds to thousands of colonic adenomas, beginning in early adolescence, and
inevitable CRC in untreated individuals. Prophylactic colectomy
(i.e., removal of part of the colon) is the ultimate treatment for FAP,
and surgery is often completed in early adulthood to try to prevent
the development of CRC.
Other rarer forms of hereditary CRCs include autosomal dominant conditions such as attenuated FAP, Peutz-​Jeghers syndrome
(PJS), and juvenile polyposis syndrome (JPS), and autosomal recessive MUTYH-​associated polyposis (MAP). The etiologies of the
remaining 25% of inherited CRCs are not completely understood.
They are likely caused by either alterations in single genes that are
less penetrant but more common than those associated with the
well-​characterized syndromes or alterations in multiple susceptibility loci that have additive effects.
Landscape of Genetic Testing Options
Genetic testing for LS currently involves a time-​
consuming
multistep process that begins with immunohistochemistry (IHC)
and/​or microsatellite instability (MSI) tumor testing for MMR deficiency associated with LS genetic variants. For assays suggestive of
deficiency or loss of function on MMR genes, a conclusive germline
sequencing test determines whether there is a pathogenic variant
present. Current guidelines recommend universal tumor screening
(UTS) of colorectal and endometrial tumors through MSI or IHC,
regardless of patients’ family history to comprehensively identify
persons at risk of LS. Patients whose tumors show abnormal MSI
or IHC results through UTS should be referred for GC and genetic
testing (gold standard).
Around 20 candidate genes connected with hereditary CRC have
been identified thus far, many of which are included in germline
CHAPTER 14 Psychosocial Issues in Genetic Testing for Hereditary Colorectal Cancer
gene sequencing panels. These include Mendelian genes with high
penetrance as well as less well-​understood genes with moderate
penetrance. Targeted or panel genetic testing for hereditary CRC is
important for prevention through screening and surveillance (e.g.,
colonoscopy), chemoprevention (e.g., Sulindac), and prophylactic
surgery (colectomy), and illness management for index patients as
well as their relatives. With increasing use of multigene panel tests,
ever more secondary and inconclusive findings are being discovered, which presents unique clinical management and psychosocial
challenges. Massively parallel sequencing of protein coding regions
of genes (through exome sequencing [ES]) are being explored to
replace traditional sequencing due to their increased ability to find
pathogenic variants and decreasing cost. However, these next-​
generation sequencing tests are not yet a part of routine clinical
testing for CRC as they present important challenges including interpretation of incidental and uncertain findings, counseling before
and after testing, and informed consent of patients.
Psychosocial Issues of Genetic Counseling
Clinical genetic testing is best accompanied by formal pre-​and
posttest GC because of the significant medical and emotional impact
genetic test results can have on patients and their family members.
Counseling is important to inform patients about the possibility of
probabilistic or uncertain information derived from genetic tests,
the consequent healthcare choices one may face, and their potential psychosocial consequences, and to offer emotional and decision
support. Yet, evidence suggests that rates of referral to GC, rates of
attendance, and availability of counseling services are suboptimal.
According to US national data from 2015, 4.8 million in the US have
undergone GC, 1.3 million for CRC, of which 49% were male and
51% female.3 The majority of participants who reported receiving
GC reported they did so because their doctor recommended it
(66%), with smaller proportions describing self (12%), family (10%),
or media (5%) influences as the primary reason.
In the clinical setting, uptake of LS GC among patients ranged
from 30% to 87%, with various logistical and psychosocial concerns
reported as barriers to uptake. Patients who were more likely to undergo GC were more educated, older, and married and had a family
history of LS-​associated cancers (85% in those with family history
vs. 35% overall).4 Cost and logistical barriers, emotional concerns,
family concerns, and low perceived personal relevance were reported
as important considerations for those declining GC. New models of
GC are being tested to counteract some of these access challenges
and to solve the lack of availability of genomics professionals to return large volumes of genetic test results. Innovative alternate modes
of counseling including telegenetic delivery of counseling via the internet, web-​based platforms, and phone counseling are noninferior
to in-​person counseling and can solve the issue of limited access to
genetic services.5
Uptake
Uptake of LS Testing
UTS offered through routine care results in high uptake of LS genetic testing and has already been integrated into standard clinical practice at many healthcare systems.6 Patients who are offered
germline LS testing as a part of UTS clinical workflow have more
active follow-​up, which facilitates referral to GC and improves completion of genetic testing. In fact, most patients who are offered LS
genetic testing through UTS tend to accept testing, although there is
some variation in uptake across studies. For example, in a secondary
care setting in the UK, all 23 defective MMR CRC cases identified
through UTS underwent GC and were offered and took up genetic
testing.7 In other clinical oncology practice settings, more patients
underwent germline testing when systematic tumor screening
programs were implemented.8
On the other hand, nonsystematic approaches to screening that
rely on clinicians or patients for referral perform less well than UTS.
Reported uptake of genetic testing for LS varies from 14% to 75%
across studies, reflecting possible cultural and sample selection
biases. Patients may miss germline testing because they were not
referred for counseling or because counseled patients did not meet
the criteria for testing. Certain subgroups of patients may be less
likely to follow through with genetic testing after receiving GC for
abnormal tumor screening results, including younger patients and
those with lower incomes. This is particularly concerning since CRC
patients diagnosed at younger ages present acutely at more advanced
stages than is typical for older patients9 and are more likely to carry
a germline mutation.10
Uptake of APC Testing
The question asked about APC testing is typically “when?” rather
than “whether?” due to the medical and psychosocial benefits for
children and adolescents of learning whether they are APC mutation
carriers. The optimal timing of APC testing occurs when the individual being tested is of sufficient age, maturity, and psychological
stability to understand the reasons that testing is being offered and
the implications of the test result. There is general consensus not to
test children before the age of 10–​12 years (in the absence of clinical
symptoms) since there are no medical benefits and there is a potential detrimental psychological impact. There are data suggesting
that uptake of genetic testing for FAP is higher than that for LS and
may be above 80% among asymptomatic at-​risk adults11 and 96% for
children ages 10–​16.12 This may be because mutation is nearly 100%
penetrant and FAP is preventable through surgery.
Population Genetic Screening
Population genetic screening, including screening for LS, is being
discussed given the increased national focus on precision health and
genomics-​informed care. Although it is not yet offered, LS is suitable
for population screening for two main reasons: (1) it has a highly
penetrant and well-​defined genetic cause, with existing clinical
interventions, and has been designated by the Centers for Disease
Control and Prevention (CDC) as “Tier 1 genomic application” and
(2) the population prevalence is almost double than previously estimated. Discrete choice research shows that the general population is
willing to participate in population genetic screening for CRC,13 but
preferences varied depending on individual experiences, perceived
anxiety, worry about colonoscopy frequency, and the probability of
developing CRC.
Access and Referral
Referral to genetic evaluation of hereditary CRC syndromes is critical for genetic test uptake; however, referral rates remain suboptimal
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Section III Screening and Testing for Germ Line and Somatic Mutations
with important disparities in access. For example, among 165 eligible
individuals who met Amsterdam II clinical criteria for HNPCC,
only 31% reported being advised to undergo GC by their doctor,
and only 7% had undergone genetic testing.14 Despite similar rates
of colorectal tumor analysis, minority patients were less likely to be
recommended for genetic evaluation or to undergo germline testing
for LS.15 Surveys of healthcare provider knowledge have consistently shown major deficiencies in the understanding of genetics risk
assessment and testing and ability to identify and differentiate risk
status. Other factors that positively affect access are clinic location,
ability to pay, insurance, discouragement by family members, patient attitudes, norms, and education level.
One barrier that needs to be overcome to improve referral rates
is the taking of complete cancer family histories. Taking a detailed
history is pivotal in identifying patients with high-​risk personal and
family history of cancer who will benefit from referral for genetic
evaluation and genetic testing. A 2014 study of 212 medical practices
with 10,466 patients found that first-​degree relative family histories
were recorded for 77% of patients and second-​degree family histories
for 61.5% of patients, with significantly better documentation for
breast cancer patients than for patients with CRC.16 However, complicating matters, in early-​onset CRC (<50 years of age), although a
significant proportion of patients carry germline cancer predisposition genes, nearly half did not have a family history and one-​fifth did
not meet the National Comprehensive Cancer Network (NCCN)
clinical criteria for relevant syndrome,17 which is why UTS may be
critical to capture all patients who may benefit from genetic testing.
Motivation
Motivation for LS Testing
Once referred, factors that positively affect test uptake include having
a personal history of cancer, having more relatives with LS-​related
cancers, higher perceived risk of CRC and related cancer, stronger
beliefs that hereditary CRC would influence one’s life and that of
one’s offspring, and more intrusive thoughts about CRC.18 Uptake of
genetic testing did not differ by gender, but higher educational level,
having a spouse or partner, and being employed correlated positively
with uptake. Both men and women appear motivated to seek testing
to determine whether offspring are at increased cancer risk. Women
may be more likely than men to want testing to determine whether
they require enhanced cancer screening and to undergo testing as a
response to recommendations of a physician or genetic counselor.19
Decliners of genetic testing for LS were more likely to report depressive symptoms, to be nonadherent to colorectal screening recommendations, to have less confidence that they could cope with a
positive test result, to be concerned about insurability, and to worry
about the emotional impact of genetic testing on self and family.18
Psychosocial issues related to secondary and uncertain findings
derived from ES, and acceptability of ES over panel testing need to
be better understood before clinical implementation. In a discrete
choice experiment conducted within a pragmatic trial of ES versus
panel sequencing, participants preferred to undergo tests that detect a higher proportion of individuals with a definitive genetic etiology and involve a shorter wait time.20 Most adults accept and were
satisfied with the results, and few reported distress or expected unsolicited findings.21 Patients who underwent ES preferred to filter
secondary findings to avoid information overload and to avoid
learning what the future holds.
Motivation for FAP Testing
Patient or parent attitudes seem to differ from professional guidelines of genetic testing for FAP. In an Australian study of young adults
with FAP, 61% had a preference to test their children at birth or very
early in life (before age 10).12 In a qualitative study of children tested
for FAP below age 10, none of the parents regretted the timing of
genetic testing and none observed changes in the mental or physical
health in their child after testing. The age at which children with a
parent with FAP had genetic testing varied in a recent study from
1 to 16 years, both overly early and late assessments.22 The major
reasons for testing at the young age were (1) testing of all children
in the family at the same moment, (2) certainty for the future, and
(3) preparing the child for future surveillance. Also, young genetic
testing did not lead to colon surveillance before it was indicated.
Genetic testing for FAP at a young age is experienced as causing no
harm by parents.23 This suggests the need for ongoing counseling
of parents with FAP about the benefits and risks of genetic testing
for their children. GC and follow-​up along the life span are recommended, in recognition of the lifelong issues raised by FAP.12
Risk Perception
Decision-​making for genetic testing assumes an accurate understanding of the admittedly complex risks that are involved. Accurate
risk perception for LS is complicated by the fact that there are multiple cancer risks to consider. Although GC increases accuracy of
risk perception for LS-​associated cancers, not all counseled individuals accurately report their cancer risks.24 Inaccurate cancer risk
perceptions among individuals undergoing GC for LS encompass
both over-​and underestimation of risk, with only one-​third to one-​
half of participants in one study accurately reporting the levels of
risk conveyed in the GC they attended.25 For example, even though
mutation carriers have higher cancer risk, there was no difference
in risk perception of HNPCC between carriers and noncarriers
by 12 months after testing,26 and perceived risk in carriers was
lower 12 months posttest compared with before undergoing genetic testing.26 Even when no pathogenic variant or low-​risk variants are identified, some patients remained in a heightened state of
risk perception.27 Perceived risk is a strong moderator of emotion
and an influential predictor of psychobehavioral outcomes,28 but it
is shaped not only by genetic results but also by lived experiences
such as previous diagnosis and family history of cancer, perceived
controllability, existing therapies for managing illness, and information provided during GC. Among a nationally representative sample
of 15,085 men and women, a higher proportion of individuals with
CRC risk perceptions concordant with their objective risk undergo
GC or testing for CRC risk.29
Emotional Impact
Psychosocial outcomes of genetic testing in the context of single or
multigene testing have been studied extensively and there is consensus that negative outcomes of genetic testing are few and far between. When observed, negative psychosocial effects are short-​lived
and participants return to baseline within a few months after testing.
Negative Emotional Impact in LS
Overall, psychosocial harms associated with communication of genomic information are mild and transient. Research suggests that
individuals who have received test results for LS-​related mutations
CHAPTER 14 Psychosocial Issues in Genetic Testing for Hereditary Colorectal Cancer
experienced immediate increased general distress,30 cancer-​specific
distress,31 and worry about cancer,30 but that the mean increases
did not raise scores above normal levels. Generally, distress receded
over the first year following genetic testing30 and was at pretest levels
by 12 months.31 One study three years after disclosure of test results showed scores similar to those before genetic testing, except
that noncarriers’ cancer-​specific distress was significantly lower
than baseline scores.32 In general, there was no difference in general
distress between carriers and noncarriers due to genetic testing or
disclosure of test result. In longitudinal studies, there was no significant change in cancer-​specific distress or worry33 between pre-​and
posttest result disclosure.
However, there are subgroups of tested individuals at greater-​
than-​
average risk of psychological distress following testing.
Women, younger people, nonwhites, and individuals with less satisfactory social support and lower educational levels had higher levels
of general and cancer-​specific distress, regardless of mutation status
in the 12 months following testing.30 Other studies have reported
that individuals with a prior history of major or minor depression
or those with more affected first-​degree relatives or those reporting
more intense grief reactions had greater distress one to six months
after disclosure.34,35 A recent study showed that reductions in distress over the first six months following disclosure for LS genetic
testing was moderated by the individual’s health information coping
style. Generally, individuals testing negative experienced relief and
decreased distress, which was long-​lasting.30 Such individuals are
advised that they no longer require enhanced screening and can
return to following general population guidelines for colonoscopy
screening. It has been found, however, that some at-​risk individuals
testing negative for LS-​related mutations evidence distrust of the test
result to the extent that they do not give up colorectal screening,36
although this has not been found in all studies.24 In fact, participants’ pretest emotional state predicts subsequent distress to a much
greater degree.
The potential psychological harms of next-​generation sequencing,
which generates vast amounts of complex data that can be highly
uncertain and reveal information unrelated to clinical context for
sequencing, is concerning, but current evidence shows no clinically
significant psychological harms of returning ES results to patients.37
Among CRC/​polyposis patients, there was no significant change in
anxiety or depressive symptoms following return of ES results pre-​
and postdisclosure.37 In a qualitative study of LS patients with variants of uncertain significance (VUS), most perceived various types
of uncertainty associated with their VUS. Half of the participants
appraised their variant as a danger and implemented coping strategies to reduce the threat of developing cancer. Problematically, the
majority of participants were unaware of the possibility of a VUS before receiving their result and expected reclassification over time.38
Individuals with VUS may also have persistent levels of genetic test–​
related distress as well as more difficulty in recalling the meaning
of their results than those with more definitive test results.38 In a
quantitative study of ES, test-​related uncertainty among adults with
colon polyps or cancer was lower than parents of pediatric patients
but higher than healthy adults.37 Among patients with clinical suspicion of hereditary cancer, 12 months after result disclosure, carriers
of moderate-​penetrance variants had higher distress and uncertainty scores compared with carriers of high-​penetrance variants.39
Research on psychosocial outcomes of secondary findings is in its
infancy and qualitative studies show that participants found secondary findings unexpected but not shocking. It is difficult to conduct quantitative studies to measure the psychosocial impact of
secondary findings as return of secondary findings without return
of primary results is uncommon.
Negative Emotional Impact in FAP
Similar to LS, psychometric data indicate that FAP patients and at-​
risk relatives as a group do not exhibit clinical symptoms of mental
health problems after clinical or genetic diagnosis. However, some
subgroups are more vulnerable to distress.
The psychological impact of testing children for FAP needs special attention. Several studies have investigated the distress of children tested for APC mutations. Mean scores for individuals in
these studies remain in the normal range on measures of anxiety,
depression, and behavioral functioning following disclosure of test
results.11 There is evidence that the impact of genetic testing of individual family members is moderated by knowledge of the results
of other family members.40 In families where some children tested
positive and others negative, the parents who were not the FAP mutation carriers had significantly increased depression scores after
disclosure of their children’s results. Similarly, in a Norwegian study
of 22 adolescent offsprings of a parent with FAP, 30–​70% fulfilled criteria for a psychiatric diagnosis.40 This finding was independent of
the FAP status of the offspring, illustrating the psychological burden
of having an affected parent. It was only in families with FAP that unaffected children sometimes described feeling a sense of guilt when
their sibling was affected.41 Individuals testing negative for APC mutations, while relieved of much of the medical burden of the disease,
often experience guilt about avoiding the lifelong worry and need for
intervention that their parents and/​or siblings often share.42 Anxiety
may be high in these children as well, and their need for support
should be considered in any plan to offer emotional counseling to
FAP family members.
In a cross-​sectional study of adults who underwent APC genetic
testing, mutation carriers had higher levels of state anxiety than
noncarriers and were more likely to have clinically significant anxiety levels. Lower optimism and lower self-​esteem were associated
with higher anxiety in this study, and FAP-​related distress, perceived
seriousness of FAP, and belief in the accuracy of genetic testing
were associated with more state anxiety among carriers. In a long-​
term follow-​up study, 20% had moderate to severe distress,43 26%
had received psychosocial support, and an additional 30% wanted
more psychosocial care. Forty percent said that work and relationships were adversely affected by FAP.43 Similarly, moderate to severe
psychological distress was reported in 30% of the partners of FAP
patients. While they also reported problems with work, leisure activities, and relationships, most partners reported good overall quality
of life.43
An Australian study of 18-​to 35-​year-​old young adults with
or at risk for FAP, which utilized FAP-​specific measures of distress, suggested that unmarried (i.e., single) individuals and those
who had had more extensive initial surgery had greater distress.11
Psychological functioning was highest among subjects who had
not yet had any surgery, with more negative outcomes related to
body image, sexual functioning, and affect reported by those who
had had ileal pouch–​anal anastomosis surgery. Having such intrusive surgery during the period of young adulthood when sexual
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Section III Screening and Testing for Germ Line and Somatic Mutations
identity and sexual relationships are being established is, the authors believe, highly problematic. They advise that when medically
feasible, psychosocial factors should be incorporated into surgical
decision-​making.
Positive Emotional Impact
There are psychological benefits of genetic testing for people who
do not inherit the high-​risk mutations, such as short-​and long-​term
decreases in cancer worry, general anxiety, and depression.44 They
also have the removal of uncertainty, the assurance of knowing that
their children are not at risk, avoidance of intensive cancer surveillance, and removal of concerns regarding genetic discrimination.44
ES for CRC/​polyps showed no difference in positive feelings.37
However, these findings of positive and negative emotional impact
should be considered in light of the fact that most studies conducted
to date are biased toward Caucasian women with high education
and socioeconomic status and do not generalize to subpopulations
of people who are particularly vulnerable. Clinicians should still be
vigilant about negative effects on their patients. Interventions to
manage psychosocial problems have been evaluated and shown to
be promising in reducing the problems.
Decision Aids
Given the complexity of the decision to undergo genetic testing, researchers have begun to test innovative strategies to facilitate education and decision-​making about inherited cancer risk and genetic
testing. These include development of disease-​specific decision aids
to enhance the counseling experience,45 to inform pretest counseling for incidental genomic results,46 and for reproductive decisions.47 Decision-​making about genetic testing for LS is a multistep
process, and decision aids may be particularly useful in this context.
Cancer Screening
An important determinant of the success of GC and testing is the
degree to which at-​risk individuals who are found to be mutation
carriers alter their prevention behaviors. Among at-​risk carriers,
compliance with screening recommendations assessed from six
months to seven years after genetic testing showed increases. Rates
of appropriate surveillance was higher among individuals who had
undergone genetic evaluation compared with those who had not
and in those who had a first-​degree relative with CRC.48 Screening
adherence in carriers may be enhanced by increasing commitment
and self-​efficacy regarding colonoscopy, as well as greater perceived
benefits and fewer perceived barriers of screening.49
Lack of consistent and clear advice about surveillance recommendations, especially for rarer cancer types, is a barrier to adequate risk management behavior among LS carriers. Providers
surveyed across 21 countries reported that most (78%) provided
recommendations or made referrals for gynecologic screening,
but only 46% made recommendations for urologic screening, and
most did not recommend screening/​surveillance for other types
of cancers such as neurologic, pancreatic, and hepatobiliary.50
Chemoprevention with aspirin as a risk management strategy was
used least commonly (35%) compared to recommendations for
colonoscopy.50
The burden and challenge of LS can be significantly reduced by
finding knowledgeable providers who clearly and empathetically describe the complex, ongoing need for screening and the results of
screening tests. System barriers include difficulty navigating visits
of numerous specialists, who are often in different hospital systems
and often have differing expectations for the type and frequency of
screening tests needed. These problems highlight the need for coordinated, multidisciplinary care by specialists familiar with hereditary cancer.
Family Communication and Cascade Testing
Psychosocial predictors of familial communication of genetic information have largely focused on families with known mutation
carriers and higher risk. Research shows that a family-​mediated approach of familial communication of genomic risk is complex, and
often selective and incomplete. Patients are motivated to share due
to feelings of responsibility or obligation toward relatives, due to a
desire to prevent disease in relatives,51 and because the family members are emotionally close and share information.52 First-​degree
relatives, especially female siblings, children, and parents, are told
about genetic results more often than second-​or third-​degree relatives.51,53 On the other hand, inhibiting influences include difficulty conveying cancer risk information,53 and 57% of respondents
being informed by a family member found it burdensome.5. Little is
known about family communication in FAP families.
Despite the importance of germline testing for family members,
uptake is still considerably lower than 100%, with LS test uptake
rates among at-​risk family members reported between 41% and
90%.55 Predictors of being tested include age, gene, one or more
tested siblings, no siblings, and parent under endoscopic surveillance.56 Nontested differed from tested respondents in that they
were younger, they were less closely related to the index patient,
and a lower proportion had children. The most important reasons
for declining genetic testing were anticipating problems with life
insurance and mortgage, being content with life as it is, and not
experiencing any physical complaints.54 Unaffected members of
mutation-​carrying families who declined genetic testing reported
the following barriers: a lack of knowledge of the availability of genetic testing, a lack of trust in genetic test information, a desire to
see a stronger benefit from genetic testing before proceeding, and a
sense that there may be more negative than positive outcomes from
genetic testing.57
There is an unmet need for better/​innovative access to counseling/​
testing to identify at-​risk individuals in extended families of mutation carriers. For instance, tailored in-​person or telephone formats
for providing CRC risk counseling, incorporating behavioral interventions, appear to improve knowledge and risk perceptions, with
high client satisfaction.58 A family-​mediated approach of communication, although generally acceptable to most patients,54 is less effective than provider-​initiated approaches at increasing cascade testing
rates.55 Although uptake following a proband-​mediated contact was
higher for LS than for hereditary breast and ovarian cancer (HBOC)
families,55 there is both a need and a desire for more direct contact of
at-​risk family members to inform them of their risk and invite them
to participate in GC and testing.59
CHAPTER 14 Psychosocial Issues in Genetic Testing for Hereditary Colorectal Cancer
Influence of Genetic Testing on Childbearing
Data is emerging about attitudes toward childbearing and prenatal
genetic testing among individuals at risk for LS. Among 161 individuals assessed just prior to undergoing clinical genetic testing for
LS, the majority already had at least one child, and only 9% said that
their familial cancer risk had led them to decide not to have (more)
children. When asked if it was ethical to offer prenatal testing (preimplantation genetic diagnosis [PGD] or prenatal genetic testing
), 66% agreed/​strongly agreed, 25% were neutral, and only 9%
strongly disagreed. Of the 48 subjects planning future pregnancies,
56% thought their test result would not influence their childbearing
plans, 29% thought they would plan to have their children earlier
in order to have prophylactic oophorectomy sooner, 27% would
consider adoption, and only 10% said they would not have children
if they were found to be a mutation carrier. At one-​year posttest
follow-​up, however, considerably fewer mutation carriers evidenced
interest in prenatal testing, with only 22% considering PGD for a
future pregnancy.60
Of 17 MMR mutation carriers, 57% preferred spontaneous natural
conception versus 28% and 35% who chose prenatal genetic testing
and PGD, respectively.61 None of the main sociodemographical,
psychological, or medical variables (including fear of transmitting mutations) were significantly associated with the reproductive
preferences.61
Prenatal genetic screening seems higher among adults with FAP
than among those undergoing testing for LS.62 Studies reported
high interest in PGD among affected subjects but also indicated
that many young adults with FAP are not routinely informed about
PGD and prenatal genetic testing options.63 Most would not consider terminating the pregnancy if the fetus was affected. Due to the
nearly 100% penetrance, early age of onset, and doubt over whether
colectomy is a “real treatment,” PGD for FAP was approved by organizations like the Human Fertilisation and Embryology Authority
despite their initial misgivings.
Future Directions
The literature on the psychosocial aspects of hereditary CRC is considerably more limited than that on the psychosocial aspects of GC
and genetic testing for hereditary breast and ovarian cancer, but it
has grown substantially in recent years. Generally, psychosocial factors influence the decision for genetic testing and risk management
strategies; uptake of GC and genetic testing varies across studies; and
distress following LS testing, particularly in the long term, is low for
both carriers and noncarriers, although distress is slightly elevated
following genetic testing for FAP. Distress may be related to the intensity of recommended screening, single marital status, test results
of other family members, or the impact of the surgery. These factors,
many tied to psychological rather than medical variables, suggest
that counseling, both genetic and psychological, is important for
individuals dealing with hereditary disease, not just at the time of
testing, but also at many other points along the trajectory of patient
care for these diseases. One of the differentiating features of hereditary disease is that, as patients have said, “It’s never over.” As such,
support services must be geared to the ongoing needs of those who
continue to face genetic risk for serious diseases. Future research will
help to define the best ways to provide such services.
The issues of how best to inform relatives about familial mutations
predisposing to markedly elevated, early cancer risks and the definition of duty to warn in the context of genetic testing for diseases
where potentially life-​saving interventions exist raise interesting and
challenging questions. Attitudes may be changing about the relative
value of confidentiality and privacy and the need to inform at-​risk
relatives about their high levels of cancer risk and about options to
detect or prevent cancer. Recognizing that there are some families
where relatives do not communicate puts the onus on medical professionals to communicate with such members. To save lives, all
family members of someone carrying a deleterious mutation must be
informed by whomever is able to do so (family member, physician,
or genetic counselor). Being notified of the possibility twice versus
not being notified at all is a much better solution to this problem.34
Important but underexplored psychosocial issues exist regarding
the increasing use of multigene panel testing, especially as genes of
varying penetrance, associated cancer risks, and uncertainties are
introduced. Research is needed to examine possible patterns of patient responses to various types of genetic information to develop
approaches to help patients prepare for and adapt to these test results. In addition, research is needed to alleviate current methodological challenges including lack of sensitive instruments to detect
subtle psychological responses expected in response to genetic
testing, which may be limiting our abilities to accurately quantify
psychosocial outcomes.
Psychosocial factors play a large role in the impact of cancer genetic testing for CRC. Uptake of testing, adherence to screening
recommendations, surgical choice, and family communication are
likely to be influenced by the individual’s experience of hereditary
illness in their family, the individual’s affective style and information
preferences, and other little-​studied social factors, such as socioeconomic status and access to genetic health services. Such factors will
impact the ultimate integration of genetic testing into general medical practice. It is also important that routine taking of multigenerational cancer family histories for all CRC patients becomes standard
of care. Hereditary CRC offers a model illustrating the potentially
life-​saving value of genetic testing where critical attention to psychological issues and support needs may optimize utilization.
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109
15
Psychosocial Issues in Genomic
Testing, Including Genomic Testing
for Targeted Therapies
Megan Best
Introduction
Cancer may be regarded as the product of cumulative somatic genetic changes, with some arising in individuals who have inherited
a germline predisposition to cancer, modified by environmental exposures.1 Genomic testing has now entered clinical practice, driven
by improved technology, patient demand, and the need for more
effective cancer treatment. At a time when increased costs of clinical research have slowed the development of therapeutic options,
advances in genomics offer great promise of improving outcomes
in the prevention and treatment of cancer through personalization
of medical care tailored to individual genetic status. Traditionally,
tumors have been named after the organ in which they developed
and categorized on the basis of histology (microscopic anatomy).
However, these methods do not reflect the complicated underlying
molecular events that drive the cancer process. By surveying thousands of genes at once, using DNA arrays (genomic tests), it is now
possible to read the molecular signature of an individual patient’s
tumor as well as their whole genome. Analysis of tumor molecular signatures has revealed new classes of cancer that go beyond
distinctions based on histological appearance alone.2 This allows
oncologists to offer personalized treatment for cancer, potentially
identifying new cancer therapies for selected patients who are likely
to respond. At the same time, it may be possible to reduce unnecessary side effects and toxicity by avoiding unnecessary treatments
in patients who will not benefit. It also allows for identification of
those who are, or are not, at increased risk of developing a particular
cancer, allowing for personalized prevention strategies. However,
for this promise to be fully realized, patients need to cope with the
testing process and act on the results.
The process of genomic testing can be highly complex. The human
genome contains approximately 23,000 genes. Genomic testing always involves examination of multiple genes. This may be a “panel” of
whole genes or single nucleotide polymorphisms (SNPs) (changes in
nucleotides within genes), the whole exome (the part of the genome
that codes for proteins), or the whole genome. Testing can assess
genes in the germline or somatic changes in the individual cancer.
The psychological impact of single gene testing has been well
studied. However, there are important differences between both
germline and somatic genomics and single gene testing that have
implications for psychological outcomes, making it difficult to assume that response to single gene results will generalize to the genomic setting.
Complexity
Single gene testing involves examining a gene of known significance,
so that the result will be either positive or negative for a particular
variant. Genomic testing, in contrast, can deliver a number of different outcomes, and in some cases can represent an unprecedented
volume of results to process.
Germline testing is performed on a sample of “normal” cells
and can reveal pathogenic variants (which may have also been inherited by blood relatives) that are (1) relevant to the target cancer
and clinically actionable, guiding risk prevention; (2) relevant to
the target cancer but nonclinically actionable (no proven treatments); (3) secondary (relevant to other cancers and diseases) and
clinically actionable, guiding risk prevention; (4) secondary and
nonclinically actionable (no proven treatments); or (5) of unknown
or uncertain significance (variants of unknown significance [VUS]).
Patients with pathogenic germline variants that signal high risk
of a particular disease can be offered more intensive risk management strategies.
Somatic testing involves genomic testing of tumor (either fresh
or archived tissue or liquid biopsy) for patients who have solid tumors such as lung, colon, breast, kidney, and liver cancers. It is commonly used in two ways. The first is to assess patient prognosis to
guide treatment choices. This is known as risk for recurrence (RFR)
testing. The second is to identify biomarker genes that can be linked
to specific treatments directed against the genetic mutations in the
tumor. It is increasingly clear that there are molecularly distinct
subtypes of various common cancers, with different therapeutic approaches required for each subtype.
CHAPTER 15 Psychosocial Issues in Genomic Testing, Including Genomic Testing for Targeted Therapies
A number of molecular targets have been identified, with ongoing enrollment of patients in clinical trials to assess predictive
biomarkers of efficacy. This type of test is known as molecular tumor
profiling (MTP). MTP can identify (1) somatic variants (relevant
only to the patient) that are clinically actionable (guiding treatment)
and treatment may or may not be accessible to the patient; (2) somatic variants that are not clinically actionable (no proven treatments); (3) no somatic variants; or (4) genes of unknown significance
(GUS) (genes known to be a biomarker for a different cancer to the
patient). There is a small chance that pathogenic variants identified
in the tumor by MTP may have germline (inherited) origin. If suspected, further testing is required for confirmation. These findings
have implications for blood relatives.
Uncertainty
Although uncertainty pervades medical information, its scope in genomics may be unprecedented. The taxonomy of medical uncertainty
of Han et al.3 identifies three principal sources of uncertainty: indeterminate outcomes (probability), imprecise risk estimates, and
complexity, all of which are relevant in genomics. Genomic testing
is technically complex through all its steps, from sample acquisition, to analysis, to clinical report generation and interpretation, to
communication of results to the patient—​each of which introduces
uncertainty regarding, for example, the accuracy and reliability of
test results. The clinical uses of genomic testing introduce other uncertainties regarding the benefits and harms of genomic test information, the optimal strategies for communicating this information
to patients, and the consequences of genomic testing for patients,
family members, the health care system, and society.4
Practitioners who obtain consent to genomic testing from patients
face the challenge of conveying these uncertainties to ensure informed
choice and mitigate unrealistic expectations, while patients must absorb and cope with the information both before and after testing.
Germline results, whether identified by somatic or germline
testing, have implications for future health and reproductive choice,
and communication within families may be required to ensure
everyone potentially affected is aware of their risk. Findings of unknown/​uncertain significance, whose meaning may or may not become clearer over time, can be confusing and worrying to patients
and physicians. In addition, results may be both diagnostic (confirming the subtype of cancer) and predictive (indicating future
cancer risk), which have traditionally had different ethical norms
guiding practice.
While patient autonomy and shared decision-​making are established standards in health care, there are currently no guidelines
on what information patients should be told, nor how uncertainty
should be approached, in genomic testing. The current evidence
base primarily reports on the general or noncancer population,
where the potential benefits of a positive result (such as access to
novel therapeutic options) will differ.
Mainstreaming
Oncologists were among the first clinicians to incorporate tumor genomics into routine management to guide treatment choice (e.g.,
the KRAS gene in colorectal cancer, the BRAF gene in melanoma).5
Given the rapidly falling costs of all types of genomic tests and the
increasing number of targetable variants, it is likely that oncologists
will exponentially increase the number of genomic tests ordered.
These factors have paved the way to mainstreaming of genomic
testing. Mainstreaming refers to genomic testing ordered by non-​
genetics-​trained health professionals. This enables higher uptake of
appropriate germline genetic testing in cancer patients at suspected
risk for hereditary cancer as well as RFR and MTP to guide therapy.
Although the use of MTP to discover novel therapy appears to
be well understood and accepted by patients,6 there are significant
challenges involved with moving genomic testing into mainstream
medicine. First, patient knowledge of other types of genomic testing
appears to be low.7 Second, genomics is a rapidly evolving area
where it is also difficult for practitioners to stay up to date with interpretation of results and therapeutic options. Third, the potential
for gene changes such as germline, secondary, and VUS/​GUS means
that both patients and families may be confronted with information
they had not been seeking nor were prepared to face; oncologists
are not used to dealing with healthy family members in relation to a
cancer patient’s test results. Furthermore, genomic test results can be
difficult for nongenetically trained staff to interpret.
This situation requires a new skill set for oncologists. There is
ample evidence that nongenetics health professionals have deficits
in genetic literacy, which may limit their ability to explain genomic
testing results to their patients (and their families) effectively.
Nongenetics health professionals report difficulties in family history
taking and risk communication and have been shown to misinterpret test results, possibly leading to incorrect management.8 The
American Society of Clinical Oncology identified the need to assist
oncologists in the task of adopting genomic medicine as a matter
of priority.9 In the short term, there is a shortfall of knowledge and
expertise in communication within the oncology community with
regard to supporting cancer patients undergoing testing, which further increases the chance of psychological risk.
Psychological Issues in Genomic Testing
Research on the psychosocial impact of genomic testing so far has
been biased toward breast cancer and Caucasian women with high
socioeconomic status and education,7 and internationally, genomic
datasets are dominated by Caucasian populations. As a result, VUS
will be reported more frequently in ethnic minority patients, who
may also have lower health literacy, and therefore may represent a
group at higher risk of psychological sequelae to genomic testing.
Germline Testing
Knowledge and Understanding
There is no relevant validated measure of genomic knowledge
that allows comparison across studies. The Knowledge of Genome
Sequencing (KOGS) is currently being validated in a cancer cohort for the first time.10 A recent review7 showed that knowledge of
germline panel testing is sometimes poor but increases significantly
after counseling, particularly knowledge of the limitations of testing.
In one study included in the review, of patients with a family history of cancer, higher knowledge was associated with lower avoidance of receiving genomic results and higher decisional satisfaction.
However, the study also reported that a minority of patients misunderstood test results, with VUS findings interpreted by 4% as
111
112
Section III Screening and Testing for Germ Line and Somatic Mutations
equivalent to a negative result, and 20% of patients not realizing that
a positive result indicated increased cancer risk.
