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cancercontroljournal.org Vol. 22, No. 4, October 2015
H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE, AN NCI COMPREHENSIVE CANCER CENTER
Integrating Palliative Care Into Oncology: A Way Forward
Improving the Quality of Palliative Care Through
National and Regional Collaboration Efforts
Palliative Pharmacotherapy: State-of-the-Art
Management of Symptoms in Patients With Cancer
Pharmacological Management of Cancer-Related Pain
Clinical Implications of Opioid Pharmacogenomics in
Patients With Cancer
Palliative Sedation in Patients With Cancer
Integrating Psychosocial Care Into Routine Cancer Care
Systematic Review of Palliative Care in the Rural Setting
New Frontiers in Outpatient Palliative Care for Patients
With Cancer
Palliative Care in Adolescents and Young Adults With
Cancer
Palliative Care in Older Patients With Cancer
Prognostication of Survival in Patients With Advanced
Cancer: Predicting the Unpredictable?
Cancer Control is included in
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PROVIDED BY
Editorial Board Members
Editor:
Lodovico Balducci, MD
Senior Member
Program Leader, Senior Adult Oncology Program
Moffitt Cancer Center
Deputy Editor:
Julio M. Pow-Sang, MD
Senior Member
Chair, Department of Genitourinary Oncology
Director of Moffitt Robotics Program
Moffitt Cancer Center
Editor Emeritus:
John Horton, MB, ChB
Professor Emeritus of Medicine & Oncology
Guest Editors:
Diane Portman, MD
Assistant Member
Department Chair, Supportive Care Medicine
Program Leader, Palliative Medicine
Moffitt Cancer Center
Sarah Thirlwell, MSc, MSc(A), RN
Nurse Director, Supportive Care Medicine
Department of Supportive Care Medicine
Moffitt Cancer Center
John V. Kiluk, MD
Associate Member
Breast Oncology
Richard D. Kim, MD
Associate Member
Gastrointestinal Oncology
Bela Kis, MD, PhD
Assistant Member
Diagnostic Radiology
Rami Komrokji, MD
Associate Member
Malignant Hematology
Conor C. Lynch, PhD
Assistant Member
Tumor Biology
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Assistant Member
Head & Neck Oncology
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Cancer Control:
Journal of the Moffitt Cancer Center
12902 Magnolia Drive – MBC-JRNL
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Phone: 813-745-1348
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Pathology - Clinical
Moffitt Cancer Center
Journal Advisory Committee:
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Senior Member
Drug Discovery
Daniel A. Anaya, MD
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Gastrointestinal Oncology
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Assistant Member
Malignant Hematology
Aliyah Baluch, MD
Assistant Member
Infectious Diseases
Lubomir Sokol, MD, PhD
Senior Member
Hematology/Oncology
Dung-Tsa Chen, PhD
Associate Member
Biostatistics
Hatem H. Soliman, MD
Assistant Member
Breast Oncology
Hey Sook Chon, MD
Assistant Member
Gynecological Oncology
Jonathan R. Strosberg, MD
Assistant Member
Gastrointestinal Oncology
Jasreman Dhillon, MD
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Pathology - Anatomic
Sarah W. Thirlwell, MSc, MSc(A), RN
Nurse Director
Supportive Care Medicine Program
Jennifer S. Drukteinis, MD
Associate Member
Diagnostic Radiology
Eric M. Toloza, MD, PhD
Assistant Member
Thoracic Oncology
Clement K. Gwede, PhD
Associate Member
Health Outcomes & Behavior
Nam D. Tran, MD
Assistant Member
Neuro-Oncology
Sarah E. Hoffe, MD
Associate Member
Radiation Oncology
Jonathan S. Zager, MD
Associate Member
Sarcoma and Cutaneous Oncology
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Cancer Control are available at
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Cancer Control: Journal of the Moffitt Cancer Center (ISSN 1073-2748) is published by H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612.
Telephone: 813-745-1348. Fax: 813-449-8680. E-mail: ccjournal@Moffitt.org. Internet address: cancercontroljournal.org. Cancer Control is included in Index Medicus ®/MEDLINE® and EMBASE®/
Excerpta Medica, Thomson Reuters Science Citation Index Expanded (SciSearch®) and Journal Citation Reports/Science Edition. Copyright 2015 by H. Lee Moffitt Cancer Center & Research Institute.
All rights reserved.
Cancer Control: Journal of the Moffitt Cancer Center is a peer-reviewed journal that is published to enhance the knowledge needed by professionals in oncology to help them minimize the
impact of human malignancy. Each issue emphasizes a specific theme relating to the detection or management of cancer. The objectives of Cancer Control are to define the current state of
cancer care, to integrate recently generated information with historical practice patterns, and to enlighten readers through critical reviews, commentaries, and analyses of recent research studies.
Disclaimer: All articles published in this journal, including editorials and letters, represent the opinions of the author(s) and do not necessarily reflect the opinions of the editorial board, the
H. Lee Moffitt Cancer Center & Research Institute, Inc, or the institutions with which the authors are affiliated unless clearly specified. The reader is advised to independently verify the effectiveness of all methods of treatment and the accuracy of all drug names, dosages, and schedules. Dosages and methods of administration of pharmaceutical products may not be those listed in
the package insert and solely reflect the experience of the author(s) and/or clinical investigator(s).
October 2015, Vol. 22, No. 4
Cancer Control 377
Table of Contents
Letter From the Editors
A New Step Rather Than a New Era
381
Lodovico Balducci, MD, and Julio M. Pow-Sang, MD
Editorial
Perspectives, Progress, and Opportunities for Palliative Care in Oncology
382
Diane Portman, MD, and Sarah Thirlwell, MSc, MSc(A), RN
Articles
Integrating Palliative Care Into Oncology: A Way Forward
386
Kavitha Ramchandran, MD, Erika Tribett, MPH, Brian Dietrich, MD,
and Jamie Von Roenn, MD
Improving the Quality of Palliative Care Through National and
Regional Collaboration Efforts 396
Arif H. Kamal, MD, MHS, Krista L. Harrison, PhD, Marie Bakitas, DNSc, CRNP,
J. Nicholas Dionne-Odom, PhD, Lisa Zubkoff, PhD, Imatullah Akyar, PhD, RN,
Steven Z. Pantilat, MD, David L O’Riordan, PhD, Ashley R. Bragg, Kara E. Bischoff, MD,
and Janet Bull, MD
Palliative Pharmacotherapy: State-of-the-Art Management of
Symptoms in Patients With Cancer
403
Eric E. Prommer, MD
Pharmacological Management of Cancer-Related Pain 412
Eric E. Prommer, MD
Clinical Implications of Opioid Pharmacogenomics in
Patients With Cancer
426
Gillian C. Bell, PharmD, Kristine A. Donovan, PhD, and Howard L. McLeod, PharmD
Palliative Sedation in Patients With Cancer 433
Marco Maltoni, MD, and Elisabetta Setola, MD
378 Cancer Control
October 2015, Vol. 22, No. 4
Table of Contents
Articles, continued
Integrating Psychosocial Care Into Routine Cancer Care
442
Paul B. Jacobsen, PhD, and Morgan Lee, MA
Systematic Review of Palliative Care in the Rural Setting 450
Marie A. Bakitas, DNSc, CRNP, Ronit Elk, PhD, Meka Astin, MPH,
Lyn Ceronsky, DNP, GNP, Kathleen N. Clifford, MSN, FNP-BC,
J. Nicholas Dionne-Odom, PhD, RN, Linda L. Emanuel, PhD, MD,
Regina M. Fink, RN, PhD, Elizabeth Kvale, MD, Sue Levkoff, ScD, MSW,
Christine Ritchie, MD, MSPH, and Thomas Smith, MD
New Frontiers in Outpatient Palliative Care for Patients With Cancer
465
Michael W. Rabow, MD, Constance Dahlin, ANP-BC, ACHPN, Brook Calton, MD,
Kara Bischoff, MD, and Christine Ritchie, MD, MSPH
Palliative Care in Adolescents and Young Adults With Cancer
475
Kristine A. Donovan, PhD, Dianne Knight, MD, and Gwendolyn P. Quinn, PhD
Palliative Care in Older Patients With Cancer 480
Lodovico Balducci, MD, Dawn Dolan, PharmD, and Sarah A. Hoffe, MD
Prognostication of Survival in Patients With Advanced Cancer: Predicting the Unpredictable?
489
David Hui, MD, MSc
Departments
Pathology Perspective: Is DOG1 Immunoreactivity Specific to Gastrointestinal Stromal Tumor?
498
William Swalchick, MA, Rania Shamekh, MD, and Marilyn M. Bui, MD, PhD
Case Report: Occurrence of Multiple Tumors in a Patient 505
Special Report: Association of Cancer Stem Cell Markers With Aggressive
Tumor Features in Papillary Thyroid Carcinoma
508
Elaine Tan, Mark Friedman, MD, and Domenico Coppola, MD
Zhenzhen Lin, MD, Xuemian Lu, MD, Weihua Li, MD, Mengli Sun, MD, Mengmeng Peng, MD,
Hong Yang, MD, Liangmiao Chen, MD, Chi Zhang, PhD, Lu Cai, MD, PhD, and Yan Li, MD, PhD
October 2015, Vol. 22, No. 4
Cancer Control 379
Table of Contents
Departments, continued
Special Report: Should Vital Signs Be Routinely Obtained Prior to
Intravenous Chemotherapy? Results From a 2-Center Study
515
Smitha Menon, MD, Nathan R. Foster, MS, Sherry Looker, RN, Kristine Sorgatz, RN,
Pashtoon Murtaza Kasi, MBBS, Robert R. McWilliams, MD, and Aminah Jatoi, MD
Special Report: Advancing Cancer Control Through Research and Cancer Registry Collaborations in the Caribbean 520
Rishika Banydeen, MPH, Angela M.C. Rose, MSc, Damali Martin, PhD, MPH, William Aiken, MD,
Cheryl Alexis, MBBS, MSc, MRCP, Glennis Andall-Brereton, PhD, Kimlin Ashing, PhD,
J. Gordon Avery, MB, ChB, MD, Penny Avery, SRN, Jacqueline Deloumeaux, MD, PhD,
Natasha Ekomaye, Owen Gabriel, MD, Trevor Hassel, MBBS, Lowell Hughes, MBBS, Maisha Hutton, MSc,
Shravana Kumar Jyoti, MD, Penelope Layne, RN/RM, Danièle Luce, PhD, Alan Patrick, MD,
Patsy Prussia, MBBS, Juliette Smith-Ravin, PhD, Jacqueline Veronique-Baudin, PhD,
Elizabeth Blackman, MPH, Veronica Roach, SRN, Camille Ragin, PhD
Ten Best Readings Relating to Palliative Care for Oncology
531
Peer Reviewers, 2015
532
Index for 2015, Volume 22
533
About the art in this issue:
Lisa Scholder is a multimedia artist whose canvas is the human body. Her technique involves applying body paint to nude models, then digitally photographing the painted body. The explosion of illuminating color on the human form is Scholder’s artistic trademark. All of the models shown in this issue
are survivors of breast cancer of varying ages and body types, and they are part of the Bodies of Courage project.
Scholder takes several hours to hand-paint the model with a crème-based paint and often incorporates other body-painted images in the final
piece, which does not include the face of her model. Her artwork focuses on the abstract portrayal of the body infused with vibrant colors. Scholder’s
late father-in-law, renowned Indian artist Fritz Scholder, had an unmistakable influence on her bold color combinations. Each model’s unique strength
is represented with abstract and, at times, expressionist art forms on her body. The artist’s driving force is the self-empowerment that this process can
bestow on her model, enabling her to see her body as a colorful, unique piece of art.
With no formal art training, she began body painting in 2000 and developed her distinct body painting and photography style. Her first public exhibition was in 2004, and she progressed to gallery and art museum exhibitions since then.
Bodies of Courage is an Arts in Medicine project (www.bodiesofcourage.org) in partnership with the Faces of Courage Foundation
(www.facesofcourage.org), which provides day outings and overnight camps at no cost for women, children, and families diagnosed with any type of
cancer. Lisa Scholder and Peggie D. Sherry, the founder of Faces of Courage, began this project 5 years ago as a way to raise awareness and as an
artistic therapy for survivors of cancer. This project is an artistic testimony to the strength and determination of these survivors throughout their battles
with cancer, their celebration of life, and their reconnection with the beauty of their own bodies.
For information about the traveling gallery, please contact Peggie D. Sherry at psherry@facesofcourage.org or 813-948-7478. Further information
on these projects is available at www.bodiesofcourage.org and www.facesofcourage.org.
Cover: Linear. 20" × 24"
Articles:
Enlightened. 16" × 24"
Road Between Art. 16" × 24"
Sunlit Legs. 16" × 22"
Solid Stance. 16" × 24"
Greener Pastures. 16" × 22"
Organic Walk. 16" × 24"
Seizing the Light. 16" × 20"
Masculine. 14" × 22"
Family. 16" × 24"
Sunlit. 16" × 24"
Duality. 18" × 24"
Dive Forward. 16" × 24"
380 Cancer Control
October 2015, Vol. 22, No. 4
Letter From the Editors:
A New Step Rather Than a New Era
Dear Readers,
Beginning with the January 2016 issue, Cancer Control: Journal of the Moffitt Cancer Center will be published in
digital format only. With the launch of our new and improved website, readers will still be able to download and
print the articles they wish to keep by visiting us at cancercontroljournal.org (formerly MOFFITT.org/ccj). The
new URL links to our existing webpage under MOFFITT.org and will redirect readers to the new website as soon
as it is available. Reprint requests will continue to be handled by the editorial office and will be reviewed and responded to on an individual basis.
The decision to abandon the paper edition was based on considerations of cost effectiveness paramount for
all fields of health care today. As the price of paper continues to rise and more and more people utilize electronic
devices to read books, newspapers, and magazines, the increasing costs of printing no longer appear justified.
Limited resources may be better utilized in maintaining and improving the quality and timeliness of our publication. For those of us who grew up in the pre-electronic era, who were used to waiting with anticipation for the new
issue of our favorite medical journal in the mail, this change is a little disconcerting, as is the experience of seeing
a daughter, now an adult, leave home and start her new family. It is disconcerting but necessary: as much as we regretted retiring our cherished stethoscope, we conceded that an echocardiogram was a more precise way to detect
valvular disease or myocardial dysfunction than the human ear.
Indeed, we plan to utilize the resources of the journal to fulfill our ongoing commitment to quality and practicality. Since its inception more than 20 years ago, Cancer Control promised to provide practicing oncologists with
exhaustive and user-friendly reviews of important issues that could not be otherwise found in the literature.
John Horton, MB, ChB, the founding editor and the quintessential clinical teacher, received universal praise
for the impact Cancer Control had on the practice of oncology in the country and around the world. John C. Ruckdeschel, MD, the first chief executive officer of the H. Lee Moffitt Cancer Center & Research Institute and cofounder
of Cancer Control, gave unlimited support to the educational mission of Moffitt and considered the journal to be
the most effective means to fulfill this mission.
The scope of oncology is rapidly enlarging and diversifying, and the practitioner is exposed to a barrage of
new information that is both incomplete and contradictory. The main challenge of oncology education is to harness the energy of this scientific upsurge into a coherent discourse that highlights scientific advances together
with new clinical questions. Fully committed to guide the practitioner to a safe exit from this informational maze,
Cancer Control will devote the next issues to novel and timely topics. These include minimally invasive surgery,
prospective radiosurgery and interventional radiology, imaging techniques based on biological markers, the use of
genomic testing, the interpretation of results from clinical trials of targeted therapy, the use of mathematical models to predict tumor progression, overviews of tumor immunology and signal transduction, and the new scope of
palliative care. Since establishing Cancer Control, Moffitt has grown to be the third largest comprehensive cancer
center in the country. Basic, translational, and clinical investigators working at Moffitt illustrate the array of treatments and clinical trials available at our institution for the patients of Florida, the United States, and the world.
A digital publication will allow us to focus unimpeded on the exciting and continual progress of cancer care.
We would like to think that the adoption of a digital format represents a new step, rather than a new era, in the life
of our journal — a step congruent with technological and scientific changes that will permit us to fulfill our mission in a rapidly changing world.
Lodovico Balducci, MD
Senior Member
Program Leader, Senior Adult Oncology Program
Editor, Cancer Control
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Florida
Lodovico.Balducci@Moffitt.org
October 2015, Vol. 22, No. 4
Julio M. Pow-Sang, MD
Senior Member and Chair, Department of Genitourinary Oncology
Chief, Surgery Service
Director, Moffitt Robotics Program
Deputy Editor, Cancer Control
H. Lee Moffitt Cancer Center & Research Institute
Professor, Departments of Urology and Oncologic Sciences
University of South Florida
Morsani College of Medicine
Tampa, Florida
Julio.Powsang@Moffitt.org
Cancer Control 381
Editorial
Perspectives, Progress, and Opportunities for
Palliative Care in Oncology
In 2010, Temel et al1 demonstrated improved outcomes, including longer survival, in patients with
metastatic non–small-cell lung cancer receiving palliative care along with usual oncology treatment. A provisional opinion published in 2012 by the American
Society of Clinical Oncology further supported early
palliative care for any cancer patient with advanced
disease or high symptom burden.2 The Center to Advance Palliative Care, the American Cancer Society,
and other national organizations have been instrumental in the advancement of the education, research, and
literature base for supportive and palliative care in
cancer settings. They have led the charge to support
patient and family quality of life and align care with
patient goals. Study results have demonstrated improved costs of care while maintaining quality, leading
to significant advances in the penetration and growth
of palliative care programs nationwide.3-6
However, more than a decade after the Institute
of Medicine first studied the quality of cancer care,
the obstacles to provision of quality palliative care
for patients with cancer remain formidable. Patients
frequently do not receive adequate symptom control
or management of treatment-related side effects, and
decisions about care often are not patient-centered
or rooted in the most recent scientific evidence.7 In
Dying in America, the Institute of Medicine’s 2014
consensus report on care of the dying, a committee
of experts found that improving the quality and availability of medical and social services for patients and
their families could not only enhance quality of life
through the end of life, but may also contribute to a
more sustainable care system.8
In this issue of Cancer Control, we present topics
on palliative care that highlight the progress made to
support the well-being of patients with cancer and the
challenges to continued integration and advancement
of the field of palliative care in oncology.
Dr Ramchandran and colleagues review the compelling case for palliative care integration, the barriers to progress, and summarize key lessons gleaned
from randomized controlled trials in palliative care
integration in both the inpatient and outpatient oncology settings. Employing a case-study approach,
they discuss means to integrate palliative care into
oncology care and offer guidance for sustainability of
integration. Among the strategies for scalable integration, the importance of quality measures and metric
382 Cancer Control
development is emphasized.
Dr Kamal and associates provide insight into quality improvement for palliative care achieved through
collaborations that examine how care is delivered and
may be improved. Their article describes endeavors
to enhance the provision of quality palliative care at
regional and national levels through cooperative efforts within an expansive group of community and
academic palliative care providers. The development
of the innovative, evidence-based Quality Data Collection Tool and its utilization are described as means to
generate quality improvement projects aligned with
national quality measurement initiatives. Such projects are an impetus for identifying and addressing
troubling symptoms associated with serious illness,
such as those frequently encountered in patients with
cancer.
The management of symptoms in cancer is updated in Dr Prommer’s article on state-of-the-art palliative pharmacotherapy. The treatment of prevalent
symptoms that compromise the well-being of patients
and their caregivers throughout the course of cancer
care is emphasized, with particular focus on those
that engender distress as disease progression occurs.
Symptom mechanisms, means of assessment, and
management approaches utilizing both medicationbased treatments and nonpharmacological therapies
are described.
In a second article, Dr Prommer reviews the
pharmacological management of cancer pain. The
World Health Organization analgesic ladder for
the management of cancer pain of varying intensity is described, with detail provided on use of
specific agents among the familiar “tried and true
gold-standard” medications and more recently available agents. The additional value of adjuvants and
interventional pain modalities is represented along
with approaches to medication conversions and management of common opioid side effects. The epidemiology of malignant pain and the understanding
of opioid responsiveness in the context of opioid
receptor interactions are elucidated together with
approaches to opioid-resistant pain.
Given the use of opioids for cancer pain, Dr Bell
and coauthors explore the basis of opioid analgesic
responsiveness with a review of clinical studies that
have assessed the connections between the effects of
opioids and the genetic variants in the many genes
October 2015, Vol. 22, No. 4
that govern their actions. The evidence is examined
for associations between specific genetic variants
and modulation of opioid response with variability
in treatment results. Despite the challenges identified and the need for prospective studies comparing
pharmacogenetic-guided opioid treatment to standard
practice, the authors’ suggestion of the potential use
of genotyping to achieve more effective therapy in
cancer-related pain palliation is compelling.
Dame Cicely Saunders, the founder of the modern hospice movement, emphasized the need for
palliative care to manage “total pain”: The spiritual,
psychological, social, and emotional elements that
together with physical distress can cause intolerable suffering.9 Drs Maltoni and Setola review the
controversial topic of palliative sedation for relief
of refractory physical symptoms. Their article focuses on the application of proportionate palliative
sedation at the end of life, consistent with national
and international guidelines, as an ethical modality
without effect on survival.
The multifaceted understanding and management
of total pain in cancer goes beyond relief of physical
suffering and necessitates the integration of psychosocial care.10,11 Drs Jacobsen and Lee review progress in
this area, describing the application of standards, key
clinical practice guidelines, and quality monitoring.
They describe the effect of such monitoring on quality
in psychosocial care. Models are provided to demonstrate efforts to enhance provision of psychosocial
care by implementing such standards and guidelines
in community settings.
Dr Bakitas and colleagues discuss the limitations
to access and the dissemination of comprehensive
palliative care for patients with cancer living in rural settings. They have gathered empirical evidence,
largely focused on patients with cancer, and describe
the present state in rural palliative care research and
practice. The article reveals a dearth of research in this
arena and a paucity of rural palliative care services,
resulting in limited care. However, the successful initiatives described demonstrate opportunities to establish palliative care practice services and standards
specific to rural settings.
Dr Rabow and associates describe other areas
of importance in community-based palliative care in
their article about outpatient oncological palliative
care. Recognizing the fundamental but minority role
played by hospital palliative care in the context of the
totality of palliative care required in oncology is pivotal. The article describes the current state in oncology palliative care and highlights vanguard elements
in outpatient oncology palliative care, including the
setting and timing of palliative care integration into
outpatient oncology, quality and measurement, research, electronic and technical innovations, finances,
October 2015, Vol. 22, No. 4
and the relationship between primary and specialty
palliative care.
Specialty palliative care distinguishes the activity of specialty-trained providers managing complex
refractory symptoms, existential and psychosocial distress, medical futility, and advanced communications.
However, specialty palliative care in oncology also
encompasses expert palliative care that may be provided to special populations of patients with cancer
who have unique needs. The particular challenges of
these groups and their care are described in the articles on palliative care in adolescent and young adult
patients with cancer by Dr Donovan and coauthors
and palliative care of older patients with cancer by
Dr Balducci and associates.
The article by Donovan and colleagues highlights
the limited provision of palliative care and research
studies on palliative care in adolescent and young
adult patients with cancer. Gaps in care with high
potential for distress and opportunities for earlier
inclusion of palliative care are also identified. The
article features guidelines supporting the integration
of palliative care, the options for advance care planning, and challenges to implementation in this patient
population.
Balducci et al focus on palliative care for older
patients with cancer and provide a comprehensive
overview of the effects of advancing age. They emphasize specialized palliative care concerns pertaining
to this expanding population, a group also frequently
affected by nononcological medical issues. The priorities elucidated include setting goals, prevention and
management of treatment complications, management
of cancer-related symptoms, and management of older
survivors of cancer.
Survival prediction principles and recent literature
on prognostication are reviewed by Dr Hui in the
context of examining clinician prediction of survival
in patients with advanced cancer. With emphases on
prognostication as a process, the evolution of prognostic factors over time, the variability in prognostic
accuracy, and the overriding principle of unpredictability of the exact time of death, Dr Hui highlights the
uncertainty in survival prediction. Yet, use of existing
validated prognostic models and factors still enable
clinicians to provide approximated time frames. These
can facilitate clinical decision making in the present,
and the future holds promise for multiple opportunities in prognostication research.
We have compiled this compendium of topics in
palliative care in oncology in the hopes of advancing
our understanding and adoption of palliative care in
cancer. Our goal is partnership to enhance patient
and caregiver quality of life throughout the cancer
continuum. We are gratified with the progress made
and motivated by the opportunities that remain.
Cancer Control 383
Diane Portman, MD
Guest Editor
Department Chair, Supportive Care Medicine
Program Leader, Palliative Medicine
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Florida
Diane.Portman@Moffitt.org
Sarah Thirlwell, MSc, MSc(A), RN
Guest Editor
Nurse Director, Supportive Care Medicine
Department of Supportive Care Medicine
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Florida
Sarah.Thirlwell@Moffitt.org
References
1. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients
with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733-742.
2. Smith TJ, Temin S, Alesi ER, et al. American Society of Clinical Oncology
provisional clinical opinion: the integration of palliative care into standard oncology care. J Clin Oncol. 2012;30(8):880-887.
3. Morrison RS, Dietrich J, Ladwig S, et al. Palliative care consultation
teams cut hospital costs for Medicaid beneficiaries. Health Aff (Millwood).
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4. Parikh RB, Kirch RA, Smith TJ, et al. Early specialty palliative care —
translating data in oncology into practice. N Engl J Med. 2013;369(24):2347-2351.
5. Penrod JD, Deb P, Dellenbaugh C, et al. Hospital-based palliative
care consultation: effects on hospital cost. J Palliat Med. 2010;13(8):973-979.
6. Hughes MT, Smith TJ. The growth of palliative care in the United
States. Annu Rev Public Health. 2014;35:459-475.
7. Levit L, Balogh E, Nass S, et al, ed. Delivering High-Quality Cancer
Care: Charting a New Course for a System in Crisis. Washington, DC: National
Academies Press; 2013.
8. Committee on Approaching Death. Dying in America: Improving Quality
and Honoring Individual Preferences Near the End of Life. Washington, DC:
National Academies Press; 2014.
9.
Saunders C. Cicely Saunders: Selected Writings 1958-2004. New York:
Oxford University Press; 2006.
10. Hallenbeck J, McDaniel S. Palliative care and pain management in the
United States. In: Moore RJ, ed. Biobehavioral Approaches to Pain. New York:
Springer; 2009:493-513.
11. Surbone A, Baider L, Weitzman TS, et al. Psychosocial care for patients
and their families is integral to supportive care in cancer: MASCC position statement. Support Care Cancer. 2010;18(2):255-263.
384 Cancer Control
October 2015, Vol. 22, No. 4
Department of Supportive Care Medicine
H. Lee Moffitt Cancer Center & Research Institute
The Department of Supportive Care Medicine at the H. Lee Moffitt Cancer Center & Research Institute is engaged in clinical care, training and research. The department includes the sections of Palliative, Behavioral, and
Integrative Medicine. Consultative and management services are offered in both the outpatient and inpatient
settings. The activities of the department address the physical, emotional, social, and spiritual challenges that
occur throughout the course of cancer care.
Department Chair
Diane Portman, MD
PALLIATIVE MEDICINE
BEHAVIORAL MEDICINE
INTEGRATIVE MEDICINE
Diane Portman, MD
Young D. Chang, MD
Ritika Oberoi-Jassal, MD
Sahana Rajasekhara, MD
Joshua Smith, MD
Cynthia Brown, ARNP
Leah Crist, ARNP
Laura Donovan, ARNP
Ann Guastella, ARNP
Jessica Latchman, ARNP
David Craig, PharmD
Robin Lawson, LCSW
Mareda Kennedy, MDiv
Margarita Bobonis, MD, Section Chief
Barbara Lubrano di Ciccone, MD
Marguerite Pinard, MD
Margaret Booth-Jones, PhD
Kristine Donovan, PhD
Lora Thompson, PhD
Lora Thompson, PhD, Director
Liem Quang Le, LAc, Acupuncture
Sharen Lock, Mindfulness & Yoga
Mary Marton, Massage Therapy
Elaine Payne, Massage Therapy
Jonatha Wright, Massage Therapy
Program Support
Clinical Support
Department Administrator
Carol Knop, MBA
Clinic Operations Manager
Kathy Loufman, RN, MS
Nurse Director
Sarah Thirlwell, MSc, MSc(A), RN
Registered Nurses
Medical Assistants
Patient Services Specialists
Supervisor
Peggy Kirwin
Community and
Patient Programs
Education
and Training
Yoga Classes
Meditation Classes
Finding Balance with Cancer
Program
USF College of Medicine
• Medical Students
• Hospice and Palliative
Medicine Fellows
• Hematology-Oncology
Fellows
Breast Surgical Oncology Fellows
International Visiting Scholars
Management Assistants
For more information about the Department of Supportive Care Medicine,
call the department at 813-745-6045 (during normal business hours).
www.MOFFITT.org
October 2015, Vol. 22, No. 4
Cancer Control 385
Palliative care should be
initiated early in the treatment
continuum of cancer.
Photo courtesy of Lisa Scholder. Enlightened. 16” × 24”.
Integrating Palliative Care Into Oncology: A Way Forward
Kavitha Ramchandran, MD, Erika Tribett, MPH, Brian Dietrich, MD, and Jamie Von Roenn, MD
Background: Patients with cancer have complex physical, psychosocial, and spiritual needs that evolve
throughout their disease trajectory. As patients are living longer with a diagnosis of cancer, the need is growing
to address the morbidity due to the underlying illness as well as treatment-related adverse events. Palliative
care includes treating physical symptoms as well as addressing psychosocial and spiritual needs. When these
needs are addressed, the quality of care improves, costs decrease, and goals are aligned between the medical
care provided and the patient and family. However, how best to integrate palliative care into oncology care
is still an area of investigation.
Methods: The authors conducted a literature search, including randomized clinical trials and practice
reviews, to evaluate the evidence for integrating palliative care into oncology care. Barriers to integration
as well as sustainable paths forward are highlighted. The authors also utilize case studies as representative
examples of integration.
Results: Current studies demonstrate that integrating palliative care into oncology care improves symptom
control, rates of patient and family satisfaction, and quality of end-of-life care. However, for systemwide
integration to be successful, commitment must be made to quality improvement, an infrastructure must be
built to support palliative care screening, assessment, and intervention, and stakeholders must be engaged
in the program. In addition, value must be demonstrated using metrics that affect quality, care utilization,
and patient satisfaction.
Conclusions: Even though most US cancer centers have a palliative care program, palliative care remains
limited in scope. An integrated approach for palliative care with oncology care requires a systems-based approach, with agreement between all parties on shared common metrics for value.
Introduction
Significant progress has been made in the management
and treatment of cancer, but morbidity rates continue
From the American Society of Clinical Oncology (JV), Alexandria, Virginia, Stanford Cancer Institute (KR), and Stanford University School of Medicine (ET, BD), Palo Alto, California.
Submitted April 15, 2015; accepted September 2, 2015.
Address correspondence to Jamie Von Roenn, MD, American Society of Clinical Oncology, 2318 Mill Road, Suite 800, Alexandria, VA 22314. E-mail: Jamie.VonRoenn@asco.org
No significant relationships exist between the authors and the
companies/organizations whose products or services may be referenced in this article.
386 Cancer Control
to increase.1,2 An estimated 1,658,370 new cancer diagnoses and 589,430 cancer-related deaths are expected
to occur in the United States in 2015.3 These data reflect a 22% decline in overall cancer mortality, translating to approximately 1,519,300 fewer cancer-related
deaths from 1991 to 2011.3,4 This decrease in mortality
may be associated with an increase in cancer morbidity, because a growing number of survivors experience
the late-onset and long-lasting effects of cancer and its
treatment.2 Patients and families experience physical,
psychological, and spiritual symptoms throughout the
disease trajectory, sometimes leading to poor quality of
life and suboptimal treatment outcomes.5
October 2015, Vol. 22, No. 4
Palliative care can help relieve symptoms and improve well-being in patients and their families living
with a serious illness.6 The World Health Organization
(WHO) defines palliative care as7:
An approach that improves the quality
of life of patients and their families facing the
problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and
impeccable assessment and treatment of pain
and other problems, physical, psychosocial
and spiritual.
Palliative care should be initiated at the point of
diagnosis and continued throughout survivorship
and end of life. Many pivotal studies have demonstrated improvements in outcomes when palliative
care is integrated into the continuum of care, including quality of life, mood, the utilization of health
care, patient satisfaction, patient understanding of
prognosis, and survival.8-10
Call for the Integration of Palliative Care
Major organizations, such as the American Society of
Clinical Oncology (ASCO), National Comprehensive
Cancer Network (NCCN), Institute of Medicine (IOM),
WHO, and the European Society for Medical Oncology (ESMO), endorse the integration of palliative care
into comprehensive cancer care.11-15 ASCO published a
vision for optimal oncology care for 2020 that identified integrated palliative care as an essential component of optimal cancer care.16 In a provisional clinical opinion, ASCO recommended integrated care for
all patients with metastatic disease or high symptom
burden.11 NCCN developed guidelines to facilitate the
integration of palliative and oncological care with
schematics for screening, assessments, interventions,
reassessment, and after-death care.12 IOM explains
that involving palliative care is a requirement for comprehensive care.13 WHO developed guidelines in 1990
for providing palliative care to patients with malignancy.14 ESMO has been a strong proponent of integrating palliative and cancer care.15 As a component
of this effort, it created an accreditation program to
identify cancer programs with well-integrated palliative care services.15
Barriers
Significant barriers still prevent the effective integration of palliative care into the continuum of cancer
care. Such barriers include an inadequately trained
workforce, cultural stigma (eg, palliative care equates
to end-of-life care), lack of payment models supporting early and regular palliative care, and a need for
well-defined metrics for quality palliative care.17 In
addition, guidance on methods for integration is lacking. At a minimum, integrating palliative care into
October 2015, Vol. 22, No. 4
cancer care requires 3 components: (1) routine identification of palliative care needs through screening, (2) standardized assessment of palliative care
needs, and (3) management and treatment of identified needs. Clarity is lacking on how to accomplish all
3 areas.5,18,19
Moving from evidence to practice requires an
understanding of the barriers and strategies to identify, assess, and manage palliative care needs. This
review will focus on key lessons learned from randomized controlled trials focused on the integration
of palliative care and provide possible strategies for
implementing and integrating scalable, patient- and
family-centered models of palliative care into cancer care.
Evidence and Implications
Providing concurrent palliative care and standard
care for the management of cancer has proven benefits. Studies of integrated care in the inpatient/hospital or home setting have shown that the addition
of palliative care to standard care reduces hospitalbased costs and improves the quality of end-of-life
care and symptom management.17,20-22 Because medical oncology is increasingly provided in the ambulatory setting, more relevant data to assess the impact
of integrating cancer and palliative care arise from
studies performed in the outpatient setting. The results of 3 randomized controlled trials demonstrated
improved outcomes for study participants randomized to the palliative care intervention.8-10 An investigation of these studies provides insights for the integration of palliative medicine into cancer care.
Temel et al8 randomized 151 patients with newly
diagnosed metastatic lung cancer to receive either
early palliative care in conjunction with standard oncology care or standard oncology care alone. Early
palliative care consisted of a visit with a palliative
care team at intervals of at least 30 days, from the
point of diagnosis until end of life.8 Outcomes measured included changes in mood and quality of life,
aggressiveness of end-of-life care (chemotherapy
≤ 14 days before death, lack of hospice care, or admission to hospice ≤ 3 days before death), and understanding of prognosis.8 Study patients assigned
to the integrated palliative care arm had significant
improvement in quality-of-life scores compared
with those assigned to the standard oncology care
(P = .03), as well as fewer depressive symptoms
(P = .01) and less-aggressive, end-of-life care
(P = .05).8 Despite less-aggressive, end-of-life care,
study patients in the concurrent palliative care arm
had prolonged rates of survival compared with
those assigned to the standard treatment arm (8.9 vs
11.6 months; P = .02).8 In addition, those in the integrated care arm had a more accurate understanding
Cancer Control 387
of their prognosis, were more likely to have resuscitation preferences documented, and were less likely
to receive chemotherapy at the end of life than their
counterparts (9% vs 50%; P = .02).8 At baseline, approximately one-third of all study participants said
they thought their disease could be cured with treatment.8 The investigators hypothesized that this decreased utilization of chemotherapy at the end of life
may account for the improved survival rates.
In Project Educate, Nurture, Advise, Before Life
Ends, Bakitas et al9 led a randomized study of a
telephone-based educational intervention in a rural
setting. A total of 312 patients with advanced solid
tumors and life-limiting prognoses (approximately
1 year) were randomized to receive usual care or
usual care plus nursing intervention. The nursing
intervention was based on a chronic care model
that focused on patient empowerment and encouraged patient self-management and problem solving.
It consisted of 4 weekly sessions focused on symptom management, communication and social support, problem solving, and advance care planning,
followed by at least monthly telephone contact. Outcomes measured included symptom intensity, quality
of life, mood, and resource use. Compared with those
in the usual care group, those in the intervention
group reported significant improvement in quality
of life (P = .02), depression (P = .02), and a favorable
trend in symptom intensity (P = .06). No difference
was seen in the use of health care resources between the study groups, as measured by the number
of emergency department visits or days in the hospital or intensive care unit. Bakitas et al concluded
that a nurse-led intervention had the potential to impact quality of life and mood, but it was less likely
to impact symptom intensity or resource utilization.
Rather, they hypothesized that a more intensive intervention (eg, in person) might be more likely to
significantly impact symptoms and resource use, although they admitted that such a model is less feasible for patients living in rural areas.
A Canadian trial by Zimmerman et al10 also supports the finding that the early integration of palliative care into cancer care in the outpatient setting
improves patient outcomes. This cluster-randomized
controlled trial of 461 patients with advanced solid
tumors from 24 clinics in Toronto, Canada, assessed
the impact of early consultation and follow-up by a
palliative care team in addition to standard oncology
care compared with standard cancer care alone.10 Eligible participants had advanced cancer and a clinical
prognosis of between 6 and 24 months.10 Those in
the intervention arm had an initial consultation with
a palliative care team and at least monthly followup visits.10 Outcomes measured included symptom
severity, quality of life, satisfaction with care, and
388 Cancer Control
patient/family difficulties communicating with their
health care team.10 At 3 and 4 months, patients in the
intervention arm reported improvements in quality of
life (P = .05 and P = .003, respectively) and satisfaction with care (P = .0003 and P < .001, respectively).10
Improvement in symptom severity was noted at the
4-month time point alone (P = .05).10 The authors noted that quality of life is a broad construct that can improve, even when a change in symptoms is lacking.10
The randomized trials conducted by Temel et al,8
Bakitas et al,9 and Zimmermann et al10 provide key
lessons for integrated practice, including (1) the benefits of normalizing the standard integration of palliative care for all patients, (2) the impact of integrating
palliative care on the psychosocial domain of care,
and (3) the need for sustainable management of palliative care resources and value-driven metrics.