In two studies of participants undergoing SNP testing included in
the review, recall of test results up to 5 months was accurate but had
no impact on risk perception. Risk perception was often shaped by
family or personal history of cancer and did not change after counseling. There were no changes from baseline to after receiving results
in perceptions of heredity or perceived risk of finding a heritable
cause for cancer, and expectations of heredity were not associated
with distress, coping style, or illness perception.7 Another hypothetical study asking primary care patients about SNP testing for colon
cancer risk found that most people preferred information about the
test to be delivered in person by a health care professional rather
than by written information.11
Psychological Impact
Several studies have shown no impact of germline testing on generalized anxiety, depression, or cancer-​specific anxiety between
baseline and follow-​up.7 However, another study that compared
groups according to whether or not they were affected by cancer, and
whether or not they were positive for a pathogenic variant, found
that unaffected patients with a family history of breast or ovarian
cancer who received positive results had significantly higher levels
of intrusive thoughts, avoidance, and distress.7 Intermediate levels of
some measures of distress were reported among unaffected patients
with VUS results. In this study, distress was higher in those with
lower knowledge scores and among African Americans compared
with Caucasians. Qualitative studies of participants undergoing SNP
testing reported emotional responses such as reassurance, surprise,
or disappointment when results did not match family or personal
history of cancer.7
Measurement of illness perception between baseline and follow-​
up indicated no impact from germline testing in one study.7
The psychological impact of receiving genomic test results
can be measured by the Multidimensional Impact of Cancer
Risk Assessment (MICRA) questionnaire and consists of three
subscales: test-​
related distress, positive experience, and uncertainty. It was used in two studies.7 One showed no change and the
other found higher distress scores in unaffected participants with a
pathogenic variant or VUS finding, compared to others defined by
cancer status and variant status. Distress was higher among African
Americans and those of younger age. In the cohort characterized
by cancer status and test results, test-​related positive experience
was lowest among the no cancer/​VUS and the cancer/​pathogenic
variant–​positive groups. Lower positive experience was associated
with younger age. Receipt of results had no impact on uncertainty in
two studies, and intolerance for ambiguity does not appear to impact
on coping ability.7 In one study, no association was found between
ambiguity tolerance and the MICRA, avoidance and distress, or satisfaction with decision-​making.7
Decisional satisfaction and satisfaction with genetic services were
high and not altered by counseling, test results, or cancer status
in three studies.7 Satisfaction was reduced with lower knowledge,
lower levels of education, younger age, and Asian and Hispanic race
compared to Caucasian. Satisfaction with the decision to undergo
testing decreased over time since testing. Regret was uncommon,
and dissatisfaction was not related to the testing itself, but the long
wait for results.7
One hypothetical study found that cancer patients valued genomic results over standard test results.7 In qualitative studies, patients have expressed concern about the psychological burden of
risk information, and insurance and privacy concerns. Reported
concerns about discrimination are uncommon.7
Behavioral Impact
Investigation so far suggests that people are more likely to use their
germline panel test results in decision-​making if they have a positive result, in the form of taking up additional screening among
people currently unaffected by cancer and making treatment choices
among those diagnosed with cancer. However, in one study, some
people with a VUS or negative result, which does not necessarily
indicate no risk, also acted on their results.7 For those undergoing
SNP testing, there is limited evidence that it can independently predict behavioral change. Suggested factors associated with behavioral
change as a result of the testing process include education during
counseling and patient anxiety.7
Family communication has been studied for those undergoing
SNP germline testing. Two studies found that sharing of results with
relatives was motivated by perceived “shared risk” or with the goal of
motivating health behavior change.7 Patients with high-​risk results
were more likely to report the result to their health care professional
compared to those with average or low risk.7
One study examining perceived utility of germline genomic
testing showed no significant impact, although in that study, a
change in management as a result of testing occurred for a small
minority only.7
Somatic Testing
By definition, all somatic testing is performed on patients with a
cancer diagnosis. Early research demonstrated that cancer patients
had positive attitudes and expectations of genomic testing to assist in guiding therapy, although those who have a strong interest
are likely to overestimate its potential benefit.7,12 A recent review7
found that somatic RFR testing (used to guide chemotherapy uptake
in early cancer) may be associated with negative psychosocial outcomes. Few studies have described cancer patients’ views of MTP.
Much of the scant research in this area to date has been hypothetical
or conducted on noncancer patients.13
Knowledge and Understanding
From this review, it is seen that generally patient knowledge of genomics is low, although most participants in these studies who were
undergoing RFR testing understood that the results could aid chemotherapy decisions. Fewer understood that the test result indicated
the future chance of metastasis. In two North American studies, the
majority of patients did not understand terms such as “precision
medicine” or “personalized medicine.”13,14 Even among patients
with higher health literacy, less than 40% reported familiarity with
terms like “personalized medicine,” “genomics,” and “biomarkers.”14
Another study of advanced cancer patients found a median of 75%
knowledge questions correctly answered.15 Qualitative studies suggested that patient misunderstanding about RFR somatic testing
prompted increased anxiety. Participants with higher knowledge
scores were more likely to prefer an active role in decision-​making,
have fewer concerns about testing, be highly educated, be younger,
be diagnosed more recently, have less comorbidity, have higher
CHAPTER 15 Psychosocial Issues in Genomic Testing, Including Genomic Testing for Targeted Therapies
income, be more likely to be employed full time, have relatives who
previously underwent chemotherapy, and be of Caucasian ancestry.
Inadequacies in knowledge pose barriers to the adoption of testing.
For example, one survey of patients with advanced cancer found that
less than half (48%) felt they had sufficient knowledge of benefits
and risks to make an informed decision about whether to pursue
genomic testing, and 34% of patients wanted formal genetic counseling before participating in MTP.15
One study of early-​stage breast cancer patients in the review
found that 62% of their cohort sought information about their results, and those who sought information were significantly more
knowledgeable. Perceived risk was significantly reduced after RFR
somatic testing and correlated with actual risk scores of recurrence
posttest. Previous studies have documented confusion among patients regarding whether the results refer to the identification of
germline or somatic mutations (i.e., results that may be relevant to
blood relatives versus those that pertain to the patient only).13 It is
not known how communication about test results can be best tailored to improve understanding of this distinction.
In view of the finding that self-​perceived deficiencies in understanding represent a barrier to test utilization, it has been recommended that education and information tools be developed to
support patients undergoing somatic tumor screening.7,13,15 Those
undergoing somatic testing have also expressed a desire for professional support in the event of communicating unsolicited genetic
information to family members.16 This underscores the importance
of providing adequate information and counseling before results are
returned. Written information has previously been described as reducing patient anxiety and assisting patients in returning genetic information to their family.17
Psychological Impact
A study included in the review showed that state anxiety for RFR
testing decreased 12 months after receiving results and was positively correlated with decisional conflict both before and after
testing.7 Increased anxiety was also associated with receiving results,
a delay in return of results, or misconceptions about the meaning of
the results. In addition, increased anxiety was associated with more
cancer-​related distress, higher actual recurrence risk, inaccessible
results, and discordance between the clinical recurrence score and
the genomic result. One author found high levels of cancer-​specific
distress in over one-​third (38.7%) of RFR participants. Higher perceived RFR was associated with lower satisfaction, higher levels of
worry, and Caucasian ancestry. In several studies, women who prefer
a passive role in decision-​making and who received intermediate-​
recurrence risk results had higher cancer-​related distress, but not
worry about recurrence.7
Targeted treatment is an area of rapid development, and at present the number of patients matched to targeted treatment, and the
number of targeted treatments available to patients, is small. This is a
reflection of the challenge of accessing novel drugs for patients with
cancer, as well as the need for more research to identify anticancer
therapies that target identified tumor biomarkers. Care should be
taken to manage patient expectations.
Patients have also reported some concerns, including worries
about psychological harm related to intrusive thoughts due to unwanted knowledge.7 It is possible that patients with a cancer diagnosis may hold high hopes for MTP to provide new treatments and
feel disappointed if no actionable result is found, even if they had
been advised that the chances of a useful outcome were low. Equally,
if clinically actionable results are found and the relevant drug is not
available to the patient, or they are deemed too unwell for treatment,
they may feel angry and abandoned.12
Attitudes
The recent review found that most patients undergoing RFR thought
that the test results were accurate and useful. Reported benefits of
undergoing somatic testing included the ability to reduce uncertainty and improve treatment options, thus empowering the participants. Overestimation of the validity of the tests increased its
value.7 In hypothetical scenarios, patients are generally willing to
undergo testing with the belief that genetic information about their
cancer will improve their care.13,15,18 However, participants also attributed advantages to somatic testing that are normally attributed
to germline testing, such as cancer prevention and motivation for
behavior change.13 Most patients undergoing RFR said they would
have it again and recommend it to others. One study found that
decisional conflict lessened after results were received, and satisfaction with decision persisted to follow-​up one year later.7
Reported drawbacks of somatic testing in hypothetical studies
included learning things about the cancer that were better left unknown, as well as concerns over psychological harm and test accuracy.13 In the case of targeted treatment, drawbacks included the risk
of disappointment from a negative result or a positive result but no
access to the relevant treatment.7 Concerns were increased in participants with a higher perceived risk of recurrence.7
In deciding to undergo MTP, the primary motive for advanced
cancer patients was personal benefit. Seen as cutting-​edge technology, MTP was perceived as a source of hope, offering promises of
targeted and therefore more effective therapy.12,15
Studies in cancer patients who have actually been offered MTP
have primarily noted unequivocal patient acceptance, but also reports of information overload and misunderstanding, causing unrealistic expectations, anxiety, and uncertainty.6,7,16,19 Self-​perceived
lack of knowledge did not reduce willingness to participate. Patient
hopes of benefit were enhanced by the promise of novel and targeted
treatment but challenged by nonfindings or by limited access to relevant trials.12
In hypothetical studies, cancer patients have identified disadvantages of MTP such as disclosure of unwanted information or that
reporting of results could counteract denial. Concerns over psychological harm and test accuracy were also noted.13 Studies of cancer
patients have identified differences between racial groups. One
study reported that, even if testing was financially covered, nonwhite participants were less willing to undergo MTP for the selection of approved drugs or experimental drugs.18 Another reported
that concerns over psychological harm were higher among blacks as
compared with whites.13 The most important factors that might discourage MTP were the potential for complications if a biopsy were
required and a delay in treatment while waiting for results.15
While not a major concern, cancer patients have listed concerns
about privacy and confidentiality of test results and potential for test
results to lead to health, life, or disability insurance discrimination
as reasons not to pursue somatic genomic testing for cancer.13,15
Insurance concerns appear greater in countries with private health
care systems, and it is noted that several countries have passed
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Section III Screening and Testing for Germ Line and Somatic Mutations
legislation to prevent discrimination based on genetic testing. Cost
has also been listed as a disadvantage.13,15
Preferences for Receipt of Results
Most participants want to be informed of results that had implications for treatment with discussion focused on practical issues relevant to treatment.12,18 In one study 35% of patients only wanted to
receive MTP results that would directly influence their own treatment decisions.15
For cancer patients undergoing MTP, family obligations informed
a willingness to receive information about germline results (a rare
outcome, but which can occur). This information tended to be perceived as burdensome given the advanced disease of the patient and
the challenges of coping with illness. Cancer risk information could
also be perceived as irrelevant for a patient with a short prognosis.7,12
Possibly reflecting this ambivalence was the finding that in a small
sample of gastrointestinal cancer patients undergoing somatic genome testing, one of eight patients decided not to go ahead with tests
to confirm a germline finding following genetic counseling, therefore leaving the implications for blood relatives unknown.20 Thus,
although the result is rare, somatic genomic sequencing must be accompanied by a plan for return of germline results, in partnership
with genetic counseling. This information will be important for any
blood relatives who wish to undergo germline testing themselves, as
the target variant (index case) for that particular family will then be
known, and test utility will increase as a result.21
Behavioral Impact
Little attention has been given to communication of germline results
in somatic testing. Somatic RFR results and the level of risk both
influenced chemotherapy decisions in the majority of cases, though
the most influential factor for some patients remained the doctor’s
opinion.7
In a qualitative hypothetical scenario, one study found that almost all cancer patients undergoing somatic genome testing had a
positive attitude toward receiving unsolicited findings from MTP.16
However, after receiving information about the types of unsolicited
findings and possible psychological, social, and financial impacts,
most participants wanted to receive only subsets of genetic information. Their main concern was their own and others’ (including
family members) ability to cope with the increased risk of having a
genetic disorder and the anticipated emotional burden. Even when
family members were happy for the participant to receive all possible
information, the gatekeeper role persisted.
Future Directions
Genomic testing in cancer can identify germline and somatic genetic changes that have implications for the prevention, diagnosis,
and treatment of cancer. The growing understanding of the molecular basis of disease is revolutionizing cancer care by allowing the
personalization of patient management. However, challenges in
the testing process include its innate complexity, the uncertainty it
can generate, and the increased demands on oncology staff due to
the mainstreaming of genetics. Current understanding of patient
responses to single gene testing may not translate to the genomic
sphere. Research is in its early stages, but early reports of poor patient understanding of genomic testing, mixed results regarding distress from testing, and variable impact of results on patient behavior
indicate the need for further investigation.
Future research directions should include a better understanding
of what information should be included in the consent process, how
patients can be best supported in communication of germline findings to relevant family members, and ways to motivate individuals
to adopt preventative strategies to reduce their risk of developing
cancer. Due to the current bias in research to female Caucasians, a
broader range of cancers and populations should be included in future studies. In this way the full benefits of genomic oncology may
be realized.
REFERENCES
1. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J,
Koskenvuo M, et al. Environmental and heritable factors in the
causation of cancer—​analyses of cohorts of twins from Sweden,
Denmark, and Finland. New England Journal of Medicine.
2000;343(2):78–​85.
2. Liotta L, Petricoin E. Molecular profiling of human cancer. Nature
Reviews Genetics. 2000;1(1):48–​56.
3. Han PKJ, Klein WMP, Arora NK. Varieties of uncertainty in health
care. Medical Decision Making. 2011;31(6):828–​838.
4. Han P, Umstead K, Bernhardt B, Green R, Joffe S, Koenig BA,
et al. A taxonomy of medical uncertainties in clinical genome
sequencing. Genetics in Medicine. 2017;19(8):918.
5. Allegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond
EH, Hayes DF, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response
to anti–​epidermal growth factor receptor monoclonal antibody
therapy. Journal of Clinical Oncology. 2009;27(12):2091–​2096.
6. Liang R, Meiser B, Smith S, Kasparian N, Lewis C, Chin M, et al.
Advanced cancer patients’ attitudes towards, and experiences
with, screening for somatic mutations in tumours: a qualitative
study. European Journal of Cancer Care. 2017;26(6):10.1111/​
ecc.12600.
7. Yanes T, Willis AM, Meiser B, Tucker KM, Best M. Psychosocial
and behavioral outcomes of genomic testing in cancer: a systematic
review. European Journal of Human Genetics. 2018;27(1):28–​35.
8. Ha VTD, Frizzo-​Barker J, Chow-​White P. Adopting clinical genomics: a systematic review of genomic literacy among physicians in
cancer care. BMC Medical Genomics. 2018;11(1):18.
9. Robson ME, Storm CD, Weitzel J, Wollins DS, Offit K. American
Society of Clinical Oncology policy statement update: genetic
and genomic testing for cancer susceptibility. Journal of Clinical
Oncology. 2010;28(5):893–​901.
10. Sanderson SC, Loe BS, Freeman M, Gabriel C, Stevenson DC,
Gibbons C, et al. Development of the Knowledge of Genome
Sequencing (KOGS) questionnaire. Patient Education and
Counseling. 2018;101(11):1966–​1972.
11. Leventhal K-​G, Tuong W, Peshkin BN, Salehizadeh Y, Fishman
MB, Eggly S, et al. “Is it really worth it to get tested?”: primary care
patients’ impressions of predictive SNP testing for colon cancer.
Journal of Genetic Counseling. 2013;22(1):138–​151.
12. Best MC, Bartley N, Jacobs C, Juraskova I, Goldstein D, Newson
AJ, et al. Patient perspectives on molecular tumor profiling: “why
wouldn’t you?” BMC Cancer. 2019;19(1):753.
CHAPTER 15 Psychosocial Issues in Genomic Testing, Including Genomic Testing for Targeted Therapies
13. Gray SW, Hicks-​Courant K, Lathan CS, Garraway L, Park ER,
Weeks JC. Attitudes of patients with cancer about personalized medicine and somatic genetic testing. Journal of Oncology
Practice. 2012. doi:JOP.2012.000626.
14. Williams JR, Yeh VM, Bruce MA, Szetela C, Ukoli F, Wilkins CH,
et al. Precision medicine: familiarity, perceived health drivers, and
genetic testing considerations across health literacy levels in a diverse sample. Journal of Genetic Counseling. 2019;28(1):59–​69.
15. Blanchette PS, Spreafico A, Miller FA, Chan K, Bytautas J, Kang S,
et al. Genomic testing in cancer: patient knowledge, attitudes, and
expectations. Cancer. 2014;120(19):3066–​3073.
16. Bijlsma RM, Wessels H, Wouters RHP, May AM, Ausems MGEM,
Voest EE, et al. Cancer patients’ intentions towards receiving unsolicited genetic information obtained using next-​
generation
sequencing. Familial Cancer. 2018;17(2):309–​316.
17. Hallowell N, Murton F. The value of written summaries of genetic
consultations. Patient Education and Counseling. 1998;35(1):27–​34.
18. Yusuf RA, Rogith D, Hovick SR, Peterson SK, Burton-​Chase AM,
Fellman BM, et al. Attitudes toward molecular testing for personalized cancer therapy. Cancer. 2015;121(2):243–​250.
19. Schrader KA, Cheng DT, Joseph V, Prasad M, Walsh M, Zehir
A, et al. Germline variants in targeted tumor sequencing using
matched normal DNA. JAMA Oncology. 2016;2(1):104–​111.
20. Catenacci DVT, Amico AL, Nielsen SM, Geynisman DM, Rambo
B, Carey GB, et al. Tumor genome analysis includes germline genome: are we ready for surprises? International Journal of Cancer.
2015;136(7):1559–​1567.
21. Morrow A, Jacobs C, Best M, Greening S, Tucker K. Genetics in palliative oncology: a missing agenda? A review of the literature and
future directions. Supportive Care in Cancer. 2018;26(3):721–​730.
115
16
Psychosocial Issues Related to Liquid
Biopsy for ctDNA in Individuals at Normal
and Elevated Risk
Jada G. Hamilton, Amanda Watsula-​Morley, and Alicia Latham
Introduction
With the advent of next-​generation sequencing (NGS) and improved
understanding of the genomic changes underlying cancer initiation
and progression, there is increasing interest in the potential for liquid
biopsy. Liquid biopsy involves the minimally invasive sampling of
blood or plasma to detect biomarkers indicative of cancer. Liquid biopsy can detect cell-​free DNA (cfDNA), defined as small fragments
of nucleic acid found in the peripheral circulation. In cancer patients,
a percentage (estimated at less than 1% in early-​stage disease and up
to 40% in advanced disease) of this unbound nucleic acid is specific
to and derives from the patient’s dying tumor cells and is referred
to as circulating tumor DNA (ctDNA).1,2 Analyzing genetic alterations (i.e., single base substitutions, translocations, insertions, and
deletions) in ctDNA through NGS platforms has recently emerged
as a potential method to monitor response to oncological treatment
and assess for early disease recurrence. Higher levels of ctDNA are
generally detected in metastatic disease and specific tumor types, as
certain cancers are more prone to ctDNA shedding.2,3
Background
Clinical Applications
Analysis of ctDNA has the potential for application in multiple contexts and populations. One primary context is in the management
of patients who are already diagnosed with cancer. For instance,
ctDNA assays may be useful for informing treatment selection in patients with advanced cancers, consistent with the goals of precision
medicine. A few Food and Drug Administration (FDA)-​approved
ctDNA assays exist, including the Cobas EGFR Mutation Test v2
that detects variants in the epidermal growth factor receptor (EGFR)
gene among patients with metastatic non–​small cell lung cancer, and
the therascreen PIK3CA assay that detects variants in the PIK3CA
gene among patients with metastatic breast cancer.4 In these cases,
ctDNA is analyzed to identify known somatic (i.e., tumor) gene variants that can be targeted with specific therapeutics.
There is hope that ctDNA can be used to inform decisions about
adjuvant therapy for patients with cancer following primary surgery
or radiation treatment, because it is not always clear how to best
treat patients who lack evidence of residual or metastatic disease.5
For example, there is some retrospective evidence to suggest that
analysis of ctDNA as a marker of residual disease could offer insight
into whether such patients would benefit from adjuvant therapy.5–​7
Similarly, ctDNA analysis could ultimately provide earlier warning
about relapse or disease recurrence among cancer survivors than
other existing surveillance methods.5,7
An additional promising context for ctDNA analysis is as a cancer
screening tool among healthy individuals. The prospect of having a
blood-​based, minimally invasive test that could be widely deployed
in the population to detect cancer at its earliest stages is extremely
appealing. Such a test would be a powerful tool for reducing cancer
morbidity and mortality in the general population. However, to
achieve this goal, a ctDNA-​based screening assay would need to both
be cost-​effective and have extremely high specificity—​that is, the test
would need to have a high probability of classifying those without
cancer as negative, as well as return few false-​positive results.5
Benefits
Analysis of ctDNA has a number of important advantages when
compared to traditional biopsy of solid tumor tissue. For one, given
that ctDNA assays only require a blood sample, this approach is
much less invasive and burdensome to the patient and has the potential to be used in cases where accessing an adequate tissue sample
is difficult. Analysis of ctDNA may also provide information about
the spectrum of genetic changes (i.e., genetic heterogeneity) that exist
within a given tumor or among multiple tumor sites (e.g., metastases)
within a patient, the entire scope of which may be missed with the
biopsy of tumor tissue alone. In addition, ctDNA can be more easily
and economically sampled serially over time, and could therefore
provide improved longitudinal information about how a patient’s
CHAPTER 16 Psychosocial Issues Related to Liquid Biopsy for ctDNA in Individuals at Normal and Elevated Risk
disease responds to treatment. This stands in contrast to serial imaging studies that have multiple risks including radiation and heavy-​
metal exposure in many high-​resolution contrasted studies.4,6,8
Limitations
Despite the exciting promise of ctDNA assays for use among both
cancer-​affected and unaffected populations, these tests currently
have crucial limitations. For most applications, evidence is lacking
to support the clinical validity or clinical utility of these tests.
Clinical validity is the ability of a test to accurately detect or predict
the clinical disorder of interest. Clinical utility is the ability of a test
to significantly improve measurable patient clinical outcomes including morbidity and mortality.9,10 A 2018 review conducted by the
American Society of Clinical Oncology and the College of American
Pathologists concluded that except for specific ctDNA assays that
have received regulatory approval, such as those used in a few types
of advanced cancer, currently most ctDNA tests have insufficient evidence to demonstrate clinical validity, and most have no evidence to
support clinical utility.6 Therefore, presently there is insufficient evidence to demonstrate the clinical validity or clinical utility of ctDNA
tests in most advanced cancer settings, as well as in early-​stage cancer,
treatment monitoring, and detecting residual disease, or for cancer
screening in asymptomatic individuals.6 Consequently, there is a serious need for additional research including well-​designed clinical
trials to confirm the anticipated clinical benefits of ctDNA assays.
Psychosocial Considerations
As future research seeks to establish the clinical utility of ctDNA assays, psychosocial outcomes should be included in the balance of
risks and benefits of these tests. Although virtually unexplored empirically at this time, there are notable potential psychosocial implications of ctDNA assays.
Incidental Discovery of Germline Variants
One relevant consideration arises from the fact that it is not currently possible to separate ctDNA at the time of testing from other
circulating DNA within a patient.4 Thus, efforts to sequence ctDNA
will invariably involve analyzing normal (i.e., germline or heritable)
DNA as well. Distinguishing somatic variants from germline variants is not always easily achieved, and this process has the potential
to lead to the incidental detection of disease-​predisposing germline
DNA variants.6 For example, a variant in the gene BRCA1, which is
associated with hereditary breast and ovarian cancer, or in the gene
TP53, which is associated with Li-​Fraumeni syndrome and elevated
risks for breast cancer, brain cancer, sarcomas, and other cancers,
may be detected and require additional clinical testing to determine
if it arises from the tumor or the germline. If such a variant is found
to be germline in origin, this can have far-​reaching medical and psychosocial implications for patients and their families because it reveals important information about their future cancer risks.11,12
Overtreatment and Overdiagnosis
Additional psychosocial considerations relate to the prospect of
false-​positive results arising from ctDNA assays, particularly in the
context of screening healthy, asymptomatic individuals.6 If a ctDNA
assay provides false-​positive results, then the potential exists for
engendering substantial emotional distress among individuals, as
well as leading to unnecessary overtreatment with physical, psychological, and financial costs of whichever medical interventions
are subsequently adopted. A ctDNA test could also detect genetic changes that would never actually develop into cancer; such
overdiagnosis, or the diagnosis of a medical problem that would
have not ultimately caused harm, is a risk that has been recognized
in other cancer screening settings such as with mammography in
breast cancer and prostate-​specific antigen (PSA) testing in prostate
cancer.6,13,14 Nonetheless, many individuals do not fully understand
the risks of overdiagnosis,15,16 which can complicate communication
about the harms and benefits of screening tests and present challenges in promoting patients’ informed medical decision making
about test adoption.
Uncertainty and Anxiety
Even if ctDNA assays are developed with acceptable levels of sensitivity and specificity, these tests will not be perfect in their classification of individuals as cancer-​affected versus unaffected, and the
possibility exists for medical uncertainty, confusion, and anxiety on
behalf of patients as well as their healthcare providers. For example,
ctDNA assays may accurately detect a relevant genetic change but
will likely be unable to provide insight into where a tumor is located
within the body;2 if a developing tumor cannot be detected with additional clinical work-​up (e.g., imaging), how should a patient with
an abnormal ctDNA result be treated and followed? How will this
ambiguity be effectively communicated to a patient in a way that
balances the potentially conflicting goals of ensuring adequate comprehension, minimizing anxiety, and sustaining motivation to participate in what may be a protracted diagnostic process? Uncertainty
can be a substantial source of stress, and patients can experience a
variety of negative emotional, cognitive, and behavioral responses to
medical uncertainty;17 determining how to manage and minimize
these negatives outcomes of the uncertainty that will arise from
ctDNA assays represents an important area for future investigation.
Quality of Life
It is also unclear what the impact on overall quality of life will be for
a patient who learns of their risk of cancer development, progression, or recurrence through a ctDNA assay that does not align with
other clinical tests or symptom experiences; these patients may need
to undergo long-​term, repeated surveillance without clear guidance
for their medical management. Larger questions remain about how
ctDNA as an early marker of cancer may have implications for insurability or discrimination, or how equitable access to this potential
innovation in cancer control will be achieved so that existing health
disparities are minimized rather than exacerbated. These issues are
similar to some of the ethical, legal, and social concerns that have
been highlighted, and remain largely unresolved, in the setting of
genetic testing for disease predisposition.18–​20
Future Directions
Using ctDNA as a biomarker detectable through liquid biopsy has
great promise for improving disease outcomes among patients affected by cancer, as well as healthy individuals who could benefit
from a novel cancer screening test. However, despite substantial
117
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Section III Screening and Testing for Germ Line and Somatic Mutations
enthusiasm for ctDNA assays, evidence is generally lacking for the
clinical validity and clinical utility of these tests in many settings.6
Carefully designed clinical trials are required to provide empiric
support for the highly anticipated benefits of ctDNA assays. Future
research is needed to clarify the benefits and risks of these tests not
only in terms of cancer morbidity and mortality but also to address
the difficult questions regarding potential psychosocial effects of
ctDNA assays that currently lack clear answers.
REFERENCES
1. Pantel K, Alix-​Panabieres C. Real-​time liquid biopsy in cancer patients: Fact or fiction? Cancer Res. Nov 1 2013;73(21):6384–​6388.
2. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating
tumor DNA in early-​and late-​stage human malignancies. Sci Transl
Med. Feb 19 2014;6(224):224ra224.
3. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz
LA, Jr., Kinzler KW. Cancer genome landscapes. Science. Mar 29
2013;339(6127):1546–​1558.
4. Snow A, Chen D, Lang JE. The current status of the clinical
utility of liquid biopsies in cancer. Expert Rev Mol Diagn. Nov
2019;19(11):1031–​1041.
5. Mattox AK, Bettegowda C, Zhou S, Papadopoulos N, Kinzler KW,
Vogelstein B. Applications of liquid biopsies for cancer. Sci Transl
Med. 2019;11(507):eaay1984.
6. Merker JD, Oxnard GR, Compton C, et al. Circulating tumor DNA
analysis in patients with cancer: American Society of Clinical
Oncology and College of American Pathologists joint review. J Clin
Oncol. Jun 1 2018;36(16):1631–​1641.
7. Tie J, Wang Y, Tomasetti C, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence
in patients with stage II colon cancer. Sci Transl Med. Jul 6
2016;8(346):346ra392.
8. Neumann MHD, Bender S, Krahn T, Schlange T. ctDNA and CTCs
in liquid biopsy—​Current status and where we need to progress.
Comput Struct Biotechnol J. 2018;16:190–​195.
9. Teutsch SM, Bradley LA, Palomaki GE, et al. The Evaluation
of Genomic Applications in Practice and Prevention (EGAPP)
SECTION IV
Screening and Assessment
in Psychosocial Oncology
Wendy W. T. Lam (Section Editor)
17 Screening and Assessment for Distress 121
Alex J. Mitchell
18 Assessment, Screening, and Case Finding
for Depression and Anxiety in People with
Cancer 130
Kristine A. Donovan and Paul B. Jacobsen
19 Screening for Delirium and Dementia in the
Cancer Patient 137
Christian Bjerre-​Real, James C. Root, Yesne Alici,
Julia A. Kearney, and William S. Breitbart
20 Screening and Assessment for Cognitive
Problems 146
Alexandra M. Gaynor, James C. Root, Elizabeth Ryan, and
Tim A. Ahles
17
Screening and Assessment for Distress
Alex J. Mitchell
Introduction
Distress is a very common and clinically relevant complication
of cancer that can occur at any time on the patient pathway.1 The
United States National Comprehensive Cancer Network (NCCN)
recommends screening patients at the initial visit soon after diagnosis and at each visit, although the screening schedule may be
revised as clinically indicated (Box 17.1).2 The exact prevalence of
distress is difficult to summarize precisely because it is influenced
by numerous variables. However, large datasets show that distress is
highest within the first 3 months of a cancer diagnosis and decreases
within the first year in most patients (see Figure 17.1). Whereas 8%
of the general population and 20% of primary care attendees experience distress at any given time, 35% to 80% of cancer patients report
distress when they are asked.3–​5 Scores from 10,000 patients’ scores
on the Distress Thermometer (DT) are shown (see Figure 17.2).
Rates of zero, mild, moderate, and severe distress are approximately
15%, 40%, 30%, and 10%, respectively (Figure 17.2). Predictors of
distress are concurrent complications such as cancer pain, function
limitations, and reduced quality of life, which are more powerful determinants of distress than cancer type or cancer stage. That said,
patients with prostate cancer appear to have about 30% lower rates
of distress across multiple studies.
Distress is often overlooked in clinical practice, and clinicians’
opinions on distress often do not correspond with patients’ self-​
reported views.6 Mitchell and colleagues looked at identification of
distress by chemotherapy cancer nurses across 400 nurse-​patient
consultations.7 Nurse practitioners had a detection sensitivity of
50% and specificity of 80%. Unresolved distress is associated with
lower adherence to treatment, slower rehabilitation, lower satisfaction with care, higher costs of overall care, and poorer survival
rates.8–​11 Distress is not a formal psychiatric diagnosis alone but a
symptom of emotional upset arising from any cause, which is an
important “red flag” that indicates there are unresolved problems
and should prompt further inquiry, follow-​up, and appropriate psychosocial help. Even mild distress can be an indicator of underlying
unmet needs as well as more severe psychiatric disorders such as
depression and anxiety. Our group found twice the rate of unmet
needs (defined using a custom problem list) in patients with mild
distress versus no distress in 480 cancer patients in Leicester, UK
(see Figure 17.3).
Recognition and Screening for Distress
Most organizations agree that recognizing distress (as well as the
source of distress) should be a priority for all clinicians, not specifically psychologists, psychiatrists, and social workers. Many, but
not all, also recommend that distress screening should be integrated
into a comprehensive assessment of well-​being and conducted routinely.12 Indeed, there was an attempt to unify national cancer plans
to integrate a comprehensive psychosocial approach in cancer care.13
Yet, despite the potential benefits, uptake has been slow, particularly
in low-​income countries. Screening is designed to quickly ascertain
which individuals in a large population need further assessment
(Box 17.2; Figure 17.4), and therefore most instruments are not
intended to be diagnostic but aim to open a dialogue and provide
a simple severity rating. Early studies concentrated on tool development and validation. However, screening tool accuracy does not
mean screening will necessarily bring patient benefits. To be successful, evidence-​based treatment also has to be available, and also
has to be offered (where needed) and accepted. This does not always
happen (see Evidence base for Implementing Distress Screening in
Clinical Settings). Many authors have pointed out that the evidence
base for distress screening is complex and needs to be interpreted
with care. Previous narrative reviews have come to different conclusions about the merits of distress screening. For example, some
have failed to find any relevant randomized controlled trials, while
Box 17.1. Phases of Cancer Risk When Screening Might Be
Considered (from National Comprehensive Cancer Network)
•
•
•
•
•
•
•
•
•
•
Finding a suspicious symptom
Being informed about the diagnosis
Awaiting treatment
Change or end of treatment
Discharge from hospital
Surviving cancer
Failure of treatment
Recurrence or progression of disease
Advanced phase of illness
Approaching the end of life
National Comprehensive Cancer Network (NCCN): Distress management. Version
2.2017.
122
SECTION IV Screening and Assessment in Psychosocial Oncology
0.4
0.4
0.37
0.35
0.3
0.18
0.17
0.235 0.24
0.24
0.23
0.2
0.2
0.16
0.18
0.23
0.25
0.18
0.1
0
<3 months
6 months
12 months
5 years
3 years
BJGP Open 2019; 3 (3)
Older Cancer Patients
Middle Aged Cancer Patients
Older Primary Care Controls
Figure 17.1. Distribution of DT scores across 10,000 individual patient data returns.
DT = 10
3.0%
DT = 9
3.0%
DT = 8
7.0%
DT = 7
9.0%
DT = 0
16.0%
DT = 1
10.0%
DT = 6
8.0%
DT = 2
11.0%
DT = 5
14.0%
DT = 3
11.0%
DT = 4
8.0%
Figure 17.2. Distribution of DT scores across 10,000 individual patient data returns.
15
12.8
11
10
6.4
5
17
0
No distress
(score –0)
Mild distress
(score 1–4)
Moderate distress
(score 5–7)
Severe distress
(score 8–10)
Mitchell et al (2020) unpublished data
Figure 17.3. Frequency of unmet needs on a problem list according to DT scores in 480 mixed cancer patients.
CHAPTER 17 Screening and Assessment for Distress
80%
60%
63%
40%
34%
20%
0%
Help from family
and friends
Does not
recognize need
10%
8%
6%
Don’t know
who to ask
Question about
availability
Other
reasons
Figure 17.4. Reasons for declining psychosocial help.
Box 17.2. Phases of Distress Screening
Screening Study
The application of a diagnostic test or clinical assessment to optimally
rule out those without the disorder with minimal false negatives (missed
cases).
Case Finding Study
The application of a diagnostic test or clinical assessment to optimally identify those with the disorder with minimal false positives.
Implementation Trial
A comparison of one group of clinicians (or center) using screening compared with another group without screening, ideally randomized.
others have omitted data from nonrandomized trials or observational screening studies.14,15
Distress Screening Tools
Clinicians and researchers wishing to identify and measure distress
have a choice between a growing number of tools that have good evidence of acceptability and accuracy in oncology and palliative settings
(Table 17.1).16,17 It is generally accepted that brief tools taking around
5 minutes or less to complete are most practical for busy clinical settings. Longer tools may still find a use particularly in waiting rooms,
in reception areas, and at home. In 1998 the NCCN released a one-​
item visual analog scale (VAS) known as the Distress Thermometer
(DT). It is often used with the 39-​item problem checklist of unmet
needs, which takes around 2 minutes to complete. The cutoff for significant distress is still debated, but most commonly a threshold of ≥
5 (sometimes ≥ 4) is recommended.18,19 Using the Hospital Anxiety
and Depression Scale summary score (HADS-​T)20 as the criterion
reference and at a prevalence of distress of 23%, Ma et al.21 found that
the DT has a pooled sensitivity of 82%, a specificity of 73%, a positive
predictive value of 48%, and a negative predictive value of 93%. Using
the clinical utility index (http://​www.clinicalutility.co.uk), the DT appears to be a relatively “poor” case-​finding tool but a “good” method
of screening for distress (Table 17.1). A number of alternatives to the
DT exist, including the Psychological Distress Inventory (PDI), Brief
Symptom Inventory (BSI), General Health Questionnaire (GHQ),
and Symptom Checklist 90-​R (SCL-​90), but they all have limited evidence in cancer and/​or a narrow focus. Two broader multidomain
tools, namely the Edmonton Symptom Assessment System (ESAS)
and the Emotion Thermometers (ET), are promising as they cover a
broader range of relevant conditions while retaining a brief format.
Multidomain tools allow the clinician to screen for mental symptoms such as anxiety and depression and not simply distress. Both
the ESAS and ET have undergone considerable independent validation as well as recent implementation studies. The ESAS includes six
physical symptoms of cancer (pain, tiredness, nausea, drowsiness,
appetite, and shortness of breath) and three psychosocial symptoms
(well-​being, depression, and anxiety). Provisional evidence suggests
reasonable performance in diagnostic validity studies of distress
based on the HADS-​T. The ET (http://​www.emotionthermometers.
com) includes four core emotions—​distress, depression, anxiety, and
anger—​and uniquely inquires about need for help. It can also be extended with quality of life, memory, and pain add-​ons. The ET has
the same 11-​point VAS as the DT. Validation from 17 studies in early-​
and late-​stage cancer settings suggest that the ET improves upon the
accuracy of the DT.22,23
Evidence Base for Implementing Distress
Screening in Clinical Settings
Several groups have examined the key question of whether distress screening actually improves clinical care.24,25 Well-​designed,
large-​scale studies comparing care before and after implementation of screening (sequential cohort) or in groups randomized
to screening have been gradually forthcoming (Table 17.2).15 Of
these implementation studies, only one reasonably consistent
outcome measure is receipt of psychosocial referral. An early
Cochrane review found only three qualifying studies and failed to
demonstrate any effect of distress screening on meaningful outcomes. Carlson et al. found 13 randomized and 10 nonrandomized
trials of screening for distress/​quality of life that measured patient
well-​being.15 Of the RCTs, 5 of 13 studies reported additional
123
124
SECTION IV Screening and Assessment in Psychosocial Oncology
Table 17.1. Updated Summary of Distress Tools Validated in Multiple Cancer Settings
Compared with
Weighted
Any Mental Disorder Sensitivity
(Incl. Adjustment
Disorder)
Weighted
Specificity
Weighted Positive
Predictive Value
HADS (N = 16)*
(overall accuracy = 73.3%)
65.2%
(95% CI = 62.3%–​68.1%
77.2%
(95% CI = 75.5%–​79.0%)
58.2%
82.0%
(95% CI = 55.4%–​61.0%) (95% CI = 80.4%–​83.7%)
0.379
(95% CI = 0.379–​-​0.380)
Qualitative grade = “poor”
0.634
(95% CI = 0.633–​0.634)
Qualitative grade = “fair”
Distress Thermometer
(N = 9)**
(overall accuracy = 69.9%)
84.0%
(95% CI = 80.0%–​88.0%)
63.0%
52.4%
89.0%
(95% CI = 61.0%–​66.0%) (95% CI = 49.0%–​55.8%) (95% CI = 86.8%–​91.2%)
0.449
(95% CI = 0.448–​0.450)
Qualitative grade = “poor”
0.558
(95% CI = 0.557–​0.559)
Qualitative grade = “fair”
Compared with
HADS-​T Distress
Weighted Sensitivity Weighted
Specificity
Weighted Positive
Predictive Value
Distress Thermometer
(N = 27)**
(overall accuracy = 75.1%)
82.0%
(95% CI = 80.0%–​84.0%)
47.6%
93.1%
(95% CI = 45.7%–​49.4%) (95% CI = 92.4%–​93.9)
0.390
(95% CI = 0.389–​0.391)
Qualitative grade = “poor”
0.680
(95% CI = 0.679–​0.680)
Qualitative grade = “good”
Single Verbal Depression
Question (N = 3)***
(overall accuracy = 62.3%)
76.1%
59.8%
(95% CI = 67.2.0%–​85.0%) (95% CI = 55.4%–​64.1%)
25.7%
93.2%
(95% CI = 20.4%–​31.0%) (95% CI = 90.4%–​96.0%)
0.195
(95% CI = 0.191–​199)
Qualitative grade = “very
poor”
0.557
(95% CI = 0.555–​0.559)
Qualitative grade = “fair”
Two Verbal Depression
Questions (e.g., PHQ2)
(N = 3)***
(overall accuracy = 73.3%)
75.5%
(95% CI = 67.3%–​83.7%)
72.6%
37.6%
93.1%
(95% CI = 68.63%–​76.5%) (95% CI = 31.1%–​44.1%) (95% CI = 90.6%–​95.7%)
0.283
(95% CI = 0.279–​0.288)
Qualitative grade = “very
poor”
0.676
(95% CI = 0.675–​0.677)
Qualitative grade = “good”
Single-​item Anxiety
VAS (AnxT or ESAS-​A )
(N = 3)***
(overall accuracy = 71.9%)
77.9%
(95% CI = 73.0%–​82.8%)
71.1
(95% CI = 68.1%–​74.1%)
44.6%
91.5%
(95% CI = 40.1%–​49.1%) (95% CI = 89.4%–​93.6%)
0.348
(95% CI = 0.335–​0.350)
Qualitative grade = “very
poor”
0.651
(95% CI = 0.650–​0.661)
Qualitative grade = “good”
Single-​item Depression
VAS (DepT or ESAS-​D)
(N = 3)***
(overall accuracy = 71.9%)
76.8%
(95% CI = 64.0%–​87.5%)
70.5%
(95% CI = 55.7%–​83.3%)
43.2%
91.0%
(95% CI = 39.2%–​48.2%) (95% CI = 88.9%–​93.2%)
0.336
(95% CI = 0.334–​0.338)
Qualitative grade = “very
poor”
0.642
(95% CI = 0.641–​0.643)
Qualitative grade = “good”
73.0%
(95% CI = 72.0%–​74.0%)
Weighted Negative Clinical Utility for
Predictive Value
Case Finding (CUI+)
Weighted Negative Clinical Utility for
Predictive Value
Case Finding (CUI+)
Clinical Utility for
Screening (CUI-​)
Clinical Utility for
Screening (CUI-​)
All calculations from http://​www.clinicalutility.co.uk
* Data from Mitchell AJ, Meader N, Symonds P. Diagnostic validity of the Hospital Anxiety and Depression Scale (HADS) in cancer and palliative settings: a meta-​analysis. J Affect
Disord. 2010 Nov;126(3):335–​48.
** Data adapted from Ma X, Zhang J, Zhong W, Shu C, Wang F, Wen J, Zhou M, Sang Y, Jiang Y, Liu L. The diagnostic role of a short screening tool-​the distress thermometer: a meta-​
analysis. Support Care Cancer. 2014 Feb 8 [Epub ahead of print].
*** New calculation for this chapter.
added benefits on patient well-​being in screened compared with
unscreened patients. Perhaps the most important message was that
screening without mandatory follow-​up care was consistently unsuccessful. Screening with mandatory follow-​up is likely to be beneficial compared with no screening (and treatment as usual), but
even in this case only if follow-​up is consistent and local psychosocial resources adequate.24 We previously showed that combining
implementation studies using mandatory follow-​up in a meta-​
analysis reveals that “enhanced screening” increased the chances of
receiving a psychosocial referral by twofold (risk ratio [RR] = 2.03;
95% confidence interval [CI] = 1.13 to 3.65; p < 0.01) compared to
those with nonenhanced screening.26
A new study from Schuurhuizen et al. adds additional insights
into the pros and cons of screening.27 They conducted a cluster randomized trial across 16 hospitals where patients in the screening
arm were screened for psychological distress with the HADS and
the DT (including the Problem List) on three occasions and then
offered stepped care in comparison to usual care. Of 349 randomized patients, 184 received screening and 60% of these patients
screened positive for psychological distress, but despite this, the
study was halted. Only 46 patients (25.0%) entered stepped care
after screening; instead, many used watchful waiting (15%) and
11% used other steps. The course of distress did not differ among
patients assigned to the stepped care group versus the care as usual
group most likely due to the low uptake of stepped care. The low
uptake of care, despite a high prevalence rate of distress, is consistent with findings in other studies showing low acceptance rates
of psychological treatment (see Uptake of Help as a Key Barrier to
Screening Success). Some patients needing psychological support
show no signs or symptoms of distress, whereas others with elevated levels of distress do not report unmet needs or a desire for
professional help.28 These effects reduce the effectiveness of distress
screening outcomes.
Has Widespread Dissemination of Distress
Screening Been Successful?
Screening together with follow-​up in settings where resources are
adequate can improve clinical outcomes, but does screening offer
more benefits than risks? Large-​scale studies are beginning to accrue
that inform us regarding the difficulties of implementing distress
screening in clinical practice and help answer the question, when
is screening successful and when is it unsuccessful? For example,
CHAPTER 17 Screening and Assessment for Distress
Table 17.2. Summary of Comparative Distress Implementation Screening Studies
Author
Country
Screening Target
Screening
Beneficial?
PROs
Improved?
Referrals Improved?
Communication
Improved?
Acceptability
of Screening?
Distress | Depression
No
No
NR
No
NR
Rosenbloom et al. US
(2007)
Mood | Quality of life No
No
NR
NR
NR
Mills et al. (2009)
UK
Quality of life
No (deleterious)
No
NR
Yes, but not
significantly
High
Braeken et al.
(2011)
Germany
Distress
No
No
Yes, but not significantly
NR
Mixed
Hollingworth
et al. (2012)
UK
Distress | Quality
of life
No
No
NR
NR
High
Ploos van Amstel
et al (2019)
Netherlands Distress
No
No (QoL)
NR
NR
NR
van der Meulen
et al (2018)
Netherlands Distress
No
No (QoL /​ NR
Depression)
NR
Yes
Geerse et al
(2017)
Netherlands Distress
No
No (QoL /​ NR
Depression)
NR
NR
Yes
Randomized Unsuccessful
Maunsell et al.
(1996)
Canada
Randomized Partially Successful
Sarna (1998)
US
Distress
Yes
NR
Yes
NR
McLachlan et al.
(2001)
Australia
Distress | Depression
| Quality of life
Partial (in depressed Yes (in
patients)
depressed
only)
NR
Yes (in depressed only)
NR
Detmar et al.
(2002)
Netherlands Quality of life
Partial
No
NR
Yes (but only for social
functioning, fatigue,
and dyspnea)
NR
Velikova et al.
(2004)
UK
Distress | Quality
of life
Yes
Yes
NR
Yes, but not
significantly
Mixed
Macvean et al.
(2007)
Australia
Depression | Quality
of life | Unmet needs
Yes
Yes
NR
(depression)
NR
Good
Girgis et al. (2009) Australia
Depression | Quality
of life | Unmet needs
Partial (in
communication
and action)
No
Yes, and significant (but
full data not presented)
Yes, and significant (but High
full data not presented)
Carlson et al.
(2010)
Canada
Distress
Yes (in breast and
lung cancer)
No
Yes, significantly
NR
High
Carlson et al.
(2012)
Canada
Distress
No
Yes
Yes (access to services),
significantly
NR
High
Klinkhammer-​
Schalke et al.
(2012)
Germany
Quality of life
Yes
Yes
NR
NR
Not reported
Singer et al.
(2016)
Germany
Depression/​anxiety
No
No
(Distress)
Yes
NR
NR
Schuurhuizen
et al (2019)
Netherlands Depression/​anxiety
Partial (patient
satisfaction
and cognitive
functioning)
No
(Distress)
Yes, but not significantly
(16% vs. 12%)
NR
Yes (87%)
Nonrandomized unsuccessful
Boyes et al. (2006) Australia
Depression | Anxiety | No
Unmet needs
No
NR
NR
Yes
Mitchell et al.
(2012)
Distress | Depression
| Anxiety
No
NR
NR
Partial
UK
Not significantly
(continued )
125
126
SECTION IV Screening and Assessment in Psychosocial Oncology
Table 17.2. Continued
Author
Country
Screening Target
Screening
Beneficial?
PROs
Improved?
Referrals Improved?
Communication
Improved?
Acceptability
of Screening?
Quality of life
Partial (in
communication
and action)
Yes
NR
Yes, but not
significantly
NR
Pruyn et al. (2004) Netherlands Distress
Yes
NR
Yes, significantly
Yes, but not
significantly
High
Bramsen et al.
(2008)
Netherlands Distress | Quality
of life
Yes
Partial
Yes, significantly
NR
NR
Hilarius et al.
(2008)
Netherlands Quality of life
Partial (in
recognition and
action)
No
Yes, but not significantly
Yes, significantly overall NR
Thewes et al.
(2009)
Australia
Distress | Unmet
needs
Partial (in referral
delay)
No
Yes, but not significantly
NR
Yes
Shimizu et al.
(2010)
Japan
Distress
Partial (in referral)
No/​
Unknown
Yes, significantly
NR
NR
Ito et al. (2011)
Japan
Distress
Partial (in referral
delay)
No
Yes, significantly
NR
NR
Grassi et al. (2011) Italy
Distress
Partial (in referral)
No
Yes, significantly
No
NR
Zemlin et al.
(2011)
Distress
Partial (in
communication)
NR
NR
Yes, significantly
Yes
Nonrandomized Successful
Taenzer et al.
(2000)
Canada
Germany
Gotz et al. recently examined results from a comprehensive cancer
center in Zurich where 4,541 of 11,184 inpatients completed the
DT (40.6%).29 Of these, 45.8% screened above the threshold (≥ 5),
and 48.2% of these at-​risk patients were screened a second time. Of
those that screened positive, only 23.2% wanted a psycho-​oncology
referral compared with 4.8% of those that screened negative. An additional 30% wanted a referral for spiritual or social care. However,
one in five of screened positive patients had already been recognized and referred prior to the screen taking place. In Canada, beginning in 2015, the System Performance Initiative at the Canadian
Partnership Against Cancer (http://​systemperformance.ca) implemented widescale ESAS-​r screening to assess patient-​reported outcomes in over 200,000 patients. Approximately 46.6% were distressed
and 53.5% nondistressed.30 Outcomes have yet to be fully reported,
but preliminary evidence suggests that screening prompted a significant increase in psychosocial social work referrals and palliative care
referrals.31
The American College of Surgeons’ Commission on Cancer (ACS
CoC) adopted routine distress screening as an accreditation requirement in 2015.23 In an early review of 8,409 electronic health records
across 55 American cancer centers, 62.7% followed a prescribed distress screening protocol, although this rate was 43.3% in National
Cancer Institute (NCI)-​designated Cancer Centers.32,33 Screening
rates may be increasing, however. In a new 2019 survey of 27 NCCN
Member Institutions, Geske and Johnson found that 87% of centers
were conducting routine screening for distress. However, follow-​up
screening remained inconsistent, as did documentation of psychosocial screening results and receipt of psycho-​oncology care.34 In the
same sample, only 65% of institutions routinely tracked clinical contacts and referrals, and 70% tracked rates of adherence to screening
protocols.35
Uptake of Help as a Key Barrier
to Screening Success
A number of studies have addressed the important question of how
many cancer patients are offered and then accept psychosocial help.
The current literature suggests that of patients with unmet psychosocial needs, 40% are offered some kind of psychosocial help and
30% are offered a referral to a psycho-​oncology specialist. Clearly
this number is limited by the uneven international provision of
dedicated psycho-​oncology teams, particularly in low-​and middle-​
income countries. Research suggests that 40% of patients who were
offered specific psychosocial interventions are willing to immediately consider this psychosocial help (rather than defer or refuse),
but ultimately only one in three of distressed patients actually attend
for psychosocial help. Several larger studies on this topic offer valuable information. Thalén-​Lindström and colleagues followed 495
patients’ screening using the HADS in Uppsala, Sweden. Fifty-​seven
percent of screen-​positive patients refused further assessment, but
ultimately enhanced screening led to support and treatments for
24% of the screen-​positive patients vs. only 2% in those screened
under usual care conditions.36 Riedl et al. retrospectively analyzed
routine data from 944 cancer outpatients treated at the Department
of Therapeutic Radiology, Innsbruck.37 Only 20% were identified
as distressed, and 42.7% of these wished for psycho-​oncology support. Six percent of patients scoring as nondistressed also wished for
psycho-​oncology support.
Skaczkowski et al. conducted retrospective analysis of cancer
care in Melbourne, Australia, covering 833 patients seen in 2015.38
Eighty-​six percent consented to distress screening. Half scored 4
or higher on the DT. Seventy-​seven percent of distressed patients
CHAPTER 17 Screening and Assessment for Distress
were offered a referral for help, and of the remainder, 83% had a
discussion with their clinician about support care; thus, only 3% received nothing despite a high distress rate. Interestingly, a referral
offer from a clinician was significantly predicted by a higher level
of distress, but acceptance by the patients was significantly related
to lower distress. Also, physical treatment was accepted by 87%, but
emotional support was accepted by only 53%. Reasons for declining
support (Figure 17.4) include male sex, not feeling depressed, perceived overload, and feeling well informed about psychological
support.39,40
Future Directions
Screening for distress in clinical practice remains a challenge.
Despite the successful development and validation of numerous instruments and large-​scale implementation in a number of cancer
centers, several key barriers (Box 17.3) have prevented screening
from being universally approved. Additionally, the evidence base
for the effect of screening implementation on patient outcomes or
referral rates has been disappointing, not necessarily due to inadequacy of distress screening itself, but rather due to a failure to unify
essential components of high-​quality care such as patient follow-​up
or the offer of appropriate treatment options. Without all components of quality of care in place, and without a demonstrable difference to patients seen locally, routine screening is almost always seen
as an unnecessary burden to patients and staff.
The NCCN was among the first to call for routine screening of
distress in patients with cancer in 1999.1 In 2015 the ACS CoC
mandated a systematic protocol for distress screening and referral
that made screening a requirement for cancer center accreditation.5 The success of screening in routine care depends as much on
Box 17.3. Barriers to Screening Success
1. Inaccuracy Barrier
Screening is not 100% accurate and will yield false positives and false
negatives.
2. Double-​Counting Barrier
A proportion of cases identified by screening will already be known
to be distressed and in receipt of care.
3. No Suitable Treatment Barrier
No suitable treatment is available or offered to screen-​
positive
patients.
4. No Follow-​Up Barrier
No adequate follow-​up is available or offered to screen-​positive
patients.
5. Worried Screen-​Negative Persons/​“Worried Well”
Some patients (approximately 10%) who screen negative still want
help regardless of the absence of distress.
6. Burden Barrier
Clinicians will often see screening as too time consuming and results
too difficult to interpret.
7. Interpretation Barrier
Clinicians may have difficulty following the algorithm or interpreting
the score on complex screening tools.
8. Declining Help Barrier
A major proportion of patients who screen positive will decline help
that is available.
acceptability as it does on accuracy. Acceptability is the rate-​limiting
step in screening implementation. This is acceptability not just for
the screening procedure, but also for its scoring interpretation and
any linked follow-​up and treatment. Several studies have reported
that under optimal conditions, it is possible to screen large numbers of patients with few refusals. These large screening programs
are often assisted by funded researchers or investment in computerized touch-​screen terminals. Reception to screening programs
run by frontline clinicians is more mixed. For example, physicians
in Leeds, UK, found quality-​of-​life screening at least quite useful in
43% of encounters but of little use in 30%.41 Mitchell et al. reported
that British cancer clinicians felt screening was useful in only 43%
of assessments and not useful in 36%.42 Zebrack et al. found that between 15% and 35% of clinicians felt screening slowed down clinical
procedures, and between 40% and 80% felt screening helps patients
receive appropriate care.43
Given these limitations, how can screening processes be improved in the future? First, clinicians should not be given the task
of screening without time to perform it, an understanding of how
it might help, and regular feedback of screening success. Second,
patients should not be expected to complete lengthy questionnaires
outside of their first language. Third, screening should focus on
unmet needs that can be addressed. Distress is a red flag, but it is
identification of the underlying cause that is paramount. Not uncommonly, concerns unrelated to cancer contribute to cancer patients’ distress. Finally, having identified unmet needs, clinicians
have a duty of care to attempt to resolve them using the best treatment option available, while keeping the patient informed.
Despite strong recommendations of many professional societies and accreditation agencies, to date very few cancer centers
have adopted routine screening for distress, depression, quality of
life, or unmet needs (Box 17.3). Screening success thus depends
on three key variables: accuracy, acceptability, and high-​quality
follow-​up care. Psychosocial needs remain the most overlooked of
all cancer complications. Psychological assessment and enhanced
distress screening together with appropriate follow-​up and tailored acceptable interventions will help reduce this gap in unmet
psychosocial needs.
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CHAPTER 17 Screening and Assessment for Distress
care problem identification in a comprehensive cancer service.
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with the decline of psychological support in hospitalized patients
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129
18
Assessment, Screening, and Case Finding
for Depression and Anxiety in People
with Cancer
Kristine A. Donovan and Paul B. Jacobsen
Introduction
The development of the field of psychosocial oncology has been
spurred by research using assessment instruments capable of
documenting the negative impact of cancer and its treatment on patients’ emotional well-​being. The need to address these problems has
led to many of the same instruments being used as outcome measures in studies evaluating the benefits of interventions designed to
maintain or improve patients’ emotional well-​being. In both instances, the field has been advanced by having instruments available
that possess good psychometric properties and are suitable for use
with people with cancer. In this chapter, we identify assessment instruments commonly used to assess depression and anxiety in psychosocial oncology research and summarize the evidence regarding
the relative merits of these instruments.
Over the past decade, there has been growing interest in extending
the use of assessment instruments into everyday clinical practice.
This interest has been driven, in part, by clinical practice guidelines
and consensus statements, which recommend that patients’ emotional well-​being be routinely assessed to identify those patients in
need of psychosocial care. These recommendations have stimulated
considerable research examining how well brief assessment instruments function as ways to screen for clinically significant problems
in emotional well-​being and to identify cases of mood and anxiety
disorders. Given these developments, we also identify in this chapter
brief assessment instruments that can be used for depression and
anxiety screening and case finding and summarize the available evidence regarding how well they function when used for these purposes in adults with cancer.
Judging the relative merits of assessment instruments is a complex
task. Among the issues to be considered are (1) the criteria by which
to select instruments to review, (2) the criteria by which to evaluate
the instruments, (3) the evidence to be used as part of the evaluation
process, and (4) the evaluation of the available evidence. Systematic
reviews and meta-​reviews are very useful in this regard given the requirements that these types of reviews clearly specify their selection
and evaluation criteria, the evidence used for evaluation purposes,
and the methods used to form evaluations. Accordingly, in this
chapter, we draw as much as possible on published systematic and
meta-​reviews of assessment, screening, and case finding for depression and anxiety in adults with cancer.
Assessment of Depression
As stated previously, psychosocial oncology has been advanced
through the use of assessment instruments to document cancer’s
negative impact on emotional well-​being as well as the potential
benefits of interventions designed to maintain or improve emotional
well-​being. A 2010 publication by Luckett and colleagues1 remains,
to the best of our knowledge, the most recent systematic review to
evaluate the relative merits of patient-​reported outcome measures
for assessing depression in adults with cancer. The stated purpose
of this review was to identify optimal patient-​reported outcome
measures (PROs) of depression (as well as anxiety and distress) for
evaluating psychosocial interventions for English-​speaking adults
in active treatment for cancer. The authors searched publications
appearing between 1999 and 2009 to identify all PROs used to assess depression, anxiety, and distress in randomized controlled trials
(RCTs) enrolling English-​speaking cancer patients. This process resulted in the identification of 30 instruments. These measures then
underwent a review that excluded those (1) not suitable for people
with any type or stage of cancer, (2) in which one-​third or more of
the items were considered to be confounded by cancer or its treatment, and (3) for which there were no published data on reliability
and validity in an English-​speaking cancer sample.
The measures remaining, including 10 instruments assessing
depression, were then evaluated on the following eight criteria
based on data compiled from relevant articles, websites, and manuals: validity, reliability, ability to identify treatment effects in RCTs,
criterion validity against a diagnostic interview, availability of comparison data, number of psychological constructs, length, and ease
CHAPTER 18 Assessment, Screening, and Case Finding for Depression and Anxiety in People with Cancer
of administration and cognitive burden. Scores (0, 5, or 10) were assigned for each criterion based on the extent to which the available
evidence suggested the measure possessed favorable features, with
higher scores indicative of more favorable features. Finally, scores for
four of the criteria (validity, reliability, ability to identify treatment
effects, and criterion validity against a diagnostic interview) were
weighted (i.e., were multiplied by) 1.5, while the remainder were
weighted 1.0. A summary of the weighted scores for the 10 measures
assessing depression appears in Table 18.1. It should be noted that
several of these measures feature multiple subscales, one of which
measures depression (e.g., Hospital Anxiety and Depression Scale
[HADS]), while others only measure depression (e.g., Center for
Epidemiological Studies Depression Scale [CES-​D]).
As shown in Table 18.1, the HADS earned the highest overall
score among measures assessing depression followed by the Profile
of Mood States-​37 (POMS-​37) and the CES-​D. The HADS’ highest
overall score reflects the abundant evidence of its psychometric
properties and its efficiency in assessing depression, anxiety, and distress using only 14 items. The HADS also scored highly for the availability of comparison data and its ability to identify treatment effects
in RCTs. The HADS Depression Scale (HADS-​D) consists of seven
of the 14 HADS items. The review notes that all seven items assess
emotional experiences consistent with major depressive disorder.
The HADS is notable for its deliberate omission of somatic items
designed to avoid possible confounding of psychological symptoms
with disease-​or treatment-​related symptoms.
The POMS-​37 is an unofficial short form of the 65-​item POMS
that was developed specifically for use with cancer patients to reduce
test burden. It scored consistently well on most measures of psychometric properties. In contrast, it scored poorly in terms of criterion
validity due largely to limited evidence of its criterion validity relative to a diagnostic interview. The Depression-​Dejection subscale
makes up eight of the 37 items.
The CES-​D also scored consistently well on most measures of psychometric properties, but like the POMS-​37 scored poorly in terms
of criterion validity due to limited evidence. Another feature that
counted against the CES-​D is that it requires 20 items to assess a
single construct (i.e., depression). Although short forms of the CES-​
D have been developed, they have not been used widely in studies of
cancer patients.
The authors’ decision to exclude measures in which one-​third or
more of the items could be confounded by symptoms or side effects
(e.g., loss of appetite) resulted in the exclusion of at least two widely
used measures of depression: the Beck Depression Inventory-​
II (BDI-​
II) and the Patient Health Questionnaire-​
9 (PHQ-​
9).
Although concerns have been raised that a measure’s performance
characteristics may be compromised by the presence of somatic content, results of two studies using the PHQ-​9 challenge the view that
items assessing somatic symptoms reduce a measure’s accuracy in
identifying depression in the context of cancer.2,3 Accordingly, future reviews of instruments to assess depression in cancer should
Table 18.1. Weighted Scores for Patient-​Reported Outcome Measures Assessing Depression and Anxiety
Criterion
Validity
Summary Ratings
Reliability
Ability to
Identify
Treatment
Effects
Criterion
Validity
Comparison
Data
No. of
Constructs
Length
Ease and
Burden
Raw
Score (/​
80)
Weighted
Score (/​100)
Weight
1.5
1.5
1.5
1.5
1.0
1.0
1.0
1.0
HADS
(D, A)
7.5
7.5
15
7.5
10
10
10
10
65
77.5
POMS-​37
(D, A)
15
7.5
7.5
0
5
5
10
10
65
77.5
CES-​D
(D)
7.5
7.5
15
15
5
0
0
5
40
55
POMS-​65
(D, A)
7.5
7.5
15
0
5
5
5
10
45
55
BSI-​18/​53
(D, A)
7.5
0
7.5
0
10
5
10
10
45
50
SCL-​90-​R
(D, A)
7.5
7.5
7.5
0
5
5
5
10
40
47.5
GHQ-​28
(D, A)
0
0
0
7.5
5
5
10
10
35
37.5
CES-​D-​15
(D)
7.5
7.5
0
0
5
0
5
5
25
30
MHI-​38
(D, A)
0
0
0
0
5
5
10
5
25
25
C-​SOSI
(D)
0
7.5
0
0
0
0
10
10
25
27.5
Adapted from Luckett et al.1
HADS = Hospital Anxiety and Depression Scale; POMS = Profile of Mood States; CES-​D = Center for Epidemiologic Studies Depression Scale; BSI = Brief Symptom Inventory;
SCL = Symptom Checklist; GHQ = General Health Questionnaire; MHI = Mental Health Inventory; C-​SOSI = Calgary Symptoms of Stress Inventory; D = Depression measure; A = Anxiety
measure.
131
132
SECTION IV Screening and Assessment in Psychosocial Oncology
consider also evaluating the relative merits of measures that incorporate somatic content.
Assessment of Anxiety
Using the same search and exclusion procedures described earlier,
the review by Luckett and colleagues1 yielded seven measures of
anxiety (see Table 18.1). These measures were evaluated and rated
based on the same criteria used with the depression measures. All
seven of the anxiety measures feature multiple subscales, one of
which measures anxiety. The list does not include any measures that
only assess anxiety.
As with the depression measures, the two top-​scoring anxiety
measures are the HADS and the POMS-​37. The third highest scored
measure is the full-​length POMS-​65. Strengths of the HADS have
been described previously. The HADS Anxiety Scale makes up seven
of the 14 HADS items. The review noted that three of these items assess emotional experiences as distinct from generalized anxiety disorder, thus raising concerns about criterion validity. The strengths
and weaknesses of the POMS-​37, which also apply to the POMS-​65,
have been described previously. The Tension-​Anxiety subscale of the
POM-​37 consists of six items and the corresponding subscale of the
POMS-​65 consists of nine items.
One additional anxiety measure merits discussion. The State-​Trait
Anxiety Inventory (STAI) consists of 20 items assessing trait anxiety and 20 items assessing state anxiety. It was excluded from full
evaluation by Luckett and colleagues1 based on a lack of sufficient
evidence of its validity and reliability despite the STAI having been
used in 30 RCTs identified by the authors. Additional research conducted subsequent to this review may suggest a reconsideration of
the usefulness of the STAI in assessing anxiety in people with cancer.
Screening and Case Finding for Depression
In 2015, Wakefield and colleagues4 published a meta-​review (i.e., a
review of reviews) evaluating the strengths and weaknesses of depression measures used for screening and case finding in adults
diagnosed with cancer. Consistent with prior work, screening was
defined as the ability to rule out patients without depression with
minimal false negatives, and case finding was defined as the ability
to rule in patients with depression with minimal false positives.
Systematic and narrative reviews published in English between 1999
and 2014 were eligible for inclusion. Measures of general distress
were excluded unless they were specifically evaluated as screening
or case finding methods for depression. The search yielded 12 systematic and seven narrative reviews that encompassed 372 original
studies and assessed more than 50 depression measures. The authors
note that 11 of the 12 systematic reviews met at least 20 of the 27
Preferred Reporting Items for Systematic Review and Meta-​analyses
(PRISMA) criteria. Ten reviews assessed the suitability of depression
measures for screening and three reviews assessed their suitability
for case finding. As part of their evidence synthesis, the authors
summarize the positive and negative features of the most commonly
reviewed and recommended measures of depression.
Similar to assessment, the HADS was the most widely evaluated measure. Positive features identified include its strength as
a screening measure. Limitations include its weakness as a case
finding measure and the variability in the recommended cut-​points
reported in the literature. Additionally, there was concern as to
which HADS scale or subscale (HADS-​Total, HADS-​A, or HADS-​
D) is most suitable because different reviews have evaluated different
combinations of HADS scores. Similar to assessment, the BDI or its
variations (BDI-​II) and the CES-​D have also been widely evaluated.
Strengths of BDI-​based measures include their adequate screening
and case finding performance. Weaknesses include the length of the
full measure (21 items) and its extended recall period (two weeks)
that may limit use in certain contexts. Strengths of the CES-​D include its adequate performance as a screening measure and the ease
of completion. Weaknesses include concerns about its suitability for
geriatric patients given the scope of item content.
Two additional measures mentioned in the meta-​review merit
discussion. The Distress Thermometer (DT) is a single-​item measure
that, although designed to screen for distress, has been evaluated as
a depression screening measure. The authors note that one review
included in their meta-​review concluded that the DT performed adequately as a screening method for depression. However, another
review concluded that, given the high rate of false negatives, the DT
and other ultra-​short instruments should not be used in isolation in
screening for depression. The PHQ-​9 is a nine-​item measure developed originally for use in primary care and obstetrics-​gynecology
settings to screen for major depressive disorder. The item content
corresponds with the diagnostic criteria for major depressive disorder. Although the PHQ-​9 was noted to have strong psychometric
properties in medical populations, it has been rated poorly in prior
reviews based on concerns about the two-​week recall period, the
presence of somatic content, and reportedly low reliability and validity in patients with cancer. It should be noted that more recent
research suggests that the PHQ-​9 possesses desirable properties as
a depression screening and case finding instrument in people with
cancer.4
The picture that emerges from this meta-​review is that there is no
single measure for which unqualified support was evident and that
no single measure is ideal for all types of patients and time points.
Additionally, caution is urged regarding the omission of somatic
symptoms since omission of such content does not appear to substantially improve the screening performance of common depression measures.
Screening and Case Finding for Anxiety
In 2009, Vodermaier and colleagues published a systematic review
designed to identify and evaluate instruments used to screen for
emotional distress in cancer patients.5 The authors systematically
searched for published English-​language studies using terms that
were consistent with the definition of distress as “a state of negative
affect that is suggestive of affective disorders (i.e., minor or major depressive disorder and dysthymia), anxiety disorders, and adjustment
disorders (depressive, anxious, or mixed).” Studies were included if
they attempted to validate an interviewer-​administered or standardized self-​administered instrument in a sample of cancer patients.
The review was further restricted to studies evaluating measures
consisting of 50 or fewer items. This process led to the identification of 33 instruments, including instruments designed to measure
CHAPTER 18 Assessment, Screening, and Case Finding for Depression and Anxiety in People with Cancer
anxiety alone or both depression and anxiety. As previously noted,
in their systematic review, Luckett and colleagues1 also identified instruments used to evaluate anxiety alone or with depression in RCTs
of psychosocial interventions in cancer patients. For purposes of this
chapter, we have combined findings from both reviews, selecting
among the identified instruments those that were evaluated in more
than one study or RCT and are generally considered to be suitable
for screening and case finding for anxiety, either alone or in combination with depression.
The HADS was recommended by both Luckett et al.1 and
Vodermaier et al.5 as a screener when anxiety or mixed affective disorders are of concern based on the strength of the large body of evidence for its psychometric properties and its length. Both reviews
noted the evidence for its superiority in screening for anxiety over
screening for depression but ultimately concluded that the HADS-​
D is superior to the HADS-​A and HADS-​T in ruling out, and similar to in ruling in, cases of mixed affective disorders (depression,
anxiety, adjustment disorders combined). This conclusion was supported by findings of a 2011 systematic review and meta-​analysis
by Vodermaier et al.6 that examined the accuracy of the HADS as
a screening tool for mental disorders (not specifically anxiety disorders) and depressive disorders alone compared to a structured or
semistructured clinical interview. Based on the review and pooled
validation of 28 studies, they concluded that the HADS-​A was inferior to the HADS-​T and HADS-​D subscale in screening for depression and for any mental disorders. Both subscales had lower
diagnostic accuracy than the total scale; this may reflect the fact that
cancer patients often have symptoms indicative of adjustment disorders where symptoms include a mix of depression and anxiety. As
noted in all three reviews, optimal cutoff scores for the HADS have
varied across studies, making its screening and diagnostic accuracy equally variable. Nevertheless, studies that have compared the
HADS with other candidate measures as well as structured clinical
interviews suggest the HADS performs better or comparably with
other measures.
The POMS-​37 was also recommended by Luckett et al.1 based
on the evidence for its validity and responsiveness. Items from the
tension-​anxiety scale of the POMS-​37 (and POMS-​65) were noted
to closely resemble clinical diagnostic criteria though with an emphasis on cardinal symptoms of anxiety rather than the full range of
possible symptoms.
Two additional measures warrant attention. The Post Traumatic
Stress Disorder Checklist (PCLC) was the only anxiety-​specific instrument evaluated by Vodermaier et al.5 The PCLC is a 17-​item
measure that corresponds to key symptoms of posttraumatic stress
disorder (PTSD). The instrument can be modified to fit a specific
timeframe and any (nonmilitary) traumatic event. Although data
regarding its use are limited, its psychometric properties are considered adequate.
The Generalized Anxiety Disorder scale (GAD-​7) is a seven-​item
instrument that screens for typical symptoms of anxiety disorders in
the previous two weeks. It includes two items from the PHQ-​4A and
five additional items that facilitate screening for GAD. While anxiety
disorders include phobias, panic disorder, social anxiety, and generalized anxiety, it is recommended that cancer patients be screened
for GAD specifically. This is because GAD is the most common anxiety disorder and frequently occurs with other mood or anxiety disorders. A recent study by Esser et al.7 used data from a multicenter
study of more than 2,000 cancer patients to examine the diagnostic
accuracy of the GAD-​7 and HADS-​A in detecting GAD compared
to the Composite International Diagnostic Interview for Oncology,
a standardized interview for cancer patients. Overall accuracy as
measured by the area under the receiver operating characteristics
curve for the GAD-​7 and HADS-​A were identical and adequate.
Notably, the choice of optimal cutoff points for both measures differed from the recommended cutoffs. Sensitivity and specificity for
identifying GAD was optimal at >7 for the GAD-​7 rather than the
recommended >10, and at >8 rather than the recommended >11
for HADS-​A. The researchers suggest that high levels of anxiety in
cancer patients may not be indicative of pathological GAD and that
the diagnostic accuracy and optimal cutoffs of both the GAD-​7 and
the HADS-​A may be different in cancer patients.
Clinical Practice Guideline Recommendations
for Depression and Anxiety Screening
In this section, we review recommendations for depression and anxiety screening contained in three clinical practice guidelines: the
Pan-​Canadian practice guideline for screening, assessment, and
management of psychosocial distress, depression, and anxiety in
adults with cancer developed by the Canadian Partnership against
Cancer and the Canadian Association of Psychosocial Oncology;8 an
adaptation of the Pan-​Canadian practice guideline developed by the
American Society of Clinical Oncology9 (ASCO); and guidelines for
the screening, assessment, and management of anxiety and depression in adults cancer patients developed for the Psycho-​oncology
Co-​operative Research Group (PoCoG) in Australia.10
The Pan-​Canadian guideline was first issued in 2010 and updated
in 2015.8 It is based on a combination of expert panel recommendations, adaptation of existing guidelines, and a systematic review
of evidence on management of distress, depression, and anxiety.
A notable feature of this guideline is the identification of the source
and strength of evidence for key recommendations. In general, recommendations related to screening were rated as being based on
moderate-​or low-​quality evidence. Regarding depression-​specific
screening measures and processes, the guideline recommends an
initial screening using any of three brief screeners: the depression
item from the Edmonton Symptom Assessment System-​revised
(ESAS-​r), the DT, or the PHQ-​2. For patients who score at moderate or severe levels on the ESAS-​r or DT (i.e., >3), a more focused
assessment is recommended that may include administration of
the full PHQ-​9 and evaluation of diagnostic criteria for depressive
disorders. Subsequent triage to different clinical care pathways involves a determination of whether depressive symptoms are minimal, moderate, or more severe based in part on whether PHQ-​9
scores are 1 to 7, 8 to 14, and 15 or greater, respectively. Regarding
anxiety-​specific screening measures and processes, the guideline
recommends an initial screening using the anxiety item from the
ESAS-​r. For patients who score at moderate or severe levels (i.e.,
>3), a more focused assessment is recommended and may include
administration of the GAD-​7. Subsequent triage to different clinical care pathways involves a determination of whether anxiety
symptoms are minimal, moderate, or more severe based in part
on whether GAD-​7 scores are 0 to 9, 10 to 14, and 15 or greater,
respectively.
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The ASCO adaptation of the Pan-​Canadian guideline was published in 2014.9 The adaptation was conducted by an expert panel
with multidisciplinary representation. Although very similar to the
Pan-​Canadian guideline, several differences are apparent. For example, instead of ESAS-​r items, the ASCO adaptation recommends
initial screening with the PHQ-​2 for depression (followed by the
full PHQ-​9 for patients who score >1) and with the full GAD-​7 for
anxiety. PHQ-​9 and GAD-​7 cut-​points identical to those described
in the Pan-​Canadian guideline are then recommended to triage patients into different care pathways based on whether they have mild,
moderate, or more severe symptomatology. It should be noted that
although the focus is on the PHQ-​9 and the GAD-​7, both the Pan-​
Canadian guideline and the ASCO adaption identify several other
measures of depression (e.g., CES-​D) and anxiety (e.g., STAI) that
can be used to classify symptoms as mild, moderate, or severe.
The clinical pathways described in the Australian guidelines
were published in 2015.10 They were developed based on a review
of existing guidelines, systematic reviews, and meta-​analyses relevant to screening, assessment, and management of anxiety and depression in cancer patients and the general public; interviews with
key multidisciplinary staff; an online Delphi process that engaged
PoCoG members; and input from a multidisciplinary panel. Similar
to the Pan-​Canadian guideline, these guidelines recommend initial
screening for depression and anxiety using the ESAS-​r and the DT.