Normalizing Palliative Care
Among the 3 randomized controlled trials presented,
all patients in the intervention arms were connected to palliative or supportive consultation.8-10 Temel
et al8 attributed some benefits of the intervention to
immediate eligibility and enrollment of patients with
a new diagnosis of advanced cancer. Also notable is
that the study dropout rate was 1%, suggesting that,
once initiated, utilization of palliative care may be
driven by patient satisfaction, family member satisfaction, or both.8 A national poll conducted by the Center to Advance Palliative Care revealed that 7 out of
10 people are unfamiliar with palliative medicine,
but, once it was described or offered to them, 92%
said they would consider it as support to improve
quality of life and symptom management.23 In addition, the results of a qualitative study from Schenker
et al24 suggested that patients with unmet physical
and psychosocial symptoms are likely to perceive a
need for specialist palliative care. No significant association was seen between perceived need and likelihood to request palliative services.24 However, patients were more likely to see palliative specialists if
their oncologist recommended the service.24 Based on
these data, educating the public and establishing palliative care as a standard of care at the time of a cancer diagnosis is likely to be acceptable to patients and
families. In addition, oncologists are key players in introducing patients to and supporting palliative care
for those with an identified need.24
Psychosocial and Decision-Making Support
Palliative medicine is traditionally associated with
the management of physical symptoms and transitioning to end-of-life care.22 However, evidence suggests that palliative medicine can be a source of psychological and decision-making support.8-10 In the
study by Temel et al,8 the palliative care clinicians in
October 2015, Vol. 22, No. 4
the trial focused their attention on assessing psychosocial symptoms, establishing goals of care, assisting with decision-making regarding treatment, and
coordinating care. This focus was associated with
significant improvement in quality of life, decreased
depressive symptoms, and greater understanding of
prognosis among the study participants.8 Likewise,
Zimmerman et al10 realized a more pronounced impact on quality of life than on physical symptoms as
a result of the palliative care intervention. Bakitas
et al9 also found a positive effect on quality of life
and mood in the palliative care intervention group.
A summary of evidence in support of the early
integration of palliative care proposed the following
dominant mechanisms by which palliative care may
affect outcomes26: psychological support, knowledge of illness, and coping behaviors (Fig 1). Caring for psychosocial health, as well as empowering
decision-making skills for patients and families, is
integral to optimal cancer care.
Sustainable Management of Palliative Resources
Primary palliative care is defined as the “basic skills
and competencies required of all physicians and other health care professionals.”27 For example, primary
palliative care may include neuropathy management
by an oncologist during routine care. Secondary palliative care refers to practices of “specialist physicians and organizations that provide consultation and
specialty care.”27 Specialists may be consulted when
Early, Integrated
Palliative Care Model
Practices and Processes
• Team approach
• Decision-making
• Education/support
Patient-Level Targets
• Physical
• Psychological
• Sociocultural
• Spiritual/existential
• Ethical/legal
Caregiver Support
Oncology Team
Palliative Care Team
Specialist Palliative Care
Primary Palliative Care
Patient +
Family
Fig 2. — Patient-centered model of primary and specialist palliative care
that leverages oncology and specialist teams.
symptoms are challenging to control with initial interventions (eg, complex pain syndromes, refractory
anxiety; Fig 2).
Temel et al8 utilized a high-resource, specialist model in which patients met with their assigned
palliative care clinicians in coordination with their
oncologists. Alternatively, Bakitas et al9 described a
Quality of Life
Physical Symptoms
Mood
Illness, Knowledge,
and Understanding
Health Behaviors:
Anticancer therapies
End-of-life-care
Survival
Coping
Behaviors
Fig 1. — Hypothesized relationships between early palliative care interventions and clinical outcomes.
From Irwin KE, Greer JA, Khatib J, et al. Early palliative care and metastatic non-small cell lung cancer: potential mechanisms of prolonged survival.
Chron Respir Dis. 2013;10(1):35-47. Reprinted by permission of SAGE Publications.
October 2015, Vol. 22, No. 4
Cancer Control 389
nurse-led approach that equipped the nursing team
with palliative care skills, including didactic training and reference tools, and incorporated patient
self-management. Both interventions realized significant improvements in quality of life and depression.8,9 Given the increased palliative care needs of
people affected by cancer and the limited specialist
workforce, models such as Project Educate, Nurture,
Advise, Before Life Ends that utilize scripted interventions to build capacity for palliative care are critical to
the sustainable provision of services.9 Scalable models
for palliative care integration will require education
of all health care professionals who provide primary
palliative care as well as adequate support (eg, time,
reimbursement). In addition, appropriate guidelines
and referral criteria must be put into place for specialist support.
Establishing Standard Measurements and
Defining Value
Integrating palliative care into oncology could have
a higher likelihood of success if its value is clearly defined and accurately and consistently measured.28,29 In addition, clarity is needed on which
components of a palliative care intervention affect
which outcomes. For example, what interactions
and with whom are absolutely necessary to achieve
improved psychosocial well-being? The randomized studies by Temel et al,8 Bakitas et al,9 and Zimmermann et al10 all included well-defined primary
and secondary outcome measures. Comparisons
between interventions and future investigations require an accepted common set of quality indicators
that reflect the goals and scope of the specialty.
Several groups have proposed quality metrics
for palliative care.28-31 ASCO’s Oncology Practice Initiative includes metrics on symptom measurement
(pain, dyspnea, and constipation) as well as quality of end-of-life care (time on hospice, location of
death).30 The Center to Advance Palliative Care also
convened a panel to establish a common set of metrics to measure patient/family, clinical, operational,
and financial outcomes (Table 1).31 Its consensus
recommendations included metrics for symptom assessment, goals of care, family support, and transition management. It also recommended measurements of satisfaction among patients, their family
members, and the health care team. Kamal et al28
reported on the landscape of quality measures relevant to palliative care utilizing domains defined by
the National Quality Forum (Table 2). They identified metrics in physical, psychological, cultural, social, ethical, end of life, and spiritual care.28
Metrics in some studies have focused on the alleviation of physical symptoms, quality of life, and
the quality of end-of-life care.8-10,21-23,32 However, these
390 Cancer Control
measures are but a starting point; further delineation of cause and effect (eg, which component of the
palliative care intervention affects which measure) is
needed. Better understanding is needed of how patients, their families, and health care teams measure
success in achieving optimal quality of living with a
cancer diagnosis.
Table 1. — Categories and Examples of Common Metrics
to Assess Palliative Care Consultation Programs
Categories
Common Metrics
Patient/family
Satisfaction scores
Clinical
Symptom control scores
Psychosocial assessment scores
Operational
Demographics
Disease diagnosis and staging
Referring health care professional
Emergency department visits
Hospital admissions/readmissions
Hospital and intensive care unit lengths of stay
Hospice referral
Financial
Daily pre- and post-consultation hospital cost
Net loss/net gain for inpatient deaths
From Weissman DE, Meier DE. Identifying patients in need of a palliative care assessment in the hospital setting: a consensus report from
the Center to Advance Palliative Care. J Palliat Med. 2011;14(1):17-23.
Copyright © 2011, reprinted by permission of Mary Ann Liebert, Inc.
Table 2. — National Quality Forum Domains and Select
Quality Metrics for Palliative Care in Oncology
Care Domain
Example Metrics
Physical
Symptom assessment and management
(pain, dyspnea, fatigue, nausea)
Psychological
Psychosocial support
Caregiver depression
Depression
Grief and bereavement
Social
General management
Family satisfaction
Family preferences
Spiritual
Spiritual support
Value of life
Spiritual need
Cultural
Communication needs
Culturally sensitive care
End of life
Pain at end of life
Information at end of life
Death recognition
Peace at death
Ethical aspects
Respect
Insight into illness
Impaired capacity
Advance care planning
Patient preferences
From Kamal AH, Gradison M, Maguire JM, et al. Quality measures for
palliative care in patients with cancer: a systematic review. J Oncol
Pract. 2014;10(4):281-287. Copyright © 2014, reprinted by permission
of American Society of Clinical Oncology.
October 2015, Vol. 22, No. 4
Designing Sustainable Palliative Care:
2 Case Studies
Several organizations have been using innovative approaches to develop models of integration that incorporate knowledge from randomized trials as well as an
understanding of local systems, culture, and stakeholders.33-36 Cancer Care Ontario (CCO; Toronto, Ontario,
Canada) and Stanford Health Care (Palo Alto, California) are 2 case studies that offer strategies for integrating
palliative care into cancer care beginning with routine
screening and assessment. Both include efforts to define
the roles and resources required for primary and specialist palliative care to accomplish this and manage the
needs of patients and their families. CCO implemented
a provincewide screening for symptoms, whereas Stanford Health Care is establishing value-based palliative
care at a single academic medical center.33,37 Both are using a participatory, quality-improvement approach.
Cancer Care Ontario: Symptom Management
CCO, which is the provincial agency responsible for
continually improving cancer services, launched the
Provincial Palliative Care Integration Project (PPCIP)
to improve care through systemwide screening, assessment, and management of cancer-related symptoms.33 CCO developed this quality-improvement
initiative based on evidence that better symptom
management and collaborative care “improves the
patient experience across the cancer journey.”38 In
the first iteration of the PPCIP, the Edmonton Symptom Assessment Scale (ESAS) was used to screen
for physical and psychosocial symptoms, and toolkits were developed to facilitate follow-up assessment and symptom management.39 The project was
pilot tested in 1 clinic, but it expanded throughout
the province to include more than 25,000 symptomintensity screenings.33 CCO established a consistent
reporting mechanism, the Interactive System Assessment and Collection, which allowed regional cancer
centers to track the success of ESAS as a tool and use
patient data to inform treatment decisions.39 Interactive System Assessment and Collection is now embedded within electronic health records at 11 hospitals.39 It captures physical symptoms through ESAS
and functional status using the Patient-Reported
Functional Status tool.39
In 2008, the results were publically reported and
symptom screening became a quarterly performance
indicator for each regional cancer care program.33
Survey results published in 2012 reported that 89%
of patients thought ESAS was important to complete,
79% thought their health care professionals used the
results to help formulate their care plan, and 78% reported that their symptoms had been controlled to
a comfortable level.33 As the CCO initiative evolved,
health care professionals outside of the initial PPCIP
October 2015, Vol. 22, No. 4
could view these results and request participation in
the program.39 Participation increased from 6 hospitals in 2007 to 29 hospitals by 2013, and provincial
screening has steadily increased, averaging 58% en
route to their target of 70%.39
CCO provides a promising example of integrating at least 1 essential component of palliative
care — symptom management — into oncology.
It established a specific aim for symptom management, developed standard processes at the regional
level, and created a transparent measurement system to track screening, symptom intensity, and functional status over time. In addition, it has normalized
the integration of palliative care into routine cancer
care from the point of diagnosis.
Stanford Health Care: Value-Based Palliative Care
In 2013, a patient with lymphoma receiving treatment
at Stanford Health Care asked whether palliative care
was supposed to be patient-centered. Indeed, the
health care delivery model was not designed with a
patient or family member in mind. The conversation
prompted a design initiative at the Stanford Cancer
Institute to improve quality of life for all 3 stakeholders — patients, their family members, and the health
care team — by incorporating their values into the
core processes and measures of palliative care delivery. This project is 1 component of the Stanford Cancer Institute Transformation Initiative, a joint project
of the School of Medicine and Stanford Health Care
to transform the experience of patients with cancer
through comprehensive, coordinated, and compassionate care.37
Stanford Health Care aims to routinely identify, assess, and manage the palliative care needs
of patients and families from the point of diagnosis
through survivorship and end of life. The institutional target is 100% screening for palliative care needs
utilizing a global screening tool, the Patient Reported
Outcomes Measurement Information System, which
is a patient reporting tool that evaluates physical,
emotional, social, spiritual, and functional needs.
The hypothesis is that the primary oncology team can
manage 50% of palliative care needs, and 50% will be
referred to specialist services. Data will be gathered
via electronic medical records of Stanford Health Care
and will be documented on a dashboard visible to all
stakeholders.
Stanford Health Care has engaged a diverse
group (called the Core Innovation Team) of patients,
family members, administrators, and physicians in
oncology and palliative medicine to codesign strategies for primary and specialist palliative care. Baseline data to inform the work of the Core Innovation
Team include interviews with patients and family
members about their perceptions and knowledge of
Cancer Control 391
palliative care as well as their personal values and goals.
Physicians were interviewed to determine their understanding of palliative care, what components of palliative care they practiced, and when and how they integrated specialist palliative care. Physician values and
goals were also assessed as well as how their own wellness might be improved in the context of their work.
An initial design session with the Core Innovation Team and several external stakeholders, including experts from health care consulting, marketing,
and CCO, used the baseline data to identify high-impact areas for process improvement. Participants in
the workshop defined quality of life as a key target
from the outset and brainstormed how palliative care
might promote improved quality of life for patients,
families, and the health care team (Fig 3).
Similar to CCO, Stanford Health Care is utilizing rapid quality-improvement cycles to test new approaches. Solutions are selected based on feasibility and
potential impact within the domains of primary, secondary, and specialist palliative care delivery (Table 3).
Proposed solutions are being tested with disease-oriented, multidisciplinary practice teams (eg, gynecological oncology and hematology) before scaling across
disease groups and the entire cancer center.
Fig 3. — Word cloud illustrating responses from patients, family members, and health care professionals to the question, “How would you describe quality of life in 1 word?”
Key Lessons for “Practical” Integration
The PPCIP of CCO is one of the first of its kind to
create a successful system for the real-time screening for palliative care needs.33 However, because of
differences in culture and payment models, CCO’s
processes must be modified to work within the US
health care system. Thus, Stanford Health Care is
Table 3. — Potential Solutions Being Piloted and Modified to Improve Quality-of-Life Care at Stanford Cancer Institute
Potential
Solution
Description
Resources
Process
Education
Communicating
Value
Two questions for
quality of life
Oncologists are prompted to ask questions that help document goals and priorities in a patient’s health care plan.
x
“What to expect”
symptom
management
and transition
tool series
Patients and family members are provided tailored
symptom and adverse-event descriptions and
management strategies at key stages along the care
continuum.
x
x
x
“Here when you
need me” shadow
and buddy system
Nurse navigators are paired with palliative care and oncology social workers for shadowing, communication role play,
and ongoing “on-call” buddy support for complex needs.
x
x
x
x
Palliative
Care Always
(online course)
Oncology fellows, residents, nurse navigators, and social
workers participate in a case-based, interactive course
focused on patient experience, communication, and
primary palliative competencies.
x
x
x
Standard
screening,
assessment,
and referral
Oncology teams co-develop a standard screening process
using the PROMIS global screening and referral algorithm
for supportive services. Triggers are embedded to prompt
discussion of PROMIS and potential specialist support.
Focus is placed on social work as in-house support.
x
x
x
Specialist
“hub” with triage
support for
noncurative
needs
Specialist teams form a single service group and call
center for complex needs. Screening, ad hoc oncology, and
patient-initiated referrals are sent to the “hub”
and connected with the appropriate specialist based on
patient-centered referral criteria.
x
x
x
Core panel of
quality metrics
and reporting
mechanism
Process and outcome measures for physical, emotional,
spiritual, social, cultural, and ethical domains for quality of
life are regularly reported to clinical teams, patients, and
administration. Results help define future modifications.
x
x
x
PROMIS = Patient Reported Outcomes Measurement Information System.
392 Cancer Control
October 2015, Vol. 22, No. 4
attempting to create a modified process by learning from CCO’s best practices and allowing areas
for flexibility in order to maximize the likelihood of
success within a different health care system. Both
organizations share common strategies for integrating palliative care.
Quality Improvement Strategy
CCO and Stanford Health Care employ a structured,
quality-improvement process to guide the integration
of palliative care into the clinical workflow. CCO leadership coached regional teams in Canada to use the
Institute for Healthcare Improvement’s model to create and test concepts that might “achieve significant
results in quality and innovation”; the questions utilized appear in Fig 4.40
What are we trying
to accomplish?
How will we know that a change
is an improvement?
What changes can we make that
will result in improvement?
Act
Study
Plan
Do
Fig 4. — Institute for Healthcare Improvement’s model for improvement
leveraged by Cancer Care Ontario and Stanford Health Care.
From Institute for Healthcare Improvement. Science of improvement:
how to improve. http://www.ihi.org/resources/Pages/HowtoImprove/
ScienceofImprovementHowtoImprove.aspx. Reprinted with permission of
the Institute for Healthcare Improvement.
October 2015, Vol. 22, No. 4
The central team at CCO and Stanford Health
Care developed firm aims and target metrics (question 1 and 2; see Fig 4), and then local teams were given the flexibility to develop steps that could gain traction at their own institutions and lead to the desired
improvements (question 3; see Fig 4).40 The teams
test potential solutions using various cycles (see
Fig 4) and visible, rapid reporting mechanisms to provide feedback to stakeholders.40 In the case of CCO,
immediate data availability and visibility compelled
additional hospitals to join the initiative.39 Reporting
also revealed opportunities for improvement.33 Stanford Health Care is starting its program with limited
test pilots with single clinical teams. Data will be reported back in real time to the physicians, thus allowing for rapid learning and refining of the initial care
delivery prototypes.
Screening Is Necessary But Insufficient
Although a standardized process for screening is
necessary, resources for assessment and management are also required. CCO created a symptom
management toolkit with a mobile application
as a resource for health care professionals. As the
screening rate edges closer to the provincial target of 70%, symptom management of severe symptoms is still inadequate.38,39 For example, patients
with severe pain do not always receive an opioid.39
Thus, CCO continues to work toward improved patient symptom assessment and treatment, including strategies to modify their reporting system, to
better capture how clinical teams address severe
symptoms, and further engage health care professionals.39 Stanford Health Care is harnessing these
insights to establish an evidence-based process for
screening and is also evaluating the assessment and
management processes to ensure that palliative care
needs are met.
Stakeholder Engagement
Physician engagement was a key strategy for CCO
for managing process changes throughout Ontario.33
Regional and local teams recruited self-identified
clinical champions who prioritized patient experience as a philosophy of care, and these champions
participated in forums to assist the executive leadership with decisions about next steps for improved
care delivery and evaluation.33 Stanford Health Care
is also engaging physicians, patients, and families at
every level of development and testing. Patient representatives are co-developing interventions and
are involved in the implementation and evaluation.
Stanford Health Care has taken this 1 step forward by
ensuring that patients and families are also trained
in leadership skills so as to more advocate for their
needs during the process.
Cancer Control 393
Conclusions
Although most US cancer centers report the existence
of a palliative care program in their centers, palliative
care remains limited to the inpatient setting in the
majority of these centers.41-43 Even fewer cancer centers have integrated practices, involve palliative care
in tumor boards, or embedded educational opportunities.40 Barriers to integrated practice have been described and include knowledge and attitudes regarding palliative care, limited trained workforce, and
lack of care and payment models that support early
and regular palliative care. The early integration of
palliative care into the treatment of patients with cancer is recommended.44-46
How best to integrate palliative care into cancer
care is an area of active investigation and interest.
Lessons from clinical trials, as well as examples from
Cancer Care Ontario and Stanford Health Care, provide strategies for scalable integration.8-10,33,38,39 These
strategies include:
• Create reproducible outcomes with flexible
structure: Exact models for integration will
evolve and vary by institution and patient population. However, even with model variability in
care delivery, a consistent expectation is the early
identification and assessment of palliative care
needs for all patients with cancer, from the point
of diagnosis through survivorship and end of life.
Establishing this as a new standard of care will
improve patient and family outcomes.
• Start small and learn quickly: Significant opportunity lies in the principles of quality improvement and rapid learning.47 Utilizing the Institute
for Healthcare Improvement approach with a set
aim, clear metrics, and rapid iterative cycles is feasible and necessary to create new and successful
models for integration.
• Leverage primary and specialist palliative care
teams: Understanding the role of primary teams
for the provision of palliative care is critical for
integrating palliative care into the continuum of
cancer care. Providing education, training, and infrastructure to support the team’s role as palliative
care providers is a promising strategy for meeting
patient needs with a limited workforce. An interdisciplinary approach that includes social work
and chaplaincy may further increase efficiencies
in primary palliative care delivery in psychosocial
and spiritual areas.
• Measures matter: Current metrics utilized in
palliative care studies evaluate quality of care
within a narrow framework primarily limited
to quality of end-of-life care and assessment
of mood and physical symptoms. The development of a broad range of metrics that align with
the domains of palliative care (eg, decision394 Cancer Control
making, empowerment, connection) has the potential to demonstrate the anticipated increased
value of integrated practice.
These strategies are a starting point for institutions and health care systems to begin their own processes for integrated care. This is crucial to improve
quality of care for patients with a cancer diagnosis
and their families. Routinely identifying palliative
care needs early on and assessing such needs both
have the potential to change the conversation between patients and health care professionals and create a health care paradigm in which the values of patients and their families come front and center in the
delivery of cancer care.
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with care and lower costs: results of a randomized trial of in-home palliative
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Opinion Strategies. New York: Center to Advance Palliative Care; 2011.
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24. Schenker Y, Park SY, Maciasz R, et al. Do patients with advanced
cancer and unmet palliative care needs have an interest in receiving palliative care services? J Palliat Med. 2014;17(6):667-762.
25. Schenker Y, Crowley-Matoka M, Dohan D, et al. Oncologist factors that influence referrals to subspecialty palliative care clinics. J Oncol
Pract. 2014;10(2):e37-e44.
26. Irwin KE, Greer JA, Khatib J, et al. Early palliative care and metastatic non-small cell lung cancer: potential mechanisms of prolonged survival. Chron Respir Dis. 2013;10(1):35-47.
27. von Gunten CF. Secondary and tertiary palliative care in US hospitals. JAMA. 2002;287(7):875-881.
28. Kamal AH, Gradison M, Maguire JM, et al. Quality measures for
palliative care in patients with cancer: a systematic review. J Oncol Pract.
2014;10(4):281-287.
29. Ramsey S, Schickedanz A. How should we define value in cancer
care? Oncologist. 2010;15(suppl 1):1-4.
30. Neuss MN, Desch CE, McNiff KK, et al. A process for measuring
the quality of cancer care: the Quality Oncology Practice Initiative. J Clin
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31. Weissman DE, Meier DE. Identifying patients in need of a palliative care assessment in the hospital setting: a consensus report from the
Center to Advance Palliative Care. J Palliat Med. 2011;14(1):17-23.
32. Temel JS, Greer JA, Admane S, et al. Longitudinal perceptions of
prognosis and goals of therapy in patients with metastatic non-small-cell
lung cancer: results of a randomized study of early palliative care. J Clin
Oncol. 2011;29(17):2319-2326.
33. Dudgeon D, King S, Howell D, et al. Cancer Care Ontario’s experience with implementation of routine physical and psychological symptom
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34. Hydeman J. Improving the integration of palliative care in a comprehensive oncology center: increasing primary care referrals to palliative
care. Omega (Westport). 2013;67(1-2):127-134.
35. Dyar S, Lesperance M, Shannon R, et al. A nurse practitioner directed intervention improves the quality of life of patients with metastatic
cancer: results of a randomized pilot study. J Palliat Med. 2012;15(8):890-895.
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Assessment System and performance status initiatives. J Oncol Pract.
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40. Institute for Healthcare Improvement. Science of improvement:
how to improve. http://www.ihi.org/resources/Pages/HowtoImprove/ScienceofImprovementHowtoImprove.aspx. Accessed September 3, 2015.
41. Hui D, Elsayem A, De la Cruz M, et al. Availability and integration
of palliative care at US cancer centers. JAMA. 2010;303(11):1054-1061.
42. Goldsmith B, Dietrich J, Du Q, et al. Variability in access to hospital
palliative care in the United States. J Palliat Med. 2008;11(8):1094-1102.
43. Morrison RS, Augustin R, Souvanna P, et al. America’s care of serious illness: a state-by-state report card on access to palliative care in our
nation’s hospitals. J Palliat Med. 2011;14(10):1094-1096.
44. Hui D, Elsayem A, De la Cruz M, et al. Availability and integration
of palliative care at US cancer centers. JAMA. 2010;303(11):1054-1061.
45. Gelfman LP, Morrison RS. Research funding for palliative medicine. J Palliat Med. 2008;11(1):36-43.
46. Abrahm JL. Integrating palliative care into comprehensive cancer
care. J Natl Compr Canc Netw. 2012;10(10):1192-1198.
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Respir Dis. 2012;9(1):51-61.
October 2015, Vol. 22, No. 4
Cancer Control 395
Quality-improvement
collaborations will continue
to grow in the field of
palliative care.
Photo courtesy of Lisa Scholder. Road Between Art, 16" × 24".
Improving the Quality of Palliative Care Through National
and Regional Collaboration Efforts
Arif H. Kamal, MD, MHS, Krista L. Harrison, PhD, Marie Bakitas, DNSc, CRNP, J. Nicholas DionneOdom, PhD, Lisa Zubkoff, PhD, Imatullah Akyar, PhD, RN, Steven Z. Pantilat, MD, David L O’Riordan, PhD,
Ashley R. Bragg, Kara E. Bischoff, MD, and Janet Bull, MD
Background: The measurement and reporting of the quality of care in the field of palliation has become
a required task for many health care leaders and specialists in palliative care. Such efforts are aided when
organizations collaborate together to share lessons learned.
Methods: The authors reviewed examples of quality-improvement collaborations in palliative care to understand the
similarities, differences, and future directions of quality measurement and improvement strategies in the discipline.
Results: Three examples were identified that showed areas of robust and growing quality-improvement collaboration in the field of palliative care: the Global Palliative Care Quality Alliance, Palliative Care Quality
Network, and Project Educate, Nurture, Advise, Before Life Ends. These efforts exemplify how shared-improvement activities can inform improved practice for organizations participating in collaboration.
Conclusions: National and regional collaboratives can be used to enhance the quality of palliative care and
are important efforts to standardize and improve the delivery of palliative care for persons with serious illness,
along with their friends, family, and caregivers.
From the Duke Cancer Institute, Durham, North Carolina,
Capital Caring (KLH), Falls Church, Virginia, School of Nursing (MB, JND-O, IA), University of Alabama at Birmingham,
Birmingham, Alabama, White River Junction Veterans Affairs
Medical Center (LZ), White River Junction, Vermont, Palliative
Care Program (SZP, DLO, ARB, KEB), University of California,
San Francisco, California, and Four Seasons Compassion for
Life (JB), Flat Rock, North Carolina.
Submitted May 12, 2015; accepted July 30, 2015.
Address correspondence to Arif H. Kamal, MD, MHS, Duke
Cancer Institute, 2400 Pratt Street, Durham, NC 27710.
E-mail: arif.kamal@duke.edu
Dr Harrison is an employee of Capital Care and was involved
with the Global Palliative Care Quality Alliance and Palliative
Care Research Cooperative Group during the writing of this manuscript. Dr Bull is an advisor for Aspire Health. No significant
relationships exist between Ms Bakitas and Bragg or Drs Kamal,
Akyar, Dionne-Odom, Zubkoff, O’Riordan, and Bischoff and the
companies/organizations whose products or services may be referenced in this article.
396 Cancer Control
Introduction
Over the last few years, use and acceptance of palliative care have been growing for the complex care and
needs of patients with cancer and their loved ones.1
This reflects an increased understanding and acceptance of the care philosophy, the value of interdisciplinary teams that focus on the patient and his or her
family as the unit of care, and the understanding that
the goals of palliative care align with the priorities of
all stakeholders.2 More patients are receiving palliative
care because the scope of practice has expanded from
community-based hospices to inpatient hospitals to the
offices of primary care physicians, and the number of
health care professionals seeking specialized continuing education and support to improve palliative care
has increased.3 In parallel with this clinical growth,
October 2015, Vol. 22, No. 4
collaborations to improve the quality of palliative care
are also becoming more common, aiming to share data
across sites and settings to translate quality improvement activities across the discipline.4
Quality-improvement collaborations aim to clarify how care is delivered and how care might be enhanced through realistic and sustainable interventions.
The challenges to such collaborations vary by type
and setting of practice, but capturing the diversity of
care-delivery systems is paramount to understanding
the variation of palliative care in settings, ranging from
community-based organizations to large, academic
medical centers. Collaborative initiatives to study the
quality of care reflect our increasing reliance on data
collection and analysis to understand broader patterns
across health care, whether for program development,
reimbursement, health services research, or quality assessment. Thus, this article will focus on 3 efforts to
improve the quality of the delivery of palliative care at
regional and national levels.
Global Palliative Care Quality Alliance
The Global Palliative Care Quality Alliance (GPCQA) is
a novel, community/academic quality assessment and
improvement collaboration for consultative palliative
care that aims to5:
• Collect data on the quality of care delivery using a
standardized, point-of-care delivery approach
• Facilitate conversations between practices of all
sizes and locations regarding challenges and sustainable solutions to improve care
• Use a Institute of Medicine–recommended rapidlearning health care approach to simultaneously
inform clinical care, quality measurement, and
outcomes research
• Monitor patients along the continuum of care
• Allow for benchmarking and sharing of best
practices
The GPCQA originally began in 2007 as the Carolinas Consortium for Palliative Care. Realizing the need
to test and adopt this model of quality improvement,
its founders set out after initial planning in 2005 to establish an academic/community collaboration between
Duke University (Durham, North Carolina) and community partners. The Carolinas Consortium for Palliative Care was originally composed of 5 sites throughout North Carolina: Duke University Medical Center
(Durham) and 4 palliative care organizations, namely
Four Seasons Compassion for Life (Flat Rock), Forsyth
Palliative Care (Winston-Salem), Hospice of Wake and
Horizons Palliative Care (Raleigh), and Charlotte Hospice and Palliative Care (Charlotte). Data from patients
were collected by health care professionals near the
point of care, entered into a local database, and intermittently transmitted to a centralized dataset maintained at Duke University for analysis and quality reOctober 2015, Vol. 22, No. 4
porting. The information contributed to a growing data
resource, the palliative care database (PCD), which is
used for quality assessment and research purposes.
From 2008 to 2011, a total of 6,957 unique patient data
were collected. Data analyses also supported organizational, quality-improvement objectives and descriptive research about the population served by the Carolinas Consortium for Palliative Care, providing proof
of concept that collecting data on quality is feasible
in community settings and that these data can inform
both clinical practice and institutional priorities in
community-based palliative care.6 However, data collection processes were inefficient and the data collected did not always map to emerging quality measures.
Further, a need exists to expand beyond the Carolinas
to include partners from across the United States and
the world so as to represent greater diversity in practice and patient needs. A contemporary-based solution
was needed that could be electronically implemented
in various institutions outside the region.7
In 2012, the Quality Data Collection Tool (QDACT)
for palliative care was created, leveraging an iterative design in which modular components could be
changed as quality measures in palliative care evolved.
To develop a quality-assessment tool applicable to everyday practice, 6 steps were involved.
The first step was to review the experiences from
participants of the PCD project.6 This proof-of-concept
pilot confirmed that collecting data on quality was feasible in community settings.5
The second step was to perform a systematic review of all published quality measures relevant to palliative care, supportive oncology, and end-of-life care
to identify measures from which the Consortium could
choose to establish priorities for assessment.8
The third step was to develop a list of validated
tools from a literature review that would inform these
quality measures. We aimed to incorporate tools familiar to palliative care providers, when available, like the
Palliative Performance Scale. In some instances, the Carolinas Consortium for Palliative Care added metrics and
associated data elements based on group consensus.
The fourth step involved developing QDACT, an
instrument that demonstrated scalability across expected future changes in the collection and sharing
of data relating to palliative care. Electronic health
systems and platforms for collecting data evolve
and change, so it was important that the tool be
generic and operable on different — rather than specific — operating systems, computer hardware, or
Internet platforms and be compatible with diverse
information technology resources used by palliative
care programs nationwide. This process included the
development of a data dictionary to support the quality measures.
The fifth step was to test the entire process, from
Cancer Control 397
data collection to transmission, storage, analysis, and
management; in addition, the process was tested to ensure that it conformed to the highest data security standards for protected health information, including those
of the Health Insurance Portability and Accountability
Act. This included thorough understanding of the challenges to data security that stem from both hardware
and software used at the point of care as well as the
potential risks of transmitting data over diverse networks to a shared database.
The sixth step was to expand the project and test
its usability on a national scale.
The Carolinas Consortium for Palliative Care was
renamed GPCQA in 2014, and it has 14 members who
represent community and academic settings and span
outpatient and inpatient palliative care programs. Reporting on quality metrics is performed each quarter
for all sites, with a feedback loop to improve graphics and visual features. More than 33,000 patient encounters are represented in the database. The quality
reporting has been used to support grant funding, to
demonstrate the value of palliative care to hospitals
and partnering organizations, to understand the patient population served at each participating institution, and to inform quality-improvement projects.
QDACT displays real-time, immediate feedback
via a color-coded alert system while having built-in
logic to help inform clinical decisions while health care
professionals enter data. For example, a color-coded
system reflects whether responses meet an alarm
threshold, which is an evidence- or consensus-based
parameter (eg, pain score > 4 out of 10). At that point,
a screen opens to prompt the user to input what treatments have been offered, if any, and a list of available
evidence-based options are displayed. In this example,
the alert color (red) will remain present until the pain
is brought below the threshold. Other aggregate reports include longitudinal summaries customizable to
the health care professional and his or her organization. Members of the GPCQA can request reports that
provide both numerical and graphical presentations of
descriptive statistics on patient needs, conformance to
quality measures, comparative performance between
reporting levels, and longitudinal changes. Reports
under development include those aligned to national
quality measurement initiatives (eg, National Quality
Forum, American Academy of Hospice and Palliative
Medicine’s Measuring What Matters, Physician Quality
Reporting Structure), financial projections, and costavoidance reports.
This infrastructure has been used to conduct several quality-improvement projects. One project simultaneously measured and assessed adherence to quality measures for timely assessment and management of
pain, dyspnea, and constipation. Using reports tailored
to the performance of individual health care profes398 Cancer Control
sionals along with peer-related benchmarks, and then
confidentially sharing those reports with those health
care professionals, we observed an improvement of the
timely management of these 3 important symptoms to
levels above 95%. Longitudinal data collection will inform whether these results are long lasting.
Another quality-improvement project involved assessing spirituality and existential distress during the
first palliative care visit in all care settings. Using a goal
of more than 75% for the completion of the spiritual assessment, the results of the project demonstrated 80%
compliance with completing the spirituality question
across all of the providers within the GPCQA.
The GPCQA is also looking to expand its membership. Further plans include customized modular
build-outs as part of QDACT, expansion of reporting
features, integration with electronic health records
(EHRs), introduction of a mobile application, and features that enable programs to pull data directly from
the software platform. As the landscape of quality
measure reporting increases in an era of value-based
health care delivery, the GPCQA will look to continuously evolve its efforts to minimize the burden of data
collection by health care professionals while maximizing the return on investment to health care professionals through reports, information to support program
growth and sustainability, and financial benefits that
reward health care professionals for actively promoting
a culture of quality assessment and improvement.
Palliative Care Quality Network
The Palliative Care Quality Network (PCQN) is a continuous learning collaborative committed to improving
the quality of palliative care services provided to patients and their families. The PCQN was established in
2009 by 20 established palliative care services in California with a shared vision for improving the quality
and value of care. The PCQN developed a core dataset that includes care processes (eg, psychosocial assessments) and patient level outcomes (eg, symptom
scores) that all members collect on every patient visit.
Data are entered into the secure, web-based PCQN database that analyzes data and produces custom reports
in real time for individual teams, with comparisons to
the entire PCQN. PCQN data allow for coordinated,
quality-improvement projects, benchmarking, and the
identification of best practices.
The PCQN is composed of 34 palliative care teams
from hospitals across the United States and includes
community, academic, and public institutions. To date,
19 palliative care teams collect and submit data to the
PCQN database and use those data to monitor and improve care. The PCQN database includes more than
13,000 patient encounters.
An important goal of the PCQN is to create and
foster a professional community that contributes to the
October 2015, Vol. 22, No. 4
growth and sustainability of palliative care teams and
the professional development of the health care professionals that staff them. The PCQN achieves this goal by
providing education in clinical care, leadership, team
dynamics, and self-care, creating a forum for members
to share successful strategies, offering a software program to calculate the financial impact of palliative care
at each institution, and establishing a supportive network of like-minded health care professionals.
Guided by the goals of the prospective collection
of operational and clinical outcomes data to support
real-time patient care and quality improvement, efficiency, and adherence to national guidelines, including the NCP and NQF, the PCQN undertook a modified Delphi process to develop the PCQN core dataset.
Overall, the 20 founding palliative care service members collected 96 unique data elements. Through a
survey of all members, the PCQN identified 48 “must
collect” elements. The PCQN data committee evaluated
these elements against published preferred practices
to create a 23-item core dataset that includes demographics, processes of care, and patient-level clinical
outcomes, including daily symptom scores. The data
committee also created a data dictionary to define each
data element to ensure consistency across health care
professionals and care sites.
A key goal of the PCQN was that the database
would include all data that teams needed to collect; no
PCQN member would need to maintain a secondary
database. To that end, the PCQN adopted optional data
elements requested by individual teams for monitoring
care at their site. To date, the PCQN has added 22 optional data elements.
The PCQN then developed a secure, web-based
database for convenient data entry. PCQN members
directly enter data at the point of care into any Internet-connected device or on paper for later data entry.
Teams can also collect PCQN data in the EHR, download those data to a spreadsheet file and then upload
the file to the PCQN. When data are entered into the
PCQN database, they are included in analyses.
The PCQN is collaborating with teams using several EHR platforms to fully integrate the collection
of these data. Each member organization owns its
data and can download all of the data at any time to a
spreadsheet. Data are confidential; only member organizations know which data are theirs.
The PCQN database performs analyses that compare data from the entire network. Members can
generate 4 types of summary reports in real time, including reports on demographics, processes of care,
disposition and length of stay, and symptoms. Trend
reports of data over time and member-comparison reports show the data of the member organization highlighted alongside the unidentified data of the other
member organizations. The PCQN is also creating reOctober 2015, Vol. 22, No. 4
ports that will allow members to compare themselves
with others in their health care system. In addition,
members can submit information about the structure
of their team and characteristics of their institution to
compare themselves with similar teams as well as to
the entire database.
The PCQN database also produces reports on data
completeness and identifies missing data so that members can monitor data-collection efforts. PCQN data
align with the Measuring What Matters measures of
the American Academy of Hospice and Palliative Medicine/Hospice and Palliative Nurses Association have
been used by members to achieve The Joint Commission advanced certification in palliative care.9
The PCQN has developed a financial software
program, CaseMaker PCS (San Francisco, California),
to calculate the financial outcomes of palliative care
at each member institution. CaseMaker PCS combines
PCQN data with financial data supplied by member
institutions to produce an editable summary of the financial impact of the palliative care team’s work. Combined with outcomes data demonstrating quality and
comparative data on team composition, the financial
analysis information provides palliative care teams information needed to demonstrate value and proof for
sustaining and growing their service.