If potential depression or anxiety is identified using either of these
instruments based on cutoff scores (ESAS depression item >1; ESAS
anxiety item >2; DT >3), the guidelines recommend administration of a more detailed screening tool such as the HADS. Should
scores on either the HADS anxiety or depression subscales exceed
7, a formal assessment is then recommended to confirm caseness of
depression or anxiety. Subsequent triage to care pathways is based
on clinical assessment as to whether symptoms are minimal, mild,
moderate, severe, or very severe.
This brief review illustrates similarities and differences in depression and anxiety screening recommendations across these three
clinical practice guidelines. Similarities include recommendations
for a two-​stage screening process in which administration of a one-​
or two-​item measure is used to decide whether administration of
a longer screening measure is warranted. Differences include the
specific measures recommended for the initial and subsequent
screening. While the Pan-​Canadian and Australian guidelines include recommendations to use ESAS-​r items or the DT as part of
initial screening, the ASCO adaptation focuses on use of the PHQ-​2
based on a view that the ESAS-​r is not widely used in the United
States. This decision raises questions about the extent to which practical considerations (i.e., regional preferences) should guide measure
selection relative to other factors (i.e., psychometric considerations
and screening objectives). Regarding additional screening, the major
difference is that the Pan-​Canadian guideline and the ASCO adaptation focus on use of the PHQ-​9 and GAD-​7, while the Australian
guidelines focus on use of the HADS. Although all of these measures have demonstrated their utility as screeners, they differ notably
in item content. The PHQ-​9 and GAD-​7 feature items consistent
with diagnostic criteria for mood and anxiety disorders, whereas the
HADS features items designed to assess nonsomatic symptoms of depression and anxiety. These two different approaches reflect a major
difference in how to approach screening. That is, should screening
be conducted with measures of emotional distress developed specifically for medical populations (i.e., the HADS) or with measures
developed specifically to capture symptoms of mental disorders in
a wide range of populations? The answer would seem to lie in research that directly compares these two approaches in routine clinical practice. For example, a randomized trial could be conducted
to examine whether differences occur in referral for full assessment
and assignment to pathways when clinics employ the HADS versus
the PHQ-​9/​GAD-​7 and, if so, whether these differences have implications for the overall management of depression and anxiety in the
patients screened.
Future Directions
This chapter has provided detailed information about the relative
merits of several commonly used English-​language instruments for
assessment, screening, and case finding for depression and anxiety
in cancer patients. Based on the evidence presented, several conclusions can be drawn and future directions suggested.
First, the CES-​D and HADS are the instruments that consistently
received positive ratings across existing reviews. Among their notable features are the favorable ratings they earned for reliability,1,5
validity,1 availability of comparison data,1 ability to identify treatment effects,1 screening performance,1,5 and overall rating.1,5 That
said, these two instruments are not without their weaknesses, especially when used for screening purposes. As previously noted,
while the depression subscale of the HADS possesses good accuracy as a screening tool for depression, the performance of the anxiety subscale has been found to be inferior.6 Similarly, the HADS
has performed reasonably well in identifying individuals without
mental disorders but is not recommended to be used alone to identify individuals with suspected mood, anxiety, or mixed mental
disorders.11 Thus, while these instruments have demonstrated psychometric rigor and some degree of diagnostic accuracy, research is
still needed to identify those instruments optimally suited for assessment, screening, and case finding for depression and anxiety.
Second, it is clear that no single instrument can be recommended
for all possible applications. Clinicians and researchers must make
choices depending on the circumstances for which they intend to
use an instrument. In certain instances, the time available to complete an instrument will dictate the use of a very brief instrument
(e.g., ESAS-​r). In other instances, such as an intervention study, the
demonstrated ability of an instrument to identify treatment effects
(e.g., CES-​D) may be the paramount consideration. In yet other
instances, the demonstrated ability of an instrument to screen accurately for mental disorders (e.g., PHQ-​9) may drive instrument
selection. Accordingly, careful consideration of an instrument’s capabilities in relation to the intended use(s) should be the prime factor
guiding instrument selection. Thus, research is needed to fully elucidate the clinical-​and research-​related factors that may systematically guide the selection of instruments for assessment, screening,
and case finding.
Third, existing systematic reviews of depression and anxiety assessment and screening instruments are characterized by a number
of features that limit their utility. These features include lack of consistency across reviews in the methods used to select instruments
CHAPTER 18 Assessment, Screening, and Case Finding for Depression and Anxiety in People with Cancer
for evaluation, the features of each instrument evaluated, and the
criteria used to evaluate instruments on those features. With respect
to future directions, ongoing, systematic efforts to introduce greater
standardization in the reporting of psychometric properties of assessment instruments should facilitate more consistent approaches
in future systematic reviews. One effort notable in this regard is the
Consensus-​based Standards for the Selection of Health Measurement
Instruments (COSMIN) initiative, which has developed a standardized taxonomy of instrument properties, along with standardized
definitions and ratings.12,13 Another important limitation of many
existing systematic reviews is their exclusive focus on studies published in English, based on instruments written in English. With the
ever-​increasing international scope of psychosocial oncology, information about instruments available in languages other than English
is increasingly needed. Beyond information about availability, clinicians and researchers need critical appraisals of the methods used
to create versions in other languages. That is, information is needed
about the extent to which versions in other languages have been created using recommended procedures for translation and cultural
adaptation of patient-​reported outcome measures.14 Once created in
other languages, the new versions then also need to be revalidated
because it cannot be assumed that an instrument’s properties in one
language and cultural group carry over to its properties in another
language and cultural group.15
A final conclusion is that clinicians and researchers need to stay
abreast of ongoing work that is likely to influence future recommendations for depression and anxiety assessment and screening
in cancer patients. Along these lines, additional research is needed
to clarify the utility of existing assessment instruments, such as the
State Trait Anxiety Inventory16 and the Beck Depression Inventory
II,17 which have received limited attention to date in the psychosocial oncology literature. Future recommendations may also be influenced by research evaluating the utility of several newly developed
assessment and screening instruments when administered to cancer
patients. An important development in this regard is the Patient-​
Reported Outcomes Measurement Information System (PROMIS)
initiative.18 As part of this effort, item banks were developed for a
number of constructs, including anxiety and depression.19 These
item banks have been calibrated so that they can be used to create
scales of varying length, including scales in which items are selected
and presented to individuals based on their responses to previous
items. This approach, known as computer-​
adaptive testing, is
likely to grow in importance since it has the potential to reduce the
number of items that need to be administered while simultaneously
reducing measurement error.20 Another notable feature of PROMIS
measures is the availability of cross-​walk tables that permit estimation of scores on the CES-​D, the BDI-​II, and the PHQ-​9 based on
PROMIS depression scores as well as estimation of scores on the
GAD-​7, Mood and Anxiety Symptom Questionnaire (MASQ), and
Positive and Negative Affect Scale (PANAS) based on PROMIS anxiety scores.21,22 Many of these advances, which reflect the application of item response theory to development and administration of
patient-​reported outcomes measures, will spur future research and
have the potential to dramatically change future approaches to assessment, screening, and case finding for depression and anxiety in
people with cancer.
REFERENCES
1. Luckett T, Butow PN, King MT, et al. A review and recommendations for optimal outcome measures of anxiety, depression, and
general distress in studies evaluating psychosocial interventions
for English-​speaking adults with heterogeneous cancer diagnoses.
Support Care Cancer. 2010;18:1241–​1262.
2. Mitchell AJ, Lord K, Symonds P. Which symptoms are indicative
of DSMIV depression in cancer settings? An analysis of the diagnostic significance of somatic and non-​somatic symptoms. J
Affective Dis. 2012;138:137–​148.
3. Jones SM, Ludman EJ, McCorkle R, et al. A differential item function analysis of somatic symptoms of depression in people with
cancer. J Affective Dis. 2015;170:131–​137.
4. Wakefield CE, Butow PN, Aaronson NA, et al. Patient-​reported
depression measures in cancer: a meta-​review. Lancet Psychiatry.
2015;2:635–​647.
5. Vodermaier A, Linden W, Siu C. Screening for emotional distress
in cancer patients: a systematic review of assessment instruments.
J Natl Cancer Inst. 2009;101:1464–​1488.
6. Vodermaier A, Millman RD. Accuracy of the Hospital Anxiety
and Depression Scale as a screening tool in cancer patients: a
systematic review and meta-​
analysis. Support Care Cancer.
2011;19:1899–​1908.
7. Esser P, Hartung TJ, Friedrick M, et al. The Generalized Anxiety
Disorder Screener (GAD-​7) and the anxiety module of the Hospital
and Depression Scale (HADS-​A) as screening tools for generalized anxiety disorder among cancer patients. Psychooncology.
2018;27:1509–​1516.
8. Howell D, Keshavarz H, Esplen MJ, et al. A Pan Canadian Practice
Guideline: Screening, Assessment and Care of Psychosocial Distress,
Depression, and Anxiety in Adults with Cancer. Toronto: Canadian
Partnership Against Cancer and the Canadian Association of
Psychosocial Oncology; 2015.
9. Andersen BL, DeRubeis RJ, Berman BS, et al. Screening, assessment, and care of anxiety and depressive symptoms in adults with
cancer: an American Society of Clinical Oncology guideline adaptation. J Clin Onc. 2014;32:1605.
10. Butow P, Price MA, Shaw JM, et al. Clinical pathway for the
screening, assessment and management of anxiety and depression
in adult cancer patients: Australian guidelines. Psychooncology.
2015;24:987–​1001.
11. Mitchell AJ, Meader N, Symonds P. Diagnostic validity of the
Hospital Anxiety and Depression Scale (HADS) in cancer and palliative settings: a meta-​analysis. J Affective Dis. 2010;126:335–​348.
12. Mokkink LB, Terwee CB, Patrick DL, et al. The COSMIN study
reached international consensus on taxonomy, terminology, and
definitions of measurement properties for health-​related patient-​
reported outcomes. J Clin Epidemiol. 2010;63:737–​745.
13. Terwee CB, Mokkink LB, Knol DL, Ostelo RWJG, Bouter LM, de
Vet HCW. Rating the methodological quality in systematic reviews of studies on measurement properties: a scoring system for
the COSMIN checklist. Qual Life Res. 2012;21:651–​657.
14. Wild D, Grove A, Martin M, et al. Principles of good practice for the
translation and cultural adaptation process for patient-​reported
outcomes (PRO) measures: report of the ISPOR task force for
translation and cultural adaptation. Value Health. 2005;8:94–​104.
15. Eremenco SL, Cella D, Arnold BJ. A comprehensive method for
the translation and cross-​cultural validation of health status questionnaires. Eval Health Prof. 2005;28:212–​232.
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16. Spielberger CD, Gorsuch RL, Lushene R, Vagg PR, Jacobs
GA. Manual for the State-​
Trait Anxiety Inventory. Palo Alto,
CA: Consulting Psychologists; 1983.
17. Beck AT, Steer RA, Brown GK. BDI-​II Manual. San Antonio,
TX: Psychological Corporation; 1996.
18. Cella D, Riley W, Stone A, et al. The Patient-​Reported Outcomes
Measurement Information System (PROMIS) developed and
tested its first wave of adult self-​reported health outcome item
banks: 2005–​2008. J Clin Epidemiol. 2010;63:1179–​1194.
19. Pilkonis PA, Choi SW, Reise SP, et al. Item banks for measuring emotional distress from the Patient-​Reported Outcomes
Measurement Information System (PROMIS): depression, anxiety, and anger. Assessment. 2011;8:263–​283.
20. Weiss DJ. Computerized adaptive testing for effective and efficient
measurement in counseling and education. Meas Eval Couns Dev.
2004;37:70–​84.
21. Choi SW, Schalet B, Cook KF, Cella D. Establishing a common
metric for depressive symptoms: linking the BDI-​II, CES-​D, and
PHQ-​9 to PROMIS Depression. Psychol Assess. 2014;26:513–​527.
22. Schalet BD, Cook KF, Choi SW, Cella D. Establishing a common
metric for self-​reported anxiety: linking the MASQ, PANAS, and
GAD-​7 to PROMIS Anxiety. J Anxiety Disord. 2014;28:88–​96.
19
Screening for Delirium and Dementia
in the Cancer Patient
Christian Bjerre-​Real, James C. Root, Yesne Alici, Julia A. Kearney,
and William S. Breitbart
Introduction
Cognitive syndromes are commonly encountered among cancer
patients at all age groups. Although aging is an important risk
factor for cognitive disorders, in oncology settings there are additional risk factors, including primary or metastatic brain tumors,
medical comorbidities, cancer treatments, depression, and anxiety, that place all age groups at risk for varying degrees of cognitive impairment at different stages of illness trajectory. Delirium, an
acute-​onset and common cognitive syndrome among hospitalized
cancer patients, has been shown to increase risk of long-​term cognitive impairment. Delirium can be seen in acutely ill cancer patients across the lifespan. Patients with underlying cognitive deficits
are at increased risk for delirium. It is strongly recommended to
routinely screen for delirium in inpatient oncology settings to
identify patients with delirium in a timely manner, to treat underlying etiologies, and to prevent adverse outcomes associated with
prolonged delirium. Dementia syndromes, referred to as major
neurocognitive disorders in the Diagnostic and Statistical Manual
of Mental Disorders, 5th edition (DSM 5),1 are routinely screened
for as part of the comprehensive geriatric assessment among older
cancer patients. Patients with cognitive deficits may not be able to
carry out activities of daily living, such as medication maintenance,
food preparation, and transportation. Treatment adherence, vigilance in monitoring and reporting of cancer and cancer treatment–​
related symptoms, and the ability to make informed decisions on
cancer treatment options necessitate intact cognitive functioning.
Therefore, screening for cognitive syndromes among cancer patients is an important part of initial assessment, particularly in
high-​risk populations.
This chapter will provide a comprehensive review of the
screening and assessment measures used to identify and assess patients with delirium and dementia. A brief overview of common
dementia syndromes is also included as relevant to psycho-​
oncologists caring for older adults with cancer. An overview of
cancer and cancer treatment–​related cognitive impairment is provided in Chapter 36.
Delirium
Delirium is the most common cognitive syndrome encountered
among hospitalized cancer patients. The prevalence of delirium
ranges between 25% and 40% among cancer patients, with higher
rates (i.e., up to 85%) occurring among the terminally ill.2 A detailed
overview of delirium in cancer patients is provided in Chapter 44. In
the following sections, we review screening and assessment of delirium among cancer patients, along with a review of the screening
and assessment tools available for use in cancer patients.
Delirium: Screening and Assessment
Delirium is an acute change in level of alertness, awareness, attention,
cognition, and behavior secondary to a general medical condition
or medications. Sleep-​wake cycle changes, disordered thought process, incoherent speech, psychomotor retardation or agitation, and
perceptual disturbances are associated features of delirium. Patients
with psychomotor retardation are frequently mistaken for suffering
from depression by clinicians. Emergent psychiatry consults for patients with suicidal ideation not uncommonly reveal cases with unrecognized delirium. Cognitive disturbances in delirium can consist
of myriad deficits, including disorientation, executive dysfunction,
memory impairment, visuospatial deficits, and language disturbances. History obtained from family, staff, and other caregivers is
critical for delirium diagnosis. Acute onset and fluctuating course
are the main distinguishing features of delirium from dementia and
other cognitive syndromes.
Physical exam should focus on signs of infection, sepsis, dehydration, hypoxia, withdrawal states, and intoxication. Examination
for focal neurological findings, myoclonus, and frontal release signs
are the essential components of neurological exam in patients with
delirium.
Laboratory testing including comprehensive metabolic panel,
complete blood count, vitamin B12 and thiamine levels, thyroid
function tests, urinalysis, blood cultures, and brain imaging should
be considered, based on history and physical examination findings,
to identify underlying medical etiologies. Review of the medication
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SECTION IV Screening and Assessment in Psychosocial Oncology
list and recent dose changes and comparison with home medication
lists should be completed to rule out delirium due to medications.
An electroencephalogram (EEG) may be helpful in diagnosing
nonconvulsive status epilepticus that may solely present with acute-​
onset mental status changes. Generalized slowing on EEG can be
helpful in differentiating delirium from depression, where such a
finding would not be expected. Patients with dementia can also present with generalized slowing findings on EEG.
The gold standard diagnosis of delirium is the clinician’s assessment based on the DSM 5 delirium diagnostic criteria.1 There are
several assessment and rating scales developed specifically for delirium, each with its own strengths and weaknesses (see Table
19.1).3,4 The Confusion Assessment Method (CAM), developed by
Inouye and colleagues in 1990, provides a screening algorithm with
four items (acute onset and fluctuating course, inattention, and either disorganized thinking or altered level of consciousness) that
can be used by nurses and others with less advanced psychiatric
training.5 However, the sensitivity of the CAM can be significantly
affected by the experience of the user. Estimated administration
time is under five minutes. The CAM is not useful in assessing the
severity of delirium, but the CAM-​S, a recently developed version of
the CAM, can be used to assess delirium severity among medically
ill older adults.6 At our institution, the CAM is routinely administered by bedside nurses every shift to all adult patients to screen for
delirium. Ely and colleagues developed the Confusion Assessment
Method for ICU (CAM-​ICU) for use in nonverbal patients, such
Table 19.1. Overview of Commonly Used Delirium Screening and Assessment Scales
Confusion Assessment Method
(CAM)5
♦
♦
♦
♦
♦
♦
♦
Delirium Rating Scale-​R-​989
♦ Delirium Rating Scale-​R-​98 was developed by Trzepacz and colleagues to address shortcomings of the Delirium
♦
♦
♦
♦
♦
♦
Memorial Delirium Assessment
Scale (MDAS)11,35
♦
♦
♦
♦
♦
♦
♦
♦
♦
♦
Nursing Delirium Screening Scale
(Nu-​DESC)31
Rating Scale, including the inability to distinguish between subtypes of delirium, lack of a separate item for attention
deficits, and lack of clarification for “clouding of consciousness”
Includes 16 clinician-​rated items, 13 for severity and 3 for diagnosis. The rating is applicable to the preceding 24 hours
It successfully differentiates delirium from dementia, depression, and schizophrenia
Administered by trained clinicians
It has excellent psychometric properties
It is mostly used for phenomenological and treatment research purposes
It has been validated in different languages
MDAS assesses for the subtype and severity of delirium
MDAS has 10 items, rated from 0 (none) to 3 (severe), with a maximum possible score of 30
A score of 13 has been recommended as a cutoff for establishing the diagnosis of delirium in oncology settings
A cutoff score of 7 has yielded the highest sensitivity and specificity rates for delirium diagnosis in palliative care
settings25
It has excellent psychometric properties
It distinguishes between patients with delirium, dementia, or no cognitive impairment
It has been validated in a number of different languages
It is the most widely used delirium assessment scale in oncology and palliative care settings
Physician-​rated
Takes about 10–​15 minutes to administer
♦ Nu-​DESC has been adapted from a former delirium assessment tool, namely the Confusion Rating Scale
♦ Composed of 5 items including orientation, behavior, communication, perceptual disturbances, and psychomotor
♦
♦
♦
♦
♦
♦
Delirium Observation
Scale (DOS)32
Most commonly used delirium screening instrument in general medical settings, specifically among older adults
Four-​item algorithm can be used to quickly screen for delirium
Requires well-​trained raters
Excellent psychometric properties when used by well-​trained raters
Cognitive testing is required to assess the cognitive items of the scale
Validated for use in a number of languages
For severity assessment, CAM-​S has been developed
retardation
It allows for continuous symptom assessment
It has been validated for use in oncology settings
Administered by nursing
Takes about 1–​2 minutes
It has good psychometric properties
It has been validated in other languages
♦ Adapted from the Delirium Observational Screening Scale
♦ Composed of 13 items including orientation, attention, thought organization, perceptual disturbances, psychomotor
♦
♦
♦
♦
retardation, and behavior
It allows for multiple nursing shifts assessment and quantification
Administered by nursing
Takes about 1–​2 minutes
It has been used in the oncology setting
Single Question in Delirium
(SQID)16,17
♦ Single question meant to be asked to the caregiver:
♦ “Do you feel that [patient’s name] has been more confused lately?”
♦ Tested against CAM and psychiatric interview
Cornell Assessment of Pediatric
Delirium (CAPD)12
♦
♦
♦
♦
8-​question rating scale performed by nursing staff in the PICU
Takes less than 2 minutes to complete
Excellent overall sensitivity and specificity
Loses specificity with developmental delay, but sensitivity remains high
CHAPTER 19 Screening for Delirium and Dementia in the Cancer Patient
as those who are mechanically ventilated.7 It is important to limit
its use to nonverbal, mechanically ventilated patients in intensive
care unit settings due to its low sensitivity in detecting delirium in
other settings.8 The Delirium Rating Scale-​Revised 98 (DRS-​R-​98)
is a 16-​item scale (13 severity and 3 diagnostic items) that can be
used to measure severity of delirium as well as to differentiate delirium from dementia, depression, or schizophrenia. It is designed
to be administered by an experienced expert and has been found
to be highly sensitive.9 The Delirium Observation Scale (DOS) is a
nursing-​rated scale based on 13 observations that can be useful in
the screening of delirium and has shown promising results in its detection in the advanced cancer patient population.10 The Memorial
Delirium Assessment Scale (MDAS) is a physician-​rated scale that
can be used to measure the severity of delirium in addition to diagnosis of delirium (see Box 19.1). It has 10 items and takes under 15
minutes to complete. This instrument was designed to be administered at several time points in the same day to assess changes in
delirium severity.11 The MDAS and DRS-​98 include items to assess
cognitive impairment; therefore, additional cognitive assessment
tools are not required when assessing delirium with them. A cognitive assessment tool is required to reliably assess a delirious patient’s
attention disturbances and other cognitive impairment when using
the CAM algorithm to diagnose delirium.
The Cornell Assessment of Pediatric Delirium (CAPD)12 is a valid,
rapid, observational nursing screen that is used for detection of delirium in the pediatric age group. The CAPD screen is designed to
allow for behavioral and developmentally informed observations to
be scaled and summarized in a total score, which indicates whether
a child is likely to be delirious.
Adapted from the CAM-​ICU, two additional pediatric tools have
been developed for the direct assessment of children under 5 years
old (psCAM-​ICU)13 and children over 5 years old (pCAM-​ICU).14
The supportive educational videos on the icudelirium.org website
are a key educational tool in teaching clinicians how to recognize
delirium in infants and children.15
The Single Question in Delirium (SQiD) is a single directed question to the caregiver asking whether the patient has been more
confused than usual. This screening method showed moderate sensitivity/​specificity.16,17
Future Directions: Recommendations for Research
on Screening and Assessment of Delirium
in Oncology Settings
Delirium is associated with increased morbidity and mortality,
with increasing evidence for long-​term cognitive impairment following an episode of delirium. A meta-​analysis by Witlox and colleagues found that delirium in elderly patients is associated with
increased risk of death (38% vs. 28% in controls) at an average
follow-​up of 23 months, increased risk of institutionalization (33%
vs. 11%) at an average follow-​up of 15 months, and increased risk
of dementia (63% vs. 8%) at an average follow-​up of 4 years.18 The
growing data on short-​term and long-​term outcomes of delirium
strongly support the need to screen for delirium among hospitalized patients.
As more healthcare data becomes digitized in an accessible way
through the electronic health record, opportunities for the development of delirium predictive risk models based on multivariable
analysis through deep learning algorithms become a possibility.
Developing such models for the development of delirium in the
cancer population will help identify patients at highest risk for
delirium who might benefit most from delirium prevention interventions. Current guidelines on the assessment of delirium in
cancer patients, including the assessment of etiologies, risk factors, and phenomenology, are largely based on the assessment
of older adults with delirium. Evidence-​based screening and assessment guidelines in oncology and palliative care settings continue to emerge and will improve delirium care in this patient
population.
Dementia
Dementia, referred to as major neurocognitive disorders in DSM
5,1 is a progressive cognitive decline characterized by impairment
in cognitive functioning (e.g., memory, language, executive functioning, visuospatial skills) that interferes with the ability to perform
activities of daily functioning independently. It is estimated that
dementia affects between 2.4 million and 5.5 million people in the
United States.19 Cancer patients with cognitive impairment are at increased risk of functional dependence and medication nonadherence
and are at greater risk of death. Cognitive and functional assessment
for mild cognitive impairment and dementia is recommended for
all older adults with cancer. The National Comprehensive Cancer
Network (NCCN) Older Adult Oncology Guidelines(2020)20 recommend all cognitively impaired patients to be cared for by a multidisciplinary geriatric oncology team throughout their treatment. For
patients with suspected impaired cognitive function, or for patients
with self-​reported or family-​reported concerns for cognitive impairment, a consultation with a cognitive disorders specialist is recommended. The NCCN guidelines recommend periodic reassessment
of cognitive functioning for those with cognitive impairment and
for all older adults when considering changes to the treatment plan.
In this section, we will provide a review of screening and assessment
for dementia syndromes and a brief overview of different cognitive
syndromes.
Dementia: Screening and Assessment
The initial assessment of an individual suspected of having any
cognitive impairment starts with a detailed history with input
from a family member or caregiver who can provide information
on the patient’s previous level of functioning, the temporal course
and rate of cognitive decline, and any behavioral or functional
changes noted along with cognitive impairment. The time course
and associated symptoms represent the key information in distinguishing between different forms of cognitive disorders and ruling
out depression or delirium. For neurocognitive disorders such as
dementia, the onset of symptoms is gradual and progressive as
opposed to the abrupt and rapid onset usually seen in delirium.4
As part of the initial assessment, there should be a review of the
patient’s baseline and current ability to carry out his or her instrumental activities of daily living (IADLs). IADLs include use of the
telephone, shopping, food preparation, housekeeping, laundry,
grooming, mode of transportation, responsibility for medications,
and handling of finances. It is important to find out to what degree the impairment is secondary to physical impairments, as opposed to a cognitive impairment. Asking a caregiver if he or she has
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Box 19.1 Memorial Delirium Assessment Scale (MDAS)
Item 1. Reduced Level of Consciousness (Awareness): Rate the
patient’s current awareness of and interaction with the environment (interviewer, other people/​objects in the room; e.g., ask patients to describe
their surroundings).
0: none (patient spontaneously fully aware of environment and interacts appropriately)
1: mild (patient is unaware of some elements in the environment, or
not spontaneously interacting appropriately with the interviewer;
becomes fully aware and appropriately interactive when prodded
strongly; interview is prolonged but not seriously disrupted)
2: moderate (patient is unaware of some or all elements in the environment, or not spontaneously interacting with the interviewer;
becomes incompletely aware and inappropriately interactive when
prodded strongly; interview is prolonged but not seriously disrupted)
3: severe (patient is unaware of all elements in the environment with
no spontaneous interaction or awareness of the interviewer, so that
the interview is difficult to impossible, even with maximal probing).
Item 2. Disorientation: Rate current state by asking the following 10
orientation items: date, month, day, year, season, floor, name of hospital,
city, state, country.
0: none (patient knows 9–​10 items)
1: mild (patient knows 7–​8 items)
2: moderate (patient knows 5–​6 items)
3: severe (patient knows no more than 4 items)
Item 3. Short-​Term Memory Impairment: Rate current state by using
repetition and delayed recall of 3 words (patient must immediately
repeat and recall words 5 minutes later after an intervening task. Use
alternate sets of 3 words for successive evaluations [e.g., apple, table,
tomorrow; sky, cigar, justice]).
0: none (all 3 words repeated and recalled)
1: mild (all 3 repeated, patient fails to recall 1)
2: moderate (all 3 repeated, patient fails to recall 2–​3)
3: severe (patient fails to repeat 1 or more words)
Item 4. Impaired Digit Span: Rate current performance by asking subjects
to repeat first 3, 4, then 5 digits forward and then 3, then 4 backward; continue to the next step only if patient succeeds at the previous one.
0: none (patient can do at least 5 numbers forward and 4 backward)
1: mild (patient can do at least 5 numbers forward, 3 backward)
2: moderate (patient can do 4–​5 numbers forward, cannot do 3
backward)
3: severe (patient can do no more than 3 numbers forward)
Item 5. Reduced Ability to Maintain and Shift Attention: As indicated during the interview by questions needing to be rephrased and/​
or repeated because patient’s attention wanders, patient loses track, or
patient is distracted by outside stimuli or is overabsorbed in a task.
0: none (none of the above; patient maintains and shifts attention
normally)
1: mild (above attentional problems occur once or twice without prolonging the interview)
2: moderate (above attentional problems occur often, prolonging the
interview without seriously disrupting it)
3: severe (above attentional problems occur constantly, disrupting and
making the interview difficult to impossible)
Item 6. Disorganized Thinking: As indicated during the interview by
rambling, irrelevant, or incoherent speech or by tangential, circumstantial, or faulty reasoning. Ask patient a somewhat complex question (e.g.,
Describe your current medical condition).
0: none (patient’s speech is coherent and goal directed)
1: mild (patient’s speech is slightly difficult to follow; responses to questions are slightly off target but not so much as to prolong the interview)
2: moderate (disorganized thoughts or speech are clearly present, such
that interview is prolonged but not disrupted)
3: severe (examination is very difficult or impossible due to disorganized thinking or speech)
Item 7. Perceptual Disturbance: Misperceptions, illusions, hallucinations inferred from inappropriate behavior during the interview or
admitted by subject, as well as those elicited from nurse/​family/​chart
accounts of the past several hours or of the time since last examination:
0: none (no misperceptions, illusions, or hallucinations)
1: mild (misperceptions or illusions related to sleep, fleeting hallucinations on 1–​2 occasions without inappropriate behavior)
2: moderate (hallucinations or frequent illusions on several occasions with
minimal inappropriate behavior that does not disrupt the interview)
3: severe (frequent or intense illusions or hallucinations with persistent
inappropriate behavior that disrupts the interview or interferes with
medical care)
Item 8. Delusions: Rate delusions inferred from inappropriate behavior during the interview or admitted by the patient, as well as delusions
elicited from nurse/​family/​chart accounts of the past several hours or of
the time since the previous examination.
0: none (no evidence of misinterpretations or delusions)
1: mild (misinterpretations or suspiciousness without clear delusional
ideas or inappropriate behavior)
2: moderate (delusions admitted by the patient or evidenced by his or
her behavior that do not or only marginally disrupt the interview or
interfere with medical care)
3: severe (persistent and/​or intense delusions resulting in inappropriate behavior, disrupting the interview or seriously interfering with medical care)
Item 9. Decreased or Increased Psychomotor Activity: Rate activity
over past several hours, as well as activity during interview, by circling
a: hypoactive b: hyperactive c: elements of both present
0: none (normal psychomotor activity)
a b c 1: mild (Hypoactivity is barely noticeable, expressed as slightly
slowing of movement. Hyperactivity is barely noticeable or appears as simple restlessness.)
a b c 2: moderate (Hypoactivity is undeniable, with marked reduction
in the number of movements or marked slowness of movement;
subject rarely spontaneously moves or speaks. Hyperactivity is undeniable, subject moves almost constantly; in both cases, exam is
prolonged as a consequence.)
a b c 3: severe (Hypoactivity is severe; patient does not move or speak
without prodding or is catatonic. Hyperactivity is severe; patient is
constantly moving, overreacts to stimuli, requires surveillance and/​
or restraint; getting through the exam is difficult or impossible.)
Item 10. Sleep-​Wake Cycle Disturbance (Disorder of Arousal): Rate
patient’s ability to either sleep or stay awake at the appropriate times.
Utilize direct observation during the interview, as well as reports from
nurses, family, patient, or charts describing sleep-​wake cycle disturbance
over the past several hours or since last examination. Use observations
of the previous night for morning evaluations only.
0: none (at night, sleeps well; during the day, has no trouble staying awake)
1: mild (mild deviation from appropriate sleepfulness and wakefulness
states: at night, difficulty falling asleep or transient night awakenings, needs medication to sleep well; during the day, reports periods
of drowsiness or, during the interview, is drowsy but can easily fully
awaken him-​or herself)
2: moderate (moderate deviations from appropriate sleepfulness and
wakefulness states: at night, repeated and prolonged night awakening; during the day, reports of frequent and prolonged napping or,
during the interview, can only be roused to complete wakefulness by
strong stimuli)
3: severe (severe deviations from appropriate sleepfulness and wakefulness states: at night, sleeplessness; during the day, patient spends
most of the time sleeping or, during the interview, cannot be roused
to full wakefulness by any stimuli)
Adapted from Breitbart W, Rosenfeld B, Roth A, Smith MJ, Cohen K, Passik S. The
Memorial Delirium Assessment Scale. J Pain Symptom Manag. 1997 Mar;13(3):128–​137.
CHAPTER 19 Screening for Delirium and Dementia in the Cancer Patient
concerns for the patient’s safety can also provide key information
regarding the level of impairment.
The history should additionally include review of exposures to
risk factors associated with cognitive impairment, such as history
of alcohol or illicit substance use, as well as exposure to toxins.
A thorough review of a patient’s medications, including use of supplements and over-​the-​counter drugs, must be completed. Opioids,
benzodiazepines, and anticholinergic medications are often associated with cognitive impairment in vulnerable patients. Cancer
type and cancer-​related treatments received by the patient should
be reviewed as potential contributors to cognitive impairment.
Chemotherapeutic agents, radiation, hormone therapies, immunotherapies, and surgical treatments have all been associated with
cognitive changes (see Chapter 36).21 Clinicians should inquire
about history of chronic medical conditions such as hypertension,
vascular disease, hyperlipidemia, diabetes mellitus, and obesity, as
they have all been shown to increase the risk of cognitive impairment. A history of psychiatric illnesses should also be reviewed.
Patients with major depressive disorder can often present with mild
forgetfulness, previously termed “pseudo-​dementia.” Feelings of
sadness, dysphoria, hopelessness, helplessness, anhedonia, lack of
motivation, appetite disturbance, sleep disturbance, and suicidality
are supportive of a diagnosis of depression, as opposed to dementia
or other cognitive syndromes. In depressed patients, the cognitive impairments tend to be mild and would have not been present
prior to the onset of depression. During cognitive testing the depressed patient often responds, “I don’t know.” Indifference to cognitive deficits is common among depressed patients, anosognosia
is common in Alzheimer’s disease, and indifference or ignorance of
impairment is typical in frontotemporal dementia. Minimization
of even self-​recognized deficits is common in most. Fatigue secondary to cancer and cancer-​related treatments is commonly encountered among cancer patients and may contribute to cognitive
dysfunction. Patients suffering from severe fatigue could appear inattentive and sedated and can present with short-​term memory impairments. Once the fatigue is managed properly, cognitive deficits
should resolve.
A comprehensive physical examination with emphasis on neurological signs should be performed. The presence of asterixis and
frontal release signs like a palmomental reflex or grasp reflex may
be observed in cases of delirium or advanced dementia. Ataxia
and focal motor or sensory findings may be present in dementia,
especially in the presence of brain lesions or vitamin deficiencies.
Laboratory testing, including a urinalysis; basic metabolic panel;
lipid profile; liver function tests; thyroid function tests; syphilis
screen; HIV test; paraneoplastic panel; vitamin levels including
vitamin B12, thiamine, and folate; and cerebrospinal fluid are
useful in identifying reversible causes of the cognitive changes if
clinically indicated. Neuroimaging, such as a computed tomography (CT) scan or magnetic resonance imaging (MRI), is needed
to evaluate for potential structural causes of the impairment.
Information obtained through history and physical examination
should guide clinicians as to the extent of laboratory testing and
neuroimaging.
An important component of the evaluation is the objective
assessment of an individual’s cognitive abilities, either with a
screening tool in the case of overt cognitive dysfunction or with
comprehensive neuropsychological assessment in cases of lesser
severity where higher sensitivity to milder cognitive dysfunction is
required. This can be performed in the office or at the bedside with
the use of a cognitive assessment tool. Cognitive screening tools (see
Chapter 36, Box 36.1), such as the Montreal Cognitive Assessment
(MoCA)22 and the Mini-​Mental Status Exam (MMSE),23 are designed to test multiple domains of cognition, including short-​term
memory, language, generative naming, visuospatial skills, and executive functioning. Screening measures generally specify cutoffs
for normal versus abnormal performance. The NCCN Older Adult
Oncology Guidelines Version 2020 continue to indicate Mini-​
Cog as a screening tool for cognitive impairment in older adults
with cancer.20,24 Cognitive tests can provide a sense of how severe
the impairment is and can assist in making a diagnosis. Repeated
administration of the same cognitive assessment tool at different
time points is important in tracking improvements or the rate of
further decline in cognition. Comprehensive neuropsychological
testing may be required in most patients with cancer to differentiate between cancer and cancer-​related cognitive changes, neurodegenerative diseases, and vascular and other forms of cognitive
syndromes.25,26
Common Cognitive Syndromes
In this section, we will review commonly encountered cognitive
syndromes in oncology settings, particularly among older adults,
the age group most commonly affected by cancer. Table 19.2 lists the
commonly used dementia screening and assessment tools.
Dementia Due to Alzheimer’s Disease
Alzheimer’s disease is the most common form of dementia. The
most significant risk factor for Alzheimer’s disease is age, with incidence of disease doubling every five years after age 65.27,28 In
Alzheimer’s disease, the cognitive and behavioral symptoms typically have an insidious onset and gradual progression. Early in the
course the predominant feature is memory loss. Patients typically
preserve social cognition and procedural memory until very late.
Deficits in language, visuospatial impairments, and executive function are typically seen as the disease progresses. Noncognitive neuropsychiatric disturbances, including apathy, irritability, agitation,
restlessness, anxiety, and depression, are commonly seen in patients
with Alzheimer’s disease. Patients with advanced Alzheimer’s dementia can present with aggression and psychosis.4
The brain pathology in Alzheimer’s is characterized by neuronal
loss and an accumulation of misfolded proteins, known as neurofibrillary tangles and amyloid plaques.27 Genetic predisposition has
been identified in early-​onset cases, and commercial testing for mutations of the known Alzheimer’s disease genes, such apolipoprotein
E (APOE), presenilin 1 (PSEN1), or presenilin 2 (PSEN2), is available. The use of positron emission tomography (PET) scans to detect
amyloid plaque density and testing of cerebrospinal fluid for amyloid and tau levels may be useful in diagnosing cases of Alzheimer’s
when the clinical picture is unclear.4
Vascular Dementia
Vascular dementia is the second most common form of dementia
seen in older adults. In patients with vascular dementia, the onset of
cognitive symptoms typically coincides with cerebrovascular events.
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SECTION IV Screening and Assessment in Psychosocial Oncology
Table 19.2. Overview of Commonly Used Clinician-​Rated Dementia Screening and Assessment Scales
MMSE23
MINICOG24
MOCA22
SLUMS33
Freund Clock Drawing
Test34
Domains tested
Orientation, attention,
comprehension,
calculations, memory,
language, visuospatial
ability
Memory, language
comprehension, visual-​
motor skills, executive
function
Orientation, memory,
clock, visuospatial
ability, fluency, language,
abstraction, calculations,
executive function,
attention
Orientation, memory,
animal fluency, attention,
clock drawing
Memory, executive function,
visuospatial ability
Advantages
One of the most
commonly used
cognitive assessment
tools
Not strongly influenced by Better testing of
education
executive functioning,
more sensitive to mild
impairment, freely
available online in a
number of different
languages
Emphasizes memory
tasks, good for
distinguishing between
mild cognitive
impairment and
dementia
Not influenced by
education. Seven-​point
scoring of the clock draw
allows for improved
interrater reliability and
improved identification of
cognitive deficits
Disadvantages
Can miss deficits in
well educated. Limited
executive function
testing. Not freely
available
Scoring of clock drawing
test is vulnerable to
different interpretations.
Cannot be used in visually
impaired patients and
patients with impaired
manual dexterity
Cannot distinguish
Less evaluation of
Cannot be used in visually
between mild cognitive
language, constructions, impaired patients and
impairment and dementia and executive functioning patients with impaired
manual dexterity
Time to administer
10–​15 minutes
5 minutes
10–​15 minutes
The cognitive decline is especially seen in areas of executive function and working memory. Neuroimaging is helpful in identifying
the presence of cerebrovascular disease, which can range from large
strokes to small vessel disease. The cognitive impairments usually
occur in a stepwise fashion, with periods of decline followed by
periods of stability and eventually further decline. Symptoms such
as mood and personality changes, abulia, and emotional lability may
be seen. Patients often initially present with depressive symptoms
and on further screening are found to have deficits in executive
functioning. The condition is thought to be secondary to atherosclerosis and arteriosclerosis in the cerebral vessels. The common
risk factors include dyslipidemia, hypertension, diabetes mellitus,
smoking, obesity, and atrial fibrillation, as well as other conditions
that increase the risk of cerebral emboli.
Frontotemporal Dementia
Frontotemporal dementia is the most common cause of early-​
onset dementia in individuals younger than 65 years old, with the
behavioral variant accounting for approximately 50% of cases,
and nonfluent and semantic variants the rest. Frontotemporal
dementia is characterized by the gradual and progressive development of personality changes, as well as behavioral and/​or
language impairment. The hallmark behavioral changes are apathy or disinhibition. Patients can lose interest in self-​care and
socialization and can often present with socially inappropriate
behaviors. These patients are sometimes noted to be hyper-​oral,
and changes in their diet can be observed. Patients who develop
personality changes can have changes in their social style and beliefs. Cognitive deficits are less prominent in frontotemporal dementia early in the course of the disease; as the disease progresses,
executive dysfunction (i.e., changes in planning and organizing,
abstraction, and cognitive flexibility) is more common. These patients can demonstrate poor judgment and are easily distracted.
Cognitive testing frequently shows impairments in abstract
10 minutes
5 minutes
reasoning, response inhibition, and mental flexibility. Learning,
memory, and perceptual-​motor abilities tend to be spared, especially in early stages. Neuroimaging will reveal a distinct pattern
of atrophy of the frontal lobes.
Lewy Body Dementia
Lewy body dementia is the second most common type of neurodegenerative dementia after Alzheimer’s disease. Lewy body dementia
is associated with an insidious onset and gradual progression of
cognitive decline. The condition can present with fluctuating cognition with pronounced variations in attention and alertness, recurrent visual hallucinations that are often well formed and detailed,
and features of parkinsonism that appear after the cognitive decline.
Patients with Lewy body dementia are prone to frequent falls, syncope, and autonomic dysfunction. Since visual hallucinations may
be common in presentation, Lewy body dementia cases may be misidentified as a primary psychotic disorder. This is an important distinction, since Lewy body cases are very sensitive to treatment with
antipsychotics and their use may lead to neuroleptic malignant syndrome (NMS). The arousal disturbance in these patients can appear
similar to delirium, but the course of the decline is gradual, as opposed to an acute onset. Further medical workup does not reveal any
underlying medical etiologies in patients with Lewy body dementia
unless they have superimposed delirium. The disease is caused by
misfolded proteins, specifically alpha-​synuclein, and is referred to
as a synucleinopathy.
Dementia Due to Vitamin Deficiencies
Vitamins such as cyanocobalamin (B12), thiamine (B1), and folate are essential for normal functioning of the brain and nervous
system. These vitamins are essential to cell metabolism, DNA
synthesis, and energy production. When deficient in any of
these vitamins, one can develop myriad neurologic impairments, including dementia. If given a history of a patient with
CHAPTER 19 Screening for Delirium and Dementia in the Cancer Patient
cognitive deficits and poor nutritional status, persistent nausea
and vomiting, or altered gastrointestinal absorption, as seen in
gastric cancer or after bariatric surgery, one should consider a
dementia due to vitamin deficiency. Early recognition of such
cases is important because the cognitive impairments may be
reversed with repletion of the vitamin. Gait disturbances, neuropathy, anemia, weakness, cognitive impairment, depression,
and a red beefy tongue are some of the characteristic findings
of patients with dementia due to vitamin B12 deficiency. Patients
with folate deficiency may also present with mood disturbance,
cognitive impairment, and anemia. Thiamine-​deficient patients
can develop Wernicke’s encephalopathy, a condition characterized by mental status changes, gait disturbance, and ophthalmoplegia. Wernicke’s encephalopathy has long been thought of as a
condition limited to patients with alcoholism; however, recent
literature has shown that the syndrome is not infrequently seen
in those with poor nutrition. Frail patients with a malignancy,
who often suffer from low appetite and vomiting, are especially
vulnerable.29 Screening for deficiencies can be easily achieved by
ordering blood vitamin levels, and repletion can be done by vitamin supplementation.
Dementia Due to HIV Infection
HIV disease is an infection caused by exposure to the human immunodeficiency virus type I. The route of transmission is contact
with infected bodily fluids. The virus, once contracted, impairs functioning of CD-​4 lymphocytes, cells crucial to a functioning immune
system. The virus can affect a variety of brain regions, resulting in
the development of cognitive impairment. Typically, the affected
individual can present with deficits in executive functioning, processing speed, and attention; in severe cases, language, emotional
control, and affect may be affected. Other neurologic impairments
may also be present in severe cases, including incoordination, ataxia,
and motor slowing. Dementia due to HIV is more commonly seen
in patients with high viral load measured in the cerebrospinal fluid
or those who have other signs of advanced HIV. The course of cognitive impairment can vary from rapid progression to slow decline to
improvement or even resolution. One would not expect to observe
an abrupt onset of mental status changes, which would more likely
indicate a delirium, requiring a comprehensive workup to identify
potential medical causes, with special attention to ruling out the
presence of an opportunistic infection. It is important to note that
HIV-​infected patients may suffer from cognitive impairments even
in the absence of full-​blown AIDS.
Mild Cognitive Impairment
Mild cognitive impairment, referred to as “mild neurocognitive
impairment” in the DSM 5,1 is a condition defined as a modest cognitive decline from an individual’s previous level of functioning,
greater than expected for age and education level. The impairment
does not affect one’s ability to sustain independence in activities of
daily living, but the individual likely experiences a need for greater
effort, accommodation, or strategies for coping with the deficit
when managing complex tasks. Mild cognitive impairment is typically seen in adults over the age 65, with prevalence ranging from
3% to 19% of the population in that age group.30 Many patients with
mild cognitive impairment will progress to developing dementia,
and therefore they should be monitored closely. Factors like prolonged exposure to anticholinergic medications, cerebrovascular
disease, misfolded protein deposition, and genetic mutation have
been identified as potentially playing a role in the pathophysiology of the syndrome.31 Patients presenting with mild cognitive impairment may develop an Alzheimer’s dementia, a Lewy
body dementia, or other types of cognitive syndromes depending
on the underlying etiology. Patients with mild cognitive impairment secondary to cancer and cancer treatment–​related cognitive
changes may not progress to a full-​blown dementia. This continues
to be an area in need of further study among cancer patients (see
Chapter 36).
The cognitive dysfunction in patients with mild cognitive impairment may not be apparent in a casual conversation. Typically, those
close to the patient describe the individual as now being forgetful of
things they once recalled easily or of recent events that they would
normally be interested in. Cognitive assessment tools, identical to
those used in screening for dementia, can be used for diagnosing
mild cognitive impairment, but these often lack the sensitivity to
identify such subtle impairments. Comprehensive neuropsychological testing is mostly required to uncover the problem. Screening
and diagnosing mild cognitive impairment are important, as this
will help identify individuals potentially at risk of developing more
severe impairment in the coming years. This can allow individuals,
families, and healthcare providers an opportunity to plan more effectively for future treatments.
Future Directions: Recommendations for Research
on Screening and Assessment of Dementia
in Oncology Settings
In 2019, a systematic review by the US Preventive Services Task
Force (USPSTF) concluded that several brief screening instruments
can adequately detect cognitive impairment, especially in populations with a higher prevalence of underlying dementia. The review also concluded that there is no empirical evidence, however,
that screening for cognitive impairment or early diagnosis of cognitive impairment improves patient, caregiver, family, or clinician
decision-​making or other important outcomes.19 It is important
to note that the USPSTF review findings are applicable to healthy,
community-​dwelling older adults, and these findings highlight the
need to improve research on outcomes and interventions for the
cognitively impaired. In oncology settings, medical comorbidities,
cancer and cancer treatments, comorbid depression, and increased
prevalence of delirium predispose patients to cognitive deficits.
Therefore, current guidelines recommend screening for cognitive
impairment among older adults with cancer. Although older adults
are at higher risk for cognitive impairment, adults with cancer are
more likely to experience cognitive impairment than those without
a cancer diagnosis. Therefore, screening for cognitive impairment
among all patients with a cancer diagnosis should be considered.
Future research should focus on identifying risk factors for cognitive
impairment, how to best screen for cognitive impairment, studying
morbidity and mortality outcomes of cognitive impairment, and
clarifying the impact of cancer and cancer-​related treatments on
cognition among cancer patients of all age groups. The development
of predictive models in the future can help discern cancer patients at
higher risk for cognitive impairment.
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elderly cancer patients: A new challenge for oncologists. Cancer
Treat Rev. 2014 Jul;40(6):810–​817. pii:S0305-​7372(14)00046-​2.
doi:10.1016/​j.ctrv.2014.03.003
26. Ahles TA. Cognitive changes associated with cancer and cancer
treatment. Semin Oncol Nurs. 2013 Nov;29(4):229–​231.
27. Querfurth HW, La Ferla FM. Alzheimer’s disease. New Eng J Med.
2010;362(4):329–​344.
28. Hirtz D, Thurman DJ, Gwinn-​Hardy K, Mohammad M, Chaudhari
AR, Zalutsky R. How common are the “common” neurologic disorders? Neurology. 2007 Jan 30;68(5):326–​327.
29. Isenberg-​Grzeda E, Shen MJ, Alici Y, Wills J, Nelson C, Breitbart
W. High rate of thiamine deficiency among inpatients with cancer
referred for psychiatric consultation: Results of a single site prevalence study. Psychooncology. 2017 Sep;26(9):1384–​1389.
30. Gauthier S, Reisberg B, Zaudig M, et al. Mild cognitive impairment. Lancet. 2006 Apr 15;367(9518):1262–​1270.
31. Gaudreau JD, Gagnon P, Harel F, Tremblay A, Roy MA. Fast,
systematic, and continuous delirium assessment in hospitalized
patients: The nursing delirium screening scale. J Pain Symptom
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Baggett LM, Duursma SA. The
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33. Tariq SH, Tumosa N, Chibnall JT, Perry MH 3rd, Morley JE.
Comparison of the Saint Louis University mental status examination and the mini-​mental state examination for detecting dementia and mild neurocognitive disorder: A pilot study. Am J
Geriatr Psychiat. 2006 Nov;14(11):900–​910.
CHAPTER 19 Screening for Delirium and Dementia in the Cancer Patient
34. Lycke M, Ketelaars L, Boterberg T, et al. Validation of the Freund
Clock Drawing Test as a screening tool to detect cognitive dysfunction in elderly cancer patients undergoing comprehensive
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145
20
Screening and Assessment
for Cognitive Problems
Alexandra M. Gaynor, James C. Root, Elizabeth Ryan, and Tim A. Ahles
Introduction
Cognitive dysfunction associated with cancer and cancer treatment has been increasingly recognized and reported by patients.
In breast cancer survivors, the most widely investigated cancer cohort, cognitive dysfunction is experienced in 17%–​75% of women,
at time points between six months and 20 years after completion
of treatment.1 A majority of longitudinal studies utilizing objective cognitive assessments have found significant changes from
pre-​to posttreatment.2 Interestingly, studies have found evidence
for cognitive dysfunction prior to adjuvant therapy in 20%–​30%
of patients diagnosed with breast cancer.2 Due to this research and
the increasing awareness of potential cognitive difficulties by patients, objective measures of cognitive functioning that can detect
subtle declines in function are necessary. This chapter focuses on
the relative utility of brief screening measures and more extensive
neuropsychological batteries to detect cancer-​associated cognitive
dysfunction (CACD) in survivors.
Overview of Screening Measures
A wealth of screening instruments has been developed for the detection of cognitive difficulties and impairment in general, as well
as in a wide range of specific neurological syndromes. Screening
measures have the advantage generally of being relatively brief while
at the same time sampling from multiple cognitive domains. As a
result, these measures have been suggested as a first-​line evaluation
of potential cognitive impairment preceding or in parallel with comprehensive neuropsychological assessment. A significant drawback
to the use of cognitive screening measures in cancer survivors is the
limited sensitivity of these measures to mild cognitive dysfunction,
which may be more typical in this cohort. Most screening measures were developed for the detection of moderate to severe cognitive impairment, such as that seen in traumatic brain injury and
degenerative dementing conditions. In contrast, the mild cognitive
difficulties that are sometimes exhibited following cancer treatment
will often remain undetected when cognitive screening measures are
used. A related drawback to the use of screening measures lies in the
fact that results are generally interpreted categorically in reference
to a threshold score (i.e., cognitively impaired or intact), rather than
on a continuum of ability (i.e., in relation to an individual’s relative
position on a normal distribution). As a result, even meaningful decline in a cancer survivor from the high average to average range
of ability would be classified as intact when based solely on the results of a cognitive screening measure. A further complication in
using cognitive screening measures in the detection of subtle cognitive dysfunction is the likely ceiling effect that will be exhibited
across most screening instruments, particularly in previously high-​
functioning individuals.
These issues notwithstanding, cognitive screening measures may
be useful in the early stages of evaluation of cognitive difficulties in
cancer survivors when interpreted cautiously and when the limitations and relative insensitivity to subtle cognitive decline are kept in
mind. The choice of cognitive screening measure should be guided
by the expected severity of cognitive decline, as well as the potential
etiology of cognitive difficulties. They will be particularly useful in
cases in which significant cognitive dysfunction is suspected, as in
specific neurological syndromes and dementing disorders in later
life. They will be less useful in cases of subtle cognitive dysfunction,
as in CACD. To date, no screening measure has been developed and
tested specifically for the detection of treatment-​associated cognitive
difficulties following cancer treatment. As a result, we focus on the
sensitivity and specificity of these measures in detecting dementing
conditions as well as mild cognitive impairment (MCI), with the caveat that CACD is far less severe than dementia and likely less severe than MCI in the majority of cases. For this review, six common
cognitive screening measures are discussed. The Mini-​
Mental
State Exam, the Mini-​Cog, and the Blessed Orientation Memory
Concentration Test were developed to detect relatively frank and
severe dysfunction, while the Montreal Cognitive Assessment, the
High Sensitivity Cognitive Screen, and the Repeated Battery for the
Assessment of Neuropsychological Status were developed to detect
relatively milder or subtler cognitive dysfunction.
CHAPTER 20 Screening and Assessment for Cognitive Problems
Mini-​Mental State Exam
Montreal Cognitive Assessment
The Mini-​Mental State Exam (2nd edition; MMSE-​2) is a brief (10–​
15 minutes) 30-​item measure that assesses orientation to time and
place, registration, language function, short-​term memory, working
memory, and construction.3 Significant improvements have been
made with the second edition, including age and education corrections. Traditionally, a cut score of 24, but as high as 26, has been used
on the MMSE to suggest a greater probability of cognitive impairment. Sensitivity and specificity vary, depending on age, ethnicity,
and education, as well as disease. In a meta-​analysis of 34 dementia
studies, the MMSE exhibited sensitivity and specificity of 80% and
81%, respectively.4 Significantly, in a sample of highly educated, primarily Caucasian individuals using the original MMSE, a cut score
of 26 or below yielded a balance of sensitivity and specificity of 89%
and 91%, respectively, indicating that demographic factors can be
expected to alter clinical interpretation of MMSE performance.5 In
identifying cases of MCI, in contrast either to healthy subjects or
to Alzheimer’s dementia (AD), the MMSE has been found to perform poorly.4 Given that treatment-​related cognitive effects are expected to be far less severe than in either MCI or frank dementia, the
MMSE-​2 is unlikely to be of clinical utility in assessing for CACD.
Studies that have administered the MMSE in research protocols
evaluating the effects of cancer treatment on cognitive function do
so to either screen for baseline cognitive impairment for exclusion
purposes or as a primary outcome measure. Of these, two studies
found a significant effect of group status on MMSE performance,6,7
although results were somewhat limited by small sample size and
lack of control group, and further research is needed to determine
the ability of the MMSE to detect subtle cognitive deficits in cancer
survivors.
The Montreal Cognitive Assessment (MoCA) was developed as a
brief (10 minutes; 30 items) screening measure for MCI. In a validation study of the MoCA on MCI, AD, and healthy control subjects,
the MoCA outperformed the MMSE in discriminating MCI,11 with
sensitivity and specificity values for the MoCA of 90% and 87%, respectively, in contrast to MMSE sensitivity and specificity values of
81% and 100%, respectively. Greater sensitivity and specificity of
the MoCA over the MMSE has been found in subsequent studies
as well,12,13 in addition to better ability to identify domain-​specific
cognitive dysfunction missed by the MMSE. While the MoCA
is sensitive to subtler cognitive dysfunction, it is still likely that
treatment-​related cognitive effects will be of lesser magnitude in
cancer survivors. Arcuri et al.14 used Rasch analyses to examine the
psychometric properties of MoCA in cancer survivors and found
adequate item fit and measurement of a unidimensional construct
but lacked items of sufficiently high difficulty, suggesting it may not
be as useful in predicting impairment in survivors with higher cognitive ability. With regard to studies testing MoCA performance in
cancer patients, several case studies and one study of 88 male cancer
patients showed abnormal MoCA performance during or immediately after treatment, but deficits improved or resolved at one-​year
follow-​up.15,16 The potential influence of practice effects that may
better explain cognitive improvement was not addressed. In a large,
sample-​based study17 that included breast cancer survivors treated
with or without chemotherapy and a healthy control group, no difference in MoCA performance was found.
Mini-​Cog
The Mini-​Cog8 combines a three-​word recall task with the Clock
Drawing Test (CDT) and has seen increasing use in preoperative
and inpatient evaluations due to its brevity (3 minutes) and sensitivity to moderate and severe dysfunction. In a large, population-​
based study, the Mini-​Cog exhibited sensitivity and specificity
values of 76% and 89%, respectively, for detection of dementia, and
performed as well as the MMSE (79% and 88%). Aside from the
shorter administration time than the MMSE, the Mini-​Cog has also
been found to be less affected by the education, ethnicity, and language characteristics of the patient.9 In detection of MCI in a sample
with dementia and a relatively greater number of individuals classified as “cognitive impairment–​no dementia” (CIND), the Mini-​Cog
performed similarly to previous studies in identifying dementia
(sensitivity: 76%; specificity: 73%) but poorly in detecting either
dementia or CIND (sensitivity: 39%; specificity: 78%), indicating
lesser accuracy in the identification of milder cognitive dysfunction. However, one study examining the CDT in particular found
that it had promise in detecting cognitive dysfunction in cancer
survivors. Using receiver operating characteristic (ROC) analyses
for a cutoff score of ≤4, the CDT showed good diagnostic accuracy
(0.88), sensitivity (80.7%), and specificity (81.1%),10 suggesting it
might be better suited toward testing cognition in cancer survivors,
while the Mini-​Cog as a whole may be better suited to detect more
severe cognitive dysfunction.
Blessed Orientation Memory Concentration Test
The Blessed Orientation Memory Concentration (BOMC) test18 is a
brief screening measure originally developed to assess for dementia,
which has been used in geriatric populations, including older adults
with cancer. However, it has not been well validated for use in
screening for more MCIs such as those typically seen in CACD. One
recent study found that BOMC scores were associated with depressive symptoms, physical function, and limitations in social activities
in older adults with cancer prior to treatment, but even statistically
significant associations between BOMC and other measures of
function were not necessarily clinically significant.19 Therefore, although the BOMC may be useful as a screening measure given its
brief administration and association with self-​reported function in
older adults, further research is needed to establish an appropriate
cutoff score for the BOMC that reflects clinically significant cognitive deficits specific to cancer survivors.
High Sensitivity Cognitive Screen
The High Sensitivity Cognitive Screen (HSCS) is a longer (20–​30 minutes) cognitive screening measure that tests executive functioning,
visuospatial ability, psychomotor speed, attention and concentration,
language, and memory.20 Rather than a discrete cut score, the HSCS
classifies individuals into one of five categories: normal, borderline,
mild, moderate, and severe. The screen was designed to be sensitive to subtle cognitive dysfunction and has been used in previous
studies investigating cognitive effects of cancer treatments. The HSCS
has demonstrated strong diagnostic accuracy and agreement with
comprehensive neuropsychological assessment with 93% accuracy
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SECTION IV Screening and Assessment in Psychosocial Oncology
in noncancer samples. In cancer samples using the HSCS, Brezden
et al.21 found a significant difference between breast cancer patients
on active chemotherapy treatment and healthy controls, but not when
compared with breast cancer survivors with a past history of chemotherapy treatment. Tchen et al.22 administered the HSCS to women on
active chemotherapy treatment for breast cancer and healthy controls
and found a 16% rate of moderate to severe impairment in the active
treatment group compared to only 4% moderate to severe impairment
in the healthy control group. A second study by the same group,23
which followed the same patients and controls over one-​and two-​year
time points, found 4.4% and 3.8% of patients with moderate to severe
dysfunction as compared to 3.6% and 0% in the healthy control group.
Downie et al.24 administered the HSCS to a single group of women
diagnosed with breast cancer who were on active chemotherapy
treatment and compared objective results to subjective, self-​reported
cognitive dysfunction. Difficulties with language abilities (61%) and
memory (48%) were found using the HSCS, although these rates were
lower than would be expected given patient self-​report (78% and 95%,
respectively); the most significant discrepancy between objective and
subjective measures was found in attention abilities (10% objective
versus 90% subjective). Vardy et al.25 administered the HSCS over
three time points (mean interval = 17 days) to a group predominantly
composed of breast cancer survivors (94%) within two years of completion of treatment. While 30% of patients (6/​20) exhibited moderate
to severe cognitive impairment at baseline, significant putative practice effects reduced this rate to 5% (1/​19) at time 2, and this rate remained at time 3 (1/​18).
The Repeated Battery for the Assessment
of Neuropsychological Status
The Repeated Battery for the Assessment of Neuropsychological
Status (RBANS) is a brief battery addressing immediate memory,
visuospatial/​
constructional ability, language, attention, and delayed memory. Although originally developed to assess dementia in
older adults, the RBANS has been utilized in numerous other clinical populations with cognitive impairment and is appealing given
its brevity of administration, high test-​retest reliability, and minimal practice effects due to multiple equivalent alternate forms.26
A small number of studies has also suggested it may have promise in
detecting CACD in cancer patients and survivors. For example, in a
longitudinal study of breast cancer patients, Jansen et al.27 found that
scores on multiple RBANS subtests significantly declined during
treatment relative to baseline, and all but visuospatial skill deficits
returned to baseline performance at 6-​month follow-​up. The few
studies utilizing RBANS as a screening measure in cancer patients
and survivors suggest it may be more sensitive than the MMSE and
HSCS in detecting subtle cognitive impairment; however, there is
evidence that, similar to the MoCA, it is limited in its ability to detect
impairment in individuals with higher cognitive function.28
Review of Research: Screening Measures
Does screening for cognitive impairment in cancer patients lead to
better outcomes? Of the screening instruments used, the MMSE
does not appear to provide additional information. Yamada et al.29
used the MMSE with older breast cancer survivors >10 years
posttreatment to examine brief global cognitive functioning and
found lower MMSE scores in the cancer survivors; however, their
scores (mean = 27.6; standard deviation [SD] = 2.1) were still above
the MMSE cutoff. Thus, a clinician would not typically refer them
for further assessment. Complicating the interpretation of this result is the age of the sample (65 and older). The significant difference between the breast cancer survivors and the controls was 1.7
points on average, which is not likely to result in a clinically meaningful difference. As reviewed earlier, the MoCA has demonstrated
diagnostic accuracy similar to the MMSE but exhibited a return
to normal performance following treatment in single case studies,
and, in a sample of breast cancer survivors, revealed no difference
in performance between groups.17 The RBANS appears to be promising as a brief and sensitive screening measure of CACD, and is
less influenced by practice effects resulting from repeated testing,
but is limited in its ability to detect impairment in patients with
higher intellectual functioning.28 The HSCS has been used in several studies22–​25 assessing the cognitive effects of cancer treatments.
Although the HSCS has demonstrated strong diagnostic accuracy
and agreement with comprehensive neuropsychological assessment,
studies in cancer survivors suggest inconsistent sensitivity; further
limitations include longer administration times (20–​30 minutes)
and potentially significant practice effects in cases in which serial assessments may be indicated. Due to insensitivity to subtle cognitive
dysfunction and the limitations of screening instruments, comprehensive neuropsychological assessment remains the primary means
by which to assess CACD. We now turn to describing the comprehensive neuropsychological assessment process and specific recommendations for the assessment of CACD.
Overview of Comprehensive
Neuropsychological Assessment
The neuropsychological assessment begins with a diagnostic interview that determines the patient’s main cognitive complaints, cancer
treatments, and medical, neurological, psychiatric, psychosocial,
substance use, and educational/​vocational history, all of which will
help to contextualize the results of the neuropsychological assessment. If a neuropsychological assessment is considered appropriate,
formal testing is recommended, which will vary in terms of time
and measures administered, depending on patient characteristics
and referral question; time for an assessment may range from one to
several hours depending on patient-​specific factors.
A flexible approach to test selection allows the clinician to tailor
the assessment to the specific referral question; while most practitioners will employ a somewhat standard “core” battery of measures,
additional measures may be administered for specific difficulties or
symptoms (multitasking, attention/​concentration issues over longer
periods of time). Neuropsychological and psychological measures
are generally in paper-​and-​pencil as well as interview and computer-​
administered format, and should have acceptable validity and reliability. Most batteries, regardless of syndrome, will attempt to sample
cognitive ability in multiple domains, including attention and
concentration, psychomotor speed, verbal functioning, visuospatial reasoning, praxis and construction, verbal and visual learning
and recall, and executive functioning (abstraction, reasoning, cognitive flexibility, problem solving, planning and organization).
Depending on the clinician, measures of personality and emotional
CHAPTER 20 Screening and Assessment for Cognitive Problems
and psychological functioning may also be administered as either
a standard part of the assessment or when there is suspicion that
emotional distress or a significant psychiatric issue may be affecting
cognition.
Specifically, for the assessment of CACD, test selection and interpretation of results should be guided by empirical literature and
clinical experience. Four early meta-​analyses reported significant
effects in multiple domains, including in visual and verbal memory,
but these analyses included either studie s with multiple cancer types
and therapies30 or studies that measured cognitive function during
active treatment.30–​33 The most recent meta-​analysis that included
only breast cancer survivors not on active treatment found cross-​
sectional and longitudinal effects in verbal and visuospatial functioning.34 To develop a harmonized battery of measures for the
assessment of CACD, the International Cognition and Cancer Task
Force (ICCTF) brought together two working groups with experts
in cognition and cancer.1 In selecting tests, the ICCTF required adequate psychometric properties, test-​
retest reliability, suitability
for multinational application, and the availability of alternate test
forms (to eliminate practice effects in serial testing). Other criteria
considered were the frequent use of the test in a specific area of research being investigated and the use of the test by other cooperative
groups. Since previous studies revealed a frontal subcortical pattern of impairment, recommended domains included learning and
memory, processing speed, and executive functioning (especially
the more complex aspects of attention). Specific measures included
the Hopkins Verbal Learning Test-​Revised (HVLT-​R),35 the Trail
Making Test (TMT),36 and the Controlled Oral Word Association
(COWA)37 test of the Multilingual Aphasia Examination. A test of
working memory (which involves the temporary storage and manipulation of information) was not included in the core battery of
recommended tests because none of the current available measures
met all of the selective criteria outlined by the ICCTF. However, it is
recommended that the core battery be supplemented with a test of
working memory based on the neuropsychologist’s preference. We
have included a table of measures that we use as part of a flexible battery approach that is guided by the recommendations of the ICCTF,
together with previously published research, as well as our own clinical experience within our neuropsychology service (Table 20.1).
Following administration of the neuropsychological tests, patient performance on individual measures is compared to normative groups defined by age, or, increasingly, age, education, gender,
and ethnicity, to ensure the most exact matching of patients to their
respective cohorts. In contrast to a “deficit testing” model of assessment, in which performance is categorized as either normal or aberrant, comparison of patients’ performance to normative groups,
and to their own premorbid functioning, allows for finer gradations
of interpretation; test results can indicate how well, or how poorly,
an individual patient performs on a given task, and also allows for
detection not only of absolute deficits but also of deficits that are
relative to the patient’s normative cohort or to their own premorbid
functioning.
Uses of Screening and Assessment
What is the best approach to assessing the presence of CACD?
Deciding whether to administer a screening instrument or a flexible
Table 20.1. List of Commonly Used Neuropsychological Measures
in the Assessment of Posttreatment Cognitive Dysfunction
Measure
Function
Premorbid Intelligence
Test of Premorbid Functioning
(TOPF)
A measure estimating premorbid
cognitive abilities
Verbal Ability
Controlled Oral Word
Association Test
Animal Naming Test
Boston Naming Test
A timed measure of phonemic fluency
A timed measure of semantic fluency
A measure of confrontation naming
(word finding)
Learning and Memory
Hopkins Verbal Learning Test-​R
Logical Memory I and II (WMS-​IV)
Brief Visuospatial Memory Test-​R
A measure of verbal list learning
and recall
A measure of verbal story learning
and recall
A measure of visual figure learning and
memory
Attention
Digit Span (WAIS-​IV)
Arithmetic (WAIS-​IV)
Continuous Performance Test (CPT)
A measure of brief span of attention
A measure of brief span of attention
and working memory
A measure of sustained attention
Processing Speed
The Trail Making Test (Part A)
The Trail Making Test (Part B)
Digit Symbol—​Coding (WAIS-​IV)
Symbol Search (WAIS-​IV)
A timed measure of visual scanning and
motor speed
A timed measure of visual scanning,
motor speed, and set-​shifting
A timed measure of visual associative
learning
A timed measure of visual scanning and
attention
Visual Reasoning/​Construction
Rey-​Osterreith Complex Figure
Judgment of Line Orientation
Block Design (WAIS-​IV)
A measure of visual construction
A measure of visuospatial judgment
and reasoning
A timed measure of visual construction
and reasoning
Executive Functioning
Wisconsin Card Sorting Task (WCST) A measure of abstract reasoning and
Stroop Task
problem-​solving
A measure of word reading, color
naming, and inhibition
Psychological/​Emotional
Personality Assessment
Inventory (PAI)
Beck Depression Inventory (BDI)
Generalized Anxiety Disorder Scale
(GAD-​7)
A self-​report measure of psychological
functioning
A self-​report measure of depressive
symptomatology
A self-​report measure of anxiety
symptomatology
neuropsychological assessment depends on the time allotted, the
patient’s condition (i.e., fatigue), and the nature of the patient’s
symptoms (i.e., does his or her presentation or the caregiver’s report
resemble an incipient dementia, or are the symptoms more subtle?).
The limitations of screening instruments have been thoroughly reviewed. Given these limitations, it has been suggested that a combination of screening measures be used to ensure detection of subtle
impairment in cancer survivors.22,28 However, a flexible neuropsychological assessment can be tailored to the patient’s individual
reported difficulties and can be shortened or given over multiple
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SECTION IV Screening and Assessment in Psychosocial Oncology
appointments (in the case of a fatigued patient). Typically, this process is initiated once a patient reports concerns about their cognitive
function to their oncologist, nurse practitioner, or other provider
managing their care, at which point the provider should refer the patient to a neuropsychologist for a full assessment of neurocognitive
function. Therefore, the use of patient-​reported outcome measures,
such as the Functional Assessment of Cancer Therapy-​Cognitive
Function (FACT-​Cog),38 the PROMIS Cognitive Function,39 or the
measurement of Everyday Cognition (ECog),40 may be useful in
conjunction with screening measures, as high subjective complaints
of functioning in combination with suspected CACD based on
screening tests may warrant further testing using a thorough neuropsychological battery. We advocate a flexible, comprehensive neuropsychological assessment for patients with CACD because included
measures exhibit higher sensitivity and specificity and typically have
better normative data, which will ultimately yield superior information regarding the presence or absence of CACD. For a suspected
dementia, depending on the complaints and the level of impairment
(cognitive and functional), a screening instrument, sparing the
patient’s time and reducing the distress associated with poor performance, is recommended over a more extensive battery. For instance,
the brief Geriatric Assessment (GA),41 which includes a cognitive
screening component and has been validated in clinical cancer trials
and community oncology clinics, may be an appropriate screening
instrument for suspected dementia in older adults with cancer.
Future Directions
CACD has been established as a lingering problem for some non-​
CNS cancer survivors over the past two decades through multiple
research studies with increasing methodological scientific rigor.
Strong interest remains in identifying screening instruments with
sufficient sensitivity and specificity to identify patients who present
with suspected CACD. We recommend that one focus of future research should be on the development of more accurate screening
measures for CACD, and that patient-​reported outcomes be used to
determine whether further screening and assessment is warranted
using objective measures of function.
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receiving adjuvant chemotherapy: a neuropsychological study.
Brain Res. 2013;1533:63–​72. doi:10.1016/​j.brainres.2013.08.015
18. Katzman R, Brown T, Fuld P, Peck A, Schechter R, Schimmel H.
Validation of a short Orientation-​Memory-​Concentration Test
of cognitive impairment. Am J Psychiatry. 1983;140(6):734–​739.
doi:10.1176/​ajp.140.6.734
19. Nakamura ZM, Deal AM, Nyrop KA, Choi SK, Wood WA, Muss
HB. Associations of functional, psychosocial, medical, and socio-​
demographic factors with cognitive screening in chemotherapy
naïve patients with breast cancer. Psychooncology. 2019;28(1):167–​
173. doi:10.1002/​pon.4928
20. Fogel BS. The high sensitivity cognitive screen. Int Psychogeriatr.
1991;3(2):273–​288.
CHAPTER 20 Screening and Assessment for Cognitive Problems
21. Brezden CB, Phillips K-​A, Abdolell M, Bunston T, Tannock IF.
Cognitive function in breast cancer patients receiving adjuvant
chemotherapy. J Clin Oncol. 2000;18(14):2695–​2701. doi:10.1200/​
JCO.2000.18.14.2695
22. Tchen N, Juffs HG, Downie FP, et al. Cognitive function, fatigue,
and menopausal symptoms in women receiving adjuvant chemotherapy for breast cancer. J Clin Oncol. 2003;21(22):4175–​4183.
doi:10.1200/​JCO.2003.01.119
23. Fan HGM, Houédé-​Tchen N, Yi Q-​L, et al. Fatigue, menopausal
symptoms, and cognitive function in women after adjuvant chemotherapy for breast cancer: 1-​and 2-​year follow-​up of a prospective controlled study. J Clin Oncol. 2005;23(31):8025–​8032.
doi:10.1200/​JCO.2005.01.6550
24. Downie FP, Mar Fan HG, Houédé-​Tchen N, Yi Q, Tannock IF.
Cognitive function, fatigue, and menopausal symptoms in breast
cancer patients receiving adjuvant chemotherapy: evaluation
with patient interview after formal assessment. Psychooncology.
2006;15(10):921–​930. doi:10.1002/​pon.1035
25. Vardy J, Wong K, Yi Q, et al. Assessing cognitive function in
cancer patients. Support Care Cancer. 2006;14(11):1111–​1118.
doi:10.1007/​s00520-​006-​0037-​6
26. Loughan AR, Braun SE, Lanoye A. Repeatable Battery for the
Assessment of Neuropsychological Status (RBANS): preliminary
utility in adult neuro-​oncology. Neuro-​Oncol Pract. 2019;6(4):289–​
296. doi:10.1093/​nop/​npy050
27. Jansen CE, Cooper BA, Dodd MJ, Miaskowski CA. A prospective
longitudinal study of chemotherapy-​induced cognitive changes in
breast cancer patients. Support Care Cancer. 2011;19(10):1647–​
1656. doi:10.1007/​s00520-​010-​0997-​4
28. Cheung YT, Tan EH-​J, Chan A. An evaluation on the neuropsychological tests used in the assessment of postchemotherapy cognitive changes in breast cancer survivors. Support Care Cancer.