A PCQN quality-improvement collaborative was
launched in 2014 with the goals of providing education
in quality-improvement methods and using PCQN data
to drive coordinated quality-improvement projects.
Through quality-improvement workshops at biannual
conferences, monthly conference calls, and ongoing
mentoring, teams in the collaborative share strategies,
challenges, and successes to advance a quality-improvement project. Nine PCQN teams are participating
in the first PCQN quality-improvement project, which
is focused on improving pain management (a patientreported outcome).
PCQN data show that, at baseline, 69% (range,
62%–80%) of patients with moderate or severe pain
on the day of their initial palliative care assessment
had an improvement in their pain by the second palliative care assessment, but only when that assessment
occurred within 72 hours of the first. Through the
quality-improvement collaborative, participants have
identified and tested a number of strategies aimed at
improving pain management, including seeing patients with pain early in the day, contacting primary
teams and nurses with recommendations or writing
new orders immediately after seeing a patient in pain,
and conducting follow-up visits in the afternoon to reassess pain and amend recommendations or orders.
Members are monitoring these processes as well as
their associated daily pain scores to determine the
success of each test of change.
To date, improvements have been difficult to
Cancer Control 399
achieve, but the variation in performance is helping to
identify additional targets, including the value of addressing anxiety in patients with pain, and the project
is ongoing. Members with better outcomes share strategies with others on each monthly conference call,
struggling members are provided ideas about how to
overcome stumbling blocks, and regular calls motivate
all members to keep the project active and advancing.
Satisfaction with the quality-improvement collaborative is high, with 82% of respondents agreeing
that their participation motivated their member organization to engage in quality improvement, and 83%
indicating that they were interested in continuing their
participation in the quality-improvement collaborative.
The PCQN is growing and is inviting additional
palliative care teams to join. The more members, the
greater the capacity to benchmark with like hospitals
to determine with greater precision which structures
and processes of care are associated with better outcomes. The PCQN is developing outpatient and homebased palliative care datasets to link with the existing
PCQN database, allowing members to monitor and improve care across settings and over time. The PCQN is
also working with vendors of EHRs to create systems
for quality data collection within the EHR to be submitted to the PCQN database. The PCQN continues to
refine its approach to quality improvement and will
engage in additional quality-improvement projects involving more teams.
Improving palliative care is a key goal and,
thus, a broad dissemination of effective strategies to improve care is a major focus of PCQN going forward. The PCQN is partnering with other
organizations and quality initiatives within and
outside of palliative care, including the GPCQA,
to improve the quality of care across the field,
with the mission of transforming health care by
defining and promoting quality palliative care.
Project Educate, Nurture, Advise, Before
Life Ends
Project Educate, Nurture, Advise, Before Life Ends (ENABLE) is an evidence-based, telehealth, upstream, palliative care model designed to improve care and quality of life for persons with newly diagnosed advanced
cancer.10 First developed in 1999 as a demonstration
project through the Robert Wood Johnson Foundation,
Project ENABLE has undergone efficacy and effectiveness testing through 2 randomized controlled trials
funded by the National Institutes of Health.10-13 Because of its demonstrated benefits to patient quality of
life, symptoms, mood, rates of survival, and to family
caregiver depression and burden, Project ENABLE is a
scalable model of care.14-16 The project was developed
and tested in primarily rural, community-based cancer
practices; however, little guidance exists on how com400 Cancer Control
munity cancer centers can integrate this model of early
concurrent palliative care alongside standard, curative
cancer therapies.
In 2013, through a research scholar grant from the
American Cancer Society, we embarked on a 4-year
dissemination/implementation project using a virtuallearning collaborative approach in 4 racially diverse
settings. The project goals were to:
• Assess current palliative care practices and prepare for organizational/health care system change
• Tailor and implement the evidence-based, concurrent, palliative care model of Project ENABLE
• Use the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework
to assess outcomes associated with health care
institutions, patients and caregivers, and costs before and after implementation of the model
We chose a virtual-learning collaborative approach for
3 reasons because we wanted to increase access to nationwide sites in predominantly rural areas, examine
the effectiveness and scalability of this model in racially and ethnically diverse settings, and modify and
hone implementation strategies for future dissemination of the program. In addition, we chose RE-AIM because it is a well-tested framework to evaluate the impact of new public health programs.17
The first step was to establish working relationships and procedures to launch a virtual collaborative
between the School of Nursing at the University of
Alabama at Birmingham, which was the coordinating
center, and the 4 sites (Gibbs Cancer Center [Spartanburg, South Carolina], Mitchel Cancer Center [Mobile,
Alabama], Birmingham Veterans Administration Medical Center [Birmingham], and the Department of Gynecologic Oncology, Wallace Tumor Institute, University
of Alabama at Birmingham). Over the last 2 years, the
teams at each institution met every 2 weeks as a group
with the coordinating center via video conferencing using an online learning platform. During the intervening weeks, the coordinating center team met to trouble-shoot, develop, and refine processes.
Early steps included defining the essential elements of the Project ENABLE model and working with
individual sites to tailor the model’s elements to specific institutional cultures and resources. Through dialogue and consensus with sites, we also established
implementation measures guided by the RE-AIM
framework. However, because RE-AIM was not previously used in the setting of palliative care or oncology,
time was spent adapting the RE-AIM framework to suit
our model and the population of newly diagnosed patients with advanced cancer and their caregivers.
To measure the capacity of organizational characteristics to implement and sustain Project ENABLE,
we adapted the General Organizational Index scale.18
Data collection included a survey to measure the perOctober 2015, Vol. 22, No. 4
ceptions of oncologists about early and concurrent palliative care, a tool to examine implementation costs,
and a battery of patient and caregiver self-report measures similar to those used in our prior randomized
controlled trials.11,12 Mixed methods were used to collect data, including in-person site visit interviews, webbased surveys, and phone interviews.
We have experienced challenges and successes related to the implementation of this model, and we have
learned lessons along the way. For example, each site
received a small yearly stipend to offset some initial
implementation costs (eg, developing materials, fees
related to Institutional Review Boards, salary support
for conducting the program), but this stipend was not
intended to fully support a new program. As such, institutions have had to envision strategies for supporting their programs beyond the grant period.
As a result of changes in institutional leadership,
2 sites were unable to continue and the 2 replacement
sites had to quickly acclimate to the model during the
planning year. Implementation studies are uncommon to many Institutional Review Boards, so there
were many delays prior to acquiring Institutional Review Board approval in the 4 diverse community institutions (including 1 Veterans Administration medical
center).19 One success included 2 functioning programs
that introduced potentially sustainable models of early
palliative care concurrent with standard cancer treatment, thus increasing access, as was defined in the
original project aims. Another success was identifying
promising implementation strategies (guided by the
RE-AIM framework) for developing new palliative care
programs. The important lessons learned, such as institutional barriers and facilitators of implementation,
will serve as a foundation for future progress.
Our future goals within the context of this project are to refine all processes and measures to create
a toolkit that could be used by other centers wishing
to implement an early palliative care model, either in
settings with existing palliative care teams without an
outpatient or home-/community-based component
or within systems without a functional palliative care
model. In addition, we will use the current model and
methods as pilot data for a larger implementation grant
within an established practice network, such as across
the US Veterans Administration health care systems,
the Deep South Network for Cancer Control, or a research network such as the Palliative Care Research
Cooperative Group.
Discussion
Quality-improvement initiatives reflect the natural
evolution of the evidence base in palliative care. Use
of palliative care has grown in the last decade, with
its roots beginning in the hospice movement in the
late 1970s. A defined subspecialty field, with an eviOctober 2015, Vol. 22, No. 4
dence base for practice that improves daily palliative
care, should use implementation and dissemination
approaches that routinely include elements of quality measurement (often with validated measurement
tools). Federated database systems facilitate the simultaneous examination of both quality and research
questions. Administrators, health care professionals,
and researchers are beginning to recognize that robust
data analytics are crucial for improving patient- and
family-centered advanced illness care.
The 3 quality-improvement and dissemination efforts reviewed in this article all use a conceptual model
of quality improvement in palliative care to guide their
approach, highlighting the importance of collecting
uniform data. For example, all 3 efforts require participants to use a federated set of primary data elements
defined by a common database dictionary as part of
the validated collection metrics. Given the variety of
practice settings, clinician types, and stages of disease
process represented, this allows for uniformity and interoperability that ensures that data can be aggregated,
compared, and analyzed in the future to better characterize palliative care.
One significant, ongoing challenge for new and
existing quality-improvement initiatives is how to
make the effort as invisible and integrated as possible amid the fabric of usual clinical operations. As
the GPCQA has found, the dual-entry of data elements — once into the EHR for clinical purposes, and
once into a registry for aggregation and reporting — is
a significant barrier to health care professional buy-in
and effectiveness. The seamless integration of validated, quality metric data collection into EHRs is ideal but
has major cost and time implications. However, overcoming these barriers is crucial to allow for increasingly robust reporting of data, which can then be used to
aid palliative care program development, sustainability, and growth.
Future Directions
Quality-improvement collaborations are expected to
continue to grow in the field of palliative care. For
established efforts such as the 3 described in this article, this growth will manifest as a focus on how to
sustain the initiative in terms of mutually beneficial
outcomes, continued innovation, and financial viability. In turn, sustainability will allow for additional innovation, such as developing quality-improvement
initiatives focused on patient-reported outcomes and
caregiver outcomes. Programs may join forces and
align with other initiatives to allow for larger learning
networks and more robust data. By contrast, small,
issue-specific collaborations may develop where
practices are less unified, such as when palliative
care is incorporated into alternative payment model
structures (eg, medical homes, accountable care orCancer Control 401
ganizations). Similarly, local efforts may develop
among health care professionals in a single region so
that a single patient’s trajectory can be tracked — and
quality of palliative care improved — across multiple
care transitions and health care systems. As the push
for meaningful use and interoperability of electronic
health records continues, uniform and secure data collection and sharing (per the requirements of the Health
Insurance Portability and Accountability Act) should
continue to improve.
Conclusions
Health care leaders and those specializing in palliative care are faced with the challenge of providing
consistent, high-quality care that meets the needs of
patients and their family, friends, and caregivers. This
challenge can be aided by belonging to a community
of like-minded leaders focused on cooperative efforts
to define, measure, and improve the quality of palliative care delivery. Clinical palliative care is a collaborative effort, so alliances and networks of engaged
health care leaders and physicians are needed to prioritize the care processes that consistently improve
the experiences of patients with serious illnesses.
versus delayed palliative care to informal family caregivers of patients with
advanced cancer: outcomes from the ENABLE III randomized controlled
trial. J Clin Oncol. 2015;33(13):1446-1452.
14. Gomes B, Calanzani N, Curiale V, et al. Effectiveness and cost-effectiveness of home palliative care services for adults with advanced illness
and their caregivers. Cochrane Database Syst Rev. 2013;6:CD007760.
15. Smith TJ, Temin S, Alesi ER, et al. American Society of Clinical
Oncology provisional clinical opinion: the integration of palliative care into
standard oncology care. J Clin Oncol. 2012;30(8):880-887.
16. National Cancer Institute. Research-tested intervention programs:
Project ENABLE II. Updated September 25, 2014. http://rtips.cancer.gov
/rtips/programDetails.do?programId=3590238. Accessed September 10, 2015.
17. Glasgow RE, Vogt TM, Boles SM. Evaluating the public health
impact of health promotion interventions: the RE-AIM framework. Am J
Public Health. 1999;89(9):1322-1327.
18. McGovern MP, McHugo GJ, Drake RE, et al. Implementing EvidenceBased Practices in Behavioral Health. Center City, MN: Hazelden; 2013.
19. Patel DI, Stevens KR, Puga F. Variations in institutional review
board approval in the implementation of an improvement research study.
Nurs Res Pract. 2013;2013:548591.
Acknowledgment: The authors would like to recognize the dedication of our colleague clinicians and patients who make this work possible.
References
1.Center to Advance Palliative Care; National Palliative Care Registry; National Palliative Care Research Center. National Palliative Care
Registry Annual Survey Summary: Results of the 2012 National Palliative
Care Registry Survey, as of July 2014. 2014. https://registry.capc.org/cms
/por tals/1/Repor ts/National_ Palliative_Care%20Registr y _ Annual_
Survey_Summary_9.2.2014.pdf. Accessed September 15, 2015.
2. Swetz KM, Kamal AH. In the clinic. Palliative care. Ann Intern Med.
2012;156(3):ITC2-1, TC2-2-TC2-15.
3. Kamal AH, Currow DC, Ritchie CS, et al. Community-based palliative care: the natural evolution for palliative care delivery in the U.S. J Pain
Symptom Manage. 2013;46(2):254-264.
4. Kamal AH, Hanson LC, Casarett DJ, et al. The quality imperative for
palliative care. J Pain Symptom Manage. 2015;49(2):243-253.
5. Kamal AH, Kavalieratos D, Bull J, et al. Usability and acceptability of the QDACT-PC, an electronic point-of-care system for standardized
quality monitoring in palliative care. J Pain Symptom Manage. 2015;50(5):
615-621.
6. Kamal AH, Bull J, Stinson C, et al. Collecting data on quality is
feasible in community-based palliative care. J Pain Symptom Manage.
2011;42(5):663-667.
7. Kamal AH, Swetz KM, Dy S, et al. Integrating technology into palliative care research. Curr Opin Support Palliat Care. 2012;6(4):525-532.
8. Kamal AH, Gradison M, Maguire JM, et al. Quality measures for
palliative care in patients with cancer: a systematic review. J Oncol Pract.
2014;10(4):281-287.
9. Dy SM, Kiley KB, Ast K, et al. Measuring what matters: top-ranked
quality indicators for hospice and palliative care from the American Academy of Hospice and Palliative Medicine and Hospice and Palliative Nurses
Association. J Pain Symptom Manage. 2015;49(4):773-781.
10. Bakitas M, Stevens M, Ahles T, et al; Project Enable Co-Investigators. Project ENABLE: a palliative care demonstration project for advanced
cancer patients in three settings. J Palliat Med. 2004;7(2):363-372.
11. Bakitas M, Lyons KD, Hegel MT, et al. Effects of a palliative care
intervention on clinical outcomes in patients with advanced cancer:
the Project ENABLE II randomized controlled trial. JAMA. 2009;302(7):741-749.
12. Bakitas MA, Tosteson TD, Li Z, et al. Early versus delayed initiation
of concurrent palliative oncology care: patient outcomes in the ENABLE III
randomized controlled trial. J Clin Oncol. 2015;33(13):1438-1445.
13. Dionne-Odom JN, Azuero A, Lyons KD, et al. Benefits of early
402 Cancer Control
October 2015, Vol. 22, No. 4
A systematic approach to managing
symptoms related to advanced
oncological illness can improve patient
quality of life and lessen distress.
Lisa Scholder. Sunlit Legs. 16" × 22". Photo courtesy of Lisa Scholder.
Palliative Pharmacotherapy: State-of-the-Art Management
of Symptoms in Patients With Cancer
Eric E. Prommer, MD
Background: Advanced cancer produces multiple symptoms as patients progress through their disease trajectory. Identifying, measuring, and providing therapy for uncontrolled symptoms becomes important because
disease-altering therapies may be no longer possible. Symptoms other than pain that cause distress in patients
with cancer include delirium, dyspnea, anorexia, nausea, and fatigue. Precise management of these symptoms can lead to the best possible quality of life and lessen distress. This article reviews current management
strategies of these symptoms.
Methods: The epidemiology, mechanisms, assessment, and therapies of common symptoms in the advanced
cancer population are reviewed.
Results: Identifiable approaches facilitate symptom management in advanced illness.
Conclusions: Using a systematic approach to symptoms in advanced illness can improve the quality of life
and lessen distress among patients with cancer and their families, friends, and caregivers.
Delirium
Delirium is a clinical emergency characterized by
changes in consciousness, hallucinations, and changes in the sleep–wake cycle and language. Delirium
is a frequent event in patients with advanced cancer, and factors predisposing patients with advanced
cancer include drugs, infection, brain metastasis, and
underlying dementia.1 Delirium differs from dementia in that dementia does not have acute alterations
From the Division of Hematology/Oncology, Veterans Integrated
Palliative Care Program, Veterans Integrated Palliative Care, David
Geffen School of Medicine, University of California, Los Angeles,
California.
Submitted July 30, 2015; accepted September 16, 2015.
Address correspondence to Eric E. Prommer, MD, David Geffen
School of Medicine, University of California, 11301 Wilshire
Boulevard, Building 500, Room 2064A, Mail Code 10P, Los Angeles,
CA 90073. E-mail: Eric.prommer@va.gov
No significant relationship exists between the author and the companies/organizations whose products or services may be referenced
in this article.
October 2015, Vol. 22, No. 4
in consciousness.2 Delirium is classified according
to level of agitation; for example, a patient who is
agitated has hyperactive delirium and a patient who
is withdrawn and somnolent has hypoactive delirium.3 Patients usually have mixed features. Prevalence rates for delirium range from 30% to 50% for
hospitalized patients and is typical in the hours or
days before death.4 Experiencing delirium is likely to
cause distress in families.5 Patients who are delirious
are unable to communicate levels of pain or other
symptoms and cannot take part in health care decisions.6 Although delirium is often a harbinger of
a poor prognosis, it is reversible in 50% of cases.7
Health care professionals use nonpharmacological
as well as pharmacological interventions to treat delirium. Nonpharmacological approaches to delirium
include using clocks to show the time, lighting the
room, and frequent reorientation, whereas pharmacological interventions may include the use of antipsychotic medications, which can be used to palliate
Cancer Control 403
patients who are agitated (hyperactive delirium) as
well as those experiencing hallucinations regardless
of agitation level.
Mechanisms
Delirium results from underlying disorders that cause
imbalances in brain neurotransmitters. Neurotransmitters involved in delirium include dopamine, glutamate,
norepinephrine, acetylcholine, g-aminobutyric acid,
and serotonin.8 Cytokines (interleukin [IL]-1, IL-2, tumor necrosis factor [TNF], interferon) produced by the
immune system, the tumor, or cancer treatment may
mediate central nervous system effects, such as somnolence, agitation, and cognitive failure.9 Drug therapies
for delirium target imbalances in neurotransmitters,
which may play a role in developing delirium.
Assessment
A history of the patient’s baseline mental status prior
to symptom onset should be obtained from his or her
family, caregivers, or both parties. Fluctuating consciousness is the hallmark of delirium. Assessment
tools can screen or rate delirium or do both. Commonly used tools include those for screening (Mini Mental
State Examination, Confusion Assessment Method)
or rating of severity (Memorial Delirium Assessment
Scale, Disability Rating Scale). Some instruments will
address more than 1 goal. Other important considerations are time constraints, the level of expertise and
training of the investigator (the Mini Mental State Examination requires none), and constraints of the patient (eg, patient in the intensive care unit).10
Management
Nonpharmacological: Identification of reversible
causes is important. Investigations should be tailored
to each individual patient’s goals of care because 50%
of cases of delirium may be reversible.7 Health care
professionals must look for infection, dehydration, and
drug and metabolic abnormalities as potentially reversible causes of delirium. Patients with cancer should
be evaluated for central nervous system metastasis. It
is worth noting that fecal impaction and urinary tract
infection are often overlooked as causes of delirium.
Common drugs linked to delirium include opioids,
anticholinergics, benzodiazepines steroids, and select
chemotherapy agents. Inquiring about alcohol intake
is prudent because alcohol withdrawal can precipitate
delirium and responds to benzodiazepines. Nonpharmacological approaches to delirium include keeping
room lights on, having calendars and pictures at the
bedside, frequent redirection, and allowing patients to
participate in their care.11
Pharmacological: Antipsychotic drugs are the
primary therapy for all forms of delirium, in particular hyperactive and mixed delirium.12 Table 1 reviews
404 Cancer Control
Table 1. — Common Drugs for Pharmacological
Management of Delirium
Drug
Haloperidol
Dosage
Adverse
Events
Comment
0.5 mg orally
Acute
2–3 times a day extrapyramidal
events
(eg, torticollis,
oculogyric
crisis, tongue
1–2 mg intraand laryngeal
venous/subcuspasm)
taneous every
30 min to 1 h
until agitation
resolved
Mild to
moderately
agitated
elderly
patients
Risperidone
1 mg orally
each day or
every other day
QT interval
and cardiac
arrhythmia
Potent dopamine
blocker
Olanzapine
2.5–11 mg daily
QT interval
and cardiac
arrhythmia
Very
anticholinergic
Quetiapine
25–75 mg orally
every day
QT interval
and cardiac
arrhythmia
Lorazepam
0.5–1 mg
intravenous/
subcutaneous
Severe agitation
in patients
aged < 60 y
Do not use alone
Useful for severe
agitation in
conjunction with
haloperidol
Information from reference 13.
common agents used for delirium.13 Haloperidol remains the gold standard despite a paucity of clinical
trials.14 Severity of delirium and patient age are both
important considerations for dosing. In elderly patients
(aged ≥ 60 years) and in patients with mild to moderate
agitation, Canadian guidelines suggest that haloperidol
be started at low doses (ie, 0.5 mg orally 2–3 times a
day) and then be titrated to obtain an effect.15 Severe
cases and younger patients may require more haloperidol, and, in severely agitated patients, rapid dosing is
required. In this setting, parenteral doses are recommended and haloperidol doses such as 1 to 2 mg in
young patients and 0.25 to 0.5 mg in elderly patients,
repeated every 1 to 2 hours until the agitation resolves;
protocols for rapid titration are available.16 Haloperidol
is the least sedating of the antipsychotic class and can
be intravenously or orally given.17
Atypical antipsychotics may also be useful because
they are less likely to cause extrapyramidal symptoms
and have less potential for effects on cardiac conduction; however, these antipsychotics cannot be given via
the parenteral route.18 Commonly used atypical antipsychotics include olanzapine, quetiapine, and risperidone. These types of antipsychotics are also appropriate for patients with underlying Parkinson disease.
Benzodiazepines are not indicated for the management of delirium and are best used in the setting of deOctober 2015, Vol. 22, No. 4
lirium associated with alcohol withdrawal.19 Benzodiazepines can be added to haloperidol when agitation
does not respond to haloperidol alone.20
Chronic Nausea and Vomiting Unrelated
to Chemotherapy
Nausea and vomiting affects up to 70% of patients with
advanced cancer; however, nausea is more common.21
Chronic nausea is defined as nausea that lasting more
than 1 week without an identifiable precipitant, and its
causes include underlying cancer and its progressive
effects as well as medication use (eg, opioids).
Mechanisms
The nausea and vomiting reflex is governed by nuclei in the medulla. The nucleus tractus solitarius
receives input from multiple sites, and then relays to
the dorsal motor nucleus of the vagus to cause vomiting.22 Afferent input comes from the chemoreceptor trigger zone, vagus nerve, cortex, and vestibular
pathways. Neurotransmitters populate these areas
critical to the emetic reflex and include dopamine,
serotonin, histamine, substance P, and acetylcholine.23 Blocking these neurotransmitters forms the
basis for antiemetic therapy.
Assessment
Health care professionals should gather information
about duration, frequency of vomiting episodes, and
the ability of the patient to keep fluids down — all of
which may affect the route of drug administration.
Delayed nausea and vomiting due to chemotherapy
should be considered. Large-volume emesis suggests
gastric or bowel obstruction, whereas polydipsia, polyuria, and cognitive changes suggest metabolic causes.
Health care professionals should inquire about the
presence of constipation, which can also cause nausea.
Mood should be assessed. Physical examination findings may provide clues. Papilledema suggests brain
metastasis, whereas orthostatic changes suggest autonomic insufficiency. Numerical rating scales can be
used to measure the severity of nausea.
Management
Recommendations support either antiemetic therapy
based on proposed pathophysiology or a sequential trial of antiemetics.24 Response rates near 80% with these
approaches.25 Table 2 lists select antiemetics that can
be used in patients with advanced illness.21
Nonpharmacological: Operative approaches
are considered in cases of mechanical bowel obstruction. However, consideration for surgical interventions
should be individualized, with health care professionals weighing the risks and benefits of the procedure.26
Use of acupuncture to treat nausea and vomiting in advanced illness has not been evaluated.27
October 2015, Vol. 22, No. 4
Dyspnea
Dyspnea is the uncomfortable awareness of breathing,
and it is a frequent symptom in advanced illness with
prognostic importance.28 The prevalence of dyspnea is
between 20% and 80% in patients with advanced cancer.28 It has been described in various ways, including
as air hunger, suffocation, and choking. Health care
professionals typically have differing perspectives on
dyspnea, and they often under-rate it as a symptom.28
Mechanisms
Peripheral receptors involved in breathing play a role
in the perception of dyspnea. Excessive input from
receptors sensing oxygen and carbon dioxide levels
contribute to dyspnea.29 The overactivity of mechanoreceptors and respiratory muscle as well as lung and
chest-wall receptors all contribute to the sensation of
dyspnea.28,30 These receptors likely also stimulate the
cortex, thus influencing cortical perception.31
Assessment
Many tools exist to measure breathlessness, but few
Table 2. — Antiemetics in Advanced Illness
Drug
Dosage
Route
Comment
Butyrophenone
Haloperidol
0.5–2.0 mg
every 4–6 h
Intravenous
Oral
Subcutaneous
Useful with
associated
delirium
Intravenous
Oral
Subcutaneous
Prokinetic
Substituted Benzamide
Metoclopramide
10 mg every
6h
Antihistamine
For vestibular
component
Cannabinoids
Dronabinol
5 mg/m2 every
6h
Oral
Very long
half-life (≤ 56 h)
Nabilone
1–2 mg twice
daily
Oral
2-h half-life
Not detected on
urine testing
Glucocorticoid
Brain
metastasis:
4–6 mg every
6h
Intravenous
Oral
Atypical Antipsychotic
Olanzapine
2.5–7.5 mg
daily
Oral
Single daily dose
May require
another
antiemetic for
breakthrough
emesis
Information from reference 21.
Cancer Control 405
cancer-specific tools exist; however, one such tool is
the Lung Cancer Symptom Scale, and a scale, such as
the visual analog scale, numerical pain scale, or cancerspecific tool, is recommended.32,33
Management
In advanced illness, treatment should focus on comfort
and should include assessment of overall patient distress and work of breathing. Reversible causes of dyspnea and their treatment should be in keeping with the
individual patient’s goals of care.
Oxygen Therapy: Oxygen therapy can benefit
patients with chronic obstructive pulmonary disease
and hypoxia in domains such as exercise capacity, cognitive function, and survival; however, its benefits are
not clear in the oncology setting.34 Oftentimes, patients
with cancer are dyspneic but not hypoxemic. Randomized controlled trials have compared oxygen therapy
with room air for relief of dyspnea.35,36 The results of
2 studies suggested that those with cancer who were
hypoxemic on room air benefited from oxygen, and
the results of another study showed that oxygen did
not benefit those with cancer experiencing dyspnea
who were not hypoxemic.36,37
Opioids: Opioids are the preferred treatment
for refractory dyspnea, and patients typically benefit
from oral or parenteral opioids.38 Sustained-release
formulations are effective.39 All opioids as a class
are effective for dyspnea because they decrease the
perception of breathlessness. Results from a metaanalysis of 9 small, randomized studies (116 study
patients) and 1 randomized crossover trial (48 study
outpatients) showed that systemic opioids reduced
mean chronic breathlessness by approximately 20%
over baseline.40 No evidence suggests that nebulized
opioids are effective.41
Benzodiazepines: Benzodiazepines are used for
dyspnea and to relieve anxiety.42 Results from a metaanalysis of 7 studies (200 study patients) found that
benzodiazepines did not relieve breathlessness and
instead increased the risk of drowsiness; however, the
studies were heterogeneous and the sample sizes were
small.43 One controlled trial found that adding subcutaneous midazolam to an opioid enhanced dyspnea relief in patients with advanced cancer.44
Antidepressants: Current evidence for the use of
antidepressants to decrease breathlessness is inconsistent.45
Saline: A randomized, single-blinded trial of
40 people with an exacerbation of chronic obstructive pulmonary disease showed no consistent relief of
breathlessness from nebulized, isotonic saline compared with placebo.46
Furosemide: Exploratory studies are conflicting regarding the efficacy of inhaled furosemide on
breathlessness.47 Thus, the level of efficacy of furose406 Cancer Control
mide in this patient population requires confirmation
in larger clinical trials.
Cancer Anorexia/Cachexia
Cancer anorexia/cachexia is defined as “a multifactorial syndrome defined by ongoing loss of skeletal mass
(with or without loss of fat) that cannot be reversed by
conventional nutritional support and leads to progressive functional impairment.”48 A cluster of symptoms
characterizes the syndrome and includes weakness,
early satiety, and anorexia.48 Criteria for diagnosing
cachexia in patients with cancer are: weight loss of
more than 5% in 6 months (in the absence of starvation), body mass index below 20 kg/m2, and any degree of weight loss of more than 2% or appendicular
skeletal muscle index consisting of sarcopenia (men:
< 7.26 kg/m2; women: < 5.45 kg/m2).48 It has 3 stages:
precachexia, cachexia, and refractory cachexia. The
syndrome occurs in 50% of patients with cancer (many
various types).49
Associated complications include poor performance status, poor quality of life, decreased survival,
and poor response and tolerability to chemotherapy.48-50 Anorexia frequently accompanies the syndrome.51 Patients may manifest decreased muscle mass
and decreased strength, and they may experience fluctuations in resting energy expenditure and increased
psychosocial distress.52 Both lean body mass and muscle strength, as measured by handgrip strength, are
predictive of survival and quality of life.53
Cancer anorexia/cachexia limits therapeutic options.54 Weight loss correlates with treatment toxicity, poor tumor response, and lower chemotherapy
response rates.51 Loss of more than 10% of premorbid
weight before chemotherapy predicts death and is independent of disease stage, tumor histology, and performance status.55 Anorexia is also a powerful predictor of early death, and this observation persists even
after adjusting for several other prognostic parameters.56 Thus, both weight loss and anorexia predict
poor prognosis for patients with advanced cancer.
Mechanisms
The mechanisms leading to the development of cancer anorexia/cachexia are not fully understood. Anorexia/cachexia results from abnormal host responses to cancer, and the syndrome appears to result
from the interplay between tumor byproducts and
host cytokine response.57,58 In animal studies, targeting cytokines with monoclonal antibodies relieves
cachexia.59 The interplay between tumor byproducts
and inflammatory mediators creates acute-phase
proteins in the liver, and this, in turn, leads to the
breakdown of muscle protein, lipolysis of fat, insulin resistance, and an elevated level of triglycerides.51
Inflammatory mediators enter the hypothalamus,
October 2015, Vol. 22, No. 4
which is where they mimic anorexigenic neurotransmitters and cause anorexia.60
Assessment
Tools measuring cancer anorexia/cachexia include the
Edmonton Symptom Assessment System, Bristol Meyers Anorexia/Cachexia Recovery Instrument, Patient
Generated Global Assessment Instrument, and the
cancer anorexia/cachexia subdomain of the Functional
Assessment of Anorexia/Cachexia Therapy questionnaire.61-63 Clinical tools useful for assessment cancer
anorexia/cachexia include weight, midarm circumference, and hand grip.61 It is worth noting that mid-arm
circumference has prognostic value.64 Optimal methodology to assess muscle mass has not yet been determined. Computed tomography, dual energy x-ray imaging, and bioimpedance can all be used to measure
muscle mass.48 Whole-body impedance and electroconductivity are based on the principle that lean tissue
conducts electricity better than fat.
Management
Secondary reasons for weight loss should be addressed
or ruled out. Health care professionals should look for
nausea, constipation, taste alteration, depression, dyspnea, and deconditioning as possible causes. Other important patient factors contributing to cancer anorexia/
cachexia include dry mouth, difficulty swallowing, any
alteration in sense of smell, early satiety, mouth sores,
dental issues, and anxiety.
Nutritional Support: Nutritional support early
on is important and can include dietary advice, nutritional supplements, and consideration of an enteral
diet. Dietitians may recommend foods tailored to preference, portions, and an individual patient’s ability to
swallow. Pungent foods should be avoided. It is not
clear whether nutritional supplements reverse weight
loss and decline in quality of life.65
Psychosocial Intervention: Psychosocial interventions are important because patients and their
friends, families, and caregivers may be experiencing
distress. Information, support, and clinician interactions with the patient and his or her friends, family,
and caregiver can help mitigate such distress.
Pharmacologic Intervention
Megestrol: Megestrol acetate has long been an option for cancer anorexia/cachexia.66 Results of the
initial study (and subsequent studies) showed significant improvement over placebo with respect to appetite, nausea, weight gain, and food intake (megestrol acetate 800 mg/day).67 Bruera et al68 conducted a
15-day, blinded, placebo-controlled, crossover trial of
megestrol acetate 480 mg/day and found statistically
significant improvements in caloric intake, appetite,
and weight gain among the study participants. Results
October 2015, Vol. 22, No. 4
of a meta-analysis that included 3,500 participants and
25 clinical trials comparing megestrol acetate with steroids, nandrolone, eicosapentanoic acid, and dronabinol suggested consistent improvement in appetite,
weight gain, and quality of life.69 Megestrol acetate improves appetite and weight gain in approximately 30%
of patients.69 The numbers of patients needed to treat
are 8 patients for weight gain and 3 patients for anorexia.69 Megestrol acetate benefits patients with HIV/AIDS
and geriatric cachexia.70,71 Adverse events that occur
relatively infrequently include adrenal insufficiency,
thrombosis, and hyperglycemia.72-74 Rash and menstrual disorders have similar frequency.67,75 Some evidence
suggests that the drug improves fat-free body mass.71
Glucocorticoids: Glucocorticoids work by inhibiting markers of inflammation and also increase neuropeptide Y.76 Glucocorticoids, such as dexamethasone
(3–6 mg/day), prednisone (15 mg/day), and methylprednisone (32 mg/day), can improve appetite and
can cause weight gain.77 Their effects are rapid but are
of short duration than megestrol acetate.78 Glucocorticoids can be used for patients in need of a rapid effect but are more appropriately used in patients with a
short prognosis.
Cannabinoids: Dronabinol is the most-studied cannabinoid, with dosages ranging from 2.5 to
20 mg/day; compared with placebo, dronabinol reduces nausea, stabilizes weight, and increases appetite.79
Cannabinoids probably inhibit inflammatory mediators, and they also may influence leptin by activating
the cannabinoid receptor. Toxicities include euphoria,
hallucinations, tachycardia, and psychosis.79 A phase
2 study (N = 19) found that 5 mg/day dronabinol improved anorexia in 68% of study patients, but 16% of
study patients discontinued the drug due to adverse
events.79 With respect to appetite and weight gain,
dronabinol is inferior to megestrol acetate and megestrol acetate/dronabinol combinations, and it is not recommended for cancer anorexia/cachexia.80,81
Anamorelin: Anamorelin is a novel, ghrelin,
growth-hormone secretagogue taken orally for the
treatment of cancer anorexia/cachexia because it
improves appetite and muscle mass.82 Ghrelin is an
orexigenic hormone that stimulates food intake in
a dose-dependent manner in rodents and humans
by stimulating growth hormone and neurotransmitters such as neuropeptide Y. 83,84,85 Levels of ghrelin are elevated in fasting and reduced in obesity.86
It also stimulates the hypothalamus, thus causing
food intake.87 The results of a phase 3 trial showed
increased lean body mass and decreased symptoms of anorexia/cachexia in patients with stage 3/4
non–small-cell lung cancer.83
Nonsteroidal Anti-Inflammatory Drugs: Nonsteroidal anti-inflammatory drugs (NSAIDs), including
cyclooxygenase 2 inhibitors, reduce the tumor-assoCancer Control 407
ciated release of acute-phase reactants and cytokines.
The results of 2 controlled clinical trials of patients
with cancer anorexia/cachexia suggested that NSAIDs
were effective for gaining weight and muscle mass
in this study population, and this was especially true
when NSAIDs were combined with progestogens.88,89
However, larger trials are required to further study
their effect in this patient population.88,89
Thalidomide: Thalidomide has multiple immune-modulating, anti-inflammatory, and TNF-α and
IL-6–inhibiting properties. The results of 2 controlled
clinical trials show that it increased appetite, weight,
and feeling of well being in study patients with cancer
anorexia/cachexia.90,91 These initial results are promising, but they may need to be confirmed by additional
clinical trials.90,91
Melatonin: Melatonin is an endogenous hormone
secreted by the pineal gland and is used to treat sleep
disorders. It inhibits cytokines and TNF-α. Two controlled clinical trials measuring the efficacy of melatonin in 1,600 study patients with advanced cancer found
improvements in asthenia and anorexia compared with
placebo.92,93 However, another controlled clinical trial
comparing melatonin with placebo in study patients
with cancer anorexia/cachexia (N = 48) did not find any
differences between the 2 treatment groups.92 Thus,
more studies are indicated to determine its effectiveness.
Anabolic Steroids: Oxymetholone, oxandrolone,
nandrolone, and fluoxymesterone are anabolic steroids
studied in cancer anorexia/cachexia. They act to increase
muscle mass without changes in appetite or amount of
food intake. They have been evaluated for cachexia
with a nononcological origin (eg, AIDS, chronic obstructive pulmonary disease, renal impairment).94-96 One
controlled clinical trial confirmed that the efficacy of
fluoxymesterone in cancer anorexia/cachexia was comparable with that of megestrol acetate. However, its use is
not recommended due to its high rate of hepatotoxicity.78
Combination Treatment: Another approach to
cancer anorexia/cachexia is using multiple drugs on
different pathways that play a role in the disorder. A
controlled clinical trial compared 5 treatments (megestrol acetate, eicosapentaenoic acid, L-carnitine, thalidomide, and combination megestrol acetate/eicosapentaenoic acid/L-carnitine/thalidomide) during a 4-month
period.93 The results showed that the drug combination was superior to the drugs alone and improved
appetite and asthenia, reduced energy expenditure at
rest, increased fat-free mass, and reduced IL-6.93
Fatigue
Patients with cancer commonly experience fatigue,
which impacts the physical, emotional, and cognitive domains.97,98 Fatigue can impair concentration,
often manifesting as lack of motivation.61 In addition,
patients may perceive fatigue as decreased energy
408 Cancer Control
and weakness.61 Use of radiation, chemotherapy, biological therapies, and targeted therapies may cause fatigue.99,100 Moreover, fatigue can persist in cancer survivors and last for many years.101
Mechanisms
Factors contributing to fatigue in patients with cancer
can include tumor burden, oncology treatment, and
the effect of cytokines.61 Cytokine production leads
to symptoms of fever, pain, cachexia, and depression.
Patient comorbidities can also exacerbate fatigue and
may include chronic obstructive pulmonary disease,
renal insufficiency, and electrolyte, endocrine, and preexisting mood disorders.61
Assessment
Fatigue should be evaluated like any other symptom,
with the health care professional detailing its severity,
temporal features, any exacerbating and alleviating factors, associated distress, and its impact on the patient’s
daily life. Tools for the measurement of fatigue include
the Edmonton Symptom Assessment System, the Functional Assessment of Cancer Therapy-Fatigue Subscale,
the Brief Fatigue Inventory, and the Memorial Symptom Assessment Scale Short-Form.102
Management
Health care professionals can use nonpharmacological and pharmacological approaches to treat cancerrelated fatigue. Identification of anemia, infection,
hypogonadism, pain, depression, anxiety, cachexia,
dehydration, metabolic abnormalities, other comorbidities, and medication use, as well as autonomic
insufficiency and their attempted correction, are also
important. Clear relationships exist between hemoglobin levels and symptoms of fatigue and functional
and physical well-being.103 Treating anemia does improve energy and quality of life; however, transfusions can benefit patients with cancer approximately
60% of the time.103,104 Erythropoietin and other similar
treatments are impractical in patients with advanced
cancer because these treatments often take 4 to 8
weeks.104 As the disease progresses, the benefits of
transfusions lessen.104
Nonpharmacological: Exercise can be beneficial
for cancer-related fatigue because it improves cardiovascular conditioning, helps patients maintain muscle
mass, and can improve mood and sleep.105 Exercise can
also benefit patients receiving chemotherapy and bone
marrow transplants.106 However, it is important for the
health care professional to set realistic expectations
for patients when recommending exercise. Patients
with cancer may experience metabolic changes, such
as an excess lactate level, and morphological muscle
changes, such as myofibrillar and sarcomeric abnormalities, even in tumor-free muscles.107-109 DeconditionOctober 2015, Vol. 22, No. 4
ing complicates exercise goals, and use of steroids can
cause physical weakness. Thus, an ideal exercise program appropriate for all degrees of performance status
among patients with advanced illness remains to be
determined.
Pharmacological: Management options for
cancer-related fatigue include corticosteroids and psychostimulants. Glucocorticoids have been shown to
improve fatigue in advanced illness, although their
benefits are short term.110 Steroids are best reserved for
patients with a short prognosis. Doses equivalent to
dexamethasone 8 mg daily are appropriate.111 A metaanalysis of psychostimulants for cancer-related fatigue
suggested a benefit for this patient population.112 Psychostimulants such as methylphenidate and modafinil
can also be used.113
Conclusions
Symptom management in patients with advanced cancer is more effective when health care professionals
use a systematic approach to assessment. Expert management requires understanding of the pathophysiology of common symptoms in advanced cancer, use of
symptom assessment tools to measure symptom intensity, and the application of proven symptom control interventions.
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89. O’Gorman P, McMillan DC, McArdle CS. Impact of weight loss, appetite, and the inflammatory response on quality of life in gastrointestinal
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90. E. Bruera, C.M. Neumann, E. Pituskin, et al. Thalidomide in patients with cachexia due to terminal cancer: preliminary report. Ann Oncol.
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91. J.N. Gordon, T.M. Trebble, R.D. Ellis, et al. Thalidomide in the
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92. Del Fabbro E, Dev R, Hui D, et al. Effects of melatonin on appetite
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93. Mantovani G, Macci+¦ A, Madeddu C, et al. Randomized phase III
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Cancer Control 411
It is important that clinicians assess
opioid responsiveness to determine
whether adjuvant analgesics should
play a role in the treatment plan.
Photo courtesy of Lisa Scholder. Solid Stance. 16" × 24".
Pharmacological Management of Cancer-Related Pain
Eric E. Prommer, MD
Background: Pain occurs in 50% of patients with cancer at the time of diagnosis, and nearly 80% of patients
with advanced stage cancer have moderate to severe pain. Assessment of pain requires the health care professional to measure pain intensity, delineate opioid responsiveness, and clarify the impact of pain on a patient’s
psychological, social, spiritual, and existential domains. To this end, the World Health Organization (WHO)
has developed a 3-step pain ladder to help the health care professional effectively manage pain, classifying
pain intensity according to severity and recommending analgesic agents based on their strength.
Methods: Health care professionals should follow the WHO guidelines to manage cancer-related pain in
their patients. With regard to opioids, dosing, equianalgesic conversions, the management of adverse events,
and the identification of new agents are discussed. Integrating adjuvant analgesics and interventional pain
techniques into the management of cancer-related pain is also discussed.
Results: The WHO analgesic ladder is an effective tool for managing cancer-related pain. Successful pain
management in patients with cancer relies upon the health care professional to pay attention to detail, especially during the introduction of new drugs and in identifying potential adverse events. Health care professionals must assess opioid responsiveness to determine whether adjuvant analgesics should also play a role
in a patient’s treatment plan.
Conclusion: Adherence to the WHO pain ladder and understanding proper use of interventional pain techniques complement the pharmacological management of cancer-related pain.
Introduction
Pain occurs in 50% of patients with cancer at the time of
diagnosis, and approximately 80% of patients with advanced stage cancer have moderate to severe pain.1 Pain
From the Division of Hematology/Oncology, Veterans Integrated
Palliative Care Program, Veterans Integrated Palliative Care, David
Geffen School of Medicine, University of California, Los Angeles,
California.
Submitted July 29, 2015; accepted September 17, 2015.
Address correspondence to Eric Prommer, MD, David Geffen
School of Medicine, University of California, 11301 Wilshire
Boulevard, Building 500, Room 2064A, Mail Code 10P, Los Angeles,
CA 90073. E-mail: Eric.prommer@va.gov
No significant relationship exists between the author and the
companies/organizations whose products or services may be referenced in this article.
412 Cancer Control
can impact quality of life, limit function, and affect mood.
Untreated pain may sometimes lead to requests for physician-assisted suicide or unnecessary visits to the emergency department and hospital admissions.2,3 Opioids are
the cornerstone of treatment for moderate to severe pain
associated with cancer because they decrease pain and
improve function.4 Strong opioids are the initial choice for
moderate to severe pain associated with cancer, and the
World Health Organization (WHO) recommends a pain
ladder, which is a step-by-step approach for the management of chronic pain based on pain intensity.5,6
Epidemiology
Pain occurs at diagnosis in 20% to 50% of patients with
cancer.7 Cancer-related pain may be the result of the
October 2015, Vol. 22, No. 4
cancer itself, oncology treatment, and coexisting nonmalignant pain.8 Cancer types determine pain prevalence; for example, patients with head and neck cancer
have the highest prevalence of cancer pain.9 Age has
also been show to affect cancer pain; younger patients
experience more pain and more pain flares than older patients.10 In addition, elderly patients receive less
opioids than their younger counterparts.11 Patients
with cancer most commonly experience pain in the
back — prompting health care professionals to exclude
spinal cord metastasis — as well as in the abdomen,
shoulders, and hips.12
World Health Organization Pain Ladder
WHO guidelines form the basis of cancer pain management, recommending a step-by-step approach to
managing cancer pain based on pain intensity.2 The
pain ladder starts with nonopioid analgesics, such as
acetaminophen or nonsteroidal anti-inflammatory
drugs (NSAIDs), for mild pain, then adds a so-called
weak opioid if pain persists or increases, and then replaces the weak opioid with a step 3 opioid for severe
pain. Morphine is recommended as a first-line opioid
to relieve cancer-related pain; however, the evidence
level for morphine as a first-line opioid is not particularly strong.3,6 Other step 3 options for moderate to
severe pain include methadone, oxycodone, fentanyl,
and hydromorphone. Successfully using the WHO
pain ladder can help manage pain/provide effective
analgesia in 90% of patients in certain settings, although results from randomized control trials show
success rates of 70% to 80%.13-15
Step 1
Step 1 analgesics include acetaminophen and NSAIDs,
which are both analgesic and anti-inflammatory; acetaminophen is only analgesic.16,17 Dosing of acetaminophen and NSAIDs is limited by a ceiling effect,
meaning that further dose escalation will not improve
analgesia. Acetaminophen dosing is limited by concerns of hepatic toxicity at a total dose of more than
4 g/day.18 Acetaminophen has several postulated
mechanisms of action, including central inhibition of
the cyclooxygenase system, nitric oxide synthetase,
the endocannabinoid system, and the descending serotonin pathways.17 NSAIDs inhibit the enzyme cyclooxygenase, which produces inflammatory prostaglandins
that cause sustained nociceptive responses by lowering pain thresholds in nociceptive, neuropathic, and
possibly visceral pain through a process called peripheral sensitization.19 One major action of NSAIDs is the
prevention of peripheral sensitization.20 When considering the use of NSAIDs, choices should be based on
experience and the toxicity profile, which depends on
the cyclooxygenase 1:2 ratio. There is no ideal NSAID.
NSAIDs are orally administered, with the exception of
October 2015, Vol. 22, No. 4
ketorolac. Thus, loss of the oral route with advanced
illness eliminates NSAIDs from consideration for analgesia in patients at the end of life.
At the end of life, NSAIDs are typically replaced
by stronger analgesics in the setting of moderate to
severe pain. It may be important to continue NSAIDs
as long as possible, because clinical trials show additive analgesia when combined with opioids as well
as an opioid-sparing effect.21 Ketorolac, diclofenac,
and ibuprofen are parenteral NSAIDs, and ketorolac
is useful for the treatment of cancer pain syndromes
not uniformly responsive to opioid therapy.22 Ketorolac use in the advanced patient with cancer is not recommended for more than 1 week.23 Acetaminophen
has not been shown to work synergistically with opioids but has not been shown to be opioid-sparing
with opioid doses of more than 200 mg of morphine
equivalents.22 NSAIDs are useful for pain originating in tissues such as connective tissue, joints, serous
membranes, and the periosteum; in addition, visceral
pain may also respond to NSAIDs.24
Step 2
Step 2 on the WHO pain ladder is for mild to moderate cancer pain and includes recommendations for
acetaminophen products containing hydrocodone,
oxycodone, codeine, and tramadol, as well as propoxyphene and dihydrocodeine (not available in the United
States).2 Propoxyphene is not recommended for use in
cancer pain.25
Hydrocodone: Hydrocodone is structurally similar to morphine, differing only in having a single
bond at carbons 7 and 8 and a keto (=O) group at
6-carbon. Hydrocodone is metabolized by both cytochrome P450–dependent oxidative metabolism and
glucuronidation. CYP3A4 and CYP2D6 play a role
in the generation of hydrocodone metabolites: norhydrocodone and hydromorphone, respectively.26
Polymorphisms of CYP2D6 potentially affect hydrocodone metabolism and therapeutic efficacy.27 Hydrocodone has equivalent potency as morphine on a
milligram-for-milligram basis.27 Adverse events of hydrocodone are similar to other opioids.
Rodriguez et al28 evaluated 118 study patients
with chronic cancer pain and compared hydrocodone/
acetaminophen with tramadol in a double-blind, randomized controlled trial. A total of 62 study patients
received hydrocodone/acetaminophen and 56 received tramadol.28 Hydrocodone/acetaminophen decreased pain in 57% of participants at a starting dose
of 25 mg/2500 mg/day (5 doses per day).28 Analgesic
responses increased by 15% with dose doubling.28 Pain
did not respond to hydrocodone/acetaminophen administration in 29% of study patients.28
Another multicenter, double-blind, randomized,
parallel group study compared codeine/acetaminoCancer Control 413
phen phosphate with hydrocodone/acetaminophen for
moderate to severe pain.29 Study patients had chronic moderate to severe cancer pain (> 3 on a 10-cm visual analog scale and > 1 on a 4-point verbal intensity
scale).29 A total of 88% of study patients had moderate pain and 12% had severe pain; 121 participants
received either 1 tablet of codeine/acetaminophen
30/500 mg or hydrocodone/acetaminophen 5/500 mg
orally every 4 hours (total daily doses, 150/2500 and
25/2500 mg, respectively) for 23 days.29 Dose escalation occurred after 1 week if participants experienced
severe pain.29 The primary end point was the percentage of study patients achieving a decrease in their pain
score by 1 point on a 5-point verbal intensity scale.29
The secondary end point was the percentage of study
patients whose pain decreased by at least 3 cm on the
10-point scale.29 Of the 121 participants, 59 received
codeine/acetaminophen and 62 received hydrocodone/acetaminophen.29 Of the total number of cases,
59 had ages ranging from 60 to 89 years.29 A total of
58% of patients in the codeine/acetaminophen arm of
the study experienced pain relief, and an additional
8% achieved pain relief with a doubling of the dose.29
Approximately one-third had unresponsive pain.29 In
the hydrocodone/acetaminophen arm of the study,
56% experienced pain relief with a starting dose of
25/2500 mg/day.29 A total of 15% more achieved pain
relief doubling of the initial dose, and one-third
of patients did not respond to hydrocodone/acetaminophen.29
Tramadol: Tramadol is a synthetic opioid from
the aminocyclohexanol group. Tramadol has opioid-agonist properties and prevents the uptake of
norepinephrine and serotonin, making it useful for
neuropathic pain.30 Tramadol possesses low affinity for opioid receptors, with an affinity to μ receptors
10 times weaker than codeine, 60 times weaker than
dextropropoxyphene, and 6,000 times weaker than
morphine.31 Tramadol requires conversion to an active
metabolite by CYP2D6. This metabolite has affinity for
opioid receptors, but less so than step 3 opioids.31 Patients who are poor metabolizers of CYP2D6 may experience poor analgesia.32 Adverse events of tramadol
include constipation, dizziness, nausea, sedation, dry
mouth, and vomiting.33
Rodriguez et al28 evaluated 118 participants with
chronic cancer pain and compared hydrocodone/acetaminophen and tramadol in a double-blind, randomized controlled trial. In addition, Wilder-Smith et al34
compared tramadol with morphine in a randomized,
crossover, double-blind study for severe cancer pain
(N = 20). Initially, participants received either tramadol
50 mg or morphine 16 mg every 4 hours, with dose titration to achieve pain control.34 After 4 days, pain intensities did not differ between the groups, although
adverse events appeared to differ, with less-intense
414 Cancer Control
nausea and constipation noted in the tramadol group.34
The authors estimated equianalgesic doses of morphine and tramadol and found a ratio of morphine to
tramadol of 1:4.34
Tawfik et al35 compared oral tramadol with sustained release morphine for cancer pain in 64 participants with severe cancer pain in a randomized, double-blind study. Tramadol worked best in participants
with lesser pain intensity, and morphine worked more
effectively and was preferred for participants experiencing severe pain intensity.35 Good analgesia was
achieved in 2 weeks of treatment in 88% of study patients receiving tramadol and 100% of study patients
receiving sustained-release morphine. Participants
receiving tramadol experienced fatigue (15%), nausea
(8%), and sweating (8%).35 In those receiving morphine,
adverse events included constipation (35%), rash (14%),
and drowsiness (14%).35
Bono and Cuffari36 compared tramadol with buprenorphine in a randomized, crossover trial in study
patients with cancer pain. All 60 study patients received either drug for 1 week and then, after a 24-hour
wash-out period, were switched to the other drug.36
The tramadol dose was 300 mg/day and the buprenorphine dose was 0.2 mg 3 times a day.36 Tramadol was
associated with better analgesia (P < .05) and was associated with higher acceptance among study patients.36
Tramadol was better tolerated than buprenorphine
and caused less frequent and milder adverse events,
and more study drug withdrawals occurred in the buprenorphine arm.36
Tapentadol: Tapentadol is structurally related
to tramadol.37 Opioid receptor–binding studies show
that tapentadol is a strong opioid with high-affinity
binding to µ, δ, and κ opioid receptors. In human µ
opioid receptor 35S GTPγS–binding assays, tapentadol
shows agonistic activity, with an efficacy of 88% relative to morphine; tapentadol provides potent inhibition of norepinephrine uptake and its bioavailability
is lower than tramadol.31 Tmax is achieved in 1.25 to
1.5 hours, the half-life is 24 hours, and the plasma
protein binding is 20%.38 Tapentadol metabolism is
mainly by glucuronidation, with some contribution
from CYP enzymes, especially CYP2D6.39 Tapentadol
is not an inducer of CYP3A4.39 Tapentadol has no active metabolites. There is chiefly renal excretion. Tapentadol causes adverse events such as nausea, dizziness, vomiting, headache, and somnolence.40 The
manufacturer recommends against using tapentadol
in severe hepatic or renal failure, and dosing above
600 mg/day should be avoided.41 Equianalgesic dosing studies are unavailable but information from
its use in non–cancer-related pain studies suggest
morphine 60 mg is equivalent to tapentadol 100 to
200 mg.42 The current dosing recommendations is 50,
75, or 100 mg every 4 to 6 hours.40 Tapentadol does
October 2015, Vol. 22, No. 4
not affect the QTc interval.43 Prolonged-release tapentadol (100–250 mg twice daily) is effective compared with placebo for managing moderate to severe,
chronic, malignant tumor-related pain.
Codeine: Codeine is a prodrug whose analgesia
is mediated through the µ receptor by its metabolite,
morphine. A total of 10% of codeine is broken down
to morphine by CYP2D6, an enzyme lacking in 5%
to 10% of white populations.44 Codeine use is not
recommended in the setting of renal failure.45 One
placebo-controlled study has evaluated codeine for
cancer pain involving a sustained-release formulation.46 Thirty study patients with chronic cancer pain
completed the study and received either sustained-release codeine every 12 hours or placebo in a doubleblind study.46 Crossover occurred after 7 days.46 Pain
intensity was measured using a visual analog scale
as well as a 5-point categorical scale. Rescue analgesia (acetaminophen/codeine 300 mg/30 mg every
4 hours as needed) was recorded. The median doses
of controlled-release codeine doses were 277 ± 77 mg
(range, 200–400 mg). Pain intensity scores on a visual
analog scale, categorical pain intensity scores when
assessed by day of treatment and by time of day, and
need for breakthrough pain were significantly lower
in the codeine arm (P < .0001).53
Step 3
The WHO pain ladder recommends the use of step 3
opioids as first-line therapy for moderate to severe
pain (morphine, oxycodone, hydromorphone, fentanyl, levorphanol, methadone).47 Step 3 opioids differ
from those in step 2 medications in terms of potency
and dosing. Although many step 2 medications often
have a ceiling dose due to fixed formulations with acetaminophen, step 3 opioids do not have this ceiling.
Dosing can increase to achieve adequate analgesia as
long as adverse events are tolerated. Step 3 opioids interact with opioid receptors found throughout the central nervous system and peripheral tissues, resulting in
analgesic effects, as well potential adverse events, including sedation, respiratory depression, and dependence. Opioid receptors exist throughout the intestinal
tract and, when activated, slow bowel motility.48 Varying degrees of activation and affinity for each receptor
subtype may account for the differences in efficacy and
activity between opioids. In addition, interindividual
variation is significant in analgesic response and toxicities based on genetic disparities.49 However, a reliable method to predict an individual patient’s response
does not exist and a paucity of evidence suggests superiority of one opioid over another in terms of efficacy
or tolerability.
Morphine: WHO considers morphine the drug of
choice for moderate to severe cancer pain.50 The liver is
the principal site of morphine glucuronidation.51 There
October 2015, Vol. 22, No. 4
is a minor contribution (30%) to glucuronidation from
the kidneys.52 First-pass metabolism of oral morphine
determines its systemic bioavailability. Three major
metabolites are produced: normorphine, morphine3-glucuronide, and morphine-6-glucuronide. The metabolites are principally eliminated by the kidney and
accumulate in renal failure.53 The elimination half-life
of morphine is approximately 2 hours and is independent of route of administration or formulation.54 Morphine administered by sublingual and buccal routes
has a delayed onset of action compared with oral morphine (smaller peak plasma levels, lower bioavailability, and larger interpatient variability).54 Intrathecal
morphine is 100 times as potent as its oral form, and
epidural morphine is 10 times as potent (0.5 mg intrathecally equals 5 mg epidurally).54 Morphine dosing
is minimally affected by hepatic failure but is greatly
affected by renal failure. There is a linear relationship
between creatinine clearance and renal clearance of
morphine, morphine-3-glucuronide, and morphine6-glucuronide.55 Kidney failure impairs glucuronide
excretion more than morphine excretion, increasing
the duration of action of morphine-6-glucuronide
and morphine-3-glucuronide, thus leading to adverse
events.56 Glucuronidation is largely unaffected by cirrhosis. Morphine doses must be carefully titrated or
avoided when creatinine clearance is less than 30 mL/
minute.54 Morphine continues to be considered the
standard medication for the treatment of cancer pain
partly due to familiarity with the product as well as
cost effectiveness. However, it may not always be the
ideal product due to issues associated with its metabolism and adverse-event profile.11 Almost all randomized controlled comparisons of potent opioids
have shown equivalence (ie, noninferiority) to morphine.6,11,57-59
Methadone: Methadone has features that make
it unique: It works at 3 levels to provide analgesia. It
is a potent opioid with strong interactions with the
µ-opioid receptor, and it is an N-methyl-D-aspartate
(NMDA) receptor antagonist, a receptor that is activated in chronic pain states and, when blocked, can
enhance analgesia and reverse opioid tolerance. Methadone also works on neurotransmitters, such as norepinephrine and serotonin, which play a role in descending pain modulation.59,60
Methadone is a second-line analgesic for pain that
is poorly responsive to other opioids.59 It shows promise as a first-line analgesic for cancer pain, neuropathic
pain, and as a breakthrough agent. Methadone is available in oral, sublingual, and intravenous formulations.
Methadone has different pharmacokinetics from other opioids. Methadone has a long half-life that varies
between 60 and 120 hours.59 High-dose intravenous
methadone is associated with QT prolongation and torsades de pointes.61 In fact, a retrospective study found
Cancer Control 415
that oral methadone can cause QT prolongation in 16%
of patients.62 Dosing of methadone is complicated.
Methadone shows an inverse relationship of its starting dose to the total morphine equivalent daily dose
(MEDD). As the MEDD increases, the equianalgesic
dose of methadone progressively decreases.
Clinical trials comparing methadone to morphine
have not shown superiority of methadone; in fact,
3 studies have compared morphine and methadone
as first-line therapy for cancer-related pain.6,63,64 Ventafridda et al63 compared methadone with morphine
for moderate to severe cancer pain in 54 study patients who had previously been taking step 2 opioids.
Patients received either morphine or methadone by
mouth for 14 days.63 Both therapies provided clear
reductions in pain intensity, there was less stability
in analgesia in the morphine arm, and study patients
receiving morphine had a higher incidence of dry
mouth.63 Otherwise, no other differences in toxicities
or the ability to achieve pain relief were seen.63 Mercadante et al64 conducted a prospective randomized
study in 40 study patients with advanced cancer who
required strong opioids for their pain management
and receiving home hospice care. Study patients were
treated with sustained-release morphine or methadone
in doses titrated to pain relief and administered 2 or
3 times daily according to clinical need.64 Results suggested that methadone more quickly achieved analgesia and methadone analgesia was more stable than
that achieved with morphine.64 Bruera et al6 compared
the effectiveness and adverse events of methadone and
morphine as first-line treatment with opioids for cancer
pain. In this multicenter, international study, 103 participants with pain requiring strong opioids were randomly assigned to receive either methadone or morphine
for 4 weeks. Participants with 20% or more reductions
in pain scores were equal in both groups. Those in both
arms reported satisfaction with their therapies. The
methadone arm had a higher number of dropouts and
required fewer dose adjustments to achieve analgesia
than those in the morphine arm.6,11
Hydromorphone: Hydromorphone is similar in
structure to morphine and is available as parenteral
and oral products. It is the best opioid for subcutaneous administration.65 The oral formulation is available
in an immediate-release formulation, and a single, daily dose, extended-release formulation has been shown
to be effective in patients with cancer.66 Administered
orally, hydromorphone has a bioavailability of 50% and
its plasma elimination half-life is 2.5 hours.67 Metabolism in the liver produces hydromorphone-3-glucuronide, which has no analgesic properties but can cause
neurotoxicity.68 Hydromorphone is effective in treating
pain in patients with renal impairment. Hydromorphone metabolites accumulate in patients receiving
chronic infusions.69 A double-blind, randomized com416 Cancer Control
parison of sustained-release hydromorphone with sustained-release morphine showed equivalence in pain
relief.70 Systematic reviews involving 11 studies and 645
study patients show that hydromorphone equals morphine in analgesic effect.71
Oxycodone: Oxycodone is available as immediate-release and sustained-release formulations. (Intravenous formulations are available in Europe.) The
immediate-release formulation has a half-life of approximately 2 to 4 hours and a bioavailability of 50%
to 60%.72 The primary difference between oxycodone
and morphine is its bioavailability: its half-life is longer
than normal in renal failure and liver failure.45,73 Several trials comparing oxycodone with morphine show
equal efficacy.72,74 Minor differences in adverse events
have been described.74 Hallucinations and nausea are
less common with oxycodone treatment.75 However,
because of its cost and lack of versatility, morphine remains the preferred analgesic.76 Bruera et al74 demonstrated that oxycodone is 1.5 times as potent as morphine when comparing analgesic potency.
Oxymorphone: Oxymorphone is a semisynthetic
μ-opioid agonist 1.2 times as potent as morphine.77 Until recently, oxymorphone was available as parenteral
injection and in suppository form; however, immediate-release and long-acting oral formulations were developed that make oxymorphone another option for
treating moderate to severe pain. Trials in malignant
and nonmalignant pain confirm its potential as another step 3 option.77 Oxymorphone is more lipid soluble
than morphine. The oral bioavailability of oxymorphone is approximately 10%, which is the lowest of the
oral step 3 opioids.77 In healthy volunteers, the half-life
ranges from 7.2 to 9.4 hours. The half-life of immediate-release oxymorphone is longer than that of morphine, hydromorphone, and oxycodone.78 Immediaterelease oxymorphone tablets may be given at 6-hour
intervals, whereas the extended-release formula is
dosed twice daily. Steady-state conditions are achieved
after 3 to 4 days. Oxymorphone is subject to hepatic
first-pass effects and is excreted by the kidneys. Oxymorphone accumulates in renal failure. Oxymorphone
has a prolonged half-life in renal failure.79 In the setting
of hepatic insufficiency, increasing the dosing interval
is recomended.80
Sloan et al81 conducted a pilot study comparing
extended-release oxymorphone and controlled-release
oxycodone in 86 study patients with moderate to severe cancer pain. The tolerability and safety profiles
(eg, nausea, drowsiness, somnolence) were similar
between the 2 drugs, and no significant differences in
daily pain intensity scores were seen between extended-release oxymorphone and oxycodone.81
Fentanyl: Fentanyl, a lipid-soluble, synthetic opioid, is available as parenteral, transdermal, and transmucosal products. Its lipophilic properties allow it to
October 2015, Vol. 22, No. 4
cross both the skin and oral mucosa.82 The transdermal formulation delivers fentanyl from the reservoir
into the stratum corneum where it then slowly diffuses
into the blood. Another formulation on the market is a
matrix-delivery system in which fentanyl is dissolved
in a polyacrylate adhesive. This formulation can be
cut.83 Both the reservoir and matrix-based patches
have similar kinetics and clinical effectiveness.83 Fentanyl is metabolized to norfentanyl under the influence
of CYP3A4.84 The concomitant use of fentanyl with
potent CYP3A4 inhibitors (eg, ritonavir, ketoconazole)
may affect its metabolism. Fentanyl is safe to use in patients with renal failure.60 The elimination half-life of
transdermal fentanyl is approximately 12 hours. Conversions to fentanyl are made by calculating the MEDD
and the using the ratio of 2 mg:1 µg to reach the starting fentanyl dose.82 Most experts do not recommend
using transdermal fentanyl for acute titration.85,86 Compared with morphine, constipation is less frequent
with fentanyl.87 Comparisons between morphine and
transdermal fentanyl have shown equal analgesic efficacy.88 When compared with morphine, daytime
drowsiness and interference with daytime activity occur at lower rates.88
The oral transmucosal administration of fentanyl
has been extensively explored. In 1 study, 25% of the delivered drug was transmucosally absorbed, with another
25% delivered through the gastrointestinal tract.82 Randomized controlled trials of oral transmucosal fentanyl
citrate show increased analgesic efficacy and patient
preference over placebo and morphine.89,90 Administration of fentanyl is being explored through other routes
(eg, intranasal).91 Rapid intravenous administration of
fentanyl in the emergency department can result in rapid improvement in pain control.92
Buprenorphine: Buprenorphine is emerging
as another option for cancer pain. Well-known as a
strong analgesic, the development of a transdermal
formulation makes it a possible option for cancer
pain.93,94 Buprenorphine is also available in intravenous and sublingual formulations, with the sublingual formulation having a bioavailability of 50% to
65% and a half-life of more than 24 hours.95 After application of the transdermal formulation, plasma concentrations steadily increase. The larger-dose transdermal formulations achieve the minimum effective
therapeutic dose sooner.
Open-label, randomized, parallel-group, multipledose pharmacokinetic studies show that the minimum
effective concentrations are reached after 31, 14, and 13
hours, respectively, with the 35, 52.5, and 70 mg/hour
patches (not available in the United States).96 Patches
reach steady state after the third consecutive application.97 Bioavailability of the transdermal formulation is
60% compared with the intravenous route.98 Effective
plasma levels occur within 12 to 24 hours and last for
October 2015, Vol. 22, No. 4
72 hours. It takes 60 hours to reach Cmax. After patch removal, concentrations decrease to one-half in 12 hours,
then more gradually decline.96
Metabolism by CYP3A4 and CYP2C8 converts
buprenorphine to an active metabolite, norbuprenorphine, which is a weaker but full-opioid agonist. Buprenorphine and its metabolite later experience glucuronidation.99 Liver disease affects buprenorphine
metabolism. With involvement of both cytochrome
oxidase system and glucuronidation in metabolism,
severe liver disease potentially inhibits formation
of norbuprenorphine through effects on the cytochrome oxidase system. Liver disease does not affect
glucuronidation as much. Buprenorphine is safe to
use in the presence of mild to moderate liver failure
as well as in the setting of renal insufficiency and
dialysis.94,100
Buprenorphine produces adverse events similar
to other step 3 opioids and include constipation, urinary retention, sedation, and cognitive dysfunction.
Buprenorphine causes less nausea than transdermal
fentanyl.101
Three phase 3, placebo-controlled studies of
mixed study populations with cancer evaluated transdermal buprenorphine for cancer pain.102-104 In these
studies, buprenorphine acted as an opioid agonist.
There was no dose ceiling or opioid antagonist activity.
Levorphanol: Levorphanol is a potent opioid
considered to be similar to methadone.105 Morphologically similar to morphine, levorphanol has strong affinity for μ, δ, and κ opioid receptors.106 Levorphanol
is a noncompetitive NMDA receptor antagonist and
blocks NMDA with the same potency as ketamine.107
Levorphanol can be orally, intravenously, subcutaneously, and intramuscularly administered.108 Levorphanol has poor absorption via the sublingual route compared with other opioids such as morphine sulfate
(18%), buprenorphine (55%), fentanyl (51%), and methadone (34%).109 The pharmacokinetics of levorphanol
are similar to methadone with a duration of analgesia
ranging from 6 to 15 hours and a half-life as long as
30 hours.110 First-pass metabolism produces a 3-glucuronide metabolite, which may have neurotoxicity.110
Metabolites of levorphanol are renally excreted. The
high volume of distribution and increased protein
binding suggest that levorphanol should not be dialyzable. In the setting of renal disease, the dosing interval should be increased. This differs from methadone.
The predominant mode of metabolism is hepatic. In
the setting of hepatic insufficiency, it is advisable to
consider an increased dosing interval.108 Experience
and clinical trial results suggest that the type and incidence of adverse events are similar to those seen with
strong opioids.108 Levorphanol has been studied as a
treatment for chronic neuropathic pain and has been
shown to be effective.111
Cancer Control 417
Interventional Pain Modalities
Clinicians consider “step 4” of the WHO pain ladder
when there is an inadequate response to step 3 agents,
adjuvants, or both.112 Treatment options include use of
nerve blocks, as well as spinal administration of local
anesthetics, opioids, and other adjuvants. Abdominal pain may be controlled by a blockade of the celiac plexus, which, if successful, can block nociceptive
input from many structures in the upper abdomen, in
particular the pancreas.113 Use of the superior hypogastric ganglion block for the treatment of malignant pelvic pain was first described by Plancarte et al.114
Opioids
Receptor Interactions
Opioids interact with opioid receptors to produce analgesia (as well as adverse events).115,116 Opioids interact with receptors, leading to receptor phosphorylation
by G protein-coupled receptor kinases. Arrestin then
binds with the activation of distal pathways.117 Opioids
intracellularly drive receptors by endocytosis, with
the receptors ultimately resurfacing.117 Opioids differ
in their G protein coupling and in their propensity to
drive receptors into the cell. For example, compared
with other strong opioids, morphine is inefficient in
its ability to promote receptor internalization.117 Some
postulate that noninternalized receptors continue to
signal and promote adaptive responses, thus causing
cellular tolerance.117
Responsiveness
Opioid responsiveness is the “degree of analgesia
achieved as the opioid dose is titrated to an endpoint,
defined either by intolerable side effects or the occurrence of acceptable analgesia.”118 Pain poorly responsive to opioids exists when intolerable adverse events,
inadequate analgesia, or both continue despite opioid
escalation. Pharmacodynamic and nonpharmacodynamic factors affect opioid responsiveness. Identifying pain poorly responsive to opioids should lead the
health care professional to consider using adjuvant
analgesics or opioid switching, changing the route of
administration, using NMDA antagonists, or interventional pain techniques.113,119-121
Routes of Administration
Opioids are available in many dosage forms, including
via the oral, rectal, subcutaneous, intramuscular, intravenous, transdermal, transmucosal, and intraspinal
routes of administration. Oral administration is simple,
cost effective, and is the preferred route of delivery.
Both immediate-release and extended-release preparations are available.
Clinicians use the subcutaneous, intravenous, rectal, transdermal, transmucosal, and intraspinal routes
when patients cannot take oral medications. Intramus418 Cancer Control
cular administration is contraindicated as it does not
confer any pharmacokinetic advantages and is painful for patients.122 Subcutaneous delivery is relatively
easy, effective, and safe.123 Intravenous routes are useful when pain is severe or pain levels have acutely increased. Transdermal fentanyl preparations are effective for patients unable to take oral medications and
have stable pain control. Other short-acting opioids
are used to control pain when transdermal fentanyl
is used, because levels of fentanyl gradually increase
during a 12- to 24-hour period until reaching steady
state.124 Transmucosal fentanyl is similar to intravenous
administration in its rapid onset, and it can be used for
acute breakthrough pain. Historically, dosing of transmucosal fentanyl was not thought to be based on dose
proportionality, but this consideration has been challenged.125 Intraspinal administration of opioids can either be epidural or intrathecal. This method is the most
invasive technique and requires a specialist for initiation. This delivery confers advantages in patients with
significant dose-limiting adverse events as systemic involvement is circumvented. Intraspinal delivery allows
the addition of adjuvant medications to opioids that
can be directly administered to the spinal cord.126
Dose Titration
Clinicians adjust opioid analgesics to balance adequate
pain control with their respective adverse events. Dosage requirements change with cancer progression.
Most patients with cancer have chronic daily pain, so
analgesics should be given on a scheduled basis.121
Breakthrough analgesics are ideally given according
to the time it takes to reach C max. The C max depends
on the route of administration. Cmax is 1 hour for the
oral route, 30 minutes for the subcutaneous route, and
6 minutes for the intravenous route.127,128 Once Cmax is
reached, another dose should be given if pain is not
adequately controlled.
Multiple approaches to opioid initiation and titration exist. The European Association for Palliative
Care recommends dose titration with immediaterelease oral morphine every 4 hours, with breakthrough dosing of the same dose given every hour
as needed.129 The scheduled dose should then be
adjusted to account for the oral MEDD. Several studies have shown acceptable pain control and adverseevent profiles with use of 5 mg every 4 hours in study
patients naive to opioids and 10 mg every 4 hours in
patients previously using a step 2 drug.129-131 After acceptable pain control occurs, patients can use extended-release preparations as this is convenient and improves compliance.132 Breakthrough dosing is 10% to
20% of the MEDD.133
Opioid titration with sustained-release formulations is slower than titration with immediate-release
formulations.129 Titration with intravenous medications
October 2015, Vol. 22, No. 4
is effective and tolerated.134 In patients on established
opioid regimens, dosing adjustment should be made
according to the level of pain. Adult cancer pain guidelines recommend an increase of 25% to 50% in the total
MEDD for moderate pain (4–6 out of 10) and 50% to
100% for severe pain (7–10 out of 10).133
Equianalgesic Conversions
When converting between opioids, equianalgesic
guidelines should be followed, although they may be
modified according to clinical judgment with regard to
adequacy of a patient’s current pain medication regimen.135 Opioid rotation may be secondary to poor analgesia, excessive adverse events, convenience, or patient
preference.136 Incomplete cross tolerance is a phenomenon that has been empirically observed.135 For various
reasons, patients may develop less of a response (eg,
poor analgesia, adverse events) to a particular opioid
over time. Patients may not show these characteristics
with a new opioid, despite similar action between opioids, and slight variations in opioid structures may account for this.137 When calculating the dose of the new
opioid, new doses should be reduced by 25% to 50% to
account for non–cross tolerance.133 This is not done for
fentanyl or methadone, and equianalgesic guidelines
should not to be used for these calculations.
Adverse Events
The development of adverse events varies between individuals based on age, comorbidities, stage of illness,
and genetic differences.116 Impaired renal function also
increases the risk of adverse events due to accumulation of active metabolites.116 The most common adverse
events include constipation, nausea, vomiting, and altered cognition.116 Other adverse events may include
xerostomia, urinary retention, respiratory depression,
myoclonus, pruritus, and hyperalgesia.116 Most adverse events from opioid use subside within days to
weeks, except for constipation for which patients do
not develop tolerance and is not dose-related. For those
symptoms that persist or are present during the initiation of opioid therapy, symptom management is a key
element of care. Constipation is prophylactically managed. Opioids inhibit gastrointestinal peristalsis; thus,
all patients should receive a stimulant laxative such as
senna, which can be combined with a stool softener
such as docusate sodium or polyethylene glycol. Dietary recommendations, such as increasing fiber in the
diet, are unrealistic in patients with advanced disease
because hydration is necessary to facilitate the action
of fiber, often something difficult to achieve in ill patients.126 Constipation is exacerbated by metabolic
abnormalities, including diabetes, hypercalcemia, hypokalemia, and hypothyroidism, that should be corrected if possible.116 Increased physical activity is often
helpful if possible. Use of quaternary opioid antagoOctober 2015, Vol. 22, No. 4
nists may be needed.116 The quaternary agents do not
cross the blood–brain barrier and do not reverse the
analgesic effects of opioids. Nausea frequently occurs
at the start of opioid therapy but seldom persists. Ongoing nausea may occur with advanced disease or as a
complication of disease treatments. Opioids can cause
nausea through several mechanisms, either through
direct stimulation of the chemoreceptor trigger zone,
increased sensitivity of the vestibular apparatus, or
delayed gastric emptying.116 Management consists of
therapies targeting these processes. Dopamine antagonists, such as prochlorperazine or haloperidol, work
on the chemoreceptor trigger zone. Antihistamines
or anticholinergics can be used in patients who have
nausea associated with movement. Metoclopramide
is both a dopamine antagonist and promotility agent
commonly used for the treatment of nausea in palliative care. Ondansetron, a serotonin receptor antagonist, is also a first-line agent for the management
of nausea.116,138 If sedation and altered sensorium are
present, then management should include evaluation
for other sources such as dehydration, drug interactions, or disease progression. Studies have investigated use of stimulants such as methylphenidate and
modafinil with varying results.139,140
If excessive adverse events limit pain control or
impair quality of life, opioid rotation is often effective at achieving greater pain control with less adverse
events.136 In addition, this method of adverse-event
management is preferable in patients for whom polypharmacy is a concern. Based on pharmacodynamic
studies, dose-response relationships exist for central
nervous system effects, such as sedation, myoclonus,
and delirium, and may improve with dose reduction.116
Treating Neuropathic Pain
Although adjuvant analgesics are often used in neuropathic pain, health care professionals should consider
opioids as another option for neuropathic pain. Opioids are recommended as part of neuropathic pain algorithms.141
Adjuvant Analgesics
Adjuvant analgesics are drugs with a primary indication other than pain that have analgesic properties.142
The group includes drugs such as antidepressants, anticonvulsants, corticosteroids, neuroleptics, and other
drugs with narrower adjuvant functions. Adjuvant analgesics are particularly useful when evidence of decreased opioid responsiveness is present.