2012;20(7):1361–​1375. doi:10.1007/​s00520-​012-​1445-​4
29. Yamada TH, Denburg NL, Beglinger LJ, Schultz SK.
Neruopsychological outcomes of older breast cancer survivors: cognitive features ten or more years after chemotherapy. J
Neuropsychiatry Clin Neurosci. 2010;22:48–​54.
30. Anderson-​
Hanley C, Sherman ML, Riggs R, Agocha VB,
Compas BE. Neuropsychological effects of treatments for
adults with cancer: a meta-​analysis and review of the literature.
J Int Neuropsychol Soc JINS. 2003;9(7):967–​
982. doi:10.1017/​
S1355617703970019
31. Falleti MG, Sanfilippo A, Maruff P, Weih L, Phillips K-​A. The nature and severity of cognitive impairment associated with adjuvant
chemotherapy in women with breast cancer: a meta-​analysis of
the current literature. Brain Cogn. 2005;59(1):60–​70. doi:10.1016/​
j.bandc.2005.05.001
32. Jansen CE, Miaskowski C, Dodd M, Dowling G, Kramer
J. A metaanalysis of studies of the effects of cancer chemotherapy on various domains of cognitive function. Cancer.
2005;104(10):2222–​2233. doi:10.1002/​cncr.21469
33. Stewart A, Bielajew C, Collins B, Parkinson M, Tomiak E. A
meta-​analysis of the neuropsychological effects of adjuvant chemotherapy treatment in women treated for breast cancer. Clin
Neuropsychol. 2006;20(1):76–​89. doi:10.1080/​138540491005875
34. Jim SL, Phillips KM, Chait S. Meta-​analysis of cognitive functioning in breast cancer survivors previously treated with
standard-​dose chemotherapy. J Clin Oncol. 2012;30:3578–​3587.
35. Shapiro AM, Benedict RH, Schretlen D, Brandt J. Construct and concurrent validity of the Hopkins Verbal Learning Test-​revised. Clin
Neuropsychol. 1999;13(3):348–​358. doi:10.1076/​clin.13.3.348.1749
36. Reitan RM. Trail Making Test: Manual for Administration and
Scoring. Tucson, AZ: Reitan Neuropsychological Laboratory; 1971.
37. Heaton RK, Miller SW, Taylor MJ, Grant I. Revised Comprehensive
Norms for an Expanded Halstead-​Reitan Battery: Demographically
Adjusted Neuropsychological Norms for African American
and Caucasian Adults. Lutz, FL: Psychological Assessment
Resources; 2004.
38. Wagner LI, Sweet JJ, Butt ZA, Lai JS, Cella D. Measuring patient
self-​reported cognitive function: development of the functional
assessment of cancer therapy-​cognitive function instrument. J
Support Oncol. 2009;7(6):32–​39.
39. Cella D, Riley W, Stone A, et al. The Patient-​Reported Outcomes
Measurement Information System (PROMIS) developed and
tested its first wave of adult self-​reported health outcome item
banks: 2005–​2008. J Clin Epidemiol. 2010;63(11):1179–​1194.
doi:10.1016/​j.jclinepi.2010.04.011
40. Farias ST, Mungas D, Reed BR, et al. The measurement of
Everyday Cognition (ECog): scale development and psychometric
properties. Neuropsychology. 2008;22(4):531–​
544. doi:10.1037/​
0894-​4105.22.4.531
41. Hurria A, Gupta S, Zauderer M, et al. Developing a cancer-​
specific geriatric assessment. Cancer. 2005;104(9):1998–​2005.
doi:10.1002/​cncr.21422
151
SECTION V
Psychological Issues Related
to Site of Cancer
Mark Lazenby (Section Editor)
21 Melanoma 155
Nadine A. Kasparian and Iris Bartula
27 Gynecologic Cancers 196
Heidi S. Donovan and Teresa H. Thomas
22 Lung Cancer 162
Marianne Davies
28 Hematopoietic Dyscrasias and Stem Cell
Transplantation/​CAR-​T Cell Therapy 203
Jesse R. Fann and Nicole Bates
23 Breast Cancer 169
M. Tish Knobf and Youri Hwang
24 Colorectal Cancer 176
Anne Miles and Claudia Redeker
25 Prostate Cancer and Genitourinary
Malignancies 182
Andrew J. Roth and Alejandro Gonzalez-​Restrepo
26 Gastrointestinal Cancers 189
Daniel C. McFarland and William S. Breitbart
29 Head and Neck Cancer 215
Loreto Fernández González, Jonathan Irish, and Gary Rodin
30 Central Nervous System Tumors 221
Alan D. Valentine
31 HIV Infection and AIDS-​Associated
Neoplasms 226
Joanna S. Dognin and Peter A. Selwyn
21
Melanoma
Nadine A. Kasparian and Iris Bartula
Introduction
Comprehensive psychological care of people with melanoma spans
all phases of the disease trajectory, including risk assessment, diagnosis, treatment, recovery, and survivorship, as well as the transition from curative to palliative care, death, and bereavement. Each
person will experience a range of physical, practical, and psychosocial challenges unique to their circumstances. A diagnosis of melanoma has the potential to change many aspects of an individual’s
life from self-​identity, body image, self-​esteem, and perceived well-​
being to family roles and relationships, career opportunities, friendships, and finances. These changes are likely to manifest differently
depending on a range of sociodemographic, disease, and psychological factors. In cancer and other chronic illnesses, high levels of
psychological distress can be associated with reduced engagement
in cancer screening, treatment and risk management recommendations, delays in seeking medical advice, lower satisfaction with clinical care, higher health care costs, poorer social functioning, greater
morbidity and mortality, and poorer overall quality of life (QOL).1
Identifying patients most likely to experience psychological distress
and impaired QOL and facilitating timely engagement with effective
interventions to ameliorate these difficulties remain important clinical and research endeavors.
The objective of this chapter is to provide all members of the
diagnostic and treatment team (dermatologists, oncologists,
surgeons, general practitioners, nurses, psychologists, social
workers, psychiatrists, pathologists, clinical geneticists, genetic
counselors, physiotherapists, occupational therapists), patients,
and families, as well as those in training and research, with an
evidence-​based overview of the psychosocial aspects relevant to
people affected by melanoma.
Melanoma Incidence
Melanoma is a cancer of melanin-​producing cells that most frequently occurs in the skin, but occasionally may present in the
mouth, intestines, or eyes. Worldwide, melanoma accounts for 3%
of all skin cancers and represents 4.5% of all new cancer diagnoses.2
Incidence is increasing, especially in fair-​skinned populations, with
Australia and New Zealand reporting the highest rates of melanoma
in the world.2,3 Increased incidence is commonly attributed to environmental factors, such as ultraviolet radiation (UVR) exposure,
as well as increased screening and early detection practices.3 While
presentations vary, a “typical” patient is most likely to be male, aged
55–​64 years, and fair-​skinned, and to present with a lesion on his
torso.2
Melanoma Risk Factors and Prevention Strategies
Awareness of melanoma risk factors can help target screening and
population-​based prevention strategies (Table 21.1).2,3
Primary prevention strategies aim to reduce UVR exposure, while
secondary prevention strategies aim to improve early disease detection (Table 21.2).
Level of implementation and success of prevention strategies vary
across countries. Effects of primary prevention strategies have been
limited in the United Kingdom, the United States, Norway, and
Sweden, while Australia has achieved a demonstrably slowing incidence of melanoma following broad implementation.3 National
screening policies also vary; Germany, for example, recommends
routine skin cancer screening for all adults aged over 35 years,
while the United States does not have a national screening program.
Clinical guidelines are consistent in recommending regular surveillance for people at high risk of melanoma.4
Melanoma Staging
Staging of melanoma includes consideration of tumor characteristics, presence of lymph node involvement, and distant metastases,
factors associated with survival. Evidence-​based guidelines outline
five stages:
• Stage 0 (melanoma in situ)—​tumor is confined to the outer layers
of the skin (epidermis), with no evidence of spreading.
• Stages I and II—​no evidence of lymph node involvement or distant metastases. Stages I and II are distinguished by lesion depth
(Breslow thickness) and presence of ulceration (invasion of surrounding tissue).
• Stage III—​evidence of regional lymph node involvement.
156
SECTION V Psychological Issues Related to Site of Cancer
Table 21.1. Melanoma Risk Factors
*
Risk Factor
Features That Increase Risk
Ultraviolet radiation (UVR) exposure
•
•
•
•
Skin, hair, and eye pigmentation
• Fairer pigmentation.
• Tendency for skin to freckle or burn in sun.
Nevi* number and characteristics
• Presence of more than 100 nevi.
• More than 2 dysplastic (atypical) nevi.
Gene mutations
(implicated in 5–​12% of all melanomas)
• Strong family history of melanoma
(≥3 first-​degree relatives with melanoma)
• One or more first-​degree relatives with a diagnosis of pancreatic cancer.
• Personal history of multiple melanomas.
• Mutations in tumor suppressor gene CDKN2A.
Intermittent, short, intense UVR exposure increases cutaneous melanoma risk.
Chronic, cumulative UVR exposure increases lentigo maligna melanoma risk.
Childhood sun exposure.
UVR exposure resulting from indoor tanning.
Collection of benign melanin-​producing cells.
• Stage IV—​evidence of distant metastases to skin, soft tissue,
muscles, nonregional lymph nodes, lungs, abdomen, bones, or
the brain.
Melanoma Survival and Mortality
Among skin cancers, melanoma has the highest mortality. Globally,
mortality rates steadily increased in the 1980s, peaked in 1988–​
1990, then maintained a slow increase.3 Females and younger patients tend to have better survival.3,4 Five-​year survival for patients
with early, localized melanoma is excellent, ranging from 82% (Stage
II) to 99% (Stage I). Five-​year survival rates for Stage III patients
range from 32% to 93%, depending on tumor characteristics and
number of lymph nodes involved. Survival for Stage IV patients is
low (15–​20%) but improving with rapid advances in new targeted
and immunotherapies.4
Melanoma Treatments
Stage I–​III melanoma is typically treated with wide local excision,
to prevent local recurrence at the margin or near the initial lesion.
Some patients may require sentinel lymph node biopsy to investigate
the presence of micro-​metastases. Surgery may be offered to Stage
IV patients with the goal of palliation (symptom management), with
some evidence of improved survival.5 Adjuvant systemic therapy is
used to prevent disease recurrence or progression (spread to other
organs).4 Targeted and immunotherapies have been shown to improve survival of Stage IV patients.4,5 Chemotherapy may be offered
to Stage IV patients for symptom control. Radiation therapy may be
offered to patients at increased risk of recurrence to achieve better
local and regional control, and to patients with metastatic melanoma
to reduce pain and neurocognitive symptoms associated with brain
metastases. It is usually used in combination with other systemic
treatements.5
Quality of Life
QOL is a key consideration, particularly as novel medical therapies
increase the likelihood of longer-​term survival for people with advanced disease. Early-​stage melanoma patients appear to have QOL
similar to that of the general population.6 QOL impairments are
most common immediately postdiagnosis and gradually improve
over time. Poorer physical health and greater comorbidities are the
most consistent correlates of poorer QOL, while patient age, sex,
and social support are inconsistently associated with QOL.6 Patients
with advanced melanoma participating in clinical trials of targeted
and immunotherapies may report improved QOL; however, evaluation of the relationship between adverse treatment effects (including
new concomitant toxicities), difficulties with ongoing adherence to
oral therapies, and QOL, without excluding patients who discontinue therapy, is needed.7
Routine QOL assessment is strongly recommended and measures can be broadly grouped into three categories: (1) melanoma
specific, (2) cancer specific, and (3) generic measures, with some
studies suggesting generic measures may not be sensitive to functional changes associated with melanoma,6 while others provide
conflicting evidence.8
Table 21.2. Melanoma Prevention Strategies
Primary Prevention Strategies
Secondary Prevention Strategies
• Sun protection policies (e.g., mandatory sun protection factor labeling
• Screening using visual skin examination. This can be achieved by inspection of the
on sunscreens).
• Population-​based education on, and encouragement of, sun-​safe
behaviors (e.g., use of broad-​spectrum sunscreen; protective clothing,
hats, and sunglasses; avoidance of outdoors when ultraviolet radiation
(UVR) is above 3).
entire skin surface, conducted by either
-​ nonphysician, usually the patients themselves (skin self-​examination [SSE]) or a
partner (partner skin examination [PSE]), or
-​ medical professional, usually a dermatologist (clinical skin examination [CSE],),
which may include the use of total body photography, dermoscopy, and/​or
confocal microscopy.
CHAPTER 21 Melanoma
Physical Functioning
Surgery may result in pain, numbness, and lymphedema (localized
swelling of the body that may result from lymph node dissection).
Physical concerns tend to be most prevalent immediately following
surgery, with most symptoms improving over time or with physical
therapy, while other difficulties (e.g., lymphedema) may require ongoing management.9 Fatigue is common following systemic and radiation therapy, or in the context of vitamin D deficiency that may
arise due to restricted sun exposure10 with consequences for QOL,
functional capacity, and well-​being. Patient age, additional chronic
health conditions, higher self-​blame and fear of cancer recurrence,
and lower social support are associated with greater fatigue. The
Clinical Oncology Society of Australia has recommended exercise
as a safe and effective strategy for managing cancer-​related fatigue,
as well as providing other physical and mental health benefits; however, implementation may be difficult, as patients often perceive fatigue as a barrier to regular exercise, despite perceiving exercise as
helpful.10
Body Image Concerns
Change in body image resulting from surgical scars or lymphedema
can alter self-​
perceptions and impact intimate relationships.9,11
Body image concerns often arise when there is a discrepancy between anticipated and actual scar appearance. People with melanoma frequently report feeling inadequately prepared for the
changes resulting from surgery and perceiving a mismatch between
surgeons’ and their own perceptions of a healing scar. Women tend
to be at greater risk of body image disturbance than men, and body
image concerns are associated with greater anxiety and depression, as well as lower QOL.9,11 Use of clothing to cover scars and
lymphedema, cognitive strategies (e.g., perspective-​taking), and social support have been identified by melanoma patients as helpful in
coping with body image concerns,9,11 but evidence-​based psychological interventions to support patients with body image disturbance are lacking.
Social Functioning
While many patients report relying mostly on family and friends for
support, some describe concerns sharing information about their
diagnosis and treatment, for fear of the emotional impact on family
members. This may leave some patients feeling isolated and preferring support from other melanoma patients with similar concerns
and experiences.9 Overall, social support tends to predict adjustment to melanoma diagnosis and treatment, with advanced cancer
patients reporting the greatest difficulties in social functioning.11
Melanoma diagnosis may also lead to altered social activities to reduce sun exposure, as well as attempts to educate family and friends
about melanoma and its risk factors. Some patients report substantial financial stress, especially if they are unable to work due to
treatment or illness. Patients have also expressed concerns the community may not perceive melanoma as a serious health condition,
given most melanomas are detected early and are associated with
good prognosis. This may minimize the validity of patients’ needs
and concerns and impede timely access to support.9
Psychological Functioning
Many patients experience the period of diagnostic uncertainty between detection of a suspicious lesion and receipt of skin biopsy
results as highly stressful.12 Following diagnosis, patients often
experience shock and intense fear, sadness, and/​or anger. Anxiety
is frequently reported by patients in the days and weeks before
follow-​up appointments and may manifest both physically and
psychologically, including symptoms such as diarrhea, nausea, and
sleeplessness. As some patients enter palliative care, anxiety about
the end of life, symptom management, and existential issues are
commonly reported. The distress evoked by these transitions may
not only cause immediate suffering but also influence a range of patient behaviors;9,11 thus, understanding the range of emotional, behavioral, and physical responses to melanoma (Table 21.3), as well
as effective and sustainable interventions to reduce distress, remains
an important clinical and research endeavor.
Mental Health
At least 30% of people with melanoma report levels of psychological
distress, particularly anxiety, indicative of a need for clinical intervention.12 While depression and anxiety commonly coexist, anxiety
is uniquely characterized by symptoms of pervasive and uncontrollable worry, whereas depression is typified by prolonged low mood,
increased irritability, social withdrawal, and diminished interest
or pleasure in activities. Reported prevalence of psychological distress varies across studies, potentially reflecting sample differences
in melanoma type and stage, time since diagnosis, treatment type,
timing and method of data collection, clinical trial involvement, environment (e.g., areas of high versus low UVR exposure), and cultural differences. Anxiety is reported by 20–​32% of patients, while
15–​19% report symptoms indicative of depression.11,12 Melanoma
Table 21.3. Common Emotional, Behavioral, and Physical Responses to the Diagnosis of Skin Cancer
Emotional Responses
Behavioral Responses
Physical Responses
•
•
•
•
•
•
•
•
•
•
•
• Social withdrawal or an increased need to be with others
• Hypervigilance with sun protection and early skin cancer detection, or
•
•
•
•
•
•
•
Shock
Feeling “numb”
Disbelief
Fear and worry
Anxiety
Anger
Confusion
Uncertainty
Sadness or distress
Depression
Grief
disengagement from screening and health behavior recommendations
• Delays in seeking medical care
• Altered interest in and disengagement from pleasurable activities
• Substance misuse
Sleep disturbance
Appetite changes
Headaches
Heart palpitations
Nausea
Changes in bowel movements
Difficulty concentrating
157
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SECTION V Psychological Issues Related to Site of Cancer
patients report the third highest four-​week prevalence of any psychological disorder (39%), behind only breast (42%) and head and
neck (41%) cancer patients.13
Fear of Cancer Recurrence or Progression
Extensive evidence shows people who have had melanoma experience marked and enduring fear of cancer recurrence (FCR). FCR
is typically defined as fear, worry, or concern relating to the possibility that cancer will come back or progress. FCR is generally
greatest in the days and weeks prior to medical consultations12
and may manifest as (1) preoccupation, worry, rumination, or
intrusive thoughts about cancer; (2) maladaptive coping; (3) impairments in daily functioning; (4) intense distress; and (5) difficulties thinking about the future. While some degree of fear is a
normal response to cancer, high levels are associated with anxiety
and depression, reduced participation in cancer screening, delays in seeking medical care, lower satisfaction with clinical care,
higher health care costs, poorer social functioning, greater morbidity and mortality, and poorer quality of life.1 An Australian
study found 72% of early-​stage melanoma patients reported levels
of FCR indicative of a need for clinical intervention at least two
years after initial diagnosis, irrespective of actual recurrence
risk.14 The uncertainty that drives cancer-​related fear and anxiety
may be even greater for those affected by advanced disease, where
the longer-​term outcomes of fast-​changing medical treatments
are not fully known.
People with melanoma want help with FCR; assistance with “fears
about the cancer spreading” is the most frequently endorsed, and
most distressing, unmet need reported by melanoma patients soon
after diagnosis and years later. A population-​based cohort study of
2,615 cancer survivors (n = 469 melanoma) found that satisfaction
with information provision was associated with lower FCR,15 suggesting that clear information about recurrence risk and management strategies may at least partially alleviate FCR. Patients with
high FCR are likely to benefit from interventions featuring both
psychoeducation and psychotherapy.16,17
Familial Melanoma and Psychological Distress
Kasparian et al.18 examined psychological responses reported by
Australians who were informed of the identification of a family-​
specific mutation in the CDKN2A gene, which, in Australia, is associated with a lifetime melanoma risk of 91%. Following notification,
levels of anxiety and depressive symptoms in this cohort were comparable to population norms.18 In a prospective cohort study examining outcomes of genetic testing for melanoma risk, Kasparian
et al.19 found that compared to baseline, individuals identified as
carriers of a pathogenic CDKN2A mutation reported significantly
reduced anxiety at 2 weeks, and reduced depression at 2 weeks and
12 months, following receipt of genetic test results. Carriers also
reported a greater frequency of clinical skin examination at 12-​
month follow-​up, providing evidence of healthy psychological and
behavioral adjustment following participation in genetic testing for
melanoma risk.
Factors That Increase Vulnerability
to Psychological Distress
A variety of factors may increase vulnerability to psychological distress in people with melanoma (Table 21.4). Beliefs about melanoma
and its treatment and prognosis may play a greater role in determining stress responses than disease factors.20 Decline in physical
functioning is also a key correlate; compared with patients experiencing low distress, those who report high distress also report worse
evaluations of current and future health, greater pain, lower energy,
and greater interference in daily functioning.21
Coping and Resilience
Psychological outcomes associated with melanoma are influenced,
at least in part, by a person’s coping responses, which can be defined as beliefs and behaviors with an adaptive purpose during
times of threat or adversity.2 Patients who adopt active coping
strategies demonstrate better adjustment to melanoma and longer
relapse-​free periods compared to those who adopt passive or
avoidant strategies (Table 21.5).12 While some patients, particularly those with advanced melanoma, may feel overwhelmed by the
physical and psychological consequences of their disease, the multidisciplinary health care team can support coping through open,
patient-​centered communication and empathic acknowledgment
of patients’ needs and concerns, and by adopting a holistic approach to QOL.11
Supportive Care Needs
A large, multicenter study carried out in Australia found that over
90% of patients with early-​stage melanoma reported at least one
unmet supportive care need following diagnosis.22 Of the 10 most
highly ranked unmet needs, three were psychological (FCR, uncertainty about the future, concerns or worries about others) and seven
were informational, including an unmet need for greater information on melanoma recurrence and progression, treatment options,
and preventive behaviors.22 Unmet supportive care needs are also
commonly reported by advanced melanoma patients, with about
Table 21.4. Demographic, Clinical, and Psychosocial Factors Associated with Increased Vulnerability to Emotional Distress in People
with Melanoma
Demographic Factors
Clinical Factors
Psychosocial Factors
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Female gender
Younger age
Lower educational attainment
Unemployment
Financial hardship
Greater physical deterioration
Lower physical quality of life
Greater functional impairments
Diagnosis of advanced melanoma
Greater treatment toxicity effects
Fatigue
Limited social and instrumental (practical) support
Absence of a spouse or a committed partner
Negative beliefs about melanoma
Greater fear of cancer recurrence or progression
Passive or avoidant coping styles
Concerns about the implications of melanoma for
one’s family
• History of mental illness
CHAPTER 21 Melanoma
Table 21.5. Common Coping Styles
Coping Style
Brief Description
Examples
Active-​behavioral coping
Overt behavioral attempts to deal directly
with melanoma and its effects
•
•
•
•
•
Active-​
cognitive
coping
Attitudes, beliefs, thoughts, and perceptions
about melanoma
•
•
•
•
Avoidance
Attempts to actively avoid the problem or
indirectly reduce emotional tension through
distraction
• Denial of the diagnosis or the need for treatment
• Disengagement from treatment or screening regimes
• Avoidance of any reminders that are associated with melanoma (e.g., not driving
Enlisting the help and support of others
Seeking and accepting professional and/​or peer support
Adhering to treatment and screening protocols
Seeking relevant information
Adopting a healthier lifestyle (e.g., improving diet, exercise, sleep, work-​life
balance)
• Use of complementary therapies in addition to recommended medical treatment
Accepting the reality of one’s illness
Acceptance of one’s emotional responses
Forming realistic beliefs and expectations
Creating time and space to think about and make sense of one’s experiences and
the cancer-​related information provided
past the skin cancer clinic)
• Overuse of distraction at the cost of quality of life
• Compulsive internet searches about diagnosis and treatment, searching for
examples of positive outcomes
• Substance use or abuse
half of patients with Stage III/​IV melanoma reporting concerns regarding their understanding of treatment options and potential side
effects, as well as unmet needs related to coping with fear of cancer
progression, living with uncertainty, anxiety, depression, and concern about loved ones.11
Mental Health Care for People with Melanoma
Clinical practice guidelines consistently recommend structured
psychological interventions be made available to all melanoma
patients. Numerous psychoeducational interventions comprising
various combinations of education (e.g., on risk of recurrence), behavioral or skills training (e.g., skin self-​examination), and/​or psychotherapy (e.g., working through emotional responses to cancer)
have been developed to meet this need.23 Interventions vary in intensity (e.g., single versus multiple sessions), mode of delivery (e.g.,
face to face, telehealth, digital or web based), delivery agents (e.g.,
psychologists, nurses, social workers, general practitioners, dermatologists, peers), and therapeutic modalities used (e.g., cognitive
behavioral therapy, brief psychodynamic psychotherapy, structured
psychoeducation)—​but all share a common goal to assist people
with melanoma to adjust physically and psychologically to the disease and its treatment.
Educational interventions appear generally effective in
improving melanoma knowledge and skin self-​examination efficacy and engagement, while psychotherapeutic interventions
have demonstrated efficacy in reducing fear of cancer recurrence, psychological distress, depression, and anxiety.23 Dieng
et al., for example, examined the effects of a brief psychological
intervention targeting FCR in patients at high risk of developing
another primary melanoma. The intervention consisted of a
psychoeducational resource25coupled with three telehealth-​based
psychotherapy sessions individualized to address each patient’s
support needs and preferences.16,17 Participants were randomized
to receive the intervention (n = 80) or usual care (n = 84), with
psychotherapy sessions timed in relation to dermatological appointments. Significant improvements in FCR severity, psychological stress, and melanoma knowledge were found for intervention
group participants immediately posttreatment and at six months
postintervention,16 and improvements in FCR persisted to at least
12 months postintervention.17
Cost-​Effectiveness of Psychological Interventions
As evidence for the efficacy of psychological interventions grows,
studies evaluating the fiscal costs of mental health care are also
needed to guide implementation and allocation of limited health resources. In Australia, Dieng et al.25 prospectively evaluated the cost-​
effectiveness of a brief psychological intervention to reduce FCR in
early-​stage melanoma patients. The mean cost of the intervention
was AU$1,614 per participant (including intervention development
costs), and the cost-​effectiveness acceptability curve demonstrated
a 78% probability of the intervention being cost-​effective relative to
the control (usual care) at a threshold of AU$50,000 per extra person
avoiding FCR. From the perspective of the Australian health system,
this represents good value for money.
Current Care and Future Directions
A stepped care approach, where people with melanoma are offered
increasingly comprehensive information and mental health care as
their level of need increases, may ensure optimal health outcomes.
As a first step, all patients presenting at a pigmented lesion, oncology,
or dermatology clinic should be provided with detailed information
regarding their condition and emotional support from their primary health care provider, to address patient needs at this highly
stressful time. Box 21.1 provides strategies to use in consultations
to facilitate patient understanding of information and psychological
adjustment.
159
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SECTION V Psychological Issues Related to Site of Cancer
Box 21.1. Interactional Skills and Communication Strategies
to Support Mental Health and Reduce Unmet Needs in People
with Melanoma
Interactional Skills and Communication Strategies
• Open and empathic discussion of the diagnosis, treatment, prognosis, and life expectancy, as well as how the cancer might affect
other aspects of the patient’s life
• Face-​to-​face communication in a quiet and private environment
• Use of verbal and nonverbal cues to show empathy and emotional
support
• Initiating communication about emotional well-​being
• Exploration of the patient’s thoughts, feelings, and concerns
• Active listening
• Providing time and space for reflection and questions
• Encouraging the patient to be involved in treatment decisions
• Full and clear explanation of all medical terms used
• Checks of patient’s understanding and recall of information
• Sensitivity to the person’s age, gender, ethnicity, literacy level, and
cultural background
• Having the people wanted by the patient present in the consultation
• Provision of information about what a patient is likely to experience
before, during, and after a procedure or clinical encounter
• Use of simple diagrams and pictures to support communication,
where appropriate
• Provision of a tape of, or written information summarizing, the
consultation
• Use of a “question prompt sheet” to help the patient ask potentially
relevant and important questions
In addition to considering the vulnerability factors for psychological distress in Table 21.4, routine screening with a brief
screening tool, such as the Distress Thermometer, may assist in
identifying patients requiring additional support. Some patients
who screen positively on the Distress Thermometer may not want
psychological treatment but could benefit from educational interventions,23 while those who screen positively and want additional
psychological care may benefit from interventions including psychotherapy alongside education.16 Recently there has been an explosion of research into online delivery of mental health care (i.e.,
eHealth or mHealth) to increase accessibility and affordability and
bring effective interventions to scale. Meta-​analytic evidence suggests small to moderate effect sizes, often equivalent to face-​to-​face
care.26 While we know of no online or smartphone applications
(“apps”) specifically designed to meet the psychological needs of
melanoma patients, there are a growing number of apps for the
monitoring or tracking of skin lesions, and this area is likely to expand exponentially in the future.
Tailored education and skills-​based training on how to recognize
and address the needs of patients experiencing psychological difficulties, including timely referral to appropriate resources and services, is recommended for health professionals. While an empathic,
patient-​centered approach can greatly assist patients and their families, recognition of the emotional challenges, including burnout and
compassion fatigue, experienced by health professionals working in
this field is also vital. Strategies to address these concerns are likely
to lead to improved therapeutic relationships and enhanced professional and patient satisfaction.
REFERENCES
1. Simard S, Thewes B, Humphris G, et al. Fear of cancer recurrence
in adult cancer survivors: A systematic review of quantitative
studies. J Cancer Survivorship. 2013;7:300–​322.
2. Yamamoto M, Sondak VK. Epidemiology, Risk Factors, and Clinical
Presentation of Melanoma. New York: Oxford University Press; 2015.
3. Matthews NH, Li W, Qureshi AA, Weinstock MA, Cho E.
Epidemiology of melanoma In: Ward WH, Farma JM, eds.
Cutaneous Melanoma Etiology and Therapy. Brisbane, Australia:
Codon Publications; 2017.
4. Schadendorf D, van Akkooi ACJ, Berking C, et al. Melanoma.
Lancet. 2018;392(10151):971–​984.
5. Ko JM, Geller AC, Swetter SM. Melanoma In: The American
Cancer Society’s Oncology in Practice. Hoboken, NJ: John Wiley &
Sons; 2018.
6. Hamel JF, Pe M, Coens C, et al. A systematic review examining
factors influencing health related quality of life among melanoma
cancer survivors. Eur J Cancer. 2016;69:189–​198.
7. Malkhasyan KA, Zakharia Y, Milhem M. Quality-​of-​life outcomes
in patients with advanced melanoma: A review of the literature.
Pigment Cell Melanoma Res. 2017;30(6):511–​520.
8. Dieng M, Kasparian NA, Cust AE, et al. Sensitivity of preference-​
based quality-​of-​life measures for economic evaluations in early-​
stage melanoma. JAMA Dermatol. 2018;154(1):52–​59.
9. Vogel RI, Strayer LG, Ahmed RL, Blaes A, Lazovich D. A qualitative study of quality of life concerns following a melanoma diagnosis. J Skin Cancer. 2017;2017:2041872.
10. Hyatt A, Drosdowsky A, Williams N, et al. Exercise behaviors and
fatigue in patients receiving immunotherapy for advanced melanoma: A cross-​sectional survey via social media. Integr Cancer
Ther. 2019;18:1534735419864431.
11. Dunn J, Watson M, Aitken JF, Hyde MK. Systematic review of
psychosocial outcomes for patients with advanced melanoma.
Psychooncology. 2017;26(11):1722–​1731.
12. Kasparian NA, McLoone JK, Butow PN. Psychosocial responses
and coping strategies among patients with malignant melanoma: A systematic review of the literature Arch Dermatol.
2009;145(12):1415–​1427.
13. Mehnert A, Brähler E, Faller H, et al. Four-​week prevalence of
mental disorders in patients with cancer across major tumor
entities. J Clin Oncol. 2014;32(31):3540–​3546.
14. Costa DSJ, Dieng M, Cust AE, Butow PN, Kasparian NA. Psychometric
properties of the Fear of Cancer Recurrence Inventory: An item response theory approach. Psycho-​Oncol. 2016;25(7):832–​838.
15. van de Wal M, van de Poll-​Franse L, Prins J, Gielissen M. Does
fear of cancer recurrence differ between cancer types? A study
from the population-​
based PROFILES registry. Psycho-​Oncol.
2016;25(7):772–​778.
16. Dieng M, Butow PN, Costa D, et al. Psycho-​educational intervention to reduce fear of cancer recurrence in people at high risk of
developing another primary melanoma: Results of a randomised
controlled trial. J Clin Oncol. 2016;34(36):4405–​4414.
17. Dieng M, Morton RL, Costa DSJ, et al. Benefits of a brief psychological intervention targeting fear of cancer recurrence in
people at high risk of developing another melanoma: 12-​month
follow-​up results of a randomized controlled trial. Br J Dermatol.
2020;182(4):860–​868.
18. Kasparian N, Meiser B, Butow P, Simpson J, Mann G. Predictors
of psychological distress among individuals with a strong family
history of malignant melanoma. Clin Genet. 2008;73:121–​131.
CHAPTER 21 Melanoma
19. Kasparian N, Meiser B, Butow P, Simpson J, Mann G. Genetic
testing for melanoma risk: A prospective cohort study of uptake and outcomes among Australian families. Genet Med.
2009;11(4):265–​278.
20. Hamama-​Raz Y, Solomon Z, Schachter J, Azizi E. Objective and
subjective stressors and the psychological adjustment of melanoma survivors. Psycho-​Oncol. 2007;16:287–​294.
21. Trask PC, Paterson AG, Hayasaka S, Dunn RL, Riba M, Johnson
T. Psychosocial characteristics of individuals with non-​stage IV
melanoma. J Clin Oncol. 2001;19(11):2844–​2850.
22. Beesley VL, Smithers BM, Khosrotehrani K, et al. Supportive care
needs, anxiety, depression and quality of life amongst newly diagnosed patients with localised invasive cutaneous melanoma in
Queensland, Australia. Psychooncology. 2015;24(7):763–​770.
23. McLoone JK, Menzies SW, Meiser B, Mann GJ, Kasparian NA.
Psycho-​educational interventions for people affected by melanoma: A systematic review. Psycho-​Oncol. 2013;22:1444–​1456.
24. Kasparian NA, Mireskandari S, Butow PN, et al. “Melanoma:
Questions and answers.” Development and evaluation of a psycho-​
educational resource for people with a history of melanoma.
Support Care Cancer. 2016;24(12):4849–​4859.
25. Dieng M, Khanna N, Kasparian NA, et al. Cost-​effectiveness of
a psycho-​educational intervention targeting fear of cancer recurrence in people treated for early-​stage melanoma. Appl Health
Econ Health Policy. 2019;17(5):669–​681.
26. Kim AR, Park HA. Web-​based self-​management support interventions for cancer survivors: A systematic review and meta-​
analyses. Stud Health Technol Inform. 2015;216:142–​147.
161
22
Lung Cancer
Marianne Davies
Introduction
In the past decade, there have been significant advances in the treatment of non–​small cell lung cancer. Despite these advances, lung
cancer remains the leading cause of cancer-​related mortality worldwide. Lung cancer is usually diagnosed at advanced stages, associated with complex disease-​related symptoms, leading to overall
poor prognosis. As a result, patients, their families, and their caregivers experience significant levels of psychosocial distress, greater
than those with other cancers. This chapter will provide an overview
of the burden of lung cancer, associated preventative risk factors,
screening recommendations, diagnostic considerations, treatment
landscape, and psychological considerations through the disease
trajectory.
Epidemiology
Lung cancer is the leading cause of cancer-​related deaths in the
United States (US) and worldwide. In 2018, over 2 million persons
were diagnosed with lung cancer, with 1,761,007 associated death
worldwide. This accounts for 18% of cancer-​related deaths.1,2 In the
US alone, it is estimated that there will be 228,820 new cases with
135,720 deaths. This accounts for 25% of all cancer deaths, more
than breast, prostate, colorectal, and brain combined.3 Survival rates
have slowly improved over the past years. Approximately 57% of
patients are diagnosed with advanced-​stage disease, with a 5-​year
relative survival of only 5%. For those diagnosed with regional disease, the 5-​year relative survival rate is 33%, and for those with localized disease, it is 61%.3 With diagnostic and treatment advances,
the number of people living longer with lung cancer is expected to
grow, contributing to a larger population living with complex needs.
Worldwide, lung cancer incidence is increasing for men and
women, with rates higher in developed countries.1 In contrast,
lung cancer death rates in the US have dropped by 51% among
males since 1990 and by 26% in females since 2002.3 This is the
most rapid decline in recent years. The decline in death rates in the
US reflects tobacco cessation patterns, while the rise in incidence
worldwide is associated with increased tobacco use. In contrast,
there is an increasing incidence of lung cancer in never smokers
(LCINS). LCINS is the seventh leading cause of death in the US and
worldwide. It accounts for approximately 15% of cases in the US and
25% of new cases worldwide.1,3 LCINS is more common in women
than men.4 There has also been an emerging trend of increased incidence of lung cancer in young women compared with young men,
not correlated with smoking patterns, suggesting gender-​specific
histologic changes in the lung over time.5
Lung cancer patterns are influenced by smoking habits, age,
gender, race/​ethnicity, socioeconomic region, and education level.
The median age of diagnosis among smokers is 70 years old. The risk
of death from smoking-​related lung cancer is correlated with age of
initiation, with greatest risk in those who begin in their early teens or
younger. It is also influenced by the number of packs smoked, total
number of years, depth of inhalation, and type of product smoked.
The incidence and mortality from lung cancer vary by race and ethnicity within each country. This may be attributed to access to care,
later stage at diagnosis, and environmental influences. Mortality
rates are higher in lower socioeconomic regions and among those
with less than a high school education.
Risk Factors
The single greatest risk for development of lung cancer is smoking,
attributed to 90% of cases, outweighing all other factors combined.
People who smoke are 15% to 30% more likely to develop lung
cancer than nonsmokers. Second-​hand smoke contributes to 7,000
deaths from lung cancer in the US alone.3 Both primary and secondary smoke impact are dose dependent. Electronic cigarettes,
sometimes called vapes, have sparked considerable controversy over
risks from long-​term use. The devices deliver nicotine, along with
other chemicals, into the lungs. Initially marketed as a tool to support smoking cessation, there has been societal uptake in use, particularly among children and young adults. Use of these devices is
associated with greater risk of subsequent cigarette smoking. There
is also an increased risk of addiction, permanent lung damage, and
cancer with use. The risk is increased for users of multiple tobacco
products.6 The Centers for Disease Control and Prevention (CDC),
US Department of Health and Human Services, and US Surgeon
General have partnered to promote a national campaign, “Know the
Risks: e-​Cigarettes & Young People,”6 aimed at the reduction of use
of e-​cigarettes in the young population.