Tricyclic Antidepressants and Selective Serotonin
Reuptake Inhibitors
The tricyclic antidepressants have been studied for use
in neuropathic pain syndromes, although study results
are conflicting about their analgesic effectiveness.143-145
Cancer Control 419
Use in the elderly may also be problematic due to adverse events, including orthostatic hypotension and sedation.146 Tricyclic antidepressants should also be cautiously used in patients with coronary artery disease or
cardiac rhythm disorders, as well as those with a history of narrow anterior eye chambers or glaucoma. The
anticholinergic properties of these drugs contribute to
delirium in the elderly or anyone at risk for delirium
such as patients whose cancer has metastasized to the
central nervous system. These drugs should be started
at the lowest dose with cautious escalation. Dose escalations are made every 3 to 4 days if analgesic response
is suboptimal.
Selective serotonin reuptake inhibitors (SSRIs)
have a limited role as adjuvants, although paroxetine
and citalopram have been evaluated for nonmalignant neuropathic pain.147,148 No studies have been
performed on cancer pain. Some SSRIs have unique
mechanisms of action that may make them useful for
cancer pain; for example, venlafaxine, which inhibits
the uptake of serotonin and norepinephrine (important in the regulation of descending pain pathways),
is effective for painful neuropathy and neuropathic
pain associated with therapy used in breast cancer.148,149 Newer drugs, such as duloxetine, can be
used to inhibit the uptake of norepinephrine, which
is also effective in neuropathic pain, especially related to chemotherapy.150 Bupropion, a noradrenergic
compound, has both analgesic and activating properties and can be effective in patients with depressionand significant neuropathic pain.151
Corticosteroids
Corticosteroids can be used for patients with bone
pain and to decrease swelling in the brain and spinal cord due to metastatic disease. Nerve root inflammation responds to corticosteroids. Corticosteroids
are often considered for painful liver metastasis and
obstruction of the ureter, although the evidence base
for this use is not strong.152 The most commonly used
corticosteroid is dexamethasone, which has low mineralcorticoid properties. Optimal dosing for palliation
may be 8 mg as this dose has no more adverse events
than placebo.153 In the case of spinal cord compression, recommendations exist for either high-dose
(96 mg/day) or low-dose (16 mg/day) dexamethasone.154 The challenge with the higher dose of steroids is the occurrence of adverse events.155 The management of edema associated with brain metastasis
can be treated with dexamethasone 4 to 6 mg every
6 hours with a taper during the last phases of palliative radiation therapy. The minimal effective dose for
brain metastasis is 8 mg/day.156 Steroids can be useful to counteract the phenomenon of radiation “flare,”
which can occur with radiation therapy when radiation is applied to painful bony sites.157
420 Cancer Control
Anticonvulsant Drugs
Anticonvulsants can be used for managing neuropathic pain.158 The most often used anticonvulsant for
neuropathic pain is gabapentin. Gabapentin is effective for cancer-related neuropathic pain.159 Gabapentin can have significant adverse events if it is started
at too high a dose or titrated too fast. Dosing begins
at 150 mg to 300 mg at bedtime, with escalations every 3 days if pain control is suboptimal. The maximum
dose is 3600 mg/day. The chief adverse event is somnolence.160 Gabapentin must be dose adjusted for renal insufficiency. Anoother anticonvulsant that may
be useful for cancer pain is phenytoin.161 Agents such
as lamotrigine, oxcarbazepine, pregabalin, topiramate
and levetiracetam have been used for nonmalignant
neuropathic pain and are considerations in the refractory case, but they have not been studied in the cancer
pain population. Levetircetam requires further study
for cancer-related neuropathy.162 Lamotrigine is not effective in chemotherapy-related neuropathy.163
Oral and Parenteral Local Anesthetics
The most common parenteral anesthetic used for
symptom management is lidocaine.164 Studies suggest
its efficacy in refractory cases of neuropathic pain.
One study in patients with cancer with refractory
pain showed improved analgesia with a single dose
of lidocaine.165 The recommended starting dose is
1 to 5 mg/kg infused for 20 to 30 minutes. In patients
who are frail, lower doses may be needed. Lidocaine
should be avoided in patients with coronary artery
disease. One potential benefit of lidocaine is prolonged pain relief that occurs following its infusion.
Lidocaine can be given subcutaneously in the home
or hospice setting.166 Mexililetine, an oral cogener of
lidocaine, has been used after lidocaine infusions.167
Clinical trial results suggest that mexiletine has a distinct adverse-event profile and may not be tolerated
by all patients.168
Transdermal Analgesics
Transdermal lidocaine (5% patch) provides another route for local anesthetics. It can be used to treat
postherpetic neuralgia, but use in other settings requires further study to clarify its role in cancer-related
neuropathy. The patch has minimal systemic absorption, and it can be applied 12 hours per day; evidence
suggests that increasing the number of patches and
extended dosing periods may be safe.169,170 It may take
several weeks to observe a maximal effect. The most
frequently reported adverse events are mild to moderate skin redness, rash, and irritation at the patch application site.105
Ketamine
Chronic pain is associated with central nervous system
October 2015, Vol. 22, No. 4
changes, including activation of the NMDA receptor,
and can lead to opioid tolerance and the development
of opioid resistance.171 Pharmacological blockade of
the NMDA receptor offers a therapeutic approach in
the setting of opioid resistance. Ketamine is a useful
NMDA antagonist to consider in the management of
cancer pain and its use often leads to reduced opioid
requirements.172 Given at subanesthetic doses (< 1 mg/
kg), ketamine is an effective analgesic in cancer-related neuropathic pain.172 Multiple routes exist for administration and include the oral, intravenous, subcutaneous, and topical routes. Ketamine is metabolized
via CYP3A4. No significant drug interactions have
been reported.173 Ketamine is recommended by the
WHO for the management of refractory pain.174 The
oral bioavailability is 17%, and onset of action of ketamine is 15 to 20 minutes. The half-life of ketamine is
2.5 to 3 hours. Ketamine has protein binding of 20% to
30%.175 Pharmacologically, no major differences exist
in the characteristics between the isomers.176 Its intravenous onset of action is within seconds and, subcutaneously, the onset of action is 15 to 20 minutes. The
half-life is 2 to 3 hours for both routes.173 The results of
1 trial of subcutaneous ketamine as an add-on option
to opioids showed no efficacy in cancer-related nociceptive pain.177
Cannabinoids
Formulations of cannabinoids, the cannabinoid extracts,
have been studied for cancer-related pain.178 Johnson
et al179 evaluated tetrahydrocannabinol (THC)/cannabidiol (CBD) in a 2-week, multicenter, double-blind,
randomized, placebo-controlled, parallel-group trial of
177 study patients with cancer whose pain was inadequately controlled despite them being on opioid therapy. The cannabinoid extract contains THC 2.7 mg and
CBD 2.5 mg per dose.179 It is formulated in ethanol/propylene glycol with peppermint flavoring and is designed
as a pump spray for self-administration and titration via
the oromucosal route.180 The study patients received
THC/CBD, THC extract, or placebo and continued
their previous analgesics.179 The THC/CBD extract arm
achieved a statistically significant improvement in pain
when compared with placebo (P < .024) as measured
on a numerical rating scale, a primary end point of the
study.179 The THC extract showed no significant changes
from baseline compared with placebo.179
Neuroleptics
Second-generation (atypical) agents, such as olanzapine, have been shown to have antinociceptive activity
in animal models.181 Clinical evaluation of its analgesic effects has been limited. Khojainova et al182 evaluated the analgesic activity of olanzapine in 8 study patients with severe cancer pain who did not respond to
increased opioid dosing and who also received olanOctober 2015, Vol. 22, No. 4
zapine for the treatment of associated anxiety and mild
cognitive impairment. Participants did not meet diagnostic criteria for delirium and the cognitive impairment was classified as not otherwise specified.182 Study
patients received 2.5 to 7.5 mg of olanzapine daily, and
their pain intensity, sedation, and opioid consumption measurements were made before administering
olanzapine and 2 days after olanzapine was given.182
Cognitive function was assessed daily.182 All participants experienced reduced pain scores, and the average daily opioid use significantly decreased in all study
patients.182 Cognitive impairment and anxiety resolved
within 24 hours of initiating olanzapine.182 The authors
suggested that olanzapine may have an intrinsic analgesic action, but they also suggested that pain scores
and opioid requirements may have resulted from improvement in cognitive function and the known anxiolytic effect of olanzapine.182
Agents Specifically Used for Bone Pain
Bone pain is a common problem in the palliative care
setting. Radiation therapy can be effective with localized pain. Systemic therapies with NSAIDs, corticosteroids, bisphosphonates, and radiopharmaceuticals can
be useful for patients with multifocal lesions.
Bisphosphonates: Bisphosphonates are analogues of inorganic pyrophosphate that inhibit osteoclast activity and can be useful in many types of cancer in which bone resorption leads to complications.
Bisphosphonates bind to calcium on bone, become
ingested by osteoclasts, and then subsequently kill osteoclasts, thus preventing bone resoprtion.183 The end
result of decreased osteoclast activity is increased bone
stability and reduced pathological fractures. The most
potent bisphosphonate is zoledronic acid, which has
been shown to reduce pain and the occurrence of skeletal-related events in breast and prostate cancers, multiple myeloma, and a variety of solid tumors, including
lung cancer.184-187 Denosumab is useful when renal insufficiency precludes the use of bisphosphonates.188
Radiopharmaceuticals: Radionuclides are agents
absorbed in areas of metastatic cancer activity. Strontium-89 and samarium-153 are effective for diffuse
bony metastatic disease, such as in the case of prostate
cancer.189
Muscle Relaxants
Pain originating from connective tissue injury is common in patients with cancer. However, use of muscle
relaxants as adjuvant agents has not been evaluated in
patients with cancer.
Use for Malignant Bowel Obstruction
Pain, along with nausea and vomiting, is a common
symptom associated with malignant bowel obstruction. Nonsurgical management of malignant bowel obCancer Control 421
struction focuses on the management of pain and other obstructive symptoms, such as distension, nausea,
and vomiting. The use of parenteral opioids, antiemetics, and antisecretory agents, such as octreotide, are
common methods of pharmacological symptom control. Octreotide has anecdotally been shown to have
analgesic properties.190
Combination Use
The treatment of neuropathic pain frequently requires
several adjuvants. For example, it is not unusual for a
patient with severe, cancer-related neuropathic pain
to require an opioid or several additional adjuvants.
When this occurs, the clinician should monitor the patient for potential drug interactions.191
Conclusions
Successful cancer pain management requires close
attention to detail, particularly when introducing
the drug; in addition, health care professionals must
be watchful for the presence of adverse events. Assessing opioid responsiveness will help determine
the role of adjuvant analgesic use. Adherence to the
World Health Organization pain ladder and understanding proper use of interventional pain techniques
complements the pharmacological management of
cancer-related pain. New drugs are being introduced
into the market and their roles in cancer-related pain
control are being evaluated.
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placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. J Clin Oncol.
2012;30(29):3611-3617.
178. Johnson JR, Potts R. Cannabis-based medicines in the treatment
of cancer pain: a randomised, double-blind, parallel group, placebo controlled, comparative study of the efficacy, safety and tolerability of Sativex
and Tetranabinex in patients with cancer-related pain. British Pain Society;
March 8–11, 2005; Edinburgh, Scotland.
179. Johnson JR, Burnell-Nugent M, Lossignol D, et al. Multicenter,
double-blind, randomized, placebo-controlled, parallel-group study of the
efficacy, safety, and tolerability of THC: CBD extract and THC extract in
patients with intractable cancer-related pain. J Pain Symptom Manage.
2010;39(2):167-179.
180. Perez J. Combined cannabinoid therapy via an oromucosal spray.
Drugs Today (Barc). 2006;42(8):495-503.
181. Schreiber S, Getslev V, Backer MM, et al. The atypical neuroleptics
clozapine and olanzapine differ regarding their antinociceptive mechanisms and potency. Pharmacol Biochem Behav. 1999;64(1):75-80.
182. Khojainova N, Santiago-Palma J, Kornick C, et al. Olanzapine in the
management of cancer pain. J Pain Symptom Manage. 2002;23(4):346-350.
183. Prommer EE. Toxicity of bisphosphonates. J Palliat Med. 2009;
12(11):1061-1065.
184. Rosen LS, Gordon D, Kaminski M, et al. Zoledronic acid versus
pamidronate in the treatment of skeletal metastases in patients with breast
cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind,
comparative trial. Cancer J. 2000;7(5):377-387.
185. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94(19):1458-1468.
186. Berenson JR, Lichtenstein A, Porter L, et al. Efficacy of pamidronate
in reducing skeletal events in patients with advanced multiple myeloma.
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187. Rosen LS, Gordon D, Tchekmedyian S, et al; Zoledronic Acid Lung
Cancer and Other Solid Tumors Study Group. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer
and other solid tumors: a phase III, double-blind, randomized trial. J Clin
Oncol. 2003;21(16):3150-3157.
188. Prommer E. Palliative oncology denosumab. Am J Hospice Palliat
Care. 2015;32(5):568-572.
189. Lewington VJ, McEwan AJ, Ackery DM, et al. A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89
in pain palliation in patients with advanced prostate cancer metastatic to bone.
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190. Penn RD, Paice JA, Kroin JS. Octreotide: a potent new non-opiate
analgesic for intrathecal infusion. Pain. 1992;49(1):13-19.
191. Bernard SA, Bruera E. Drug interactions in palliative care. J Clin
Oncol. 2000;18(8):1780-1799.
October 2015, Vol. 22, No. 4
Cancer Control 425
Pharmacogenomic data may help guide
treatment options for opioid use in patients
with cancer-related pain, but test results
should be available at the point of care.
Photo courtesy of Lisa Scholder. Greener Pastures. 16" × 22".
Clinical Implications of Opioid Pharmacogenomics
in Patients With Cancer
Gillian C. Bell, PharmD, Kristine A. Donovan, PhD, and Howard L. McLeod, PharmD
Background: Pain can be a significant burden for patients with cancer and may have negative effects on their
quality of life. Opioids are potent analgesics and serve as a foundation for pain management. The variation
in response to opioid analgesics is well characterized and is partly due to genetic variability.
Methods: We reviewed the results of clinical studies to evaluate the relationships between genetic variants
and select genes involved in the pharmacokinetics and pharmacodynamics of opioids, with an emphasis on
patients with cancer.
Results: In patients with cancer-related pain, genetic variation in OPRM1, COMT, and ABCB1 is associated
with response to morphine, which is the most well-studied opioid. Although it has not been studied in patients
with cancer-related pain, the effect of CYP2D6 variation is well characterized with codeine and tramadol.
Evidence is limited for associating the genetic variation and pain response of oxycodone, hydrocodone, and
fentanyl in patients with cancer.
Conclusion: The clinical availability of pharmacogenomic testing and research findings related to these polymorphic genes suggest that genotyping patients for these genetic variants may allow health care professionals
to better predict patient response to pain and, thus, personalize pain treatment.
Introduction
Pain is one of the most burdensome symptoms associated with cancer and its treatment and is estimated
to affect 49% to 57% of patients with curable cancer
From the DeBartolo Family Personalized Medicine Institute (GCB,
HLM) and the Departments of Population Sciences (GCB, HLM)
and Supportive Care Medicine (KAD), H. Lee Moffitt Cancer Center
& Research Institute, Tampa, Florida.
Submitted June 18, 2015; accepted September 8, 2015.
Address correspondence to Gillian C. Bell, PharmD, Mission Health,
Fullerton Genetics Center, 9 Vanderbilt Park Drive, Asheville, NC
28803. E-mail: Gillian.Bell@msj.org
Dr McLeod has disclosed that he is a consultant for Cancer Genetics.
No significant relationships exist between the other authors and
the companies/organizations whose products or services may be
referenced in this article.
Dr Bell is now affiliated with Mission Health, Personalized Medicine
Program, Asheville, North Carolina.
426 Cancer Control
and 56% to 75% of patients with advanced disease.1-3
Uncontrolled pain can have significant adverse effects on function, mood, sleep, and quality of life, and
studies suggest that pain is an independent prognostic factor for overall survival in cancer.4-7 A study of
2,761 patients with cancer reported that one-third of
patients with initial pain had a significant reduction
in pain at 1 month and one-fifth had an increase in
pain scores.8 Opioids are the most potent analgesics
available and remain the cornerstone of clinical pain
management.9 The choice of opioid analgesic depends on a number of medical and nonmedical factors.10 Nonopioid and co-analgesics (eg, nonsteroidal
anti-inflammatory drugs), as well as nonpharmacological measures, are often used to improve analgesic
control, reduce opioid requirements, or both, as well
as minimize adverse events related to opioid use.11 ReOctober 2015, Vol. 22, No. 4
gardless of the analgesic type, effective pain management depends on achieving a favorable balance between adequate analgesia and adverse events.
It is well documented that patients vary considerably in their response to pain therapies, including
medication.12 Response in analgesia and to adverse
events may vary between patients with similar pain
levels or disease status and may vary among patients
at different stages of the care trajectory.9,10,13 Increasingly, research has been aimed at identifying the
hereditary basis for interindividual differences in
drug effects to explain altered efficacy and adverse
events.12 Currently, genetic factors may be responsible for 12% to 60% of response variability in opioid
therapy.14 Using genetic variation to help guide drug
therapy choices may be helpful in balancing the exclusion of low-yield therapy, avoiding adverse events,
and achieving pain control.
Genes Modulating Opioid Response
Many genes have been studied to identify pharmacogenomic markers in opioid therapy, including genes
implicated in the pharmacodynamics (OPRM1, COMT)
and pharmacokinetics (CYP2D6, CYP3A4/5, ABCB1)
of opioids.14,15
Pharmacokinetics
Transporters
One of the most studied transporters in opioids is a
member of the adenosine triphosphate–binding cassette, sub-family B, member 1 (ABCB1), also known
as P-glycoprotein or multidrug resistance protein 1.
ABCB1 transporters are present in numerous locations, including the gastrointestinal tract, liver, kidneys, and the blood–brain barrier, and they facilitate
the absorption, distribution, and elimination of medications, including opioids such as morphine and fentanyl and their metabolites.15 Impairment of these
transporters may result in increased bioavailability of
oral medications, decreased renal excretion, and increased central nervous system concentrations.16
Specifically, the transport of opioids into the brain
through the blood–brain barrier may be affected by
variations in ABCB1 transporters at this site. ABCB1
is highly polymorphic, with more than 100 single nucleotide polymorphisms (SNPs) identified, but C3435T
(rs1045642) is the most widely studied. The 3435T variant is associated with decreased mRNA expression,
protein expression, or both in some tissues.14 Although
the results have been mixed, several studies report a
difference in pain relief and opioid doses between reference and variant genotypes.16-18
Cytochrome P450 Enzymes
Cytochrome P450s are a gene superfamily of catalytic proteins that fill important roles across the specOctober 2015, Vol. 22, No. 4
trum of cellular biochemical reactions, including
endogenous hormone production and xenobiotic
metabolism. This includes the activation of many opioids from a relatively inert compound to a pharmacologically active molecule. The enzyme CYP3A4 plays
a role in the metabolism of numerous medications,
including many opioids (eg, methadone, oxycodone,
hydrocodone, fentanyl), but few studies link genetic variations to opioid response.14 The cytochrome
P450 enzyme 2D6 (CYP2D6) influences the metabolism of 25% of all drug therapies, including codeine,
hydrocodone, oxycodone, and tramadol, as well as
tricyclic antidepressants.12,19 Genetic variation in the
CYP2D6 enzyme is one of the most studied and wellunderstood of all the drug-metabolizing enzymes.20
The effect of variation on phenotype is typically
classified into 4 major groups: poor metabolizers
(5%–10%), intermediate metabolizers (2%–11%), extensive metabolizers (77%–92%), and ultra-rapid metabolizers (1%–2%).21 These percentages are based on
data for whites and will vary for other ethnicities.21
Reports of therapeutic failure (lack of pain control,
opioid-related adverse events, or both) in patients
with specific genotypes receiving select opioids (codeine, hydrocodone, oxycodone, tramadol, fentanyl,
methadone) suggest a significant impact of CYP2D6
genetic variants on drug efficacy and adverse-event
profile.12,22 In addition, CYP2D6 metabolizer status
becomes particularly important when concomitant
medications affecting other pharmacokinetic pathways are used. Serious or fatal, inadvertent codeine
overdose can occur when a patient with cancer and
CYP2D6 ultrarapid metabolizer status is also treated
with CYP3A4 inhibitors, such as clarithromycin and
voriconazole.23 The “double hit” of hyperactivation to
morphine via CYP2D6 and the reduced inactivation
due to blocked CYP3A4 leads to life-threatening respiratory depression.24
Pharmacodynamics
OPRM1
The µ-opioid receptor gene encoded by the genetic
locus OPRM1 is the primary binding site for endogenous opioid peptides and opioid analgesics.12 As such,
OPRM1 is a biologically plausible candidate for evaluating the role of polymorphism in the clinical effects
of opioids.19 More than 100 SNPs have been described
for OPRM1.25 The most prevalent and widely studied
SNP is a nonsynonymous nucleotide substitution at
position 118 (A118G; rs1799971). The frequency of
this SNP widely varies among different races and ethnicities: 4.7% in Africans, 15.4% in Europeans, 48.5%
in Japanese, and 14% in Hispanics.26 To assess the
possible functional effect of each allele of this gene,
persons are identified by 1 of 3 genotypes: homozygous G/G, homozygous A/A, or heterozygous G/A.
Cancer Control 427
This SNP has been associated with variation in opioid
response in a number of settings, including cancerrelated pain.27 Numerous studies have examined the
relationship of OPRM1 genetic variants to pain control in the oncology setting with mixed results.17,28-31
variant in relation to pain response, adverse events,
or both in patients with cancer and have had mixed
results.15 Other variants commonly studied include
COMT Val158Met and ABCB1 C3435T.15
One study evaluated the relationship of 4 OPRM1
polymorphisms and pain control in 207 study patients
with cancer pain.29 A total of 99 volunteers who completed the Brief Pain Inventory (BPI) survey and had
adequate pain control were included in the final analysis.29 The A118G variant alone was related to morphine
dose. Participants with G/G genotype (225 ± 143 mg/24
hours) required significantly higher doses of morphine
when compared with participants with wild-type A/A
(97 ± 89 mg/24 hours) and A/G (66 ± 50 mg/24 hours)
COMT
COMT encodes an enzyme involved in the metabolism
of catecholamines, including epinephrine, norepinephrine, and dopamine, which play a role in pain modulation.32 Impairment of the catechol-O-methyltransferase
(COMT) enzyme, which results in increased concentrations of dopamine, can suppress the production of
endogenous opioids (eg, enkephalin), which, in turn,
cause subsequent opioid receptor expression upregulation.16
Table. — Summary of Select Genetic Variants Associated
The COMT gene locus contains
With Response in Cancer Pain
multiple SNPs; the most studied
SNP is Val158Met, also known as
Opioid
Study
Genetic
No. of
Results
Agent
Variant
Patients
rs4680.33 It has been postulated
that this polymorphism leads to a
Fentanyl
ReyesOPRM1 A118G
695
No difference in dose requirements for
Gibby 28
all variants
3- to 4-fold reduced activity of the
COMT Val158Met
COMT enzyme and has been assoABCB1 C3435T
ciated in patients with cancer with
CYP3A5*3
60
Greater central adverse events with
Ross 36
*3/*3 genotype
increased sensitivity to painful
ABCB1 C1236T
stimuli (for the Val/Val genotype)
COMT Val158Met
221
No difference in central adverse events
Morphine
Belfer 33
and with lower doses of morphine
(confusion, drowsiness, hallucination)
ABCB1 C3435T
required for satisfactory relief
Other COMT and ABCB1 variants
associated with central adverse events
of pain (for the Met/Met geno156
No difference in response
Branford27 OPRM1 A118G
type).28,33-35 Variation in COMT may
also affect unwanted effects of opi99
Patients with G/G genotype required
Kasai and OPRM1 A118G
higher doses of morphine when comIkeda 26
oid treatment such as sedation.36
pared with A/G and A/A genotypes
A limited number of studies
16
OPRM1 A118G
137
Patients with OPRM1 A/A identified as
Lotsch
have examined the relationship
having good responses indicated by
ABCB1 C3435T
of variants in these genes to pain
decrease in numerical rating scale
control in cancer, and nearly all
Presence of ≥ 1 OPRM1 G allele were
of these studies have involved the
found have worst response regardless
of ABCB1 genotype
acute postoperative period with
Patients with OPRM1 A/A and ABCB1
outcomes related to cancer recurT/T best responders with greatest
rence and progression.12,27 Few
decrease in scores
studies have involved patients
207
Patients with OPRM1 A/A and COMT
Ravindra- OPRM1 A118G
with cancer, and patient-reported
Met/Met combined required lowest
nathan25
COMT Val158Met
morphine dose when compared with
pain outcomes in relation to these
other combinations of genotypes
genetic variants and pain relief is
OPRM1 A118G
827
No difference in dose requirements for
Reyessparingly used.15 Commonly used
all variants
Gibby 28
COMT Val158Met
opioids in patients with cancer
ABCB1 C3435T
and the genetic variants reportCOMT Val158Met
207
Patients with Val/Val genotype
Ross 31
ed to modulate response are rerequired higher dose of morphine comviewed in the Table.14,16,25-28,31,33,36
pared with Val/Met and Met/Met
Pharmacogenomics
Morphine
Because the µ-opioid receptor is
the main site of action for morphine, numerous studies have
evaluated the OPRM1 A118G
428 Cancer Control
Oxycodone
Hajj14
CYP2D6
450
No difference in pain intensity or
adverse events (nausea, sedation,
cognition) between metabolizer status
ReyesGibby 28
OPRM1 A118G
COMT Val158Met
ABCB1 C3435T
445
No difference in dose requirements for
all variants
October 2015, Vol. 22, No. 4
genotypes.29 Those with the A/G genotype also had the
highest average BPI scores, a finding pointing to the
possible undertreatment of pain, which might explain
the lower doses administered to those with that genotype.29 In addition, the authors found no differences in
adverse-event intensity between the groups.29
A subsequent study reanalyzed the same 207
volunteers to look for a relationship between the
COMT variant Val158 Met polymorphism and morphine requirements.34 In this study, all participants
were included in the analysis. Those with the Val/Val
genotype received the highest dose of morphine
(155 ± 160 mg/24 hours) followed by those with the
Val/Met genotype (117 ± 100 mg/24 hours) and the
Met/Met genotype (95 ± 99 mg/24 hour; P = .025).34
Reyes-Gibby et al28 conducted a secondary analysis combining the results of the above-mentioned studies in the same patients to explore the joint effects of
COMT Val158Met and OPRM1 A118G variants on the
efficacy of morphine for cancer pain. Carriers of both
wild-type OPRM1 A/A and COMT Met/Met genotypes
had the lowest morphine dose (87 mg/24 hours; 95%
confidence interval [CI]: 57–116), which significantly
differed from study participants with neither Met/Met
nor A/A who had the highest dose (147 mg/24 hours;
95% CI: 100–180).28 After controlling for demographic
and clinical variables, such as age, sex, time from cancer
diagnosis, and months using morphine, the joint-effect
results remained.28
Campa et al17 evaluated the relationship of
OPRM1 A118G and ABCB1 C3435T variants to pain
response in 137 study patients with cancer receiving
treatment with morphine. Pain response was measured using an 11-point numerical rating scale (NRS)
and the main end point was a change in NRS at the
end of the first 7 days.17 At the end of the first 7 days,
study patients with wild-type OPRM1 A/A genotype
had a significantly greater change in NRS score (3.73;
standard deviation [SD] ± 1.72) when compared with
homozygous-variant study patients (0.30; SD ± 1.77).17
In addition, study patients with ABCB1 T/T genotype
had a significantly greater change in NRS score (4.39;
SD ± 2.21) than homozygous wild-type study patients
(2.31; SD ± 1.73).17 Multivariate analysis assessed the
joint effects of variation in the 2 genes. Study patients
with at least 1 OPRM1 variant were the worst responders regardless of ABCB1 genotype; conversely,
study patients with wild-type OPRM1 A/A genotype
had a good response.17 Study patients with wild-type
OPRM1 A/A and homozygous-variant ABCB1 T/T
genotype were the best responders, with an NRS
score of 4.8 ± 1.62.17
Some studies report lack of association with numerous genetic variants.30,31,36 An observational, single
time point trial with 156 study patients with cancer
found no association with the OPRM1 A118G variant
October 2015, Vol. 22, No. 4
and response to morphine.30 This study evaluated numerous genetic variants in 4 genes (OPRM1, ARRB2,
STAT6, and UGT2B7) and consisted of morphine responders (controlled on morphine for ≥ 1 month) and
nonresponders (switched alternative agents due to inadequate analgesia with titrated doses or intolerable
adverse events).30 No association was found with variants in OPRM1 and UGT2B7, but numerous variants in
the other 2 genes were associated with response.30 One
of the largest trials to date evaluated the influence of 112
genetic variants of 23 candidate genes on the efficacy of
numerous opioids in 2,201 study patients with cancer: morphine (n = 827), oxycodone (n = 445), fentanyl
(n = 695), and other opioids (n = 234).31 All drug doses
were converted to equivalent morphine doses and pain
intensity was measured using the BPI.31 Klepstad et al31
noted that all SNPs, including OPRM1 A118G, ABCB1
C3435T, and COMT Val158Met, failed to show a relationship with opioid dose. A case-control study of 221 participants with cancer treated with morphine reported
no association with COMT Val158Met or ABCB1 C343T
variants and the central adverse events of confusion,
drowsiness, and hallucination.36 Of note, other variants in COMT and ABCB1 were associated with central adverse events.36 Because of these conflicting
data, concluding whether these variants predict
morphine analgesia or adverse events is difficult.
The most benefit will likely be derived from combining these markers to identify patients with a poor-response profile for which an alternative therapy may
be preferred.
Codeine
The analgesic properties of codeine are derived from its
conversion to morphine and morphine-6-glucoronide
by CYP2D6 (Fig).21 Persons who are CYP2D6 poor
metabolizers have little or no CYP2D6 enzyme activity
and will not attain a meaningful degree of pain control. An important safety concern is that persons with
extra copies of CYP2D6 convert codeine to morphine
to a greater extent and may be at risk for adverse
events such as sedation and even respiratory depression.21 The results of numerous studies (mainly in
patients without cancer) suggest a difference in analgesia and adverse effects across CYP2D6 metabolizer
statuses and these differences have been highlighted
in a peer-reviewed guideline by the Clinical Pharmacogenetics Implementation Consortium.21 Therefore,
CYP2D6 testing is useful in determining which patients
will derive the most benefit from codeine use as well as
patients who may be at increased risk for toxicity.
Tramadol
Similar to codeine, CYP2D6 is responsible for the
conversion of tramadol to O-desmethyltramadol,
which has a 200-fold greater affinity for the µ-opioid
Cancer Control 429
UGT1A1
UGT2B7
Codeine
CYP2D6
UGT1A1
UGT2B7
Morphine
CYP2D6
Oxycodone
Noroxycodone
CYP2D6
Fentanyl
Tramadol
Hydromorphone
CYP3A4
CYP3A4/5
CYP2D6
Morphine-3-glucoronide
Oxymorphone
CYP3A4
Hydrocodone
Morphine-6-glucoronide
Norhydrocodone
Norfentanyl
O-desmethyltramadol
Fig. — Metabolic pathways of commonly used opioids.
receptor target (see Fig).21 Several studies have reported that CYP2D6 poor metabolizers display decreased
analgesic response with tramadol than those who are
extensive metabolizers.37-39 No studies have focused
on the pharmacogenomics of tramadol specifically in
a cancer population; however, given the evidence in
other pain populations, tramadol is likely to have reduced clinical benefit in patients who poorly metabolize CYP2D6.37-39
Oxycodone
The majority of oxycodone is metabolized to noroxycodone by CYP3A4 (see Fig).40 A smaller percentage
(11%) is converted by CYP2D6 to the active metabolite oxymorphone, which has a 40-fold higher affinity
and 8-fold higher potency for μ-opioid receptors than
oxycodone.21 Studies evaluating CYP3A4 variation to
oxycodone response are scarce, whereas studies in
healthy volunteers and postoperative patients have reported mixed results on CYP2D6 polymorphisms and
response to oxycodone.15 In a cross-sectional study of
450 study patients with cancer treated with oxycodone,
Andreassen et al22 reported no difference in pain intensity using the BPI or the incidence of adverse events
430 Cancer Control
(nausea, sedation, cognitive) between CYP2D6 metabolizer statuses.
In the large study of 2,201 study patients with
cancer being treated with various opioids, including
445 of whom were treated with oxycodone, Klepstad
et al31 could not determine an association with OPRM1,
ABCB1, and COMT variants (as well as numerous
other genes) and opioid requirements. Based on this
evidence, little basis exists for the use of pharmacogenomics to personalize the use of oxycodone therapy in
patients with cancer.
Hydrocodone
Hydrocodone is metabolized by CYP2D6 to the active
metabolite hydromorphone, which has a 10- to 33-fold
greater affinity for μ-opioid receptors than hydrocodone (see Fig).40 Additional metabolism includes the
formation of norhydrocodone by CYP3A4, and 40%
of clearance is attributed to non-CYP pathways.40 No
studies have focused on the pharmacogenomics of hydrocodone specifically in a cancer population. Thus,
little basis exists for the use of pharmacogenomics to
personalize the use of hydrocodone therapy in patients
with cancer.
October 2015, Vol. 22, No. 4
Fentanyl
Fentanyl is primarily metabolized by CYP3A4/5 to the
inactive metabolite norfentanyl (see Fig).15 Most of the
current literature assessing the effect of CYP3A4/5
on pain outcomes involves the postoperative patient
population, and a robust association has not yet been
discovered.15 Klepstad et al 31 studied 2,201 volunteers with cancer being treated with various opioids,
including 695 of whom were treated with fentanyl,
and found no association with OPRM1, ABCB1, and
COMT variants (as well as numerous other genes) and
opioid requirements.31 A small trial of 60 Asian study
patients with cancer who were treated with transdermal fentanyl reported more and greater-intensity
central adverse events with patients homozygous for
CYP3A5*3 when compared with patients with *1/*1
and *1/*3 genotypes.41 The authors also studied
3 ABCB1 variants (C1236T, G2677A/T, and C3435T),
and C1236T alone was associated with response with
decreased administration of rescue medication reported in the homozygous T/T variant.41 To date, the
utility of CYP3A4/5 and ABCB1 testing to personalize
fentanyl dosing is uncertain.
Implementation in Clinical Practice
The clinical availability of pharmacogenomics testing
and the research findings related to these polymorphic genes suggest that genotyping patients for some
of these genetic variants may help predict response
to pain treatment with good rates of sensitivity and
specificity and with greater benefits for patients and
decreased health care utilization.17 One key element of
using pharmacogenomics for the treatment of cancer
pain is employing a preemptive testing strategy so the
results will be available at the point of care. It is crucial
to have information on individual patient pharmacogenomics at the time of a care decision so that the data
can be used to guide therapeutic decision-making. As
part of this preemptive strategy, these results must be
readily retrievable. In addition, use of clinical-decision
support alerts has been shown to inform clinicians of
important genetic results and guide treatment at the
point of care.42
Conclusions
Opioids are heavily used in the treatment of patients
with cancer-related pain, and individual genetic variation affects the pharmacokinetics and pharmacodynamics of opioids.9 The evidence linking commonly
used opioids has been reviewed for patients with cancer and the genetic variants reported to modulate response and results. Although the results seem promising, prospective studies randomizing patients to
genotype-guided pain management compared with
standard practice are needed. In addition, further evaluation of complex interactions (drug–gene–gene and
October 2015, Vol. 22, No. 4
drug–drug–gene) must be explored. If pharmacogenomics data are used to guide treatment decisions,
then a preemptive testing strategy is a key element that
must be included and test results must be available at
the point of care.
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15. Nielsen LM, Olesen AE, Branford R, et al. Association between human pain-related genotypes and variability in opioid analgesia: an updated
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16.Lötsch J, von Hentig N, Freynhagen R, et al. Cross-sectional analysis of the influence of currently known pharmacogenetic modulators on
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17. Campa D, Gioia A, Tomei A, et al. Association of ABCB1/MDR1 and
OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther.
2008;83(4):559-566.
18. Hung CC, Chiou MH, Huang BH, et al. Impact of genetic polymorphisms in ABCB1, CYP2B6, OPRM1, ANKK1 and DRD2 genes
on methadone therapy in Han Chinese patients. Pharmacogenomics.
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codeine therapy: 2014 update. Clin Pharmacol Ther. 2014;95(4):376-382.
22. Andreassen TN, Eftedal I, Klepstad P, et al. Do CYP2D6 genotypes reflect oxycodone requirements for cancer patients treated for
cancer pain? A cross-sectional multicentre study. Eur J Clin Pharmacol.
2012;68(1):55-64.
23. Gasche Y, Daali Y, Fathi M, et al. Codeine intoxication associated with
ultrarapid CYP2D6 metabolism. N Engl J Med. 2004;351(27):2827-2831.
24. Wilkinson GR. Drug metabolism and variability among patients in
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Cancer Control 431
26. Kasai S, Ikeda K. Pharmacogenomics of the human micro-opioid
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October 2015, Vol. 22, No. 4
Communication between patients,
their relatives, and health care
staff is very important when
administered palliative sedation.
Photo courtesy of Lisa Scholder. Organic Walk, 16" × 24".
Palliative Sedation in Patients With Cancer
Marco Maltoni, MD, and Elisabetta Setola, MD
Background: Palliative sedation involves the use of sedative medication to relieve refractory symptoms in
patients by reducing their level of consciousness. Although it is considered an acceptable clinical practice
from most ethical points of view, palliative sedation is still a widely debated procedure and merits better understanding.
Methods: The relevant medical literature pertaining to palliative sedation was analyzed and reviewed from
various technical, relational, and bioethical perspectives.
Results: Proportionate palliative sedation is considered to be the most clinically appropriate modality for
performing palliative sedation. However, guidelines must be followed to ensure that it is performed correctly.
Benzodiazepines represent the first therapeutic option and careful monitoring of dosages is essential to avoid
oversedation or undersedation.
Conclusions: Proportionate palliative sedation is used to manage and relieve refractory symptoms in patients
with cancer during their last days or hours of life. Evidence suggests that its use has no detrimental effect on
survival. A different decision-making process is used to manage the withdrawal of hydration than the process
used to determine whether proportionate palliative sedation is appropriate. Communication between patients,
their relatives, and the health care staff is important during this medical intervention.
Introduction
Within the context of palliative medicine, the practice of drug-induced sedation for symptom control
— the use of all possible antisymptomatic treatments
notwithstanding — is called palliative sedation. Historically, palliative sedation was often known as terminal sedation because it was considered a last reFrom the Palliative Care Unit (MM), Istituto Scientifico Romagnolo
per lo Studio e la Cura dei Tumori, Meldola, Italy, and the Oncology
Unit (ES), Saint Giuseppe Hospital, Milan, Italy.
Submitted April 15, 2015; accepted July 15, 2015.
Address correspondence to Marco Maltoni, MD, Palliative Care
Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei
Tumori, Via P. Maroncelli 40, 47014 Meldola, Italy. E-mail:
marcocesare.maltoni@irst.emr.it
No significant relationships exist between the authors and the
companies/organizations whose products or services may be referenced in this article.
October 2015, Vol. 22, No. 4
sort in the final phase of a patient’s life. However,
terminal sedation is a confusing and inappropriate
term because it implies that the practice is designed
to shorten life; thus, more appropriate terminology
was needed and, hence, the term palliative sedation.
Its implementation into everyday clinical practice has
led to the use of the term in the majority of studies
focusing on this topic.1
By reducing the level of consciousness, palliative
sedation uses sedative medication to control refractory
symptoms in patients with cancer.2 As this approach
became more widespread and was acknowledged as
an important part of palliative care, procedural principles were needed to avoid malpractice. The guidelines
created clarified the definition and practice of palliative sedation, also underlining its inherent and intrinsic difference from euthanasia.3-10 Various guidelines
Cancer Control 433
state that sedation in palliative care is a therapy mainly
performed in the last days or hours of life, with an unambiguous aim, a precise procedure, and well-defined
results — all of which are in contrast to those of euthanasia.9-12 In addition, use of palliative sedation does not
hasten death when conducted in accordance with standard guidelines.13-15
Methods and Types
Some adjunctive characteristics of palliative sedation
have been included in more detailed definitions of the
practice.16 For example, the definition of palliative sedation as the “intentional administration of sedative
drugs in dosages and in combinations required to reduce the consciousness of a terminal patient as much
as necessary to adequately relieve one or more refractory symptoms,” considers a number of specific parameters, including short-term prognosis, proportionality of
the intervention, effectiveness of the sedation through
adequate monitoring, and refractoriness of symptoms.16
This definition also implies that palliative sedation is not
a fixed intervention; rather, it is a dynamic process that
can be adapted to the needs of the patient.16
Palliative sedation can vary in terms of depth of
sedation and correlated level of unconsciousness,
continuity, drugs used, and rapidity of implementation (Table 1). In that sense, palliative sedation is not
necessarily deep continuous sedation or continuous
sedation until death, which is the last step of a progressive process.
“Proportionality” Theme
When symptom-guided, dose-titrated, and result-assessed, palliative sedation can be a progressive or sud-
den procedure (see Table 1). Choice of sedation has a
clinical basis and is oriented toward different clinical
needs: rapid palliative sedation for catastrophic and
acute symptoms compared with proportional sedation
for progressively worsening symptoms. Thus, implementing palliative sedation is based on the suddenness
of symptom appearance.
Different methods of palliative sedation exist,
namely, the proportional method of palliative sedation (also called proportionate palliative sedation),
and sustained, deep and continuous palliative sedation from the onset, regardless of the intensity of
symptoms.17-21 The latter suggests that relational continuity between patients and relatives is not necessarily a value, that the concept of hastening or not
hastening death is irrelevant (given the patient’s condition), and that the process of drug titration may delay the clinical effect of sedation. We consider that
the supporters of this view are in favor of administering drugs in a “standardized” way, which leads to
deep sedation, and interrupting all forms of hydration and nutrition. Taking this concept to an extreme,
many patients in this setting would be candidates for
deep continuous sedation or continuous sedation until death. In our opinion, those in favor of using palliative sedation in this way do not consider that this
view is a departure from the original practice; indeed,
such an approach could be counterproductive to its
large-scale implementation.
By contrast, some proportional palliative sedation supporters view proportionality as a fundamental
characteristic of palliative sedation and maintain that
relational continuity is an important issue.6,14 They also
argue that the effects of palliative sedation on refrac-
Table 1. — Definitions of Terms Used in Palliative Sedation
Term
Definition
Depth
Superficial
Patient conserves (at least partially) the ability to communicate with family or caregivers
Deep
Patient enters a state of total unconsciousness
Continuity
Intermittent
Sedation is performed for a limited period of time for a specific symptom and discontinued if a reduction
(albeit slight) in the distress caused by the symptom has been obtained
Continuous
Drugs are administered without interruption to obtain a persistent effect, which more frequently occurs
near death and in severe cases
Use of Drugs
Primary palliative sedation
Sedatives are used to lower the level of consciousness
Secondary palliative sedation
Dosage of drugs primarily used for symptom control (ie, morphine for pain or dyspnea) is increased to
make use of an adverse event (eg, somnolence) to reduce the level of consciousness (not recommended)
Rapidity of Administration and Effect
Progressive
Most common method in which the dose of sedative drugs is monitored and modified according to patient needs
Sudden, rapid intervention method
Also called “emergency” sedation; required for a catastrophic event such as massive bleeding, severe
dyspnea, agitated delirium, or acute pain
434 Cancer Control
October 2015, Vol. 22, No. 4
Prevalence and Settings
The debates about the characteristics and how to
define palliative sedation are reflected in the wideranging prevalence of the practice observed in the literature (1%–88%),8-10,13 which can be attributed to a
number of factors:
• Different health care settings
Higher prevalence in inpatient acute tertiary palliative care units compared with home-care hospice
programs33,34
• Different case mixes in similar settings
In a comparison between 2 Italian hospices, a statistically significant difference in prevalence of
sedation initially observed in the 2 populations
disappeared when the groups were corrected for
age and duration of stay in hospice. This was interpreted as an indication that younger patients and
those admitted for acute symptoms required more
palliative sedation interventions than older patients
admitted to the hospice for psychosocial reasons35
• Degree of adherence to palliative sedation guidelines
or level of competence and expertise of health care
professionals
Little experience in managing difficult symptoms
may increase the prevalence of palliative sedation. The decision to initiate palliative sedation
should be taken together with a palliative care
specialist to ensure that all other options have
October 2015, Vol. 22, No. 4
been explored.5 In the event of insufficient psychological support, the palliative care team may
be at risk of burn out and, thus, might perform
unnecessary palliative sedation36
• Adoption of wider or narrower definition of palliative sedation may influence prevalence
However, the real frequency of palliative sedation
has also been suggested to vary: possibly between 25%
and 35% of all patients admitted to a hospice or palliative care unit.14,15 In home-care hospice programs, palliative sedation may be a feasible option. Mercadante
et al37 reported that 13.2% of patients with cancer were
sedated in their homes.
Symptoms and Refractoriness Management of refractory symptoms is the single indication for use of palliative sedation.14,27 The definition
of a refractory symptom, which was first proposed by
Cherny and Portenoy,27 is still widely accepted: “Symptom for which all possible treatment has failed, or it is
estimated that no methods are available for palliation
within the time frame and the risk:benefit ratio that the
patient can tolerate.”5,6,8 The concept of refractoriness
has been associated with that of unbearable suffering,
multidisciplinary evaluation, and a prognosis of shortterm survival.7
Prior to offering sedation, all other available medications, procedures, and interventions should be considered and offered as appropriate. When possible,
discussions should take place with patients, their relatives, and their caregivers so that an agreement can be
made about the action to be taken.7-10 All dimensions
of the symptom (physical, psychological, social, emotional, existential/spiritual) must be taken into account and help offered for each component.7-10 Physical
symptoms that are most prone to refractoriness include
delirium and dyspnea; both are frequently present as
death approaches, and their timely management is crucial. Pain and emesis may also become refractory, albeit this occurs less frequently.14,38-41 Palliative sedation
Refractory Symptoms
tory symptoms must be carefully monitored to avoid
undersedation or oversedation and that the drug dosage should be individually titrated to the minimum
effective dose level.6,14 Not every palliative sedation is
deep continuous sedation or continuous sedation until
death, and the latter approach is required in patients
for whom a lower level of sedation is insufficient to
control refractory symptoms.7,22-25 A survey carried out
by Putman et al26 on intention and practice in US physicians reported that many of these physicians preferred
the proportional method, because they did not wish to
pursue full unconsciousness in patients without monitoring the effect of such sedation.
Moreover, some of the first articles published
on palliative sedation were based on the use of a
proportional, clinical, symptom-guided form of sedation.5,6,11,27,28 This form of palliative sedation is accepted by most ethical points of view, cultural perspectives, and procedural guidelines. 8-10,28-32 ten
Have and Welie12 used the term mission creep to describe the intention of shortening life — however
small — by using deep sedation, concluding that such
an approach cannot be considered palliative sedation.
In a clinical context, mission creep occurs when a
specific practice considered appropriate in a given situation is gradually extended for use with different indications, groups of patients, and different intentions.
416 (54%)
Delirium
Dyspnea
Psychological
distress
Pain
Vomiting
Other (eg, itching,
bleeding)
234 (30%)
151 (19%)
135 (17%)
37 (5%)
30 (4%)
0
100
200
300
400
500
Patients
Fig 1. — Main refractory symptoms requiring palliative sedation
in 774 patients from 10 studies with a total of 1,003 symptoms
(some patients had > 1 refractory symptom). From Maltoni M, Scarpi E,
Rosati M, et al. Palliative sedation in end-of-life care and survival: a systematic
review. J Clin Oncol. 2012;30(12):1378-1383. Reprinted with permission.
© 2012. American Society of Clinical Oncology. All rights reserved.
Cancer Control 435
is occasionally used for intractable seizures or terminal
hemorrhage (Fig 1).14,42
Psychological distress and existential suffering are
complex and challenging. These terms encompass issues such as meaninglessness of life, sense of hopelessness, perception of self as a burden to others, feeling dependent on others, feeling isolated, grieving,
loss of dignity and purpose, fear of death of self, or
fear of the unknown. Multidimensional management
directed at the physical, psychological, and existential
aspects is recommended, with support provided by
psychologists, psychiatrists, chaplains, ethicists, or palliative care specialists.3-10
Psychological distress and existential suffering
have many peculiarities.5,8,27 Psychological distress can
occur at any time during the course of a disease, and
supportive interventions, psychological interventions,
or both types of interventions may be ineffective and
do not completely resolve the problem; however, this
does not mean that the distress is refractory.43 Rather,
psychological distress may not have a progressive
course similar to that associated with physical symptoms; its course is often unpredictable. For these reasons, frequent meetings with the palliative care team
are needed; the same may be true of spiritual assistance. Intermittent or relief sedation, rather than continuous sedation, may also be beneficial.5,8,27
Some authors have focused on the search for early
determinants for continuous palliative sedation so that
patients at risk can be identified in a timely manner
and their symptoms managed by other strategies.33,44-46
Information on determinants that more frequently
lead to use of palliative sedation could also be used
to assess the need for advanced care planning. However, study results have suggested that implementing
palliative sedation is more often linked to the attitudes
and beliefs of physicians and to organizational settings
than to the clinical needs of patients.44 Other studies
found a correlation between palliative sedation and
higher doses of opioids used prior to implementing
palliative sedation as well as between palliative sedation and younger patient age.33,45,46
Drugs
The most widely used drug for palliative sedation in
the context of palliative care is midazolam, which
is a benzodiazepine prescribed in 9 of the 11 studies evaluated (Fig 2).3,14 Midazolam is prescribed in
a wide dose range; for example, in 1 study, 61% of
patients used doses no more than 30 mg and 8% of
patients used doses of at least 120 mg.47 The highest
final daily dose of midazolam was correlated with
age (the younger the patient, the higher the dose)
and treatment duration (the longer the treatment, the
higher the dose).47 Midazolam has a rapid onset of
action and short half-life, and both of these pharmacokinetic features facilitate the titration procedure
during the first phase of sedation. When an adequate minimum dose (or, in some settings, a loading
dose) has been identified for symptom control, a
maintenance dose should be started by continuous
intravenous or subcutaneous infusion. Because midazolam has anticonvulsant, muscle-relaxant, hypnotic, and anxiolytic properties, it can be added to other
sedative classes to achieve control of these specific
symptoms.
Some studies advocate use of neuroleptics for delirium (eg, haloperidol).35-37 Haloperidol has less sedating power than midazolam, so it is typically used
to attenuate delirium; thus, it is not the most appropriate choice of drug for achieving continuous sedation. Other drugs used for palliative sedation have included levomepromazine, chlorpromazine (especially
when profound sedation is needed for acute agitated
delirium), propofol, ketamine, and dronabinol.39,48-51
If a patient undergoing sedation is treated with an
opioid for pain or dyspnea, then the opioid must not
be interrupted. By contrast, opioids should not be
used for sedation, because doing so would make use
of their secondary effect (somnolence) and would be
considered secondary palliative sedation, which is
not recommended.3,5,8-10
Duration
436 Cancer Control
191 (26%)
Chlorpromazine
Drug
The mean or median length of palliative sedation
ranges from 0.8 to 12.6 days.12 One study observed
an even larger range (0–43 days), despite mean
and median times in line with the literature (4 and
2 days, respectively).13 In this study, 10.8% of patients underwent palliative sedation for more than
10 days and 3.4% of patients for more than 20 days.13
Patients requiring sedation for more than 10 days
had fewer rates of delirium and dyspnea, milder and
more frequent use of secondary palliative sedation,
and higher rates of psychological distress than their
counterparts.13
362 (49%)
Midazolam
Haloperidol
107 (14%)
Morphine
Methotrimeprazine
Propofol
79 (11%)
22 (3%)
11 (1%)
Phenobarbital
Other
benzodiazepines
5 (1%)
161 (22%)
0
100
200
300
400
Patients
Fig 2. — Sedative drugs administered to 745 patients from 9 studies. From
Maltoni M, Scarpi E, Rosati M, et al. Palliative sedation in end-of-life care
and survival: a systematic review. J Clin Oncol. 2012;30(12):1378-1383.
Reprinted with permission. © 2012. American Society of Clinical Oncology.
All rights reserved.
October 2015, Vol. 22, No. 4
Monitoring
Guidelines for palliative sedation recommend close
surveillance of patients with respect to the management and relief symptoms and suffering, depth of sedation (level of consciousness), and potential adverse
events of sedation.3-10 Family members of patients and
their health care team should be monitored for psychological and spiritual distress.3,5,6,8 Vital signs should be
assessed in nonimminently dying patients undergoing
short-term, intermittent, or light sedation.
Evaluating symptom relief or relief of suffering
in unconscious patients can be difficult. Some scores
monitoring verbal or facial expression, body movements, and response to nonpainful stimuli may be
useful when deep sedation is performed, and some authors have suggested using the level of sedation as a
proxy for evaluating symptoms.3,25,31
Depth of sedation is a common theme in studies
and the tools used to assess it can vary. For example,
guidelines from the European Association for Palliative Care recommend the Critical-Care Pain Observation Tool or the Richmond Agitation-Sedation Scale
(RASS).52,53 A prospective study performed by Arevalo
et al54 evaluated the validity and reliability of 4 scales:
the Minnesota Sedation Assessment Tool, the RASS,
the Vancouver Interaction and Calmness Scale, and
a sedation score proposed by the Royal Dutch Medical Association. The RASS was as reliable as the score
proposed by the Royal Dutch Medical Association
and study results claimed that the RASS was the least
time consuming, clearest, and easiest to use of the
4 tools.54,55 Another study tested a modified form of
RASS (RASS-PAL) for use in patients in the palliative
care unit, observing that the tool was useful for assessing sedation; however, further validation studies are
needed to confirm these results.56
More objective methods to evaluate depth of sedation have been proposed because some sedated patients may continue to experience symptoms without
being able to communicate their distress.57,58 Deschepper57 proposed a mixed-evaluation method that combined use of a scale, a subjective assessment by professionals, as well as neuroimaging, electrophysiological
techniques, or both. However, such an approach is
impractical in end-of-life care and may be more suited to a research setting.57 A systematic review of the
literature revealed that 5 clinical studies and 1 guideline-based article included use of a validated scale to
evaluate the results of palliative sedation.58 During the
titration phase of sedation, clinical parameters should
be evaluated every 15 to 30 minutes, but the exact interval should be calculated on the basis of the drugs,
doses used, and clinical conditions of the patient; once
an appropriate level of sedation has been achieved, the
frequency of assessment can be reduced to once every
24 hours.3 One Cochrane review evaluated the impact
October 2015, Vol. 22, No. 4
of palliative sedation on quality of life and participant
well-being.15 None of the 14 studies included in the review took any of the above issues into consideration.15
The impact on symptoms was partially reported and
with different methods, thus making data pooling impossible.15 Furthermore, the studies reviewed had numerous biases, with the authors concluding that the
data are insufficient and the evidence is of poor quality with regard to the qualitative effectiveness of palliative sedation.15 They also recommended that studies
on palliative sedation focus on qualitative, rather than
quantitative, end points (ie, length of survival from the
start of palliative sedation).15
Impact on Survival
For some, the impact of palliative sedation on survival
is not an issue that merits much attention, given that
the priority of palliative sedation in the end-of-life setting is quality of life; thus, even a detrimental effect
on survival may not be considered of particular relevance.59 By contrast, some physicians may consider it
fundamental to know whether the sedation proposed
has a high, medium, or low risk of hastening the death
of their patient.14 However, this question cannot be
studied with the highest evidence-based methodology.
Although the authors of the Cochrane review were unable to pool data on qualitative outcomes of palliative
sedation, they did provide reasonably good, quantitative evidence that palliative sedation does not have a
detrimental impact on survival.15 The authors looked
at 14 studies involving 4,167 adults — nearly one-third
of whom were sedated.15 Survival time measured from
admission or referral to death was not statistically significant between those who were sedated and those
who were not.15 A prospective study of patients admitted to hospices matched patients who were sedated
and those who were not for sex, age, reason for admission, performance status, and prognostic score.13 Survival from admission to death was compared between
the 2 groups and no detrimental effect of palliative sedation on survival was found.13 Of note, even intensive
procedures, deep continuous sedation or continuous
sedation until death, did not hasten death when performed in a proportional, step-by-step manner.13 A
subsequent systematic review also identified 11 studies
totalling approximately 2,000 patients.14 No difference
in survival was seen between patients receiving hospice care who underwent sedation (median, 7–27 days)
and those who did not (median, 4–40 days).14
Such results confirm that palliative sedation can
be considered a legitimate clinical intervention from
most ethical viewpoints and that the principle of double effect is unnecessary to justify its practice. This
ethical criterion is appropriate in a small percentage
of patients receiving sedation in whom respiratory or
circulatory function depression is recorded following
Cancer Control 437
palliative sedation (3%–4%) and hypothesized as having potentially hastened death.60 In that sense, it may
be appropriate to consider this effect a serious adverse
event, which could occur after any medical or surgical
procedure.
Ethical Considerations
If a survival impact of palliative sedation was ever
demonstrated, then palliative sedation might have
been equated with “slow” or “soft” physician-assisted
suicide; however, absence of a detrimental impact on
survival is sufficient to distinguish palliative sedation
from physician-assisted suicide. The European Association for Palliative Care has identified 3 areas in which
palliative sedation differs from euthanasia11:
• The intention of palliative sedation is to provide
relief from unbearable suffering caused by a refractory symptom, whereas euthanasia is designed to end the life of someone who is suffering.
• Palliative sedation is a proportionate and symptom intensity–guided procedure using the minimum useful dose of a sedative drug (eg, a benzodiazepine); it is individually oriented and
monitored. Conversely, euthanasia uses neuromuscular relaxants and barbiturates and is not
monitored on the basis of the symptom relief obtained.61,62
• Success of palliative sedation is measured in terms
of the relief it provides from distress.
Although palliative sedation does not play a role in
hastening death, its use prevents many patients from
maintaining verbal contact with their relatives, which
makes it unique among medical interventions.63 Injudicious uses of palliative sedation include inadequate
assessment of potentially reversible causes of severe
symptoms, lack of involvement of specialists in the
condition underlying the presenting symptoms, excessive use by overwhelmed health care professionals,
performing the procedure at the request of the relatives, and untimely start (ie, too early, too late).6,12,60
Although some may view palliative sedation, deep
continuous sedation, or continuous sedation until
death as bringing patients to a sort of “living dead-like”
state in which they are no longer considered persons,
it is our opinion that patients who are sedated can be
talked to, wanted, cared for, and loved by their relatives, sometimes “answering” with their presence in
surprising and unexpected ways.22,28 The “innate” core
of personhood (“individual component”) has been suggested to persist even after relational and societal components are severely reduced.29
Nutrition and Hydration
Those who believe that palliative sedation plays a role
in hastening death may place most of the responsibility for this “secondary effect” on the simultaneous in438 Cancer Control
terruption of artificial nutrition and hydration — both
of which are considered medically assisted treatments
or as vital support interventions, at least in this patient
setting. However, medically assisted hydration is a topic more often discussed, given that artificial nutrition
may be interrupted prior to palliative sedation due to
its proven lack of impact on the duration and quality of
life of patients with a terminal disease.61-66 The role of
hydration in end-of-life care is subject to different perspectives and is widely discussed in the literature.64 In
certain situations, excess hydration can lead to water
retention and exacerbation of pleural or peritoneal effusion, among other problems; by contrast, interrupting liquids may provoke thirst and an increase in drug
metabolites, worsening delirium, and agitation, thus
making it difficult for patients to communicate distress.65 Thus, maintenance or withdrawal of hydration
must be individually evaluated and managed.
Results from a large epidemiological study on
20,480 questionnaires completed by physicians experienced in deep continuous sedation or continuous sedation until death showed that, even in this “extreme”
form of sedation, up to two-thirds of patients continued hydration for clinical reasons.66 The take-home
message is that use of palliative sedation and evaluation of whether or not to continue hydration involve
2 different decision-making processes. Thus, hydration
does not have to be automatically stopped because palliative sedation has begun.
Communication and Decision-Making
Process
Talking about death with patients and their families is
a delicate and challenging aspect of palliative care. Ideally, discussions of this kind should be initiated when
a patient’s prognosis is years to months and then reevaluated when the patient’s life expectancy decreases to months to weeks.9 The conversation should be a
balance between maintaining hope and realistic and
achievable goals.6,67 Health care professionals must
plan these end-of-life interventions by taking into account the goals, values, needs, and wishes of the patient. Patients should be asked where they prefer
to die so that adequate plans can be made to respect
their request. All decisions should be documented in
the patient’s medical records.9 When a health care professional recognizes the imminence of suffering, he
or she should discuss the possibility of sedation with
the patient, outlining the aims, risks, and benefits of
the procedure. The patient may not want to broach the
subject and may authorize the health care professional
to make decisions on his or her behalf or delegate a
caregiver to do so. If the patient is no longer capable of
making an autonomous decision, then the health care
professional may approach a family member or a surrogate decision maker to clarify the patient’s wishes.6
October 2015, Vol. 22, No. 4
A multidisciplinary team of oncologists, palliative
care specialists, psychologists, psychiatrists, nurses,
chaplains, or spiritual advisors, among others, may
also form the decision-making group, together with
the patient and his or her family.5 In particular, such
a team can help ensure that all conditions have been
met for palliative sedation, that informed consent
is obtained, that the type of intervention has been
planned, and then modify any plans, when and if necessary, during the course of sedation. Further therapeutic interventions may also be performed if other
conditions arise (eg, urinary retention, constipation,
myoclonus, “death rattle”).
Keeping an open dialog with relatives and the
patient’s loved ones throughout the palliative sedation process is fundamental so that they understand
the characteristics of this medical intervention (ie, it
is performed in the absence of other means to manage refractory and unbearable symptoms; it neither
hastens nor postpones death; it reduces or eliminates
the possibility of verbal communication with patients;
clinical conditions permitting, it is reversible in nature; it is carefully monitored to avoid oversedation
or undersedation; it is performed for the well-being of
patients).68,69
Although some relatives experience psychological
distress, Bruinsma et al69 reported that most are comfortable with palliative sedation if they are appropriately informed about the procedure and actively involved
in the decision-making process. A study of Swiss caregivers of patients who died while undergoing palliative
sedation found that most caregivers agreed about the
timing of the initiation of palliative sedation and confirmed that it led to a substantial improvement in refractory symptoms.70 In a small study of Dutch relatives
of patients receiving palliative sedation until death,
many of the relatives acknowledged that palliative sedation was indicated, but they felt that communication
between the health care professionals and the relatives
was poor.71
Although an open dialog between the health care
team, the patient, and his or her family members and
loved ones is important, we do not feel that such open
communication is always respected. In an Italian study
of communicative behavior in 2 different hospice settings, family involvement in the decision-making process with regard to palliative sedation was 100% in
both hospices, but the rate of patient participation in
such decision-making varied from 24% to 59%.35 Another study of Dutch and US physicians revealed that
open discussion among physicians, patients, and families was more diffuse in The Netherlands than in the
United States.72 However, the study involved too few
cases to conclude that an international difference exists when communication about sedation due to different cultural approaches.72 In a group of 27 sedated
October 2015, Vol. 22, No. 4
patients, a Portuguese case study determined that the
decision to begin sedation was made by health care
professionals alone in 21 cases.38 The authors attributed this result to the fact that 76% of study patients
required urgent and nonpostponable sedation.38
Nurses also play an essential role in the decisionmaking process. A survey of 576 nurses from The
Netherlands showed that most responders had cared
for at least 1 patient who received palliative sedation.73
Nearly all of the nurses indicated that they had been
involved in the decision to perform palliative sedation
and were present when palliative sedation was started,
unlike the physicians who were present in fewer than
50% of cases.73 A study of Flemish nurses also revealed
that the majority of the nurses supported use of palliative sedation for refractory symptoms.74 Patel et al75
studied the attitudes and perspectives of nurses working with patients receiving palliative sedation in 3 different settings (oncology, intensive care, and hospice),
highlighting their ability to define palliative sedation,
their skill set for administering palliative sedation, policy, and procedural guidelines, and their education on
palliative sedation and end-of-life care.
Guidelines
Many clinical associations and international agencies
have produced procedural guidelines for use of palliative sedation so as to provide health care professionals
with a framework on which to base the clinical decision-making process.3-10 Key issues in palliative sedation were also addressed in a 10-item framework created by the European Association for Palliative Care
(Table 2).5,6 An audit performed in a single center to assess adherence to guidelines on palliative sedation in
Table 2. — European Association for Palliative Care
10-Item Framework for Guidelines in Palliative Sedation
Need for preemptive discussion of potential role of sedation in
end-of-life care and contingency planning
Description of when sedation is indicated
Description of necessary evaluation and consultation procedures
Indications for informed consent requirements
Indications for need to discuss decision-making process with
patient’s family
Indications for selecting method of sedation
Indications for dose titration, patient monitoring, and care
Indications for decisions regarding hydration, nutrition, and
concomitant medications
Indications for needs of the patient’s family
Support for medical and nursing staff
From Cherny NI; ESMO Guidelines Working Group. ESMO clinical
practice guidelines for the management of refractory symptoms
at the end of life and the use of palliative sedation. Ann Oncol.
2014;25(suppl 3):iii143-11152. Reprinted by permission of Oxford
University Press.
Cancer Control 439
a palliative care unit confirmed an adherence rate of
100%.76 Conversely, a survey of Dutch general practitioners revealed a high resistance to following guidelines, and this was particularly true with regard to the
inadvisability of using palliative sedation without previous expert consultation and to the recommendation
of the involvement of a multidisciplinary palliative care
team.5,77 Without such an approach, misconceptions
about palliative sedation may be further misconstrued
and perpetuated.
Conclusions
Some patients with cancer experience refractory symptoms during the last hours or days of their life and are
no longer responsive to antisymptomatic treatments.
Managing such symptoms is the objective of palliative
sedation, a proportional medical approach that must
be individually tailored to each patient and closely
monitored.3-10 Undersedation and oversedation can be
avoided by titrating the level of sedating drugs to the
minimum useful dose (termed proportionate palliative
sedation). A different approach involving standardized
drug dosages and deep continuous sedation or continuous sedation until death risks being performed with
the total or partial intention to hasten death.3-10 However, palliative sedation should only be used in a proportional way; such a view has been accepted by many
bioethical viewpoints.
Although evidence suggests that proportionate
palliative sedation does not have a detrimental impact
on survival, further research is needed to monitor the
qualitative results of the procedure.14,15 Benzodiazepines — in particular, midazolam — are the first choice
of drugs for this type of sedation. The decision-making
process to initiate proportionate palliative sedation is
complex and should involve patients, their relatives
and loved ones, and the health care team. This process varies from those used for other clinical decisions
such as maintenance or withdrawal of artificial nutrition and hydration. Proportionate palliative sedation is
a universally accepted medical intervention that differs
from physician-assisted suicide in terms of intention,
procedure, and results.
Acknowledgments: The authors thank Gráinne
Tierney and Ursula Elbling for editorial assistance.
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Cancer Control 441
Progress has been made in recent
years for integrating psychosocial
care into routine cancer care,
but more work is needed.
Photo courtesy of Lisa Scholder. Seizing the Light. 16" × 20".
Integrating Psychosocial Care Into Routine Cancer Care
Paul B. Jacobsen, PhD, and Morgan Lee, MA
Background: Despite growing recognition that psychosocial care is an essential component of comprehensive
cancer care, evidence suggests many patients with cancer do not receive needed psychosocial care.
Methods: Four areas were identified as potentially increasing the number of patients with cancer who receive
needed psychosocial care: (1) formulating care standards, (2) issuing clinical practice guidelines, (3) developing and using measurable indicators of quality of care, and (4) demonstrating projects designed to improve
the delivery of care.
Results: Standards for psychosocial care are identified, including a standard issued in 2015 by an accrediting organization. Three clinical practice guidelines for provisioning psychosocial care are also identified
and reviewed. Methods for monitoring the quality of psychosocial care are characterized and the impact
of monitoring changes in quality are evaluated in relation to existing evidence. Examples are provided of
2 large-scale efforts designed to improve the delivery of psychosocial care in community settings.
Conclusions: Although considerable progress has been made in integrating psychosocial care into routine
cancer care, work must still be done. Additional progress will be fostered by continued efforts to promote
adherence to clinical practice guidelines and care standards for psychosocial care and by the development
and dissemination of models that demonstrate how practices can implement these guidelines and standards.
Introduction
Recognition is growing that psychosocial care is an essential component of the comprehensive care of people diagnosed with cancer.1,2 In addition to attempting
to extend survival rates in people following a cancer
diagnosis, the oncology community is recognizing the
value of quality of life. Psychosocial care, with its goals
of relieving emotional distress and promoting wellFrom the Department of Health Outcomes and Behavior (PBJ), H.
Lee Moffitt Cancer Center & Research Institute, and the Department
of Psychology (ML), University of South Florida, Tampa, Florida.
Submitted April 8, 2015; accepted July 15, 2015.
Address correspondence to Paul B. Jacobsen, PhD, 12902 Magnolia Drive, Tampa, FL 33612. E-mail: Paul.Jacobsen@Moffitt.org
No significant relationships exist between the authors and the
companies/organizations whose products or services may be referenced in this article.
442 Cancer Control
being, is central to efforts to improve quality of life.2
However, evidence suggests that many patients with
cancer who might benefit from psychosocial care do
not receive it.2
Four areas of activity have the potential to increase
the number of patients who receive needed psychosocial care:
1. Formulating care standards that address the
psychosocial component of care
2. Issuing clinical practice guidelines for the psychosocial care of patients with cancer
3. Developing and using measurable indicators
of quality of psychosocial care in oncology
settings
4. Demonstrating projects designed to promote
the greater implementation of standards for
psychosocial care
October 2015, Vol. 22, No. 4
Definitions
Standards in medical care refer to diagnostic or treatment processes that health care professionals should
follow for certain classes of patients, illnesses, or clinical circumstances. Standards may be developed based
on evidence, expert consensus, and/or ethical and
safety considerations. With regard to the psychosocial
domain, standards of care represent recommendations
for the organization and delivery of psychosocial care
that apply to patients seen in the oncology setting.
Clinical practice guidelines are systematically developed statements designed to assist health
care professionals and patients in making decisions
about appropriate health care based on specific
characteristics of the patient (eg, age, comorbidities),
illness (eg, disease severity), or clinical circumstances (eg, symptom presentation). Similar to standards,
clinical practice guidelines can be developed based
on evidence, expert consensus, and/or ethical and
safety considerations.
In general, measuring the quality of care involves
assessing the extent to which an organization and delivery of care conforms to standards of care and clinical practice guidelines. A widely used model dating
from the 1960s differentiates 3 components important
to consider in evaluating quality, namely: (1) the structure of care (eg, resources or personnel), (2) the processes of care (eg, performance of specific diagnostic
procedures or treatments), and (3) outcomes of care
(eg, survival rates).3 Methods for assessing the quality
of psychosocial care have primarily focused on evaluating processes of care.
Table. — Select Standards for Psychosocial Care
of Patients With Cancer
Professional
Group
American College
of Surgeons
Commission on
Cancer 5
Specifies standards for organizing, delivering,
and monitoring of oncology services
Presented as requirements evaluated during
accreditation review
Key example of standards for psychosocial care:
• Cancer committee develops and implements
a process to integrate and monitor on-site
psychosocial distress screening and referral
for psychosocial care
Canadian
Association
of Psychosocial
Oncology4
Specifies standards of care for organizing and
delivering psychosocial health services
Presented in sections (key principles,
organization and structure, educational
standards for providers, standards of care)
Key examples of standards for psychosocial
care:
• People at risk for or living with cancer are
entitled to psychosocial screening using
a standardized approach
• People affected by cancer are entitled
to access appropriate levels of treatment
to address their needs
Institute
of Medicine2
Specifies standards for providing appropriate
psychosocial services
Presented as processes and goals of care
Key examples of processes and goals
of psychosocial care:
• Facilitate effective communication between
patients and health care professionals
• Identify psychosocial health needs of
each patient
• Design and implement a plan to link
patient with needed services
• Follow-up on, re-evaluate, and adjust plan
National
Comprehensive
Cancer Network 6
Specifies standards of care for distress
management
Presented as imperatives focused on distress
management
Key examples of standards for distress
management:
• Distress should be recognized, monitored,
documented, and promptly treated
• Screening should identify the level and
nature of distress
• Distress should be assessed and managed
according to clinical practice guidelines
• Interdisciplinary institutional committees
should be formed to implement
standards for distress management
• Experienced licensed mental health
professionals and certified chaplains should
be available as staff members or by referral
Standards
Efforts to promote greater awareness of the importance of psychosocial care for patients with cancer received a boost following a 2008 publication from the
Institute of Medicine (IOM) summarizing evidence
regarding the deleterious effects of unmet psychosocial needs and benefits of providing psychosocial services.2 Despite evidence supporting the effectiveness
of psychosocial services, the IOM concluded that many
patients do not receive help for problems that might
benefit from this type of care.2 To address this problem, the report included a list of recommended actions,
including that all entities establishing or using standards for the quality of cancer care adopt a standard
that calls for the provision of appropriate psychosocial
health services.2 The recommendation further identifies certain processes and goals of care as being components of this standard (Table).2,4-6
Several initiatives predate the IOM report in proposing standards that address psychosocial care. For
example, the National Comprehensive Cancer Network
(NCCN) included standards of care as part of its clinical practice guidelines for the management of cancerOctober 2015, Vol. 22, No. 4
Summary and Comments
related distress first published in 1999.7 In addition to
identifying policies and procedures related to screening for and managing distress, the NCCN standards
call for the formation of interdisciplinary committees
Cancer Control 443
at each institution to implement guidelines for distress
management and for the availability of trained, on-site
professionals or by referral to deliver psychosocial care
(see Table).2,4-6
Initiatives promoting standards for the psychosocial care of patients with cancer are not limited to the
United States. For example, the Canadian Association
of Psychosocial Oncology developed standards in
1999 and updated them again in 2010.4,8 In addition to
identifying procedures for psychosocial screening and
treatment, these standards cover the organization and
structure of psychosocial services and the education
and training of psychosocial care providers.4
Most standards for psychosocial care are developed by organizations and committees composed of
members of the psychosocial oncology clinical and
research communities. Thus, concerns exist about the
extent to which the wider oncology community has
been cognizant of these standards and has adopted
them.9 Efforts to promote the adoption of such standards would benefit patients if major accrediting organizations included psychosocial care among their
standards.
One such organization is the American College of
Surgeons (ACS) Commission on Cancer (CoC), which
is a consortium of 47 professional organizations.­10 The
ACS CoC establishes cancer care standards and monitors the quality of care at approximately 1,500 hospitals, which are estimated to provide care to 70% of
patients with cancer in the United States.10 In 2012,
the ACS CoC released several standards for patientcentered care.5 Among them is a standard specifying
that a local oversight committee should develop and
implement a process for psychosocial distress screening and referral for psychosocial care (see Table).2,4-6
These standards are being evaluated in 2015 as part of
the ACS CoC accreditation process.11
Clinical Practice Guidelines
Worldwide, numerous organizations have proposed
clinical practice guidelines that include recommendations for the psychosocial care of people with cancer.12
For brevity, only the details of 3 North American–
based guidelines for psychosocial care will be covered
in this article.
National Comprehensive Cancer Network
Clinical practice guidelines from the NCCN for distress
management were first issued in 19997; they are updated every year and include recommendations for psychosocial screening, evaluation, treatment, and followup primarily presented in the form of algorithms or
decision pathways.6 Most of the recommendations represent uniform consensus among experts from NCCN
member institutions based on lower-level evidence
(eg, clinical experience of expert providers) rather than
444 Cancer Control
higher-level evidence (eg, results of randomized controlled trials).