CHAPTER 22 Lung Cancer
In the US, the second leading cause of lung cancer is due to
radon, contributing to 20,000 deaths per year.3 Radon, a naturally
occurring radioactive gas released from soil as it decays, can seep
into homes and get trapped. Persons’ exposure to asbestos, historically found in insulation, in the workplace (i.e., shipyards, building
contractors, mines, and factories) are several times more likely to
die from lung cancer. This risk is increased in people who smoke.
Additional hazardous exposures include metals (i.e., chromium,
cadmium, arsenic), radiation exposure (i.e., chest radiation), air pollution, diesel exhaust, aromatic hydrocarbons, indoor air pollution
from use of unprocessed fossil fuels, and biomass (coal and wood).
Several additional factors have been suggested to contribute to lung
cancer, including history of chronic lung infections or injuries, age,
and genetic predispositions. Diets rich in cruciferous vegetables and
fruits may exert some protection, while high intake of red meats may
increase the risk of developing lung cancer.
Prevention and Early Detection
Cigarette smoking is the number one preventable cause of disease
and lung cancer. Prevention of smoking uptake and promotion of
smoking cessation efforts is the most impactful strategy to reduce
the lung cancer burden worldwide. Smoking cessation before the
age of 40 reduces the risk of dying from smoking-​related disease by
about 90%. Former smokers remain at increased risk of developing
lung cancer; however, by 10 years after quitting, the risk of dying
from lung cancer is half of that of one who continues to smoke.6
Smoking cessation after lung cancer diagnosis offers many physical
and mental benefits. This includes better outcomes from cancer-​
directed treatment, faster recovery from treatments, improved
survival, and improved health-​related quality of life (HRQOL).7
Continuing to smoke, after a lung cancer, is associated with an increase in treatment-​related complications, decreased efficacy of
treatments, decreased HRQOL, increased risk of recurrence, development of second cancers, and decreased survival.8 Counseling
and motivational interviewing can be effective strategies to support smokers through the cessation process. Electronic cigarettes
and other nicotine substitutes may be helpful when used as part
of an evidence-​based smoking cessation program with cognitive-​
behavioral intervention. Disappointingly, many patients continue
to smoke beyond diagnosis. Stigma and nihilism, on the part of patients and health care providers, may influence referrals to and participation in smoking cessation efforts. It is imperative of all health
care providers to encourage and provide access to smoking cessation
programs.
Early-​stage lung cancer is usually asymptomatic. The survival
rate of persons diagnosed at a localized stage approximates 61%.
Unfortunately, a large percentage of patients present with advanced
disease, when a patient is symptomatic. The National Lung Cancer
Screening Trial (NLST), a large randomized controlled study of over
50,000 healthy individuals at high risk for lung cancer, demonstrated
that screening with a low-​dose computed tomography (LDCT) scan
led to a 20% relative reduction in the mortality from lung cancer
compared with standard yearly chest x-​ray.9 Based on these results,
the US Preventive Services Task Force (USPSTF), the American
Cancer Society (ACS), and several other organizations recommend
annual screening of high-​risk individuals aged 55 to 80 years with
a 30-​pack-​year smoking history who currently smoke or who have
quit within the past 15 years.10 However, there is a high rate of benign nodules, and thus false positives, identified.
Shared decision-​making strategies should be incorporated to
guide patients through the evaluation of the potential benefits, risks,
and harm of screening. The screening process may infer psychosocial benefits (i.e., earlier diagnosis and potential for behavior change
such as smoking cessation) as well as harms (i.e., worry, fear, distress with false-​positive results, or unwarranted reassurance with
false-​negative results). The American Thoracic Society (ATS) and
American College of Chest Physicians (ACCP) stress the importance of a structured, multidisciplinary screening program that includes patient counseling, support, and follow-​up.11
Patients with more advanced lung cancer often have subtle symptoms for several months before seeking medical evaluation. The
most common symptoms in patients are dry cough, dyspnea, fatigue, weight loss, chest pain, hemoptysis, and hoarseness. Weight
loss and poor performance status at presentation are poor prognostic indicators of overall survival. All patients suspected of having
lung cancer should begin prompt diagnostic evaluation.
Diagnosis, Classification, and Staging
The initial diagnostic imaging test obtained is typically a chest x-​
ray, which should be compared to prior chest imaging to determine changes. All suspicious findings on x-​ray or exam should be
evaluated further by chest computed tomography (CT) or positron
emission tomography (PET) scan. Additional diagnostic imaging,
including CT of the abdomen/​pelvis and magnetic resonance imaging (MRI) of the brain, may be indicated to determine the extent
of disease burden. The extent of disease identified will guide the next
steps in diagnosis.
Patients suspected of lung cancer on diagnostic imaging must undergo a tissue biopsy. Biopsy can be obtained through endobronchial
ultrasound (EBUS), bronchoscopy, transthoracic CT-​guided biopsy,
or thoracentesis. If the patient is a candidate for surgical resection,
a mediastinoscopy should be done for biopsy and staging of mediastinal node involvement. The least invasive biopsy with highest
potential yield of tissues is recommended. Adequate tumor tissue is
necessary for histologic classification, immunohistochemical (IHC)
analysis, and focused molecular profiling. A liquid biopsy is an alternative strategy for diagnosis if insufficient tissue is obtained at
biopsy, a tumor is not accessible by conventional methods, or the
patient is too frail to undergo an invasive procedure. Liquid biopsy
captures circulating tumor cells, and tumor DNA fragments from
blood, serum, urine, and pleural fluid can be evaluated for histologic
classification and molecular profiling.
There are two major classifications of lung cancer: non–​small cell
lung cancer (NSCLC), making up 85%, and small cell lung cancer
(SCLC), accounting for 15%. NSCLC is further classified into three
histologic subtypes: adenocarcinoma (40%), squamous cell carcinoma (25%), and large cell carcinoma (10%).12 Adenocarcinoma
is the most common variant identified in LCINS. There have been
major advances in the identification of driver gene mutations in lung
cancer through molecular profiling. All patients with confirmed
advanced-​stage lung cancer should undergo additional mutational
testing at time of diagnosis, to direct potentially efficacious targeted
163
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SECTION V Psychological Issues Related to Site of Cancer
therapies and avoidance of therapies unlikely to be of benefit. There
are several different testing platforms available and these will vary
across institutions. In some cases, tissue specimens may have to be
sent out to third-​party testing sites.
Programmed death ligand-​1 (PD-​L1) a coregulator molecule that
can be expressed on tumor cells and inhibit T-​cell-​mediated cell death.
T-​cells express PD-​1, a negative regulator. Binding of PD-​1 to PD-​L1/​
PD-​L2 leads to suppression of T-​cell activity. CTLA-​4 is a negative
regulator present in the primary lymph nodes. Immune checkpoint
inhibitors have been developed to block PD-​1, PD-​L1, and CTLA4.
The presence of PD-​L1 expression on tumors may be used to inform
treatment selection. In general, PD-​L1 expression is higher in patients
with a higher tumor mutation burden, such as that seen in smokers.
The most common single driver mutations in adenocarcinoma
are EGFR mutation (25%), EMLA-​4 ALK rearrangements (5%),
NTRK (6%), KRAS (20%), and ROS1 (1%). Additional emerging
mutations include AKT, BRAF, FGFR, ERBB2/​HER2, MET, PTEN,
and RET. Most of the driver mutations are found in never or light
smokers. KRAS, however, is more common in smokers. Rarely are
these driver mutations seen concurrently (1%–​3%). It should be
noted that the rates of mutations that have emerged vary by country,
with Asian nonsmokers harboring a higher percentage of single
driver mutations. The National Comprehensive Cancer Network
(NCCN) recommends that all patients with NSCLC be tested for
EGFR, ALK, ROS1, BRAF, NTRK, and PD-​L1.13 In addition, they
support broad profiling to help identify rarer mutations for which
there might already be effective treatments available. Regardless of
smoking history, all patients should be tested to identify patients
that might benefit from targeted therapy. Genetic mutations are
being investigated in other subtypes of lung cancer as well.
Lung cancer is staged based on the internationally accepted TNM
staging system last updated in 2018.14 Regular updates reflect advances in prognostic and survival data.
TNM stage is based on the size of the primary tumor (T) at the
greatest dimension and level of invasion into surrounding structure, extent of regional lymph node (N) involvement, and the
presence or absence of metastatic spread outside of lung tissue or
distant disease. The stages range from I to IV, with further detailed
subclassifications to help guide treatment selection. Stage I and II are
localized, Stage III is regional, and Stage IV is metastatic. Stage IV
includes oligometastatic disease as well as widespread metastases.
Historically, SCLC was classified using a two-​stage system: limited
and extensive disease. Limited disease is that which can be encompassed in a radiation therapy field.
Cancer-​Directed Treatment
The treatment of lung cancer has been evolving rapidly over the
past two decades. Advances in diagnostic approaches, molecular
profiling, and development of targeted therapies have contributed
to the improvement in survival and HRQOL. In addition, targeted
therapies and immune checkpoints, initially only used for advanced
disease, are being investigated in early-​stage disease in an attempt to
reduce recurrence of disease. Five-​year survival rates for early-​stage
localized, regional, and advanced NSCLC are 61%, 35%, and 6%, respectively. However, the rates for SCLC remain much lower at 27%,
16%, and 3%, respectively.3
Early-​stage NSCLC (Stage I) is treated with surgery as curative
intent. In Stage II, adjuvant chemotherapy or chemoradiation following surgical resection is recommended. For patients that are not
surgical candidates, definitive radiation is used.
The foundation of treatment for Stage III NSCLC is combined-​
modality treatment. Treatment includes concurrent or sequential
chemotherapy and radiation therapy prior to or following surgical
resection for Stage IIIA. In Stage IIIB, with unresectable tumor,
therapy is concurrent or sequential chemotherapy over four to six
cycles. Patients then remain in close surveillance. In 2018, the paradigm shifted in the management of Stage III unresectable disease
following combination therapy. The PACIFIC study demonstrated
improved overall survival (66.3% vs. 55%) in patients receiving
durvalumab, an anti-​
PD-​
L1 immune checkpoint inhibitor, for
1 year following definitive chemoradiotherapy treatment versus surveillance.15 It is not recommended in patients who have undergone
a surgical resection.
The goal of treatment for Stage IV NSCLC is to control disease,
palliate symptoms, and improve survival. Treatment selection is
based on histologic subtype, presence of molecular driver mutation, level of PD-​L1 expression, performance status, and presence
of comorbidities. EGFR, ALK, NTRK, BRAF V600E, and ROS 1 are
driver mutations more common in nonsmokers, for which targeted
tyrosine kinase inhibitors (TKIs) are indicated. Unfortunately, almost
all patients develop progression of disease within 10 to 12 months on
first-​generation TKIs. This is due to a tumor’s acquired mechanisms
of resistance. For EGFR, a common mechanism of resistance is the
acquired T790 mutation at exon 20 of the EGFR gene. Osimertinib
is a third-​generation EGFR-​TKI developed to overcome this mutation. It has subsequently been moved into the first-​line setting,
demonstrating improved efficacy, ability to cross the blood-​brain
barrier, and reduced toxicity profile. Similarly, first-​generation ALK
TKIs have been replaced by next-​generation alectinib for patients
with ALK translocations. The first-​generation TKIs crizotinib and
larotrectinib are currently approved for ROS1 and NTRK mutations,
respectively. Combination dabrafenib and trametinib is approved
for treatment of NSCLC with BRAF V600E mutations. KRAS mutations are found in approximately 25% of lung adenocarcinomas and
are more common in smokers. KRAS G12C is a subset that accounts
for approximately 13% of NSCLC. New TKIs targeting this subset
are currently in development with promising results.
It is likely that the accelerated rate of personalized targeted therapy
will continue to evolve. The Lung-​MAP study is a multicenter study
sponsored by the National Cancer Institute’s National Clinical Trials
Network (NCTN). Patients underdo a comprehensive genomic profiling that evaluates over 200 cancer-​related genes for alterations.
Based on genomic profiling results, patients are randomized to
substudies and matched to investigational drugs or offered an immunotherapy combination.
The benefits of a targeted TKI are convenience and overall improved toxicity profile than cytotoxic chemotherapy. However, treatment can be associated with anxiety related to the molecular tumor
profiling (MTP) process, anticipation of treatment resistance, need
for repeat biopsies, increased responsibility of self-​management,
and financial toxicity. Patients experience anxiety while awaiting the
results of MTP, hopeful to have an actionable mutation and disappointed or depressed if no mutation is identified.16 Many of the oral
oncolytics cost more than $100,000 per year.17 Copays alone can
CHAPTER 22 Lung Cancer
place a financial burden on patients and families. This can impact
adherence to therapy and treatment efficacy.
Cytotoxic chemotherapy and immune checkpoint therapy, alone
or in combination, are recommended for patients that progress
on TKI therapy or do not harbor any driver mutations. Treatment
decisions are based on performance status, underlying comorbid
medical conditions, burden of disease, and level of PD-​L1 expression. Although PD-​L1 expression can be elevated in patients with
single driver mutations, targeted therapy is recommended first.
Maintenance therapy may continue in patients who respond to
initial treatment. Radiation therapy may be indicated to palliate
symptoms or relieve obstructive disease. Stereotactic body radiation therapy (SBRT) may be useful to target small oligometastatic
disease, and gamma knife radiosurgery is recommended for brain
metastases.
Limited or early-​stage SCLC is treated with combination chemotherapy and radiation therapy. Extensive-​stage SCLC is treated with
systemic chemotherapy. Strong consideration is given to prophylactic whole brain radiation in patients with SCLC. To date, there
are no molecular driver mutations in SCLC for which there are
available drugs.
Psychological Issues Commonly Faced
in Lung Cancer
Distress, Anxiety, and Depression. Patients with lung cancer have
a high symptom burden from cancer and cancer treatments due in
part to late disease stage at diagnosis.18,19 Symptom burden can result
in impaired emotional status, social functioning, and quality of life
(QOL). The prevalence of distress in newly diagnosed lung cancer
patients has been reported to be the highest compared to other cancers, with up to 61% reporting distress that often persists through
illness.20 Anxiety and depression rates are higher in lung cancer
patients than in those with other cancers.21 Pain, fatigue, breathlessness, and sleep disturbances all contribute to higher levels of distress, anxiety, and depression.22 Smokers experience higher levels of
anxiety over nonsmokers.23 Patients who are younger at diagnosis,
female, employed, and with later-​stage disease are more likely to report greater severity of emotional problems at diagnosis.24,25
Greater severity of emotional problems is associated with worse
QOL indicators (i.e., mental, physical, social, spiritual, and emotional), an increase in physical symptoms burden, reduced adherence to treatment, and decreased survival.25–​27 In addition, this
contributes to a 4.4 times higher rate of suicide among lung cancer
patients compared to other cancer diagnoses, which is most significant at time of diagnosis and in patients over age 50.28 Despite the
high prevalence of unmet needs, psychological distress remains unrecognized and suboptimally managed, which can lead to poorer
quality of life, lower satisfaction with care, poorer adherence to
treatment, and decreased survival.25,29
Stigma. Lung cancer patients experience higher levels of internal
and external stigma through the disease trajectory. Stigma develops
due to a strong association with smoking history and perception
that the disease is self-​inflicted.30 Approximately 95% of lung cancer
patients experience at least one element of stigma.31 Internalized
Table 22.1. Lung Cancer–​Specific Assessment Tools
Instrument
No.
Items
Dimensions Measured
Coping Orientation to Problems
Experienced (COPE)
60
Problem-​focused coping and emotion-​focused coping and measures of coping responses; a Brief COPE
Inventory consists of only 28 statements
European Organization for Research
and Treatment of Cancer Quality of Life
Questionnaire Core 30 (QLQ-​C30)
30
Global health status, functional scales (physical, life role, cognition, emotional, and social), and symptom
scales (fatigue, nausea/​vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial
problems)
Lung Cancer Specific Module
(EORTC-​QLQ-​LC13)
13
Dyspnea, coughing, dysphagia, hemoptysis, sore mouth/​tongue, peripheral neuropathy, hair loss, chest
pain, pain in arm/​shoulder, other pain sites, taking analgesics
Cataldo Lung Cancer Stigma Scale
(CLSS)
31
Self-​perceived stigma; also available in short form; adapted from tools used in HIV
Lung Cancer Stigma Inventory
25
Overall stigma, perceived stigma, internalized stigma, and constrained disclosure; developed specifically for
lung cancer
Edmonton Symptom Assessment Scale
Functional Assessment of Cancer
Therapy (FACT)
FACT-​Lung Cancer
FACT-​ EGFRI-​18
9
27
7
18
Lung Cancer Symptom Scale (LCSS)
Psychosocial Screen for Cancer
(PSSCAN-​R) questionnaire
General core instrument: physical, social/​family, emotional, and functional well-​being
Lung cancer–​specific disease symptoms
Patient-​reported outcomes to assess effect of EGFRI on health-​related quality of life
Measure of six major symptoms (cough, dyspnea, fatigue, pain, hemoptysis, and anorexia) and effect on
overall symptom distress, functional activities, and global quality of life. Two scales: one completed by
patient and one by health care provider
21
Schedule for the Evaluation of Individual
Quality of Life (SEIQoL-​Q)
Sheffield Profile for Assessment and
Referral to Care (SPARC®)
Physical and psychological symptoms of anxiety and depression
Social support, psychosocial needs, and symptoms of anxiety and depression
Self-​reporting tool; 12 life domains, weighted and individual quality of life index is calculated
45
Assess level of distress in 7 broad areas including physical and psychosocial, as well as need for services
165
166
SECTION V Psychological Issues Related to Site of Cancer
stigma stems from feelings of shame and guilt, self-​blame, and anticipated stigma. Anticipated stigma may lead to constrained disclosure, the avoidance of sharing one’s diagnosis with others. External
stigma and biases lead to discrimination, blame, and social rejection. Evidence suggests pervasive societal stigma toward lung cancer
patients and their caregivers over other cancers.32–​34 Even patients
who have never smoked experience societal stigma.
Stigma is associated with reduced involvement in screening, delays in early detection for symptoms, reduced treatment adherence,
and social isolation.30,35,36 Stigma leads to increased social isolation,
loneliness, depression, and poor QOL.31,32,36,37 Patients with higher
levels of stigma are more likely to have a higher symptom burden,
decreased social support, and increased social constraints, leading
to poorer health outcomes.38 In response to the impact of societal
stigma, the Lung Cancer Alliance launched a campaign in 2012 to
combat stigma with the theme “No One Deserves to Die.” All patients diagnosed with lung cancer should be screened for stigma so
that interventions can be put into place to minimize the negative
impact on health outcomes.
Family-​Centered Concerns. Family members may be at increased
risk of developing lung cancer. First-​degree relatives living in the
same household are at double the risk.39 This leads to strain in the
relationship due to blame. The caregiver dyad may be strained by
feelings of self-​guilt if the family/​caregiver were the predominant
smokers in the household. Caring for patients with long-​term cancer
can be a long journey, as cancer survival rates have been gradually
increasing with advances in therapies and supportive care. Lung
cancer patients have higher supportive care needs due to higher
symptom burden compared to other cancers. This places strain on
the caregiver dyad. Caregiver burden is associated with the patient’s
physical and psychological functioning. Patient QOL is linked to
higher level of burden and more severe emotional problems in caregivers.40 These issues reinforce the need to address the psychological
needs of the dyad.
Table 22.2. Education and Support Services for Patients with Lung Cancer
Organization
Website/​Contact
Description and Resources
ALK Positive
http://​www.alkpositive.org
Online support for patients, families, and friends of those diagnosed with ALK-​
positive lung cancer; advocacy and education
American Cancer Society
http://​www.cancer.org
Online patient and family educational materials; support for finding and
paying for treatment; caregiver support; end-​of-​life support; support is across
the lifespan
American Lung Association
https:/​www.lung.org
Research support; anti-​tobacco campaigns; education and training; CT
screening support; LUNG FORCE Initiative: women with lung cancer
Cancer Support Community
https://​www.cancersupportcommunity.org
Merger of the Wellness Community, Gilda’s Club, and MyLifeLine; research,
advocacy, education; walk-​in centers to provide emotional and social support;
digital support network
Caring Ambassador Lung Cancer
Program
https://​lungcancercap.org/​
Mission is to help patients with lung cancer become ambassadors for their
own health; advocacy and educational resources
The CHEST Foundation
https://​foundation.chetnet.org
Supports research, community service, and patient education related to lung
disease including cancer
CURE®
https://​www.curetoday.com/​tumor/​lung
Cancer updates, research, and education
EGFResisters
https://​egfrcancer.org
Advocacy for patients diagnosed with EGFR-​positive gene lung cancer;
supports research
Global Resource for Advancing
Cancer Education (GRACE)
https://​cancergrace.org
Provides education online, in forums, and videos; online communities
GO2 Foundation for lung cancer
https://​go2foundation.org
Support@go2foundation.org
Advocacy; merger of two previous organizations, the Bonnie J. Addario Lung
Cancer Foundation (ALCF) and Lung Cancer Alliance (LCA); educational,
support, and referral services
International Association for the
Study of Lung Cancer (IASLC)
http://​www.iaslc.org
Research, collaboration, education, patient advocacy
Lung Cancer Action Network
(LungCAN®)
http://​lungcan.org
A collaborative group of lung cancer advocacy organizations joined to raise
awareness about lung cancer; educational resources; links to clinical trials and
support services
Lungevity
https://​lungevity.org
Patient advocacy organization; funds scientific and patient-​focused research;
provides information and resources to patients and families; educational
resources, online peer-​to-​peer support, and in-​person survivorship programs
Lung Cancer Research Foundation
http://​www.lungcancerresearchfoundation.
org
Supports clinical and bench research; patient and caregiver educational
materials and workshops; lung cancer support line; Free to Breath walks
Lung Cancer Foundation of
America
https://​lcfamerica.org
Supports research; patient education
Mesothelioma Applied Research
Foundation
http://​www.curemesoorg
Advocacy, education, support groups, financial assist
Stand Up to Cancer
https://​standuptocancer.org
Advocacy; funds research; education
CHAPTER 22 Lung Cancer
Survivorship Concerns. Due to poor prognosis for advanced
lung cancer, survivorship is described as beginning at 1 year
postdiagnosis. Lung cancer survivors suffer high disease burden and
endure symptoms long after therapy that negatively impact QOL indicators (i.e., global health and physical, role, emotional, cognitive,
and social functioning).41 Symptoms of dyspnea, pulmonary restrictions, pain, and poor sleep quality are some of the many residual
symptoms that have been reported up to 3 years after diagnosis,
leading to poor QOL.42 Lung cancer survivors have higher levels
of distress compared with survivors of other cancers.25,31 At least
40% of lung cancer survivors report distress that negatively impacts
QOL.19 Patients with lung cancer should continually be assessed for
the psychological impact of cancer throughout survivorship.
Assessment of Psychological Distress
Distress screening is recommended by the Commission on Cancer
(COC) and endorsed by the NCCN, Oncology Nursing Society
(ONS), and American Society of Clinical Oncology (ASCO) to be
done at least once during pivotal points in the disease trajectory.
The distress screening tool has demonstrated predictive value in
estimating 1-​year survival and may guide the integration of palliative care services.43 Several assessment tools have been developed
to assess quality of life, symptoms, functional capacity, and stigma
in cancer patients. Some of the tools are generic, while others have
been developed to capture dimensions specific to lung cancer patients. All patients with lung cancer should undergo screening for
psychological stressors at the time of diagnosis and throughout the
disease trajectory. Early identification of needs provides opportunity to intervene and support patients. A summary of tools is listed
in Table 22.1.
Supportive Services
Supportive care interventions that are aimed at reducing distress can
lead to improved QOL. Palliative care support services can improve
depression and QOL in lung patients. In the randomized study of
patients with lung cancer, early integration of palliative care services
demonstrated significant improvements in QOL with less aggressive
care at end of life with longer survival benefit.44,45 Ferrell et al.46 assessed the impact of an interdisciplinary approach versus standard
of care on lung cancer patients undergoing treatment. The intervention group patients were discussed at interdisciplinary meetings and
received additional supportive care referral and four educational
sessions. Patients in the intervention group had lower psychological distress, greater spiritual well-​being, improved symptoms, and
improved QOL.
Shared decision making (SDM) is an important element of
delivering comprehensive care to lung cancer patients, especially
for those in whom there is no curative option. SDM is an approach
in which providers present the best available evidence to patients
when making a health care decision and integrates the patient’s goals
of care in deciding on a plan of care. It is particularly helpful for
preference-​sensitive decisions. The use of SDM tools and decision
aids can guide the direction of screening, testing, and treatment.
Currently, there is a dearth of SDM tools developed specifically for
lung cancer patients.47
Professional organizations and patient advocacy groups are available to provide additional supportive care services to lung cancer
patients in the community. Table 22.2 provides a list of such organizations and descriptions of available services.
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23
Breast Cancer
M. Tish Knobf and Youri Hwang
Introduction
There are > 3 million breast cancer survivors (BCSs), and the estimates for new cancer cases in women in the United States in 2019 are
268,600 cases of invasive cancer and 48,100 of ductal carcinoma in
situ (DCIS).1 Nearly 80% of breast cancers are diagnosed in women >
50 years, and this age group accounts for the majority of deaths. A significant disparity persists between white and black women, with a 40%
higher death rate among black women, and this disparity is greatest in
young black women (< 50 years of age) compared to white women.1
A leading contributor to the disparate mortality rate is the higher incidence of triple-​negative breast cancer (TNBC), especially in younger
black women. The lack of estrogen receptors and progesterone receptors and human epidermal growth factor 2 (HER2) overexpression define TNBC, which accounts for 15–​20% of new cases but is associated
with limited treatment options and more unfavorable tumor characteristics, resulting in shorter survival and higher mortality. Beyond
TNBC, higher mortality in black women is associated with multiple
factors, such as social determinants of health, obesity, poor lifestyle
behaviors, comorbidities, and access to quality screening and care.
Diagnosis and management of breast cancer are dynamic in response
to advances in understanding the biology and the precision health
approach to treatment based on genetics and unique biologic characteristics. Widespread genetic risk testing, routine use of treatment
response predictor and prognostic tests, increased use of magnetic
resonance imaging (MRI), the dramatic rise in prophylactic mastectomy, advances in reconstructive surgery, treatment options for TNBC,
changes in the surgical management of the axilla, and a greater role for
neoadjuvant therapy are salient examples of the dynamic changes that
contribute to the complexity of the experience, the decision-​making
process, and psychosocial adjustment. The purpose of this chapter is
to describe treatment choices for breast cancer and the psychological
responses across the trajectory of breast cancer from the definitive diagnosis through disease-​free survivorship or end of life.
Psychological Responses across the Breast
Cancer Trajectory
The trajectory of breast cancer begins with diagnosis and progresses
through treatment and into survivorship (long-​term survival or
a shortened survival due to a recurrence, second cancer, or comorbid illness). There have been four distinct types of psychological distress associated with the breast cancer trajectory: chronic,
delayed, recovered, and resilient.2 Based on the literature and clinical experience, these four trajectories can easily be identified with
patient exemplars. A chronic trajectory might represent a younger
woman who experiences treatment-​induced menopause, cognitive
changes, vasomotor symptoms with associated sleep alterations, and
vaginal atrophy leading to sexual problems while managing competing life demands of school-​age children, a marital relationship,
and midcareer employment. The recovery trajectory represents the
majority of women who experience some level of physical and psychological symptoms of distress during treatment but by one year
later have improved significantly and successfully integrated the experience into everyday life.3 The delayed trajectory is similar to the
recovery one, except that some additional traumatic event or complication occurs that creates additional stress, delaying the recovery
process. The resilient type could describe a midlife or older woman
who experiences minimal physical symptoms of distress during
treatment, has strong social support, reports being well informed of
what to expect, has effective communication with her providers, and
experiences minimal life disruption.
A middle-​range theory of “Carrying On” has been proposed
to explain how women respond and behave across the trajectory
(Figure 23.1).4 There is a linear progression from the first stage of
Being Focused, but for many women, stages 2 to 4 may represent a
recursive relationship rather than a linear process. Being Focused
is the stage of entry into the oncology world, characterized by a
learning curve for information, terminology, providers, and the
scope of cancer treatment while trying to manage everyday life.
Dealing with Uncertainty is strongly influenced by information adequacy, effective relational communication with providers, symptom
assessment and management, and explanation of symptom attribution. The better prepared a woman is for the experience, the more
the level of uncertainty and associated psychological distress will
be minimized. Developing Awareness generally occurs after treatment and women begin to explore and process the meaning of the
diagnosis and the experience of treatment and treatment sequalae,
which may include persistent physical and psychological symptom
distress. They are also faced with the challenge of integrating the
experience into their lives and may be opposed to the common
170
SECTION V Psychological Issues Related to Site of Cancer
Stage
Being Focused
Dealing with
Uncertainty
Developing
Awareness
Balancing
Culture
Experience
Crisis Response
Early Adaptation
Experiencing
Treatment Side
Effects
Beginning to
Understand Scope
of Experience
Transition to
Survivorship
Behaviors
Learning
Adapting to
Treatment
Managing Everyday
Life
Getting Information
Communicating with
Providers
Relying on Self
Exploring Meaning
Living-Managing
Symptoms
Integrating into
One’s Life
Being Wary
Struggling with the
System
Keeping Healthy
Finding Support
Figure 23.1. “Carrying on”: a middle-​range theory of patient responses across the cancer trajectory.
message of returning to normal or conceptualizing life as a new
normal in the context of their distress, whether it be physical or psychosocial. The final stage is Balancing, which represents the transition work into survivorship, a time when there are less frequent
oncology provider visits, lower levels of social support, an unclear
role of primary care provider and/​or specialist (e.g., gynecologist),
and inconsistent access to survivorship resources. Keeping healthy
is an important component of Balancing,4 and lifestyle behaviors,
specifically routine physical activity, have been identified as an intervention to reduce psychological distress.5
It is critical to identify the determinants of psychological distress
and how these determinants or risk factors affect how a woman
processes the experience in the context of moving through the trajectory.2–​4 Risk factors and predictors of psychological distress for
women newly diagnosed with breast cancer include younger age,
pre-​existing psychological problems, presence of comorbid illness,
chemotherapy treatment, moderate to severe physical symptom
distress, limited available social support, non-​Caucasian ethnicity,
lower socioeconomic status, poorer functional performance, and
breast cancer recurrence.3,5 Factors such as interpersonal characteristics, preferences for information, status of family and partner
relationships, sexual orientation, role of spirituality in one’s life,
and effectiveness of patient-​
provider communication can positively or negatively influence emotional well-​being and psychosocial
adjustment.
Factors Contributing to Psychological Distress in Younger
Women. Young women (18 to 49 years of age) account for 20% to
30% of BCSs. While many BCSs experience persistent symptoms
such as anxiety, depressive mood, impaired cognitive functioning,
pain, fatigue, fear of recurrence, and sleep disturbance after completion of curative intent primary therapy (e.g., surgery, chemotherapy,
radiotherapy), younger BCSs report greater psychological symptom
distress and poorer quality of life compared to their older counterparts.6 Unique to young BCSs is the developmental stage in life,
which may include being single, being married with young children,
being in early or midcareer employment, having a heightened fear
of recurrence, and experiencing alterations in sexual function due
to premature induced menopause, all of which contribute to higher
levels of psychological distress.7
Young BCSs are at increased risk of treatment-​induced premature menopause, leading to loss of fertility. Regardless of their plan
about future pregnancies, young BCSs consider loss of fertility as
loss of options to have a child in the future.8 Women who have not
completed their families and who are younger than 40 years of age
tend to have concerns about potential infertility after treatment.9
Childless women are particularly vulnerable to intrusive thoughts
and likely to use avoidance coping.10 The emotional distress from
loss of fertility may remain throughout their lifetime.7
Impaired body image is also commonly reported, but young BCSs
have increased difficulty adjusting to their physical changes compared to older BCSs.11 Poorer body image in young BCSs is associated with type of surgery and adjuvant therapy (chemotherapy,
endocrine, radiation), resulting in physical and psychological distress and alterations in sexuality.12 Up to 50% of young BCSs report
sexual dysfunction,8 which can negatively impact the partner relationship as well as overall emotional well-​being.
Breast cancer survivorship appears unique for young women.
Concerns regarding fertility, body image, and sexual functioning
adversely influence psychological well-​being, and are not always
sufficiently addressed by providers. It is critical to identify young
BCSs who are at risk of persistent psychological distress and the underlying causes in order to appropriately intervene.
CHAPTER 23 Breast Cancer
Primary Management of the Breast
For the majority of women, initial decision-​making relates to the
primary treatment of the breast, with either breast conservation surgery (local tumor removal) with radiation therapy, or mastectomy
with or without reconstruction. For selected patients, this initial
decision-​making may also include consideration of contralateral
prophylactic mastectomy.13 These surgical options are presented for
women with invasive cancer as well as DCIS. For a subset of patients,
such as those with TNBC, HER2-​positive breast cancer, or high-​risk
luminal B subtype, initial decision-​making will include neoadjuvant
systemic therapy as an option.14
Breast Conservation Surgery with Radiotherapy
There are three decades of clinical trials that have established the
survival equivalency of breast conservation surgery/​radiotherapy
(BCS/​RT) to mastectomy. A shared decision-​making model between the patient and provider is strongly recommended to evaluate
risks, benefits, cosmetic outcomes, and patient preferences. The majority of women are eligible for BCS/​RT with few contraindications,
specifically previous thoracic radiation, pregnancy, connective
tissue disease, unfavorable tumor characteristics (e.g., large tumors),
or diffuse disease. Conventional-​fraction whole breast irradiation
(WBI) delivers 40–​50 Gy followed by a boost to the tumor bed.15
Higher-​fraction WBI (or accelerated radiation) delivers 40–​42.5 Gy
and utilizes higher fractions over a period of 1–​3 weeks compared
to 5–​6 weeks for conventional-​fraction WBI. The decision should
consider the individual patient factors, such as tumor characteristics, stage, grade, age, and patient preferences.15 Fatigue is the most
common side effect of radiation, regardless of the delivery method.
Skin changes, sensation changes, and breast swelling follow a similar trajectory to the symptom of fatigue, increasing in frequency
and severity by midtreatment through the end of radiotherapy, with
gradual improvement at 3 and 6 months after therapy is complete.16
Black women report more frequent and more severe skin reactions,
which are associated with pain, psychological distress, alterations in
body image, and interference with daily function.17 Providers need
to increase their skills in assessment and monitoring of skin changes
in patients of color. While cosmesis is generally rated as good to excellent for the majority of women who receive breast irradiation,
skin reactions, asymmetry associated with incision-​site reactions,
long-​term hypopigmentation, and fibrosis can influence a woman’s
psychological response.
Management of the Axilla
The surgical approach to axillary lymph nodes has shifted over
the past decade, with sentinel lymph node (SLN) biopsy recommended as the initial procedure.13 For patients with negative or
one to two positive sentinel lymph nodes, there is no advantage in
clinical outcomes to following with an axillary lymph node dissection. However, axillary lymph node dissection (ALND) is recommended for patients with two or more positive sentinel lymph nodes
because of prognostic implications of the extent of tumor burden
in the axilla and to inform treatment choices. The initial approach
with SLN biopsy has significantly decreased the surgical morbidity
(sensory changes, functional limitations, infection risk, and risk of
lymphedema). Lymphedema occurs in approximately 25%–​30%
of women with ALND compared to 4%–​5% with SLN biopsy.
Lymphedema can be managed but not cured and is associated with
psychological distress, functional limitations, body image concerns,
alterations in clothing, pain, and higher risk of infection, and it significantly impacts all domains of quality of life (QOL).18
Mastectomy and Reconstructive Surgery
The goal in the initial decision-​making phase is to offer the option
of reconstructive surgery if a woman is considering mastectomy as
a treatment choice. There are many factors supporting this goal: influence of surgical procedure for breast removal on reconstruction
outcomes, indication for postmastectomy radiotherapy, patient
preference, patient characteristics that may influence feasibility and
choice of reconstructive procedures, and patient expectations.19
Breast reconstructive choices include placement of an implant or
use of autologous tissue to create the breast mound. Implant reconstruction is a common reconstructive choice among women as
no donor site is needed for tissue, and there is a relatively quick recovery.19 For women desiring implant reconstruction, a common
approach is placement of a tissue expander, followed by placement
of a permanent implant. The advantage of using a tissue expander
prior to permanent implant placement is to allow the muscle and
skin to stretch over time, creating a better pocket for the permanent implant. The disadvantages of the saline tissue expander are
multiple visits for injections for the expander over a protracted
time period and discomfort or pain associated with expansion
procedures. Advances in implant reconstruction include carbon
dioxide–​filled tissue expanders, which allow for gradual expansion,
minimizing or eliminating the disadvantages of the saline protocols.20 Complications of implant reconstruction include extrusion,
implant failure, and capsular contraction, the latter being most
common and associated with additional procedures and distress for
the patient.
There have been major advances in the field of onco-​plastic surgery for breast cancer with autologous tissue reconstruction. An increase in expertise and use of microvascular tissue transfer with a
transverse rectus abdominus myocutaneous (TRAM) flap (free, or
muscle sparing), deep inferior epigastric artery perfuse (DIEP) flap,
superior inferior epigastric artery (SIEP) flap, and non-​abdomen-​
based options have changed the reconstructive options and outcomes.20 Advantages of autologous reconstruction include a more
natural-​looking breast, a long-​lasting procedure, and an option for
women with larger breasts. Disadvantages include a longer hospital
stay, risk of infection, wound dehiscence, flap necrosis (at donor and
recipient site), prolonged recovery, and donor site morbidity.19
Women who are offered reconstruction and elect to undergo the
procedure tend to be white, younger, higher socioeconomic status,
and concerned about body image. There is a disparity in reconstructive surgery between black and white women, which is partially
explained by educational level, complexity of decision-​making process, and financial/​insurance issues. Patient outcomes that have been
investigated following breast surgery include body image, quality of
life, cosmesis, and psychosocial functioning. For body image (see
Chapter 39), there appear to be small differences among women’s
evaluation of outcome, with slightly better body image for women
who had breast conservation with radiotherapy or reconstruction
compared to mastectomy.