Recommendations for the management of mood
disorders (eg, major depression) help illustrate how the
clinical practice guidelines are organized. For example,
the NCCN guidelines recommend that all patients undergo brief psychosocial screening for distress using
a valid and reliable self-report tool.6 The importance
of systematic screening is underscored by research indicating that oncologists typically underestimate the
level of distress in their patients.13-15 For patients who
have moderate to severe distress, referral to psychosocial care professionals is recommended.6 If patients are
displaying signs and symptoms of a mood disorder, the
initial recommendation is further evaluation, diagnostic studies, and modification of the factors potentially
contributing to the symptoms (eg, concurrent medications, pain).6 Based on these findings, subsequent recommendations may include initiating psychotherapy
and antidepressant medication, possibly in combination with anxiolytic medication. Consideration of referral to social work or chaplaincy services is also recommended before follow-up and re-evaluation.6
Pan-Canadian
In 2010, the Canadian Partnership Against Cancer
and the Canadian Association of Psychosocial Oncology jointly issued the Pan-Canadian guidelines based
on methodology developed by the ADAPTE Collaboration.16 Development of the guidelines began with
a systematic search to identify other relevant guidelines, systematic reviews, and guidance documents —
a process that led to the formulation of a guideline
presented in the form of recommendations (accompanied by information on the level of supporting evidence) and an algorithm describing the process for
screening, assessing, and managing depression and
anxiety.16 Unlike the NCCN guidelines that address a
wide range of psychiatric disorders and psychosocial
problems, the Pan-Canadian guidelines focus on depression and anxiety.6,16
Using depression as an example, the guidelines
include specific recommendations for screening, assessing, and treating depression.16 These recommendations are similar in many respects to those in the NCCN
guidelines, in part because the NCCN guidelines were
part of the systematic search during the creation of the
Pan-Canadian guidelines.16 However, the algorithm
does differs from the NCCN algorithm; for example,
the Pan-Canadian algorithm recommends screening
for depression rather than distress, and it identifies
separate care pathways based on the severity of depression rather than on the type of mood disorder.16
American Society of Clinical Oncology
The American Society of Clinical Oncology (ASCO)
October 2015, Vol. 22, No. 4
issued clinical practice guidelines in 2014 for the
screening, assessment, and care of anxiety and depressive symptoms in adults with cancer.17 The ASCO
guidelines were adapted from the Pan-Canadian
guidelines, so they also used ADAPTE methodology
and many of the ASCO recommendations and algorithms mirror those in the Pan-Canadian guidelines.17
However, the ASCO panel modified the Pan-Canadian
guidelines in several instances and developed new
recommendations based on additional evidence and
expert opinion.17
Using the recommendations on depression as an
example, the ASCO guidelines specify distinct care
pathways based on the severity of depression.17 By
contrast to the Pan-Canadian guidelines, which recommend use of the Edmonton Symptom Assessment
System to screen for depression, the ASCO guidelines
recommend the Patient Health Questionnaire.16,17 In
addition, the ASCO guidelines include detailed recommendations for follow-up of patients identified as having depression.17
Guideline Harmonization
Having 3 or more clinical practice guidelines from Canada and the United States, along with numerous other
guidelines from other countries, may cause confusion
among health care professionals and patients with cancer seeking guidance about when and how psychosocial care should be delivered.12 A possible solution to
this problem is a process known as guideline harmonization. One such example of guideline harmonization is the ongoing, worldwide collaboration designed
to standardize various clinical practice guidelines for
the long-term follow-up of children and young adults
with cancer; this collaboration has resulted in harmonized guidelines for breast cancer surveillance in women with cancer who have received chest irradiation.18,19
Similar to this approach, relevant stakeholders should
seek to develop a set of harmonized guidelines that
address the screening, assessment, and management
of more common psychosocial problems encountered
by people with cancer, beginning with depression
and anxiety.
Measuring Quality
A paucity of data exists about the extent to which standards and clinical practice guidelines for psychosocial
care of patients with cancer are being implemented.
One source of evidence is a survey of 20 NCCN member institutions completed by a representative of each
institution.20 Although psychosocial services were
available at 19 of these institutions, only 12 institutions (60%) were conducting routine outpatient screening for distress, as stipulated in the NCCN standards of
care and clinical practice guidelines for distress management.6,20 Among these 12 institutions, 6 reported
October 2015, Vol. 22, No. 4
routinely screening all outpatients as recommended
and 6 reported routinely screening select patients (eg,
candidates for transplant).20 Of the 14 institutions conducting any routine inpatient or outpatient screening,
13 (93%) reported that, consistent with NCCN guidelines, patients identified as being in distress were referred to a mental health professional.6,20
The IOM report and the findings of an NCCN survey suggest the need to foster greater implementation
of recommendations for the psychosocial care of patients with cancer.2,20 One way to foster greater implementation might be to measure and provide feedback
to health care professionals about the quality of the
psychosocial care their patients with cancer receive.
Research has shown that medical oncology practices
provided with feedback demonstrating their poor performance on quality indicators will improve over time
on those same indicators.21 Could psychosocial care
for patients with cancer likewise be improved by measuring and reporting to oncology practices their performance on indicators of the quality of psychosocial
care? To help answer this question, the IOM recommended that organizations setting standards for cancer
care use performance measures for psychosocial care
as part of quality-oversight activities.2
The first step in this process is to develop measurable indicators of the quality of psychosocial care.
Toward this end, the American Psychosocial Oncology Society formed a workgroup in 2007 charged with
developing quality indicators.22 Members of the workgroup included 5 mental health professionals (psychologists, psychiatrists, and social workers) with extensive
experience in the delivery of psychosocial care to patients with cancer. The committee focused on developing process measures of the quality of psychosocial
care that could be evaluated by medical record abstraction.22 Following a review of the relevant literature, including the IOM report and the NCCN guidelines, committee members identified several potential indicators
that were then reduced in number using a modified
Delphi method.2,6,22 This process resulted in selection
of measures assessing 2 components considered to be
necessary (although not sufficient) for providing quality psychosocial care.22 The first quality indicator specifies evidence
should exist in the patient’s medical record that his or
her current emotional well-being was assessed within
1 month of the patient’s first visit with a medical oncologist.22 The second quality indicator stipulates that,
if a problem with emotional well-being was identified,
then evidence should exist in the patient’s medical record supporting that action was taken to address the
problem or an explanation provided for why no action
was taken.2 Measuring these indicators is operationalized by formulating questions that can be answered
“yes” or “no” based on the review of an individual paCancer Control 445
tient’s medical record.22
Two sources offer preliminary evidence that suggests providing feedback on the quality of psychosocial care might lead to improvements in care. One
source is ASCO’s Quality Oncology Practice Initiative,
a voluntary, practice-based quality improvement program.23 In 2008, 2 quality indicators for psychosocial
care were added to its core set of measures completed
by all participating practices.24 Practices participating
in the practice initiative have the opportunity to submit chart audit information at 6-month intervals.23 Following submission of their data, practices are given
performance feedback on each indicator as well as the
average performance score of all other participating
practices.23 Using data provided by participating practices, an analysis was conducted to determine whether
performance on these indicators improved between
fall 2008 (when they became part of the core set) and
fall 2009.25 The analysis was based on 166 participating
practices and data from approximately 15,000 patients
at each time point.25 The average rate per practice for
performing an assessment of emotional well-being
improved over time, from 64% to 73% (P < .001).25 By
contrast, the average rate per practice for taking action
if a problem with emotional well-being was identified
increased from 74% to 76% (P = .41).25 Additional evidence comes from the Florida Initiative for Quality Cancer Care.26 As part of a larger project examining quality of cancer care, performance
rates for the 2 psychosocial indicators were available
for 10 practice sites in Florida that completed chart audits of patients with colorectal, breast, or non–smallcell lung first seen by a medical oncologist in 2006
(n = 1,609) and 2009 (n = 1,720).26 Following the 2006
chart audit, all 10 practices received feedback on their
performance and were encouraged to develop their
own quality improvement efforts if performance
rates were below 85%.26 The mean percentages of patients whose emotional well-being was assessed were
53.1% in 2006 and 51.3% in 2009, reflecting a nonsignificant decrease (P = .661).26 However, significant increases were seen in the prevalence of documented
problems in emotional well-being among all patients
(from 13.0% to 16.0%) and among patients whose emotional well-being was assessed (from 24.5% to 31.3%;
P ≤ .021).26 The percentages of patients for whom action was taken to address a problem in emotional wellbeing were 57.4% in 2006 and 45.3% in 2009, thus reflecting a nonsignificant decrease (P = .098).26
Taken together, these findings suggest that providing feedback alone may be more effective in promoting
psychosocial screening, identifying distressed patients,
or both, than improving the delivery of psychosocial
care to patients in need.23,25,26 Efforts to improve the
delivery of psychosocial care to patients in distress are
likely to face a number of additional barriers, includ446 Cancer Control
ing competing clinical priorities, poor reimbursement
for mental health services, and lack of psychosocial
staff to accept referrals.9,27 This situation points to the
need to conduct demonstration projects that seek to
identify and test different approaches to improving the
quality of psychosocial care in oncology settings. Consistent with this view, the IOM included a recommendation that federal funding agencies support a largescale demonstration and evaluation of how standards
for psychosocial care could be implemented across diverse treatment settings.2
Demonstrating Approaches to Improving Care
Several examples have been published of efforts to implement routine distress screening programs in oncology settings.28-31 These efforts vary widely in the tools
used to screen, the methods used to collect information
from patients and deliver it to clinicians, and whether
the information obtained from patients is present to clinicians with referral recommendations — all of which
are features that limit the ability to draw conclusions
from this literature. However, reason exists to question the value of solely implementing distress screening without also implementing referral recommendations for distressed patients. Evidence for this concern
can be found in a study that compared a usual practice condition in which oncologists rated their patients’
distress and decided whether referrals were indicated
vs a screening condition in which oncologists received
information about whether a patient’s level of distress
exceeded a cut-off, thus suggesting referral to psychosocial care.32 Findings showed that 5.5% of patients in
distress receiving standard care and 69.1% of patients
in distress in the screening condition received referrals;
in addition, 3.7% of patients in distress receiving standard care compared with 27.6% of patients in distress
in the screening condition accepted the referral.32
Two projects illustrate larger multicenter efforts
aimed at improving the psychosocial care of people
with cancer. In 2007, the National Cancer Institute
Community Cancer Centers Program (NCCCP) was
initiated to enhance cancer research and the quality of
cancer care in community hospitals.33 Influenced by
IOM recommendations, the NCCCP working group
developed a tool, the Cancer Psychosocial Care Matrix
(CPCM), that defined 10 components of care comprising a comprehensive psychosocial care program.2,33
Within each component, the CPCM delineated measurable milestones designed to guide program development toward a site’s full potential for delivering psychosocial care.33 Specifically, the site is asked to identify
which performance level (≤ 5 levels) they are demonstrating to deliver quality psychosocial care.33 For example, the CPCM includes an item that allows sites to
conduct a self-assessment of the extent to which processes are put in place for meeting the IOM report
October 2015, Vol. 22, No. 4
recommendation that psychosocial needs of patients
be identified.33 A level 1 rating reflects no systematic
screening process in place, and a level 5 rating reflects
consistent systematic screening on multiple occasions
from diagnosis through follow-up, accompanied by
a comprehensive assessment for patients who screen
positive.33 It should be noted that the NCCCP developed a similar tool for evaluating and improving palliative care services.34 Results suggest the CPCM was useful in evaluating the progress NCCCP sites had made in
their goal to improve the quality of psychosocial care
provided to their patients.33
In 2010, 16 NCCCP sites used the CPCM to provide
retrospective ratings of their psychosocial program
characteristics upon entry into the NCCCP as well as
current ratings approximately 2 years later.33 Findings
indicated that most of the baseline responses (60%) of
the sites reflected level 1 responses (ie, lowest possible
level of service delivery).33 Two years later, the majority of responses (59.4%) reflected level 2 to 4 responses
(ie, intermediate levels of service delivery).33 In addition to quantifying progress in improving care, anecdotal findings indicated that the CPCM served at most
sites to promote intentions to improve psychosocial
services and that the ordered response options facilitated incremental growth toward a desired practice.33
The other example is a project that evaluated the
feasibility of a quality improvement strategy for integrating psychosocial care at 27 medical centers in Italy.35 The strategy relied on context analysis and problem solving to facilitate implementation and involved
4 to 6 visits conducted in each center by the project
team to assist clinic staff in identifying obstacles, finding solutions, and strengthening motivation to carry
out recommended changes. Following an implementation period, the authors assessed adherence to each of
the 6 recommendations and considered the objective
to be met if the center’s adherence percentage was at
least 75%.35 Implementation was generally successful,
as indicated by the relatively few centers with adherence rates that fell below this criterion for each of the
following 6 recommendations: clinician participation in
communication skills training (1 center), provision of a
question prompt list to each patient (7 centers), assignment of a specialist nurse to each patient (2 centers),
completion of at least 1 psychosocial distress screening for each patient (3 centers), completion of at least
1 social need screening for each patient (3 centers), and
an offer to visit an information and support center for
each patient (3 centers).35 Although these results are
promising, the participating medical centers were primarily leading centers of excellence, the sustainability
of these outcomes was not assessed, and the evidence
of improvement was limited to process indicators and
not outcome indicators of quality (eg, patient psychological well-being).35
October 2015, Vol. 22, No. 4
Future Directions
In retrospect, the IOM report can be seen as a turning point in the efforts to promote the integration of
psychosocial care into routine cancer care.2 Although
the IOM’s report was useful in summarizing the benefits of addressing psychosocial needs and the liabilities of not addressing them, its major impact has been
to draw attention to the fact that many patients who
might benefit from psychosocial care are not receiving
it.2 In addition to focusing attention on the problem,
the report included a number of recommendations that
have served as an effective action plan for efforts to address the problem.2 Among the IOM report’s most important recommendations was one stipulating that entities establishing or using quality standards in oncology should include a provision of appropriate psychosocial health
services among their standards.2 Although clinical
practice guidelines for psychosocial care have been
available since 1999, many reasons exist to believe that
developing and disseminating guidelines are necessary steps but are insufficient when it comes to changing clinical practice.7 The development of standards of
care is also required but experience suggests that, for
this approach to be successful, the issuance of standards must move beyond initiatives developed and
directed primarily by members of professional societies.
A critical milestone occurred in 2012 when the
ACS CoC issued standards requiring the development
and implementation of processes for psychosocial
distress screening and referrals for psychosocial care.5
Adherence to these standards is being evaluated in
2015 as part of the ACS CoC accreditation, so considerable motivation exists for many oncology care sites
to evaluate and, if needed, improve their processes in
this area.10 In anticipation of this new standard taking
effect, several major professional societies involved
in psychosocial care have collaborated to issue recommendations that address the 6 components of the
standard36:
1. Overall plan for screening
2. Timing of screening
3. Method and mode of screening
4. Tools for screening
5. Assessment and referral
6. Documentation of screening and related actions
in the medical record
These recommendations build on published clinical
practice guidelines.6
Another important recommendation that came
out of the IOM report stipulated that the organizations
setting standards for cancer care should implement
performance measures for psychosocial care as part
of quality oversight activities.2 The Quality Oncology
Practice Initiative of ASCO is one of the largest cancerrelated quality monitoring systems in the United States,
Cancer Control 447
with more than 900 registered practices.37 Spurred in
part by the IOM report, the initiative adopted indicators of the quality of psychosocial care for its core module that are required of all participating practices.2,38
Findings based on audits of the Quality Oncology
Practice Initiative and the Florida Initiative for Quality Cancer Care suggest that providing feedback about
the quality of psychosocial care can have a positive
impact on rates of psychosocial screening.25,26 However, change is lacking for taking action in cases
where problems in emotional well-being were identified; thus, this finding suggests feedback alone is insufficient for improving the delivery of psychosocial
services.25,26 Possible explanations for such findings
include lack of referral procedures for psychosocial
care, lack of identified resources for providing psychosocial care, or both.
Oncology practices seeking to address these issues
would benefit from knowing how other practices have
responded to similar challenges. One source of information might be case studies describing how practices
improved their provision of psychosocial care. An example of this type can be found in a publication that
provided a description of how a regional cancer center
developed counseling services to address the unmet
psychosocial needs of its patients.39 The IOM report also recommended that funding agencies support a large-scale demonstration and
evaluation of how standards for psychosocial care can
be implemented across diverse treatment settings.2
This recommendation was addressed as part of the
federally funded NCCCP. Based on guidance provided by the IOM, participating sites implemented planning efforts that resulted in substantial improvements
in psychosocial care delivery.2,33 Additional reports
have provided more in-depth descriptions of efforts
to implement distress screening and psychosocial referral and the acceptability and impact on processes
of care in those efforts.28-32,35 Work in this area would
also benefit from published findings from rigorously
designed, quality improvement projects designed to
document the processes used to improve psychosocial care and the outcomes achieved, including the
impact on patient quality of life. Such studies should
also consider relevant conceptual frameworks such
as the PRECEDE-PROCEED model, which focuses on
identifying and influencing predisposing, enabling,
and reinforcing factors for implementing changes.40,41
Reports of this type have yet to appear in the literature and should be considered a high priority for future efforts to promote psychosocial care for patients
with cancer.
Conclusions
Although considerable progress has been made in recent years in integrating psychosocial care into routine
448 Cancer Control
cancer care, much work remains to be done. Additional progress will be fostered by continued efforts to
promote adherence to clinical practices guidelines and
care standards for psychosocial services and through
the development and dissemination of models demonstrating how practices can effectively implement these
guidelines and standards.
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39. Hendrick SS, Cobos E. Practical model for psychosocial care.
J Oncol Pract. 2010;6(1):34-36.
40. Green LW, Kreuter MW. Health Promotion Planning: An Educational and Ecological Approach. 4th ed. New York: McGraw-Hill; 2005.
41. Schofield P, Carey M, Bonevski B, et al. Barriers to the provision
of evidence-based psychosocial care in oncology. Psychooncology.
2006;15(10):863-872.
October 2015, Vol. 22, No. 4
Cancer Control 449
Integrating palliative care has
not always extended to rural areas;
however, some research is focusing
on future progressive solutions.
Photo courtesy of Lisa Scholder. Masculine, 14" × 22".
Systematic Review of Palliative Care in the Rural Setting
Marie A. Bakitas, DNSc, CRNP, Ronit Elk, PhD, Meka Astin, MPH, Lyn Ceronsky, DNP, GNP,
Kathleen N. Clifford, MSN, FNP-BC, J. Nicholas Dionne-Odom, PhD, RN, Linda L. Emanuel, PhD, MD,
Regina M. Fink, RN, PhD, Elizabeth Kvale, MD, Sue Levkoff, ScD, MSW, Christine Ritchie, MD, MSPH,
and Thomas Smith, MD
Background: Many of the world’s population live in rural areas. However, access and dissemination of the
advances taking place in the field of palliative care to patients living in rural areas have been limited.
Methods: We searched 2 large databases of the medical literature and found 248 relevant articles; we also
identified another 59 articles through networking and a hand search of reference lists. Of those 307 articles,
39 met the inclusion criteria and were grouped into the following subcategories: intervention (n = 4), needs
assessment (n = 2), program planning (n = 3), program evaluation (n = 4), education (n = 7), financial
(n = 8), and comprehensive/systematic literature reviews (n = 11).
Results: We synthesized the current state of rural palliative care research and practice to identify important
gaps for future research. Studies were conducted in the United States, Australia, Canada, Africa, Sweden,
and India. Two randomized control trials were identified, both of which used telehealth approaches and had
positive survival outcomes. One study demonstrated positive patient quality of life and depression outcomes.
Conclusions: Research to guide rural palliative care practice is sparse. Approaches to telehealth, community–academic partnerships, and training rural health care professionals show promise, but more research
is needed to determine best practices for providing palliative care to patients living in rural settings.
Introduction
In 1990, the World Health Organization revised its
comprehensive Cancer Pain Relief and Palliative Care
report to include palliative care.1 Since then, strides
have been made worldwide in providing patients with
cancer access to palliative care, and professional medi-
From the School of Nursing (MAB, JND-O), Center for Palliative and Supportive Care (MAB, EK), and School of Public Health (MA), University
of Alabama at Birmingham, Birmingham, Alabama, College of Nursing (RE) and College of Social Work (SL), University of South Carolina,
Columbia, South Carolina, University of Minnesota Medical Center (LC), Minneapolis, Minnesota, St Luke’s Mountain States Tumor Institute
(KNC), Boise, Idaho, Buehler Center on Aging, Health and Society (LLE), Northwestern’s Feinberg School of Medicine, Chicago, Illinois, University of Colorado Hospital and University of Colorado College of Nursing (RMF), Aurora, Colorado, University of California (CR), San Francisco,
California, and Johns Hopkins Medical Institutions and Sidney Kimmel Comprehensive Cancer Center (TS), Baltimore, Maryland.
Submitted July 6, 2015; accepted October 12, 2015.
Address correspondence to Marie A. Bakitas, DNSc, CRNP, School of Nursing, Center for Palliative and Supportive Care, University of Alabama
at Birmingham, 1701 University Boulevard, Birmingham, AL 35233. E-mail: mbakitas@uab.edu
Dr Bakitas receives support from R01NR011871-01 and the American Cancer Society Research Scholar Grant. Dr Dionne-Odom is a postdoctoral fellow supported by the University of Alabama at Birmingham Cancer Prevention and Control Training Program (5R25CA047888)
and by a National Palliative Care Research Center Junior Faculty Career Development Award. Dr Elk receives support from NIH/NIA:
1R21AG046772-01A1. No significant relationships exist between the other authors and the companies/organizations whose products or services may be referenced in this article.
450 Cancer Control
October 2015, Vol. 22, No. 4
cal organizations have recommended early palliation
for patients with advanced cancer.2-7 However, access
and the dissemination of palliative care advances to
the 40% to 60% of the global population who live in
rural areas have been limited.8
Although persons with cancer are more likely than
those with other, nononcological, progressive, and lifelimiting illnesses to receive palliative care, those with
cancer living in rural communities continue to be underserved.9 The limited focus on palliative care in the
rural setting is evident in the lack of guidance by national organizations to address the unique challenges
and barriers faced by these patients and health care
professionals.10 Clinical guidelines on quality palliative
care from the National Consensus Project do not contain the term rural nor do they address how these standards should be applied in rural settings.11 Not only
must performance indicators of palliative care need to
be modified, but the reality is that many rural health
care facilities do not have access to any type of specialty oncology or palliative care resources.10
Thus, the purpose of this paper is to synthesize empirical evidence, much of which has focused on persons
with cancer, to describe the current practice and state
of research relating to palliative care in the rural setting,
and to identify important gaps for future research.
Methods
We conducted a systematic review of 2 large databases
from January 1990 to February 2014. The search revealed 248 relevant articles and we identified an additional 59 articles through networking and a hand
search of reference lists. We screened titles and abstracts of 307 articles and assessed the full text (focused on methodology sections to identify original
research) of 225 articles. Thirty-nine articles met the
inclusion criteria of being a research study or systematic review and had a rural focus. Papers meeting the
inclusion criteria were included regardless of study
quality so we could obtain the broadest possible representation of the state of research.
Articles were grouped into 7 categories and 1 or
2 authors reviewed and synthesized each category. Studies reports represented the United States (n = 13), Australia (n = 7), Canada (n = 4), Africa (n = 2), Sweden
(n = 1), and India (n = 1). Category definitions and summaries of the studies are described in Tables 1 and 2.12-49
Intervention Studies
Four papers representing 2 randomized controlled trials (RCTs) were identified.12-15 Both RCTs offered early
palliative care approaches to patients with advanced
cancer and their family caregivers using a telehealth/
telephonic intervention. The settings, which were rural
New Hampshire and Vermont outpatient cancer clinics that included a US Veterans Affairs Medical Center,
October 2015, Vol. 22, No. 4
were the same for both studies.12,13 Each study generated separate papers focused on patient or caregiver
outcomes.12-15 Positive patient quality of life (QOL), depression and survival and positive caregiver outcomes
were reported.12,13,15
Needs Assessment
Two US studies focused on needs assessments and
the development of rural palliative care.16,17 Ceronsky
et al17 focused on palliative care quality practices and
utilized a learning collaborative methodology to assist
communities to establish and strengthen palliative care
capacity in rural Minnesota. A program-development
evaluation survey assessed the benefits of the Minnesota Rural Palliative Care Initiative and satisfaction
with participation.17 All the program components were
rated well and an increase was seen in participant
knowledge of pain management and goals of care discussions.17 Fink et al16 used an investigator-developed
needs assessment instrument to determine awareness,
knowledge, barriers, and access to resources of palliative care services in 236 Rocky Mountain–area rural
hospitals. They found that 99% of health care professionals were familiar with the palliative care concept,
76% had a contract with a local hospice organization,
72% participated in a program to promote advancecare planning, 56% had access to palliative care resources, and 72% had palliative care education offered
in the past year.16
Program Planning
Three studies addressed program planning for rural
palliative care services and programs; 2 were conducted in Australia and 1 in Canada.18-20 The Australian studies found that palliative care had moved
from being marginalized to a key component of rural
health care delivery.18,19 Blackford and Street18 developed and evaluated the effectiveness of a model to
improve advance-care planning in the community
setting. Their model consisted of 5 domains: servicelevel governance, advance-care planning education,
advance-care planning documentation, community
engagement, and quality processes.18 They found that
an advance-care planning model is feasible in the rural
community and should focus on advance-care planning conversations and involve families rather than
just advance-care planning completion rates.18 Phillips
et al19 evaluated the applicability of the Predisposing,
Reinforcing, Enabling, Causes in, Educational Diagnosis and Evaluation (PRECEDE) and Policy, Regulatory, Organizational Constructs in Educational and Environmental Development (PROCEED) model in the
development of targeted, nursing-led chronic illness
interventions. They studied an aging population with
rural, unmet palliative care needs and a disadvantaged
urban community at high risk for cardiovascular disCancer Control 451
Table 1. — Selected Studies of Palliative Care in Rural Settings
Study
Design/
Intervention
Sample
Setting
Measure
Outcome
Comment
Intervention
Bakitas12
Prospective RCT
ENABLE phonebased coaching
vs usual oncology
care
322
NH/VT
Outpatient
cancer clinics
and VAMC
FACIT-Pal
CES-D
Edmonton Symptom
Assessment Scale
Resource Use
Improved QOL and depression
(both P = .02)
Trend toward improved symptoms (P = .06)
One of the first
studies to describe
benefits of early
palliative care
O’Hara14
Prospective RCT
Patient-directed
ENABLE phonebased coaching
vs usual oncology
care
222
NH/VT
Outpatient
cancer clinics
and VAMC
Caregiver burden
MBCBS
After-death interview
Complicated grief
No differences in caregiver
burden
Higher caregiver objective and
stress burden related to lower
patient QOL
No specific intervention offered to these
caregivers, but they
were allowed to
participate in patient
intervention
Bakitas13
Prospective,
wait-control RCT
ENABLE phonebased coaching
at diagnosis vs
3-mo delayed
207
NH/VT
Outpatient
cancer clinics
and VAMC
CES-D
FACIT-Pal
QUAL-E
Survival
Resource use
Immediate group had improved
survival (15%, P = .38) compared with delayed group at
1y
Failure to achieve
recruitment target
may have impacted
ability to demonstrate differences
between groups
DionneOdom15
Prospective,
wait-control RCT
ENABLE
phone-based
coaching at
diagnosis vs
3-mo delayed
122
NH/VT
Outpatient
cancer clinics
and VAMC
QOL-CG
CES-D
MBCBS
Immediate group had improved depression at 3 mo
(P = .02); decedent caregivers
had improved depression
and subjective burden (both
P = .01)
—
Needs Assessment
Ceronsky17
Quality improvement/learning
collaborative to
assist communities to establish/
strengthen
palliative care in
rural Minnesota
using theory and
NQF preferred
practices
10
Rural Minnesota
MRPCI
Program development
Evaluation survey to
assess benefit of
MRPCI and satisfaction with participation
Teams grew from 1 to 6
All components of program
rated well
Increased knowledge of pain
management by 73% and
goals of care discussion by
81%
10 teams represented
64 organizations;
used community
capacity development
theory
Fink 16
Descriptive,
determine awareness, knowledge,
barriers, and
resources of
palliative care
services in rural
hospitals
374
236 Rocky
Mountain rural
hospitals
(< 100 beds)
in Montana,
Wyoming, Utah,
New Mexico,
Colorado,
Kansas, and
Nebraska
Investigator-developed
qualitative/quantitative
7-section needs assessment instrument
covering current palliative care services,
professional education
programs, desired
learning methods, satisfaction with and barriers to palliative care,
community resources,
and populations needing assistance
99% familiar with palliative
care concept
76% had a contract with
hospice
72% participated in advancecare planning program
56% had access to palliative
care resources
9% had board certified physicians in hospice and palliative
medicine
72% offered palliative care
education in past year
Ethical issues and psychosocial
support least satisfied
Barriers: Patients avoiding
discussions of dying and inadequate policies and education
36 surveys did not
list location
40% response rate
continued on next page
452 Cancer Control
October 2015, Vol. 22, No. 4
Table 1. — Selected Studies of Palliative Care in Rural Settings (continued)
Study
Design/
Intervention
Sample
Setting
Measure
Outcome
Comment
Multisite, action
research to design
and evaluate the
feasibility of an
advance-care
planning program
3 community sites
n = 611
(urban)
n = 460
(urban)
n = 186
(regional)
3 community
palliative care
services: 1
regional and 2
metropolitan,
urban in Victoria,
Australia
Client and service
management audits
(pre- and post-implementation of the
program/model
Key informant interviews (n = 9)
Development and
evaluation of efficacy
of a model to improve
advance care planning
in the community
setting
Model to implement advance
care planning in the community is feasible
Documentation of advance
care planning discussions with
clients and families is a more
useful outcome than completing advance-care planning
Community palliative care
services needs to engage with
local communities
Leadership essential ingredient
to change the process
Reflective case
study approach
to demonstrate
the applicability
of model to the
development
of nursing-led
chronic illness
interventions
2 case
studies/
populations
Regional
coastal Australian aging
population with
rural, unmet
palliative care
needs
Urban area in
Sydney, Australia: Disadvantaged urban
community at
high risk for
cardiovascular
disease
PRECEDE-PROCEED
model used
Needs assessment
conducted (social,
epidemiological,
behavioral, environmental, educational,
and ecological)
Data shaped development of
a multifaceted intervention
focusing on increasing aged
care personnel’s palliative
care capacity, access to
resources, development of
evidence-based guidelines,
and evaluation
Assess feasibility of pilot study
and explore
symptom, cost,
and satisfaction
outcomes
44 initial
consultations and
28 followup visits
Canada
Videoconferencing
to provide specialist
palliative care and
radiotherapy consultation to those with
cancer living in rural
settings and explore
symptoms, cost, and
satisfaction outcomes
Videoconferencing is feasible,
may improve symptoms,
results in cost savings, and
satisfactory to patients and
HCPs
1 case
study
Rural and
remote Griffith,
Australia
Evaluation of Griffith
Area Palliative Care
Service model
Key elements included:
• 24-h access
• Governance and
staffing
• Case management
review
• Enhanced primary
care
• Information
management
• Outcomes and
evaluation
• Weekly multidisciplinary team meeting
Coordinated integrated application of existing resource
Investment of new resources
Formal evaluation
Program Planning
Blackford18
Phillips19
Watanabe20
­
—
—
—
Program Evaluation
Hatton21
2-y pilot project
delivering
palliative care
services
Plans for future
dissemination
identified
continued on next page
October 2015, Vol. 22, No. 4
Cancer Control 453
Table 1. — Selected Studies of Palliative Care in Rural Settings (continued)
Study
Design/
Intervention
Sample
Setting
Measure
Outcome
Comment
Program Evaluation (continued)
Wilkes22
Descriptive
evaluation of a
pilot project of a
palliative care
telephone call
service
48 HCPs
21 afterhours
telephone
support
nurses
New South
Wales, Australia
Telephone logbook
(12 calls), text analysis
of reflective journals,
questionnaire, interviews
Major themes:
• Program preparation and
introduction
• After-hours telephone support service for families and
HCPs
• Nurse experiences (personal
impact and support)
Lack of HCP knowledge about service
Bensink 23
Evaluation of the
acceptability of
videotelephony/
webcam
17
Tertiary pediatric
oncology service in Brisbane,
Australia
Interview (face to face
or telephone)
Cost analysis
92% participation rate
Families receiving videotelephone calls found them to be
more useful than a telephone
call
2 RCTs previously
attempted and
abandoned following
difficulty with family
recruitment
Evaluation of
videotelephony was
conducted
Logie24
Program evaluation
8
5 hospices
3 homebased care
organizations
Zambia
Multiple methods rapid
field evaluation:
• Desk surveys
• Facility interviews
• Data from 2 field
visits (practice observation, trainee
feedback, interviews
with key personnel
and funders)
Program enhancement with
modest funding included:
• Training program (rural and
urban)
• Improved access to morphine
and other drugs
• Increased government lobbying to support palliative
care and hospice and to
improve standards
For palliative care to
thrive in a resource
poor country, public
health system integration is crucial and
long-term funding
needed
Smith31
Qualitative
program evaluation of providing
specialists in
2 rural community hospitals
6,958
audited
patient
charts
pre-RCOP
and 7,572
post-RCOP
RCOP of the
Massey Cancer
Center
Medical College
of Virginia
No formal measurement; anecdotal
observations include
ability to keep patients
with cancer in their
local communities
Rural practitioners able to
safely administer cancer
therapy
Focused on
outcomes for local
clinicians
Thulesius25
Comparison of
learner-centered
education program and control
group
460
Rural areas in
Sweden
Intervention
and control
groups
sepa-rated by
20-mile-wide
rural district
Matched in
terms of
demography
and home care
structure
20-item attitude questionnaire
HADS administered
to staff
Postintervention:
Significant differences on 17
of 20 items between 2 groups
Preintervention:
Significantly higher in education group
Postintervention:
Significantly lower in education group
Improved attitude about care
and improved mental health
well-being of staff
Education program
was evidence-based,
mixing small group
work with lectures,
seminars, and
discussion
Objective was to
produce local guidelines for end-of-life
care
Only study reviewed
with control group
Education
continued on next page
454 Cancer Control
October 2015, Vol. 22, No. 4
Table 1. — Selected Studies of Palliative Care in Rural Settings (continued)
Study
Design/
Intervention
Sample
Setting
Measure
Outcome
Comment
Education (continued)
Retrospective
analysis of the
Ontario Ministry
of Health educational palliative
care program
delivered in last
8y
353
Pre- and postdesign
14 workshops
for general
practitioners
tailored to
specific patient
symptoms
149
Kaufman28
Prospective
design study
of educational
presentations to
HCPs (nurses =
half-day conference; physicians
= grand rounds)
Easom29
Pre- and postdesign study
of educational
presentations
to rural nurses
and licensed
practical nurses
in assisted-living
and nursing
home environments
Kelley 26
Reymond27
Ontario
Questionnaires
(26 questions)
83% said training very significant compared with other
sources of learning
87% reported practice of palliative care changed
91% shared palliative care
knowledge with others
68% reported palliative care
delivery in their community
much better than prior to
training
70% now had palliative care
team (compared with 9% prior
to training)
Remote areas in
Australia
Cost of training
Evaluation of education
and clinical objectives
Goal to evaluate intervention
aimed at increasing knowledge
and capacity of palliative care
95% general practitioner
satisfaction with workshop in
teaching palliative care skills
(91% for nurses and other
HCPs)
Confidence in managing palliative care cases increased from
2.9 to 3.9 (5-point scale)
HCPs reported improvement
in confidence at 3 mo
27
New Mexico
Change in hospice
utilization pattern:
• Subsequent referral
to hospice
• Patient referral
pattern
• Length of stay
• Diagnosis at
admission
• Nursing home
referral pattern
Significant increase in hospice
utilization (33 to 61)
113/254 eligible for hospice
were referred (65%)
Increase in referrals by community nursing homes (but
not other sources)
• Not significant in time in
days in hospice
• Not significant in terms of
diagnosis
• Significant increase in
frequency of referral from
2 nursing homes
9
Assisted living
facility in
southeastern
United States
End-of-life attitudes
survey
End-of-life knowledge
assessment
Open-ended questions
Post-test results significantly
higher than pre-test knowledge on end-of-life care
Most knowledge growth on
response to pain medication,
administration of opioid analgesics for pain, and interventions to relieve nausea
Significant difference in
attitudes
—
—
Goal to increase
hospice utilization in
rural community
Effective for changes
in referral by nursing
homes alone (no
change in physician
referrals)
Training conducted
by local HCPs at very
low cost
—
continued on next page
October 2015, Vol. 22, No. 4
Cancer Control 455
Table 1. — Selected Studies of Palliative Care in Rural Settings (continued)
Study
Design/
Intervention
Sample
Setting
Measure
Outcome
Comment
Education (continued)
Determine
staff needs for
palliative care
education, then
develop 15-h
interprofessional
curriculum
Program piloted
in 3 facilities
128
Ontario (remote,
rural, and longterm care facilities)
Identify 3 most impor- Highest ranking topics: stress
tant learning needs and management for staff (73%),
preferred format
for individual and family (71%),
understanding emotional
needs of dying person (67%)
Majority preferred education in
face-to-face format, liked
interdisciplinary focus, teambuilding, felt empowered by
program
Approach can serve
as a model for palliative care education
in other rural areas
Smith31
Pre- and postfinancial analysis
of RCOP
1 site
3 rural clinics
serving 3–5
counties in
Virginia
Chart audits after 3 y
of operation (postRCOP) compared with
2-y results (pre-RCOP)
Profitable for rural hospitals
Revenue-neutral for academic
centers
Cost saving for society
Successful enough
to be a required part
of all comprehensive cancer center
programs
Desch32
Pre- and postfinancial data
analysis of RCOP
1 site
Low-income
areas in rural
Virginia
Main outcome
measures:
• Costs (estimated
reimbursement from
all sources)
• Revenues
• Contribution margins
• Profit (or loss)
Rural hospitals generated
> $500,000 USD/y after RCOP
Total cost per patient in network decreased from $10,233
USD to $4,392 USD (57%
decrease)
Programmatic part
of all National
Cancer Institute
centers
Uys 33
3-mo, multisite
home-based care
project providing
palliative care
for patients with
AIDS
7 sites
rural = 2
periurban = 2
urban = 3
Underserved in
South Africa
Evaluation of costs:
• Setup (training,
equipment, and
planning)
• Cost per site
• Site operating cost
(total and average
per patient)
• Average hospital
inpatient
• Hospital outpatient
• Primary care clinic
costs per participating patient
Palliative home-based care
increased in rural areas where
a vehicle is required for staff
transport
Impossible to know
whether home-based
care adds services
or can cost-effectively substitute for
hospital services
Cassel34
Analysis of
Rappahannock
Rural Palliative
Care Program
1 site
Northern
Virginia, located
in a 5-county
rural farming
area
Seacoast area
on Chesapeake
Bay
Collected data from
consults, physician
billing, and receipts to
calculate hospital
charges for patients
treated with concurrent
palliative care
Cost per day decreased to
$400 USD/y (25% of total)
Generated $80,000–100,000
USD in savings in reduced
hospital charges and cost per
year
Single site pilot
survey of patientcaregiver dyads
11
Trivandrum,
Kerala, India
Southwest coast
of India
Pilot study of economic
impact and openness to
training
100% reported decreased
family earnings
Families surveyed averaged
$1,082 USD of debt
8 of 11 caregivers open to
training
KortesMiller 30
Financial
Emanuel38
—
—
continued on next page
456 Cancer Control
October 2015, Vol. 22, No. 4
Table 1. — Selected Studies of Palliative Care in Rural Settings (continued)
Study
Design/
Intervention
Sample
Setting
Measure
Outcome
Comment
Project has expanded
Did not take into account cost avoidance
or hospitalization
cost avoided
Medicare hospice
benefits: cost equivalent to US
Medicare hospice
benefits and lower
than average alternate level of care and
hospital costs within
Ontario, Canada
Education (continued)
Klinger35
Analyze resource
utilization and
costs of Niagara
West End-of-Life
Care Project
over a 15-mo
period
3 small
towns
Public health
system of
Ontario, Canada
Economic evaluation
to establish evaluations in monetary units
and Expenditure Panel
Survey
Total costs for all patient-related
were $1,625,658.07 CAN
($17,112.19 CAN/patient and
$117.95 CAN/patient/d)
Costs within parameters of
Medicare hospice benefits
Simon37
Pilot survey of
working-age
adults with a family member with a
serious/long-term
illness
81 workingaged US
adults
Web-based
US adults
Cost of illness-related
health care
Changes in economic
behaviors
Changes in employment
or education behaviors
Mean reported cost of medical
bills paid by respondents
($17,108 USD)
29.4% of respondents sold
possessions as a result of family illness
42.4% reduced work hours as a
result of family illness
Bradford36
Cost minimization 95 home
analysis comparing video conactual costs of
sultations
HTP consultations
with estimated
potential costs
associated with
face-to-face
consultations
occurring by
either hospitalbased consultations in outpatient
department or
home visits from
pediatric palliative
care specialists
Royal Children’s
Hospital (Brisbane, Australia)
Data from 95 home
video consultations
occurring over 2 y
Included costs associated with projected:
clinician time and
travel, costs reimbursed
to families for travel
through the Patients
Travel Subsidy scheme,
hospital outpatient
clinic costs, project
coordination, and
equipment and infrastructure costs
Mean costs per consultation calculated for
each approach
Air travel (n = 24) significantly
affected results
Mean cost of HTP intervention
was $294 USD and required
no travel
Estimated mean cost per
consultation in the hospital
outpatient department was
$748 USD
Mean cost of home visits per
consultation was $1,214 USD
Face-to-face consultations are gold
standard of care, but
families located at a
distance from the
hospital may find
video consultation in
the home to be an
effective and cost
efficient method to
attend a consultation
Video consultation
in the home ensures
equity of access to
services and minimum disruption to
hospital-based
palliative care teams
P ≤ .05 is considered statistically significant.