171
172
SECTION V Psychological Issues Related to Site of Cancer
Musculoskeletal Upper Extremity Problems after Breast
Cancer Treatment. Musculoskeletal problems after primary therapy
for breast cancer occur in 25%–​30% of women, resulting in physical
and psychological distress and interference with everyday activities.
The common upper extremity problems include decreased range of
motion (ROM), reduced joint mobility, flexion and abduction impairments, decreased muscle strength, weakness, stiffness, tightness,
and pain and are associated with ALND (6%–​31%) and SLND (3%–​
24%), and radiation increases the risk of upper extremity dysfunction.21 Upper extremity problems may persist for years and impact
activities of daily living, leisure-​time and work activities, and quality
of life. Assessment of the arm and shoulder and impact on everyday
function is recommended over the first year after treatment. Upper
extremity problems will not usually resolve without treatment, and
patients should be referred to an orthopedic provider and/​or physical therapist for treatment.
Prophylactic Mastectomy
Decision-​making for women who are genetically predisposed to
breast cancer is complex (see Chapter 13). Bilateral prophylactic
mastectomy (BPM) is an option for women who are gene carriers
and have a strong family history, high-​risk histologic features, and/​
or surveillance issues.22 While BPM significantly reduces the risk
of future breast cancer (> 90%), it is extensive surgery with a prolonged recovery. Yet, women report being satisfied with the decision and having lower psychological distress (e.g., anxiety, fear), and
many rate body image favorably despite sensory changes and mixed
effects on sexuality and relationships.22 Contralateral prophylactic
mastectomy (CPM) is an option for the noncancerous breast, often
chosen by women who elect mastectomy rather than BCS/​RT for
the affected breast.13 There has been a dramatic increase in women
with early-​stage breast cancer choosing to have a CPM. A positive
family history, younger age, worse tumor characteristics, fear of
future breast cancer, the experience of multiple repeated imaging,
heightened surveillance, and a desire for symmetry characterize
those women who are more likely to choose contralateral prophylactic surgery.23 CPM is associated with a 90%–​95% reduction in
risk for a future breast cancer, but women need to be well informed
about individual risk for optimal decision making and understand
that CPM does not provide 100% protection and has no influence
on risk of local recurrence in the affected breast.13,23 While many
women report satisfaction with their decision, the type of informational preparation and actual experience following surgery have resulted in psychological distress related to body image, problems with
implants, poor cosmetic outcomes, and alterations in sexuality. For
women with implant reconstruction, some have not felt prepared for
the feel of the implant, potential complications (i.e., failure, capsular
contraction), pain and discomfort with tissue expander procedures,
and the unnatural look of the implanted breast mound. Sexuality issues have focused on the loss of erotic nipple sensations and distress
about not being informed of such changes. For women with autologous reconstructive surgery, many expressed feeling unprepared for
the length of recovery, numbness, pain, scarring (two sites: recipient
and donor), body image, and the need for emotional preparation
and psychological support.
Adjuvant and Neoadjuvant Therapy
Indications and treatment for adjuvant and neoadjuvant therapy
have dramatically evolved over the last two decades.14 There has
been a trend of escalation and de-​escalation in the field in an attempt to determine which subgroups of patients will benefit from
additional or combined treatment and which patients will benefit
from less therapy with potential for lower toxicity.24 Treatment decision making is highly complex and dependent on tumor pathology,
tumor subtypes, axillary lymph node involvement, status of estrogen
and progesterone receptors, HER2 status, gene profiling, and patient
characteristics such as age, comorbid illnesses, perception of risks
and benefits, and preferences. The subtype of TNBC limits treatment options, and most women with TNBC are offered neoadjuvant
therapy with chemotherapy and/​or targeted agents. As TNBC is
considered the most immunogenic subtype of breast cancer, with
higher programmed cell death-​1 (PD-​1) expression, this has led to
exploration of therapy with immune checkpoint inhibitors, especially for women with residual disease following neoadjuvant treatment.25 Checkpoint inhibitors are associated with a broad spectrum
of significant organ system immune-​related adverse events,26 which
adds to the complexity of the decision-​making process for women
with TNBC. The first known study exploring the psychological response to TNBC was conducted and women described TNBC as “an
addendum” to breast cancer.27 The supporting themes addressed the
impact of learning the prognostic implications of TNBC and uncertainty (due to limited treatment options), described as “flying
without a net” and having a steep learning curve due to the volume
of information and compressed decision-​making process. In summary, the experience for women with TNBC was characterized by
fear, uncertainty, insecurity, and emotional distress.27
Adjuvant and neoadjuvant therapies for non-​TNBC include chemotherapy, endocrine therapy, and targeted therapies, which can be
delivered as a single modality but more often are combined and/​or
delivered sequentially, dependent on the tumor pathology and characteristics.24,28 Chemotherapy agents in these regimens generally
include anthracyclines, docetaxel, cyclophosphamide, carboplatin,
and capecitabine. Anti-​estrogen therapy with tamoxifen and aromatase inhibitors (AIs) are used for hormone-​positive postmenopausal
women and for hormone receptor–​positive premenopausal women;
tamoxifen or an aromatase inhibitor combined with ovarian suppression has become a therapy option,24 but the routine use of an
aromatase inhibitor with ovarian suppression remains controversial
based on current evidence.29
HER2-​positive breast cancer occurs in approximately 20%–​30%
of patients. The initial anti-​HER2 agent trastuzumab (Herceptin) has
been shown to significantly improve disease-​free and overall survival.30 The identification of novel anti-​HER2 agents with different
mechanisms of action has been a focus in the last decade and includes
pertuzumab, trastuzumab-​emtansine (TD-​M1), lapatinib (reversible HER2 growth factor receptor kinase inhibitor), and neratinib
(irreversible pan-​HER2 inhibitor).24,30 Breast cancer survivors with
HER2-​positive disease at low risk for recurrence will be recommended nonanthracycline adjuvant therapy with trastuzumab, and
those at higher risk will have adjuvant or neoadjuvant treatment recommended with an anthracycline or nonanthracycline multiple
drug regimen combined with an anti-​HER2 agent or agents.14,24,28,30
CHAPTER 23 Breast Cancer
The duration of anti-​HER2 agents continues to be studied for efficacy and research continues to identify the optimal therapy for
subgroups of patients as there is considerable heterogeneity among
HER2-​positive tumors.30
Side Effects and Psychological Responses. Physical symptoms
are frequently associated with psychological distress, especially if the
patient did not feel prepared, the physical symptoms were rated as
moderate to severe, and/​or interventions were not timely or effective.
Adjuvant chemotherapy regimens are associated with a varied physical symptom profile, including but not limited to fatigue, peripheral neuropathy, changes in memory and concentration, alopecia,
premature menopause, weight gain, skin and nail changes, and alterations in sleep, most of which persist after therapy is completed.
Both tamoxifen and AIs are associated with menopausal symptoms
of hot flashes, night sweats, sleep alterations, vaginal discharge (tamoxifen), vaginal dryness, and dyspareunia (AIs). AI therapy is
associated with moderate to severe musculoskeletal symptoms, resulting in one-​half to two-​thirds of women discontinuing therapy,
compromising the survival benefit. The most common barrier to
adherence is musculoskeletal symptoms, but there are several other
contributing socioeconomic factors (e.g., younger age, ability to
pay) and psychosocial variables, specifically poor patient-​provider
communication, psychological depressive symptoms, and lack of
perceived efficacy.31 Two late side effects include bone loss related
to premature menopause and AI therapy and cardiac toxicity related to anthracyclines, anti-​HER2 agents, and emerging targeted
agents.32,33 No evidence was found on the psychological responses
to being informed of these potential long-​term adverse effects, but
women can be at risk for psychological distress when sequalae such
as osteopenia, osteoporosis, fractures, and decreased cardiovascular
function and heart failure occur.
Patients need to be adequately prepared with understandable information for acute, persistent, and long-​term effects of therapy,4 as
feeling unprepared for what is going to happen leads to greater uncertainty, distress, and ineffective coping. Pharmacologic, psychologic,
and biobehavioral interventions have been evaluated for symptom
management. Several therapy side effects are reviewed in Section VI
(Chapters 32–​37). Physical activity, specifically moderate-​level activity of 30 minutes most days of the week, is a behavioral intervention
that has been shown to improve fatigue, depressive symptoms, anxiety, quality of life, cardiovascular fitness, joint pains, and sleep.34,35 As
many breast cancer patients are medication averse, physical activity
is an excellent evidence-​based intervention that should be recommended during and after therapy to minimize physical and psychological symptom distress and improve function and well-​being.5,34,35
Transition to Survivorship
The end of treatment and the beginning of the transition into survivorship are associated with emotional distress; anxiety; uncertainty; diminished support from providers, the healthcare system,
and family; and persistent physical symptoms.3 By the end of 1 year,
QOL and psychological adjustment significantly improve for the
majority of women. However, the psychological responses associated with ending therapy, the process of reintegrating into life, and
addressing the expectation to “return to normal” have resulted in
emotional highs and lows over the first year. The vulnerability
associated with cancer and the side effects of cancer treatment make
many women question the concept of normal, or even the suggested
“new” normal, as they perceive themselves as forever changed by
the experience. Many will embrace the pink ribbon breast cancer
survivor image, but some women feel that the emotional concerns
of uncertainty and fear of recurrence are contrary to a perception of
being a survivor.3 How well a woman adjusts over the course of the
first year can also depend on persistent physical symptoms, degree
of symptom distress, informational adequacy to manage symptoms,
and known risks for late effects, such as osteoporosis and cardiovascular disease. Younger age, limited social support, poor communication with providers, personal life stressors, prior or pre-​existing
psychological problems, and decreased ability to work or carry out
desired activities can further challenge a woman’s psychological
recovery. The American Society of Clinical Oncology provides a
guideline for assessment of treatment effects, evidence-​based recommendations for management (e.g., acupuncture, physical activity for musculoskeletal health), surveillance, health promotion,
and care coordination.36 An important part of the guideline is health
promotion to minimize risk of comorbid illness, breast cancer recurrence, or a new cancer. Healthy eating and physical activity are
two key components to health promotion. As black women have a
higher rate of obesity and sedentary behavior, interventions to address this population are critical and should be tailored to cultural
and socioeconomic factors.37 Black breast cancer survivors are interested in staying healthy and avoiding comorbid illness (e.g., diabetes, cardiovascular disease), and culturally designed interventions
are feasible and can improve healthy lifestyle behaviors.38
Metastatic Breast Cancer: Transition to Long-​Term
Therapy and Palliative Care
The majority of women will have hormone-​positive cancer (≥ 75%),
and the rapidly evolving understanding of molecular mechanisms
has led to expanded therapy options. Critical to management of
metastatic breast cancer is to balance the potential treatment benefit with the toxicity profile to maximize QOL. The first line of
treatment is endocrine therapy with sequential use of agents as patients progress.39 Following endocrine therapy, four nonendocrine
drugs have been approved: the mTor inhibitor everolimus and three
cyclin-​dependent kinases (CDK 4/​6), palbociclib, ribociclib, and
abemaciclib.40 The side effect profile of endocrine therapy is mild to
moderately distressing for the majority of patients with a reported
overall good QOL. In contrast, the nonendocrine therapies have
much worse toxicity profiles. Everolimus is associated with stomatitis, pneumonitis, and gastrointestinal toxicity, while the CDKs
include dose-​limiting neutropenia, and some women develop elevation in liver enzymes and QTc prolongation.40 While most toxicities
can be managed with dose reduction or interruption, the effects of
the adverse side effects on an individual’s quality of life are not yet
fully known.40 While there is no question that these therapeutic advances have extended survival in women with metastatic disease,
it is imperative that every patient participate in the ongoing assessment of the risk-​benefit profile. Communication, support, and
introducing palliative care early on are essential as women with
metastatic breast cancer transition from sequential therapies and
beyond (see Chapters 73 and 74).
173
174
SECTION V Psychological Issues Related to Site of Cancer
Future Directions
Heterogeneity characterizes not only the biology of breast cancer
but also the women who are diagnosed. As we personalize treatment
based on the biology of the cancer, we need to personalize our interventions to address determinants of psychological distress across
the trajectory of the breast cancer continuum. Longer follow-​up
(> 1 year) for psychological responses to persistent and late effects
of therapy is indicated for BCSs. Newer advances in the treatment
of metastatic breast cancer have resulted in longer survival, and research is needed in this population related to psychological well-​
being, coping, goals of care, and decision making as one transitions
across treatment options to end of life.
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16. Knobf MT, Sun, Y. A longitudinal study of symptoms and self-​care
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175
24
Colorectal Cancer
Anne Miles and Claudia Redeker
Introduction
Colorectal cancer (CRC) is the third most common cancer and
second most common cause of cancer death worldwide, with
1.8 million cases diagnosed and 881,000 deaths in 2018. Survival
rates are strongly linked to stage at diagnosis, with 90% surviving
localized disease (Stage I) but only 10% surviving once the disease
has spread to distal organs (Stage IV). Although global CRC incidence and mortality rates are falling, different patterns are observed
between countries. Increases in incidence are seen in countries
adopting “Westernized” lifestyles, due to the causal role of lifestyle
factors such as obesity and lack of exercise in CRC onset, while declines in mortality are observed in high-​resource countries able to
offer more effective treatment and early detection initiatives, such as
screening programs.1
resonance imaging (MRI), are noisy and involve full-​body immersion into a tube, and can induce anxiety and claustrophobia in a
substantial proportion of patients. Particular sectors of the population may find scans more difficult than others. For example, high
distress and the presence of comorbidities have both been associated with finding whole-​body MRI more challenging, independent
of other demographic and clinical variables, among patients with
suspected CRC.3
In a retrospective study asking CRC patients in Canada what
their specific needs had been during the diagnostic phase, 31.6% reported informational and 20.3% reported emotional needs. While
the majority felt their needs had been met at the time, 77.9% reported that they had not been offered help coping with their anxiety,
highlighting the need for increased emotional support during the
diagnostic phase.4
Diagnostic Pathways and Diagnostic Delay
Obtaining a Diagnosis
Psychological issues arise from the moment CRC is suspected,
through treatment, to living with or beyond cancer. Patients with
suspected cancer have to undergo medical investigations and attend
medical appointments, while facing the threat of a serious illness.
Research into distress during the diagnostic phase has shown that
between 33% and 60% of patients report clinical levels of anxiety
before getting a diagnosis (defined as anxiety high enough to be categorized as an anxiety disorder using psychiatric assessment tools).
These levels are equivalent to those observed in patients with a confirmed diagnosis. The majority of studies report that anxiety levels
remain the same or increase in patients ultimately diagnosed with
cancer, while anxiety typically reduces in those with a noncancer diagnosis.2 Similar effects have been observed for quality of life (QoL),
with patients with suspected cancer reporting the equivalent or
poorer QoL as patients with a confirmed diagnosis.2
The process of undergoing investigations for suspected cancer
presents numerous challenges. In addition to the anxiety associated
with waiting for test results, patients with suspected CRC may need
to undergo bowel preparations or have injections, some of which
may involve a radioactive ligand (such as for positron emission tomography [PET]/​computed tomography [CT]), promoting concerns about radiation risk. Scans, such as whole-​body magnetic
There are a number of different pathways to a diagnosis of CRC.
The most common include screening, planned pathways for the
investigation of symptoms of suspected cancer, routine referral for
the investigation of symptoms, and emergency presentation (defined as a cancer diagnosis within 28 days of either attending the
accident and emergency department of a hospital or an emergency
hospital admission). Screening and planned-​care pathways (e.g.,
urgent referral to a specialist following cancer “alarm” signals)
are designed to diagnose CRC sooner and improve survival rates.
The likelihood of experiencing these different pathways, though,
varies internationally; for example, organized screening programs
for CRC are seen in the majority of European countries but are
largely absent in most countries in Central and South America, the
Middle East, and Africa. In addition, where offered, uptake rates
vary widely from 68.2% in the Netherlands, for instance, to 16% in
parts of Canada.5
Little work has examined the psychological consequences of the
different pathways patients may take to a diagnosis. People who have
cancer diagnosed at screening are more likely to have earlier-​stage
disease, requiring simpler treatment, such as surgery alone. A quantitative study in Scotland found that CRC patients diagnosed via fecal
occult blood test (FOBt) screening reported better QoL between 3.5
and 12 years postdiagnosis than people diagnosed following a negative FOBt, or than people who were diagnosed when living in an
CHAPTER 24 Colorectal Cancer
area that did not offer screening at the time,6 highlighting superior
patient-​reported outcomes in screen-​detected patients.
Perceived quality of care following treatment for CRC in England
is also highest among patients diagnosed via screening and worse
among patients diagnosed following emergency presentation.7
While patients diagnosed via emergency presentation have longer
surgeries, longer admissions, and more readmissions, which may
negatively influence their experience of care, they give more negative evaluations of issues such as staff explanations before and after
surgery and of not being involved as much as they wanted to be in
treatment decisions.7 Hence, patient-​reported outcomes as well as
mortality rates can be improved if more CRC patients are diagnosed
via screening.
The main reason for the introduction of diagnostic pathways,
such as screening and standardized cancer patient pathways for
symptoms of suspected cancer, is to improve cancer outcomes by
diagnosing CRC at an earlier stage and reducing the time to treatment. Patients who wait longer for a diagnosis typically undergo a
higher number of medical consultations and investigations. Patients
who report a higher number of visits prior to a diagnosis, or a longer
period of time between help seeking and confirmation of their diagnosis, report lower satisfaction with their care. For example, patients
with anal cancer were more likely to be unsatisfied with their care
if they believed there had been a delay in their diagnosis, but satisfaction levels were much lower if patients believed the cause of the
delay was due to the medical profession rather than their own fault
for failing to seek prompt medical attention.8
Some delay in diagnosis can be attributed to cancer site and the
nonspecific nature of cancer symptoms, making some cancers harder
to diagnose than others. However, delay can also arise from inefficiencies or errors in care. Increased diagnostic delay has been associated with misdiagnoses, such as attributing the symptoms to a disease
other than CRC, failure to examine the patient, and negative or false-​
negative results.9 CRC false-​negative rates of 8% were reported in
a district general hospital in the UK across the three modalities of
double-​contrast barium enema, colonoscopy, and CT colonography,
with the highest false-​negative rates observed for barium enema and
the lowest for colonoscopy,10 suggesting that missed cancers are not
uncommon. Research into the psychological consequences of having
a cancer missed, though, is scant. The study mentioned earlier,
comparing psychological outcomes by method of CRC detection
in Scotland, found no evidence of adverse psychological outcomes
among people who had an “interval” cancer (i.e., a cancer diagnosis
following a negative or clear screening outcome), as compared with
people diagnosed with CRC in an area not offering screening at
the time, on measures of perceived diagnostic delay, QoL, and depression.6 However, participants were surveyed between 3.5 and
12 years postdiagnosis. Thus, having a cancer missed had probably
not proven fatal, potentially attenuating any adverse effects. The same
data showed that CRC survivors who believed their cancer could
have been diagnosed sooner reported greater cancer-​related distress
and were more likely to be classified as having posttraumatic stress
disorder (PTSD). While part of the relationship between perceived
delay and distress was explained by QoL, disease stage at diagnosis
and treatment received did not explain the association.11 The reasons
for higher distress among those who believed their cancer could have
been diagnosed sooner remain unclear, but could relate to factors associated with delay or the way in which the cancer was diagnosed.
Criteria for PTSD (in the Diagnostic and Statistical Manual of Mental
Disorders, fifth edition [DSM-​5]) specify that “Medical incidents that
qualify as traumatic events involve sudden, catastrophic events.”12 In
the context of cancer, trauma could arise from diagnostic pathways
such as emergency presentation.
Given the obvious distress associated with undergoing investigations for cancer, research has examined whether a more rapid diagnosis is associated with enhanced psychological well-​being and
patient satisfaction with care. However, a more rapid diagnosis
means a faster transition from being healthy to being a patient; the
diagnosis may be more shocking and hence harder to accept or adjust to. Again, there is little research specifically on patients with suspected CRC, but in a review of rapid diagnostic pathways (one-​or
two-​stop shops), Brocken et al. found that anxiety tends to reduce
among people with benign outcomes but is sustained or increased
among those diagnosed with cancer.2 A more rapid diagnosis therefore reduces the duration of anxiety for those with benign outcomes
but did not appear to be either beneficial or harmful for people ultimately diagnosed with cancer.
Treatment
Treatment for CRC is strongly linked to diagnostic stage. Surgery
alone is typically recommended for patients with Stage I CRC.
Patients with Stage III or high-​risk Stage II colon cancer (e.g., those
with large tumors) are offered adjuvant (postsurgical) chemotherapy,
while patients with rectal cancer are typically offered neoadjuvant
(presurgical) radiotherapy with or without chemotherapy to reduce
tumor size prior to surgery, as well as to reduce the risk of local recurrence. Such treatment for rectal cancer may also be followed by
further with adjuvant therapy to stop the emergence of distal disease. Treatment for Stage IV disease can still have curative intent
with surgical resection of distant metastases, but palliative chemotherapy has also led to reductions in tumor size, making surgical
resection possible at a later date.
Shared Decision Making
Shared decision making is central to patient-​centered care, whereby
patients take an active role in decisions about their treatment. For
patients with either Stage II or III CRC, a key decision is whether to
have adjuvant chemotherapy, and if so, which chemotherapy drugs
to take. The chemotherapy offered is typically fluorouracil or capecitabine, given on its own or in combination with oxaliplatin. In
patients with Stage II CRC, the risk of cancer recurrence is around
20–​40%, but chemotherapy can only prevent a recurrence in 3–​7%
of patients.13 Because some of the side effects of chemotherapy can
be permanent or even life-​threatening, the balance of benefits and
harms is marginal in this patient group and it is important that the
decision be based on patient preferences.
Eighty-​five percent of Stage III CRCs relapse within 5 years.
Chemotherapy can prevent relapse in up to 25% of patients and
is therefore offered routinely. However, the addition of oxaliplatin
carries the risk of permanent neuropathy and only offers small additional protection against recurrence, of around 5%.14 Recent
research has shown that reducing the duration of adjuvant chemotherapy from 6 to 3 months can halve the risk of experiencing permanent neuropathy without adversely affecting survival rates,14 and
177
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SECTION V Psychological Issues Related to Site of Cancer
that both therapy duration and therapy composition should be discussed and agreed upon with patients.
Decision Support
Current levels of patient involvement in decision making are suboptimal. For example, in England, patient perceptions of their involvement in cancer treatment decisions are currently assessed via the
Cancer Patient Experience Survey (CPES). The CPES is conducted by
the National Health Service (NHS) England to monitor cancer care
and drive forward improvements. Analysis of patient responses to the
question “Were you as involved in decisions about which treatment
you would have as you wanted?” showed that rectal and anal cancer
patients were less likely to report positive experiences of involvement
in treatment decisions than colon cancer patients. People who had had
colon cancer reported more positive responses than people with most
other cancer types.15 However, people who responded that there was
only one type of treatment suitable for them were excluded from the
analysis. People are often unaware that they have a choice of therapy, so
the proportion of positive responses to this question may be inflated.
Some rectal cancer patients may be given a choice between a permanent ostomy (a surgically created opening in the body for the discharge of bodily waste) and sphincter-​sparing surgery, provided that
the probabilities of survival and recurrence are similar. In patients
who choose, or need, an ostomy, research has shown that the postoperative period is smoother and emotionally less distressing when it
follows adequate preoperative preparation, and when the placement
of the stoma (the opening in the abdomen) has taken into account
skinfolds and patient preference (e.g., with regard to clothing).16
Even when appropriate discussions between patient and provider
take place, involving patients in shared decision making presents
a number of challenges. While patients with CRC want information about their cancer, particularly in relation to their prognosis
and treatment options, there are difficulties in effectively communicating information about likelihoods and potential outcomes of
treatment, and adequately supporting patients in making decisions
about their treatment.
Patient decision aids (PDAs) are specifically designed to assist patients, for example, by presenting likelihood information in
multiple formats (e.g., as absolute risk, and in both numeric and
graphic formats) and including a values clarification exercise to help
patients work out what is more important to them—​for example,
maximizing their chances of avoiding a recurrence or accepting a
small increased risk of recurrence to avoid long-​term treatment side
effects. Although evidence suggests that decision aids can be of benefit in increasing people’s knowledge, enhancing people’s accuracy
about the likelihood of different outcomes and helping people feel
both better about the information they receive and clearer about
what is important to them, few decision aids have been developed
to help people make decisions around CRC treatment.17 As people
are more likely to survive CRC, the difficulties they face living with
the long-​term effects of the decisions they have made, and the treatments they have had, become more important.
Living with and beyond Colorectal Cancer
CRC patients and survivors often report emotional difficulties; problems with bowel, urinary, or sexual function; and issues with body
image following major surgery, either for resection of disease, the
placement of a stoma, or both. Such problems can impact both the
patient’s social life and ability to work. The likelihood of experiencing such issues is higher among people diagnosed with later-​stage
disease and those receiving chemotherapy or radiotherapy.
Emotional Difficulties and Quality of Life
Anxiety, depression, and PTSD are frequently comorbid conditions
among cancer survivors. A meta-​analyses of the prevalence of anxiety and depression among people 2 or more years postdiagnosis
found that while rates of depression were equivalent to people
without cancer (11.6% vs. 10%), rates of anxiety were higher (17.9%
vs. 13.9%).18 Rates of PTSD are also more common among cancer
survivors than people with no history of the disease, although prevalence is typically lower than that of depression and anxiety, with a
reported 6.4% point prevalence and lifetime risk of 12.6%.19
The proportion of patients reporting emotional difficulties is usually highest shortly after diagnosis and declines over time. However,
emotional trajectories vary across patients. Dunn et al. conducted a
longitudinal, prospective study of distress among CRC patients between 5 months and 5 years postdiagnosis using the Brief Symptom
Inventory-​18 (a measure combining anxiety, depression, and somatization). They observed four patterns: consistently low distress,
observed in 19.4% of patients; medium-​level distress (going from
“case” to “noncase”) in 29.4% of patients; medium increase (going
from noncase to case) in 38.5% of patients; and high distress (remaining at case level over time) in 12.5% of patients. The odds of
being in one of the medium-​or high-​distress trajectories compared
with the consistently low-​distress group were higher for patients
with Stage III or IV disease, after controlling for age, gender, educational level, and social support. While treatment type was a significant predictor in unadjusted analyses, it was not significant in the
presence of other variables.20
Particular subgroups of the population show greater vulnerability
to emotional problems postdiagnosis. A study conducted on CRC
patients attending cancer clinics in Scotland found depression was
more likely among women, younger people, and people with higher
levels of deprivation.21
Higher prevalence of anxiety, depression, and symptoms of traumatic stress have also been reported among patients who had adjuvant radiotherapy or chemotherapy compared to those receiving
surgery alone, although the impact of disease stage, independent
of treatment received, was not examined.22 Among CRC survivors
who had completed treatment for Stage II or Stage III disease, distress was higher among people who reported treatment-​related side
effects, such as peripheral neuropathy.
QoL measures capture patients’ subjective assessment of physical, functional, psychological, and social well-​being. Different QoL
trajectories have also been observed in CRC survivors, followed
up from 5 months to 5 years postdiagnosis.23 Using the Functional
Assessment of Cancer Therapy-​Colorectal (FACT-​C), which has
physical, functional, social/​family, and emotional well-​being and
CRC-​specific symptom subscales, Dunn et al. found four different
QoL trajectories: constant high QoL, observed in 26.2% of patients;
constant medium, observed in 47.1%; medium decrease, observed
in 7.4% of patients, whereby patients reported a marked decrease in
QoL 2 years postdiagnosis; and constant low QoL, reported by 19.2%
of patients.20 Compared to the reference category of consistently
CHAPTER 24 Colorectal Cancer
high QoL, patients were more likely to be in the QoL trajectories of
medium decrease or constant low if they had more advanced disease
at diagnosis, although membership was not associated with treatment received.
However, other studies show links between specific treatments
or treatment outcomes on QoL. Adverse effects of radiotherapy on
long-​term bowel and sexual function have been reported in numerous studies, but perceived quality of care at the time of treatment (e.g., lack of treatment-​related information, poor control of
treatment-​related side effects) also predicts subsequent QoL in CRC
patients, showing that events experienced during treatment can
have a lasting impact on both patients and their family caregivers.22
Treatment-​Related Side Effects
CRC patients undergoing radiotherapy or chemotherapy may experience a number of side effects, some of which persist once active treatment has finished. A population-​based study in Ireland
on symptom burden of CRC survivors 1 to 3 years postdiagnosis
found the three most commonly reported symptoms were fatigue,
insomnia, and flatulence, all of which were reported by over 20%
of survivors.24 This study also found symptoms tended to co-​occur,
and certain symptoms were more common in patients who had
rectal cancer or had a stoma. Clinically relevant fatigue (defined as
worthy of further clinical attention) has been reported in a third of
CRC patients attending a regional center in Scotland and is more
likely among patients who have received radiotherapy or chemotherapy in the preceding 2 months.25
The chemotherapy drug oxaliplatin carries a risk of peripheral
neuropathy (PN). Symptoms of PN include insensitivity to cold,
numbness, pain, and trouble with balance. Such symptoms have
been associated with higher rates of anxiety and depression and can
affect people’s ability to sleep as well as conduct normal activities
of daily living, including work. Estimates of long-​term prevalence
vary, but one study found that 29% of patients experienced significant neuropathy 3 years after treatment.14
Radiotherapy increases the risk of bowel and urinary problems.
Bowel problems such as diarrhea can adversely affect QoL in CRC
survivors both in the short and longer term,26 resulting in poorer
QoL than among people who have never had cancer. However, incontinence following radiotherapy also depends on whether patients
have had a stoma or not, which, while reducing fecal incontinence,
confers problems of its own.
Patients with Ostomies
Rectal cancer patients’ concern about a permanent ostomy frequently
supersedes all other considerations (see Box 24.1). Difficulties with
self-​care are common, with 63% of ostomates (people with an ostomy) reporting at least one self-​care challenge.27 While there have
been many appliance improvements (e.g., two-​piece pouches, stoma
plugs, flushable pouches) to help ostomates resume social and physical activities and enhance confidence, the continuing large number
of ostomates who adjust poorly highlights the need for strategies to
increase self-​efficacy and utilizing appliance improvements to their
full potential.27
There is some evidence that female ostomates fare worse than male
ostomates. A systematic review found that in all studies included in
the analysis, female ostomates showed significantly worse QoL in
several domains (emotional, physical, and mental health) compared
to male ostomates. Ostomies also have a greater impact on QoL
in younger patients compared to older patients.28 Difficulties with
sleep appear to be another concern for ostomy patients, especially
for women. The main distress is related to pouch leaks and sleeping
positions, with some ostomy patients reporting fatigue due to sleep
deprivation.
Furthermore, complications due to the ostomy such as parastomal
hernia, parastomal abscess or fistula, retraction, stomal ischemia/​
necrosis, stoma stenosis, prolapse, bleeding, small or large bowel
obstruction, and dehydration from high ostomy output, with
peristomal leakage and skin breakdown being the most common
complications, further decrease ostomates’ QoL. Surprisingly, some
ostomates delay treatment for complications for years, waiting too
long, or do not contact a health professional at all. While ostomy
complications occur most often within the first 5 years, the risk of
developing a complication remains lifelong.
Body Image and Sexual Functioning
Sexuality and sexual dysfunction can play an essential role in the
psychosocial health of CRC survivors, including those with an ostomy. Di Fabio et al. found that 76% of rectal cancer patients reported sexual dysfunction concerns.29 Most commonly for males,
the presence of an ostomy is associated with higher erectile dysfunction and lower ejaculatory control. Genital pain and lack of
lubrication are often reported by women. Unsurprisingly, reduced
intercourse frequency is often the consequence. If unaddressed,
these sexual difficulties persist or even worsen and correlate with
reduced QoL, including body image, self-​esteem, distress, and social and physical functioning. There are several known barriers that
hinder the management of sexual dysfunction and satisfaction, such
as embarrassment, lack of or inadequate information by the care
provider before or after surgery, and the timing of interventions.29
Box 24.1. Common QoL Issues for Patients with Ostomies
The creation of an ostomy is sometimes required in the surgical resection of low-​lying rectal cancers. Permanent ostomies are associated with
psychological, physical, and social difficulties. An individual’s adaptation
and the ability to deal with an ostomy can affect quality of life (QoL).
Common QoL issues for patients with permanent ostomies include:
• Depression
• Chronic anxiety
• Social isolation
• Sexuality
• Body image and appearance
• Self-​management of ostomy
— Leaks and spillage
— Skin problems
— Embarrassment due to odor, leakage, and noise
• Dietary concerns
• Constipation
• Comorbidities
• Disrupted sleep due to pouch leaks and sleeping position
• Financial difficulties in paying for ostomy supplies
• Interference with work and social activities
• Physical activities
• Travel difficulties
• Clothing restrictions
• Constant need to adjust to living with an ostomy
179
180
SECTION V Psychological Issues Related to Site of Cancer
Most treatments for sexual dysfunction have focused on pharmacological options, with varying results. While some treatments are
effective in reversing iatrogenic erectile dysfunction, adherence may
be an issue. Treatments for women, such as topical testosterone application for low sexual desire, carry potential safety risks and thus
are not an option.
There is some evidence that psychological interventions can significantly improve sexual dysfunction in cancer survivors. Gender-​
specific approaches and timing of the intervention appear to be key
components for CRC patients. Moreover, body image concerns
may contribute to sexual dysfunction and recovery and ought to be
addressed. Patients with ostomies are more likely to have negative
feelings about their body appearance, which can lead to diminished
intimacy and greater isolation. Intimacy concerns are not just related to patients; ostomies also affect spouses and other partners.
Persson et al. found that spouses of CRC survivors with an ostomy
had difficulty with the partner’s altered body, reported feeling distant from their partners because of the distress caused by the ostomy
surgery, reported difficulty looking at the stoma, and struggled to
hide feelings of disgust.30 Twenty-​three percent of CRC survivors
with an ostomy indicated that their partner responded negatively
during the first sexual experience after ostomy surgery, and 30%
stated that their partner reacted with much caution, fearing they
would hurt the stoma. Overall, women described their husbands’
and partners’ support as central to their psychosocial adjustment
to having an ostomy.
frustrated at not being able to do what they used to do, and a quarter
reported worrying about finances. A third of patients reported often
feeling anxiety or worry, and fear of dying, with 71.4% finding uncertainty the most difficult thing to cope with. Poor coordination
of care, lack of involvement of their general practitioner or primary
care provider, and lack of access to support services were also reported. Overall experiences of having chronic cancer were worse
among younger patients, patients not currently in a relationship,
and those who had had cancer for longer. Despite the increase in
studies investigating unmet needs among cancer patients, survivors
(people who have had cancer but are currently cancer-​free), and
chronic cancer patients, interventions to address these needs have
been more limited and the majority have failed to successfully address them.33
Future Directions
People diagnosed with CRC face numerous challenges throughout
the diagnostic, treatment, and posttreatment phases. Emotional
difficulties, particularly anxiety and FCR, can persist for years.
Treatments for CRC can result in problems with bowel, urinary, or
sexual function and issues with body image following major surgery or the presence of a stoma. Such problems can impact both the
patient’s social life and ability to work, and result in financial difficulties. Fatigue and difficulty sleeping remain common problems
among patients with chronic cancer.
Fear of Recurrence and Ability to Work
Evidence, though limited, suggests that better QoL and greater
Fear of cancer recurrence (FCR) is a common worry, with a third of levels of satisfaction with cancer care are reported among patients
CRC survivors reporting concerns a median of 5 years postdiagnosis. with screen-​detected disease. However, there are marked differences
One Dutch study found no association between FCR in CRC sur- across countries in screening provision.
A substantial proportion of patients living with and beyond
vivors and disease stage or treatment received, but greater FCR was
cancer report unmet needs around living with anxiety, uncertainty,
associated with higher distress and poorer QoL.31
The impact of a cancer diagnosis on financial strain is and fear of dying, as well as the need for medical support and inforunderexplored, but research has shown that survivors of gastroin- mation. Interventions to reduce unmet needs in cancer patients have
testinal cancers are more likely to be unemployed compared with had little success to date.
Future research should aim to minimize the psychological and
people with no history of cancer (48.8% vs. 33.4%).32 Reasons for
unemployment given include physical limitations and cancer-​ physical consequences of a CRC diagnosis. Promoting earlier diagrelated symptoms. Inability to work can cause high levels of distress nosis, for example, via screening, is one of the best ways of achieving
this. More effective interventions are required to help CRC patients
in a substantial proportion of survivors.
in the challenges they face before and after a cancer diagnosis, such
Unmet Needs
as the management of long-​term side effects of cancer-​related treatImprovements in cancer treatment mean more people live with ment such as fatigue, and emotional difficulties that may persist for
cancer as a “chronic illness” (defined as people with active, ad- years. Greater patient involvement in decision making around treatvanced, or metastatic disease that cannot be cured but that can ments should be encouraged to ensure individuals decide how best
be managed and is not considered end-​of-​life care). Recent re- to balance quantity with QoL, rather than maximizing survival at
search into the symptoms and care needs of this group includes any cost.
development of a questionnaire (the Chronic Cancer Experiences
Questionnaire) and assessment of difficulties in relation to clinical
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181
25
Prostate Cancer and Genitourinary
Malignancies
Andrew J. Roth and Alejandro Gonzalez-​Restrepo
Introduction
Prostate and genitourinary (GU) cancers are common.1 With the exception of testicular cancer, the incidence of GU cancers (e.g., prostate, bladder, renal, and penile cancers) increases with advancing
age. Thus, understanding coincident life phase characteristics is important in optimizing the ability of each patient to cope with his or
her cancer. The effect of treatment on the quality of life (QOL) of
patients has become more significant as survival has improved for
many of these cancers. QOL areas of concern include coping with
body image and integrity changes, varying degrees of sexual and
physical intimacy dysfunction, and infertility. These issues compound the generic difficulties of coping with cancer, such as dealing
with pain, fatigue, and other complications of treatment, including
challenges of daily functioning, lifestyle changes, and career uncertainty. Primary treatment decisions are complicated by comparing
the curability and longevity potential of different options with
posttreatment QOL concerns, especially as newer treatments arise
that do not yet have significant track records.
Prostate Cancer
Prostate cancer is the most common nonskin cancer in males in the
United States, with almost 200,000