CAN = Canadian dollar, CES-D = Center for Epidemiological Studies Depression Scale, ENABLE = Educate, Nurture, Advise Before Life Ends,
FACIT-Pal = Functional Assessment of Chronic Illness Therapy-Palliative, HADS = Hospital Anxiety and Depression Scale, HCP = health care professional, HTP = Home Telehealth Program, ICHC = integrated community home-based care, MBCBS = Montgomery Borgatta Caregiver Burden Scale,
MRPIC = Minnesota Rural Palliative Care Initiative, NH/VT = New Hampshire/Vermont, NQF = National Quality Forum, PRECEDE = Predisposing,
Reinforcing, Enabling Constructs in Education, Diagnosis, and Evaluation, PROCEED = Policy, Regulatory, Organizational Constructs in Educational
and Environmental Development, QOL = quality of life, QOL-CG = Quality of Life Caregiver Scale, QUAL-E = Quality of Life at the End of Life Scale,
RCOP = Rural Cancer Outreach Program, RCT = randomized controlled trial, USD = US dollar, VAMC = US Veterans Affairs Medical Center.
ease.19 They suggested the PRECEDE-PROCEED model could be used to guide nursing-led interventions in
existing health care environments.19 Watanabe et al20
evaluated the feasibility of videoconferencing to provide specialist palliative care, radiotherapy consultations, and to explore symptoms in rural Canadian
persons with cancer. They found videoconferencing
to be feasible, suggested that its use may improve
symptoms and result in cost savings, as well as inOctober 2015, Vol. 22, No. 4
crease satisfaction for patients, families, and health
care professionals.20
Program Evaluation
Three Australian studies and 1 Zambian study evaluated
various, rural, palliative care delivery approaches.21-24
Hatton et al21 evaluated a pilot collaborative project
among multiple agencies in Australia to meet the challenges of providing palliative care services in rural and
Cancer Control 457
Table 2. — Selected Systematic Reviews of Rural Palliative Care in Rural Settings
Study
Purpose
Findings
Evans
Conduct systematic literature
review of studies examining
organization of rural palliative
care and views of professionals
in rural areas
No case-control, cohort, randomized controlled trials, or meta-analyses were found
Majority of studies based out of Australia (n = 16)
Role of primary care discussed in 12 studies
Problems reported in the provision of symptom control for patients
Issues with education, training, and emotional support for professionals providing
palliative care in rural settings
Accessing specialist services was reportedly difficult for professionals
Professionals and rural families described difficulties in accessing information
Developments in information technology were mentioned in a few studies as possible solutions
Need perspectives from rural primary care professionals about the optimal
organization of palliative care in the rural setting
Hughes 40
Identify needs of rural-dwelling
patients with cancer and
their caregivers in delivery
of palliative care
All studies from developed countries
No studies specifically about ethnic minorities
Noted difficulty of comparing studies due to differing methodologies and contexts
Rural caregivers may have additional care demands placed on them
Information needs may be higher in rural vs urban patients
Geographical distance a major variable in care
Jennett41
Review of readiness models
for rural telehealth
Four distinct models identified for readiness assessment
Each model discussed various themes essential for telehealth readiness
Three themes common to each discussions: appreciation of practice context, strong
leadership, perceived need to improve practice
Combining e-health and telehealth with health informatics
Theories of change, diffusion of innovations, components of telehealth readiness tools
(eg, patient, public, health care professional, organization, system) could be
reviewed and refined for application to e-health
Wilson42
Assess challenges and
other important issues/
circumstances involving
planning and providing EOL
care in rural areas Most research was single site, small sample, and exploratory
Identified and described differences between EOL care in urban and rural settings,
assessed EOL needs and wishes of terminally ill or dying persons, their family
members, and health care professionals in rural areas, explored EOL education for
rural EOL specialists
EOL care as an essential service in rural communities
Integration of EOL care into rural health care settings
Family caregivers must be provided with more information and support
(eg, home-based nursing care)
Improved linkages to specialized palliative care necessary for continuing education
Prepare and support rural health care professionals while delivering EOL care
Steers 43
Determine role played by UK
community hospitals in
provision of palliative care
Many UK community hospitals have resources to counter inequalities in access to
general palliative care
More prospective research using qualitative methods involving patients, caregivers
and nurses required to understand complexities of providing palliative care
Cox44
Literature review of quality of
care in rural areas
Rural communities more different than alike
Rural issues differ from those in urban settings
Research in rural health facilities to determine best practices for patient safety and outcomes
Must determine best practices for mental health and effective smoking cessation
programs and technological interventions
Identification of mental health programs and services providing cost-effective
quality care
Robinson45
Identify, evaluate, and
synthesize literature on rural
palliative care
Grouped into patient and caregiver perspectives, professional attitudes, knowledge,
and practice issues, and health care services
Body of research is small and eclectic
Little evidence to inform palliative policy and service development in rural settings
Coordinated programs required to develop adequate body of knowledge to support
effective service and policy development
39
continued on next page
458 Cancer Control
October 2015, Vol. 22, No. 4
Table 2. — Selected Systematic Reviews of Rural Palliative Care in Rural Settings (continued)
Study
Downing
Purpose
Findings
Explore global developments
in palliative care provision
in rural settings since
2010, highlighting models,
including challenges faced in
establishing services
Provision of care based on premise that individuals wish to die at home
Communication is a key concept to palliative care
Community volunteers and networks intrinsic to palliative care models of rural
Sub-Saharan Africa
Challenges to recruitment and sustainability of main clinical team
Lack of rural generalist providers having access to specialist support
Major challenge is the cost and time of travel to access care
Care services need to be individually tailored to specific rural communities
Use of community volunteers in care delivery may be effective
Practical issues related to access and traversing geographical distances remain challenging
Phillips 47
Review published studies
evaluating impact of continuing professional development
programs on ability of rural
nurses to provide palliative
care; inform the development
of targeted learning activities
for this population
Evaluated programs involving rural nurses and focused on increasing care capabilities
Evidence limited by the absence of randomized controlled trials
Valuable insights into barriers and facilitators to engaging rural nurses in learning opportunities
Continuing education to positively impact patient and family outcomes
Optimize opportunities for web-based technologies by developing and maintaining
computer competencies
Investigation needed of impact of specialist clinical placements capabilities to
provide palliative care among nurses
Jang48
Examine opioid availability,
caregiver burden, and
use of health care resources
at patient EOL by setting
to determine optimal setting
for palliation in Africa
Recognizing and treating symptoms occurring at the EOL
Research in Africa sparse; most from South Africa and Uganda
Use of health care resources for palliative care at EOL
More research on nurse prescribing training program, which is part of Uganda’s public
morphine program
O’Brien49
Discuss palliative care and
EOL models of care for
Aboriginal people in New
South Wales, Australia
Resistance to the idea of inpatient care due to Aboriginal Australians from their homeland
and community
Ceremonies that assist the spirit to leave the physical body and return to its sacred place
common among Aboriginal people
Lack of understanding of Aboriginal belief systems and their links to the land lead to a
disconnect for health care professionals
Aboriginal people must have culturally appropriate and locally accessible palliative
care services because they have a sense of isolation and are disconnected culturally from
accessing mainstream services
Clarification of the social, emotional, spiritual, and cultural factors that influence decision
making about accessing palliative care among Aboriginals
46
EOL = end of life.
remote areas of Australia. Key elements of the model
included enhanced primary care, 24-hour palliative
care access, weekly multidisciplinary team meetings,
case management review, and a formal outcomes evaluation of existing resources.21 Barriers comprised inequity in community palliative care support and access to
ambulatory and home services for patients with cancer
compared with those without cancer, but with no formal system for after-hours home nursing support, and
lack of dedicated palliative care beds.21 Two studies
evaluated technological support for palliative care in
rural areas.22,23 Wilkes et al22 evaluated an after-hours,
nurse-driven telephone support service and found that
its availability reduced isolation for families caring for
rural palliative care patients at home. Physicians and
nurses were satisfied with its accessibility because they
believed it decreased rehospitalization rates for seriously ill patients.22
October 2015, Vol. 22, No. 4
Bensink et al23 researched the acceptability of
video telephone services to pediatric patients in regional and remote areas. This study team attempted
2 RCTs with this patient population; however, due
to ethical constraints (eg, family reluctance to participate, patients too sick to participate) and technological issues (eg, blurred video, internet connection
problems) the RCTs were not fully carried out.23 They
suggested future research might include integration
of a videotelephony model at the time of diagnosis
with a life-threatening illness, rather than at the time
of palliative care.23
One study evaluated a synergistic, multipronged
palliative care initiative in Zambia, a country with a
high HIV prevalence rate and poor access to care.24
Eight hospices and palliative care organizations in
poor and rural areas were partially funded for 2 years,
and an extensive training program of staff was iniCancer Control 459
tiated.24 A mixed-method analysis of outcome was
conducted and determined that the palliative care environment in Zambia was strengthened with this approach.24 Funding enabled agencies to expand their
services, more reliably offer morphine, provide gas for
transportation, and support patient caregivers.24 Training enhanced staff confidence in caring for very ill
and dying patients and their families, and raised competence and confidence rates were sustained 2 years
later.24 However, once funding ended, services had to
be curtailed, which led to the determination that the
need for sustainable, long-term funding is essential to
maintain success.24
Education
Six studies evaluated palliative care services and education in rural patient settings.25-30 One study used a
retrospective design and a control group.25 The studies
used various education methods (didactic or experiential) and time allocation (half-day to multiple days).25-30
One study developed training methods by assessing
the needs of staff and another tailored the training
to specific patient symptoms (eg, pain, constipation,
dyspnea, delirium).27,30 Training resulted in enhanced
knowledge, and changes to the palliative program, including initiation of a palliative care team, increased
hospice utilization, improved staff attitudes, and improved confidence in providing care.25-28 Most educational programs were low cost but yielded significant
changes in study outcomes.
Financial
Eight studies analyzed financial data from rural-area
palliative care programs: 4 were conducted in the
United States, and 1 each in Canada, South Africa,
Australia, and India.31-38 Smith et al31 conducted preand post-financial analyses of the Rural Cancer Outreach Program (RCOP) in 3 clinics that served 3 to 5
counties in Virginia. Chart audits were performed
after 3 years of operation (post-RCOP) and results
were compared with the 2 years preceding the study
(pre-RCOP).31 Outcome measures included costs (estimated reimbursement from all sources), revenues,
contribution margins, and profit (or loss) of the program.31 RCOP generated at least $1 million in profit
for the rural hospital, even while expanding cancer
and palliative services, and reduced the net cost per
patient by about 40% due to better coordination.31
RCOP was deemed profitable for the rural hospitals,
revenue-neutral for the academic centers (a marked
increase in referrals, including 9% in nononcological
cases, from the rural areas was offset by the poor payer mix, which included uninsured and underinsured
patients), and cost saving for society; it has also continued for 25 years.31
Cassel et al34 performed an analysis of the Rap460 Cancer Control
pahannock Rural Palliative Care Program located in a
5-county rural farming and seacoast area in northern
Virginia. This study collected data from consultations,
physician billing, and receipts, and the researchers calculated hospital charges for patients treated with concurrent palliative care.34
Klinger et al35 analyzed resource utilization and
costs of the Niagara West End-of-Life Care Project during a 15-month period in rural Ontario, Canada. The
project was a success because hospital costs decreased
by more than $400 per day when palliative care was
involved, the in-hospital death rate decreased, and hospice discharges increased.35 The net effect was a sustainable program with $80,000 to $130,000 savings per
year (although this number does not include avoided
rehospitalizations).35
Uys et al33 conducted a 3-month, multisite, homebased care project providing palliative care for South
African patients with AIDS living in underserved areas.
Evaluation of costs included setup (training, equipment and planning), cost per home-based care site,
home-based care operating cost (total and average per
patient), and average hospital inpatient, hospital outpatient, and primary care clinic costs per participating
patient.33 It was not clear whether home-based care
added services or was a cost-effective substitute for
hospital services.33
Bradford et al36 conducted a cost-minimization
analysis to determine the cost of a home telehealth
consultation for pediatric palliative care patients compared with costs of either a face-to-face consultation
at a hospital or a home visit from a palliative care service. The cost for the home telehealth consultation
was cheaper than the other 2 options because the telehealth option required no travel (which substantially
increased costs).36 For families living in rural areas who
must sometimes travel long distances to get to a hospital, video consultation can help ensure equity in access
to quality palliative care.36
Two studies from the same team — one focusing
on India and the other in the United States — focused
on the economic impact of a terminal illness and the
feasibility of training caregivers as a means of stemming illness-related poverty.37,38 The pilot study conducted in India found that patients were forced to give
up work as a result of their illness and, in the majority
of families, caregivers had to change their work habits
and many had to sell assets.38 Most families indicated
that a trained caregiver would have reduced or prevented some of the household’s illness-related change,
and most caregivers said they would be interested in
becoming a trained caregiver.38 The second paper proposed a strategy that would simultaneously mitigate
household financial pressure as a result of illness as
well as train caregivers to provide care that would in
turn address the workforce talent shortage.37
October 2015, Vol. 22, No. 4
Systematic Reviews
Eleven papers were systematic reviews (see
Table 2).39-49 Six of the reviews directly assessed palliative care in rural settings, and 5 assessed some aspect of rural palliative care, though this was not specifically part of the study purposes.39-49 Robinson et
al50 identified and evaluated 79 studies to ascertain
the strength of evidence available to inform public
policy and guidelines and identify direction for future
research. Identified studies were grouped into 3 categories: patient and caregiver perspectives (n = 24),
professional attitudes, knowledge, and practice issues
(n = 28), and health care services (n = 27).50 Our review of these studies concluded that little is known
about experiences of rural patients and their caregivers because only 6 of the 24 studies directly assessed
these perspectives. In addition, a need exists to better
operationalize how palliative care specialists should
integrate with rural primary care physicians. We also
concluded that the medical literature is eclectic and
lacks focused and sustained programs of research
that specifically focus on developing and testing models of palliative care delivery in the rural setting.50
Discussion
When death is imminent, no second chance exists to improve the quality of care for the patient and family.51 Nationally, a significant increase has been seen in palliative
care programs attempting to “get it right the first time”;
however, rural areas still have limited palliative services,
thus resulting in an important disparity for seriously ill
patients with cancer and those without cancer.9 Nevertheless, as is evident from this review, through community support, academic support and partnerships,
telehealth, community advisers, and other creative
strategies, providing expert care to seriously ill patients
may be feasible, even in the most remote locations. Such
success occurs not by bringing the patient to the urban
experts, but by bringing palliative care expertise to the
patient and/or ensuring that palliative care support becomes imbedded into the fabric of the rural community.17,18,21,24 Tailoring studies and methods to the unique
aspects of a rural community likely resulted in most
studies using a quality-improvement design because the
primary goal of the initiative was to improve care in a
particular area or system rather than for the purpose of
creating generalizable knowledge.
We acknowledge that publication bias is a limitation in our review, and we are aware of many unpublished examples of the successful integration of
palliative care into rural communities. For example,
10 years ago, the Center to Advance Palliative Care,
the National Hospice and Palliative Care Organization, and the National Rural Health Association partnered to compile Providing Hospice and Palliative
Care in Rural and Frontier Areas, a comprehensive
October 2015, Vol. 22, No. 4
toolkit with exemplars of rural palliative care programs.52 Key informants from 31 programs were interviewed, representing 5 rural regions across the
United States.52 Yet, our literature search yielded few
added information about their programs since that
monograph was published.52 Nonetheless, the body of
published work that we reviewed has yielded a number of important pearls and lessons.
The first of the 2 RCTs, which used a telehealth/
telephonic approach in patients newly diagnosed with
advanced cancer, was also the first RCT to demonstrate the benefits of palliative care in any locale compared with usual cancer care.12 Despite the positive
rates of patient QOL, mood, and survival outcomes in
the first RCT and positive care giver outcomes in the
subsequent RCT, the results are difficult to generalize
due to the racial/ethnic homogeneity of the study participants.15
Quality-improvement efforts have also demonstrated positive results in rural settings. In the Minnesota Rural Palliative Care Initiative, a needs assessment
was combined with an active quality improvement
project.17 These rural communities identified diverse
community resources and a strong commitment to developing palliative care programs.17 Although palliative specialists were commonly not available, hospice
programs were identified as a primary resource for enhancing clinical knowledge.17 Improving processes of
care was an identified need and teams worked across
settings to meet quality guidelines.17
One finding in this review is that the community
is pivotal to any future plans for developing primary
palliative care services in the rural area. This includes
enhancing education within the community so that
primary care clinicians may have the knowledge to integrate 24-hour palliative care access in the rural area
to all patients with life-threatening illness, not only
patients with cancer. Educational offerings for rural
practitioners may be web-based or onsite intensives.
Partnering with local hospices to assist with palliative
care education for clinicians may be helpful because
the ability of rural health care professionals to travel
to conferences can be a barrier due to lack of time and
insufficient workload relief.9 Cancer Care Manitoba
maintains a website (www.cancercare.mb.ca) describing its long-standing Community Cancer Program Network. According to its website, the Community Cancer
Program Network, in partnership with regional health
authorities, has helped rural patients outside of Winnipeg, Canada, receive oncology care close to home in 1
of 15 community cancer programs.
A primary palliative care model geared toward the
rural setting might include the provision of palliative
care through an existing home nursing–care agency,
interdisciplinary team involvement as needed, difficult
case review with access to tertiary palliative care serCancer Control 461
vices through videoconferencing, a formal assessment
of existing resources, and subsequent outcomes evaluation. Of interest, in the rural Virginia Cancer/Palliative Outreach Program, educating rural health care
professionals was a compelling reason for the retention
of health staff.53 In addition, strategic alliances between
rural health care professionals and academic centers
made access to up-to-date consultations, telehealth,
and experts easier.32
Limited studies, many of which have focused on
rural cancer programs, have documented the cost savings/avoidance of employing palliative care services in
rural areas.54,55 This body of work suggests that the impact of palliative care on health care costs and services is similar for both rural and urban populations.54,55
For example, the $400/day savings observed in the rural Virginia study is very similar to the $279 to $374/
day savings observed in contemporary, urban hospital studies.54 Furthermore, the increased use of home
hospice always follows palliative care consultations55;
the only concern may be that reduced occupancy may
stress rural hospitals, especially if they cannot maintain a census of adequately insured patients. Palliative
care may also positively impact household economics
in rural and urban settings by keeping the patient and
family caregivers economically productive, requiring
less need for travel and time off from work.54,55
The 11 systematic reviews addressed some component of rural palliative care (either alone or combined
with urban studies), but the purposes, quality, and
methodological rigor considerably varied among them.
Thus, any direct comparison, compilation, and formal
ratings of evidence strength among the reviews were
problematic. Nevertheless, a few common themes
were noted:
• Small and insufficient literature base to guide palliative care policy development in rural areas
• Geographical distance and lack of access to palliative care specialists limit the integration of quality
palliative and end-of-life care in rural health care
settings
• Stakeholder perspectives and “on-the-ground” involvement are essential to incorporating palliative
care services to rural settings that are more dissimilar than homogeneous
• Policy and delivery models of rural palliative care
have yet to be fully developed and tested
• Although promising, emerging telehealth and ehealth methods need further testing, with emphases on improving health technology, connectivity,
and competencies of rural health care professionals
Notable gaps in these reviews included assessments of symptom management practices in rural settings and palliative care for specific illness subtypes.
Use of telehealth strategies was prominent as a
way to bring palliative support to patients. This tech462 Cancer Control
nology is ushering in a new era of medicine in which
health care will move toward becoming a commodity
among others that people can access from their home
or mobile devices.56 It is powerful and will entail rethinking the core of medicine, namely the doctor–patient relationship. Its decentralized and electronically
mediated nature and the likelihood of scaling up due
to its convenience (thus driving greater use) is likely to
make quality control and transparent accountability
both more challenging and easier.57 The types of medical errors that can occur while using mobile health
technologies will morph, and methods for reducing
medical errors must be revised to keep up. The roles
of family caregivers and local unskilled, semi-skilled,
and professional providers and distance providers will
all change, entailing adjustments to credentialing and
maintenance of professional certification.58 The economics of care delivery and the form of reimbursement
will likely change, requiring revised models for billing
and insurance. Emerging new issues that can scarcely
be predicted will require assessment of concomitant
regulatory issues.59 Policymakers will need to keep a
close eye on telehealth to keep pace with its rapid development. Given the ability of integrated care-delivery
networks to increase access to high-quality, personcentered care, the time is now to develop and evaluate comprehensive models of telemedicine that include
standardized telephone support, use of peripherals to
assess vital signs and oxygenation status, and video
care to assess and interact with patients who are in a
place of crisis.56,60 These models warrant rigorous testing and attention to the unique challenges and needs
faced by patients in rural areas.56,60
Other successful initiatives to expand palliative
care expertise in low-resource and rural areas have
included community partnerships and training local community clinicians, community health advisers, community health workers, and communication,
behavioral health, and palliative care specialists.10,61
These initiatives can be time intensive due to the
time and need for developing relationships with the
cultural leaders and within the norms of the community.10,61 However, attempting to skip this critical step
could result in efforts not relevant to or not embraced
by community members. Regardless of the strategies
employed, expanding palliative care into rural areas
will take explicit planning and multicomponent,
unique strategies.
Conclusions
Research has informed the development of professional guidelines and integration of the principles of palliation into oncology care, from the time of diagnosis to
end of life among patients with curable cancers, highsymptom burden, and metastatic disease alike. However, the rural setting has created a barrier for these
October 2015, Vol. 22, No. 4
advances to reach patients not located near specialty
centers. This global issue has been recognized and efforts are being initiated to discover novel strategies to
ensure that high-quality palliative and end-of-life care
can reach those living in rural communities.
Telehealth, community health workers, specialists
trained in various health care fields, and other volunteers trained in the approaches of palliative care have
shown promise in bringing complex comfort strategies
to many remote regions of the world. In addition, the
ability to educate all of the health care professionals
working in rural settings presents challenges that are
surmountable. Organized efforts do exist for bringing palliative care skills to rural health clinicians and
care settings. Shortages of palliative care specialists are
a reality, even in urban areas. Hence, every clinician
should have a basic set of primary palliative care skills
of communication, advance care planning, and symptom control to ensure high-quality care for all persons
with cancer and their families.
Acknowledgments: The authors wish to thank
Karen Herman for coordinating the search and Kristen
Allen and Claire Bourgeois for assistance with manuscript preparation.
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illness and the willingness to change it. J Palliat Med. 2010;13(8):941-944.
39. Evans R, Stone D, Elwyn G. Organizing palliative care for rural populations: a systematic review of the evidence. Fam Pract. 2003;20(3):304-310.
40. Hughes PM, Ingleton MC, Noble B, et al. Providing cancer and
palliative care in rural areas: a review of patient and carer needs. J Palliat
Care. 2004;20(1):44-49.
41. Jennett PA, Gagnon MP, Brandstadt HK. Preparing for success:
readiness models for rural telehealth. J Postgrad Med. 2005;51(4):279-285.
42. Wilson DM, Justice C, Sheps S, et al. Planning and providing endof-life care in rural areas. J Rural Health. 2006;22(2):174-181.
43. Steers J, Brereton L, Ingleton C. Palliative care for all? A review of the
evidence in community hospitals. Int J Palliat Nurs. 2007;13(8):392-399.
44. Cox K, Mahone I, Merwin E. Improving the quality of rural nursing
care. Annu Rev Nurs Res. 2008;26:175-194.
Cancer Control 463
45. Robinson CA, Pesut B, Bottorff JL, et al. Rural palliative care: a
comprehensive review. J Palliat Med. 2009. [Epub ahead of print]
46. Downing J, Jack BA. End-of-life care in rural areas: what is different?
Curr Opin Support Palliat Care. 2012;6(3):391-397.
47. Phillips JL, Piza M, Ingham J. Continuing professional development
programmes for rural nurses involved in palliative care delivery: an integrative review. Nurse Educ Today. 2012;32(4):385-392.
48. Jang J, Lazenby M. Current state of palliative and end-of-life care
in home versus inpatient facilities and urban versus rural settings in Africa.
Palliat Support Care. 2013;11(5):425-442.
49. O’Brien AP, Bloomer MJ, McGrath P, et al. Considering Aboriginal
palliative care models: the challenges for mainstream services. Rural Remote
Health. 2013;13(2):2339.
50. Robinson CA, Pesut B, Bottorff JL. Issues in rural palliative care:
views from the countryside. J Rural Health. 2010;26(1):78-84.
51. Higginson IJ, Hearn J, Webb D. Audit in palliative care: does practice
change? Eur J Cancer Care (Engl). 1996;5(4):233-236.
52. National Rural Health Association. Providing Hospice and Palliative
Care in Rural and Frontier Areas. Leawood, KS: National Rural Health Association; 2005.
53. Smith TJ, Desch CE, Simonson CJ, et al. Teaching specialty cancer medicine in rural hospitals: the cancer outreach program as a model.
J Cancer Educ. 1991;6(4):235-240.
54. Morrison R, Penrod JD, Cassel J, et al. Cost savings associated
with us hospital palliative care consultation programs. Arch Intern Med.
2008;168(16):1783-1790.
55. Hughes MT, Smith TJ. The growth of palliative care in the United
States. Annu Rev Public Health. 2014;35:459-475.
56. Adibi S, ed. Mobile Health: A Technology Road Map. Vol. 5.
New York: Springer; 2015.
57. Emanuel LL; Working Group on Accountability. A professional response to demands for accountability: practical recommendations regarding ethical aspects of patient care. Ann Intern Med. 1996;124(2):240-249.
58. American Telemedicine Association website. http://www.american
telemed.org. Accessed November 5, 2015.
59. American Hospital Association. Realizing the promise of telehealth:
understanding the legal and regulatory challenges. TrendWatch. Published
May 2015. http://www.aha.org/research/reports/tw/15may-tw-telehealth
.pdf. Accessed November 5, 2015.
60. Kelley AS, Meier DE, eds. Meeting the Needs of Older Adults With
Serious Illness. New York: Humana Press; 2014.
61. Kaasalainen S1, Brazil K, Kelley ML. Building capacity in palliative
care for personal support workers in long-term care through experiential
learning. Int J Older People Nurs. 2014;9(2):151-158.
464 Cancer Control
October 2015, Vol. 22, No. 4
Palliative care benefits patients with cancer
in the outpatient setting, and such
care should be concurrently and routinely
provided with oncology treatment.
Photo courtesy of Lisa Scholder. Family. 16" × 24".
New Frontiers in Outpatient Palliative Care for Patients With Cancer
Michael W. Rabow, MD, Constance Dahlin, ANP-BC, ACHPN, Brook Calton, MD, Kara Bischoff, MD,
and Christine Ritchie, MD, MSPH
Background: Although much evidence has accumulated demonstrating its benefit, relatively little is known
about outpatient palliative care in patients with cancer.
Methods: This paper reviews the literature and perspectives from content experts to describe the current state
of outpatient palliative care in the oncology setting and current areas of innovation and promise in the field.
Results: Evidence, including from controlled trials, documents the benefits of outpatient palliative care in
the oncology setting. As a result, professional medical organizations have guidelines and recommendations
based on the key role of palliative care in oncology. Six elements of the practice sit at the frontier of outpatient
oncology palliative care, including the setting and timing of palliative care integration into outpatient oncology, the relationships between primary and specialty palliative care, quality and measurement, research,
electronic and technical innovations, and finances.
Conclusions: Evidence of clinical and health care system benefits supports the recommendations of professional organizations to integrate palliative care into the routine treatment of patients with advanced cancer.
Introduction
In fundamental ways, the field of palliative care has developed in the context of oncology, and the majority of
both clinical palliative care service and palliative care
From the Divisions of General Internal Medicine (MWR), Geriatrics (BC, CR), Hospital Medicine (RB), Department of Medicine,
University of California, San Francisco, and the Hospice and
Palliative Nurses Association (CD), Pittsburgh, Pennsylvania.
Submitted April 15, 2015; accepted June 23, 2015.
Address correspondence to Michael W. Rabow, MD, University
of California/Mount Zion, 1545 Divisadero Street, Number 313,
San Francisco, CA 94143-0320. E-mail: mike.rabow@ucsf.edu
Dr Rabow and Ms Dahlin serve as paid consultants to the Center to Advance Palliative Care. Dr Ritchie is a member of the
executive committee of the Palliative Care Research Cooperative Group and is president of the American Academy of
Hospice and Palliative Medicine. No significant relationships
exist between the other authors and the companies/organizations whose products or services may be referenced in this
article.
October 2015, Vol. 22, No. 4
research involves patients with cancer and is conducted in health care centers focused on providing oncology care. Although the development of palliative care
began in the hospital setting for patients during their
last days of life, end-of-life hospital care is but a part of
the much broader approach to care defined by palliative care. Most patients spend most of their time outside of the hospital, either at home, in other residences
such as assisted-living centers, rehabilitation facilities,
and in outpatient medical offices.
Thus, outpatient or community-based palliative
care is recognized as a key frontier in palliative care,
and palliative care in the setting of oncology care is the
core of that frontier.1 Six elements at the frontier of outpatient oncology palliative care are reviewed, including the (1) setting and timing of integrating palliative
care into outpatient oncology, (2) the relationship between primary and specialty palliative care, (3) quality
Cancer Control 465
and measurement, (4) research, (5) electronic and technical innovations, and (6) finances.
Background
Palliative care is defined by the Center to Advance Palliative Care as “specialized medical care for people living with serious illness.”2 This type of care focuses on
providing relief from the symptoms and stress of a serious illness, regardless of the diagnosis. The goal of
such care is to improve the quality of life for both the
patient and his or her family. A team of palliative care
specialists, nurses, social workers, and other health
care professionals collaborate to provide “an extra
layer of support.” Because palliative care is appropriate for any patient, regardless of age or disease stage,
it can be provided along with curative treatment.2 The
National Cancer Institute defines supportive care as
“care given to improve the quality of life of patients
who have a serious or life-threatening disease.”3 We
conceive of much of traditional oncology supportive
care as included in the constellation of services offered
as part of the field of palliative care. Others have argued that supportive care is a broader model than palliative care; however, many medical organizations, including the American Cancer Society and the National
Cancer Institute, interchangeably use these terms.3-6
The field of palliative care grew out of the tradition of supporting patients facing the symptoms and
distresses of illness within healing traditions generally
and Western medicine specifically. With the failure of
the Study to Understand Prognoses and Preferences for
Outcomes and Risks of Treatment trial to improve the
care of hospitalized patients at the end of life, the Robert Wood Johnson Foundation, the Soros Foundation,
and others supported the development and growth of
the field of palliative care.7 In 2006, palliative care was
recognized by the American Board of Medical Specialties as a subspecialty of numerous boards of medicine
and surgery. The American Academy of Hospice and
Palliative Medicine and the Hospice and Palliative
Nurses Association have offered a joint annual assembly since 2004, and the technical support provided by
the Center to Advance Palliative Care has spurred on
the development of an increasing number of inpatient
palliative care services.8 The National Palliative Care
Research Center (NPCRC) and the National Institute of
Nursing Research (NINR)–funded Palliative Care Research Cooperative Group have fostered research in
palliative care, with the NPCRC registry having compiled national operational data for inpatient services.9
In addition to the Palliative Care Leadership Center Initiative from the Center to Advance Palliative Care, other major international palliative care education is led
by the End-of-Life Nursing Education Consortium.10,11
The California State University Institute for Palliative
Care also offers online education for palliative care–re466 Cancer Control
lated disciplines.12
Professional medical organizations have offered
guidelines and recommendations about the role of
palliative care in oncology.13-19 The National Comprehensive Cancer Network (NCCN) is conducting
a study of palliative care services among its member
organizations (personal communication, Jessica Sugalski, MPPA). Marking the philosophical, clinical, and
financial alignment of palliative care and oncology,
the American Society of Clinical Oncology (ASCO)
launched the first annual Palliative Care in Oncology
Symposium in October 2014.20
Benefits
The benefits of outpatient palliative care to patients
with cancer and their families and health care professionals, in addition to the health care system, have
been well documented in a series of studies.21-24 One
review catalogued these benefits, noting that much of
the research referenced came from studies in oncology.21 The most rigorous study designs include the randomized trials of early palliative care in non–small-cell
lung cancer, telephonic palliative care for rural patients
in a cancer center, and palliative care across 24 medical oncology clinics in Canada.22-24 Randomized studies
demonstrate improved satisfaction, clinical outcomes,
mortality, and health care utilization.21
In aligning patient care with individual patient
preferences, palliative care helps to prevent unwanted,
burdensome, and potentially ineffectual oncology-directed treatments at the end of life.25 The result of this
impact on utilization is a demonstrated decrease in the
overall cost of care in the setting of improved quality
care in outpatient palliative care for patients with cancer.26-29 Palliative care in the oncology setting is helping
to align quality and cost.30
Guidelines
In light of data demonstrating the benefits of palliative care for patients with cancer, ASCO issued a provisional clinical opinion that “combined standard oncology care and palliative care should be considered early
in the course of illness for any patient with metastatic
cancer and/or high symptom burden.”13 Thus, ASCO is
signaling that palliative care is a routine part of standard oncological care for patients with advanced disease. The American College of Surgeons Commission
on Cancer (CoC), which issues basic regulations for
oncology centers in the United States, issued standard
2.4 in 2011 that requires these centers to have palliative
care services on site or by referral.14 Although the CoC
is not explicit about how this standard is enforced, the
directive is a powerful statement about the central role
of palliative care in standard oncological care.
The Institute of Medicine (IOM) also focuses on
palliative care and has addressed palliative care in the
October 2015, Vol. 22, No. 4
oncology setting.15,16 A palliative focus underlies the
recommendation of the IOM and directive of the CoC
to oncology centers for universal psychosocial distress
screening.17,18 In addition, palliative care is part of the
supportive care guidelines updated every year by the
NCCN, and palliative care is included as a recommended resource in many of the other NCCN guidelines, including adult cancer pain and ovarian cancer, among
others.19,31,32
Prevalence and Characteristics of Care
Services
Given the fundamental role of palliative care in oncology care and other care programs, relatively little
is known about the prevalence and characteristics of
outpatient oncology palliative care services on a national scale.4 In 2010, Hui et al33 assessed the institutionally reported prevalence of outpatient palliative
care at US National Cancer Institute (NCI)–designated
and non–NCI-designated comprehensive cancer centers. They reported that 59% and 22% of all NCI-designated cancer centers and non–NCI-designated centers
reported an outpatient palliative care clinic, respectively.33 Rabow et al34 reported on established outpatient palliative care practices in the United States,
noting that 80% of patients referred had cancer, and
oncologists accounted for 76% of the overall referrers.
In 2013, Smith et al35 described the general landscape
of outpatient palliative care in the United States and
found that the majority of referred patients had cancer. Unpublished data also add to our understanding of outpatient oncologic palliative care practice.
In 2014, the NCCN obtained information about the
presence of palliative care services from 18 of their
23 member institutions at that time, and all had inpatient palliative care services and 16 (89%) reported
offering outpatient palliative care (personal communication, Jessica Sugalski, MPPA).
Although national data are limited, some individual states have sought to document the prevalence of
outpatient palliative care services. Rabow et al36 studied outpatient palliative care practices affiliated with
California hospitals and found that 7% of hospitals
within California had affiliated outpatient practices (a
proportion not significantly changed compared with a
survey conducted 4 years earlier), with nearly one-half
of referrals from oncology.37
Many problems exist with these prevalence data.
Prevalence estimates for the penetrance of palliative
care in oncology centers may be overestimated due to
inconsistent definitions of what constitutes outpatient
oncology palliative care and the potential inaccuracies
of self-reported survey data.38 Except for NCCN data,
as yet unpublished, much of the data are not recent.33
Although increasing attention is being paid to outpatient palliative care and many institutions appear to be
October 2015, Vol. 22, No. 4
developing services, the evidence for rapid growth is
scant. The study of outpatient palliative care affiliated
with California hospitals suggested that, although new
palliative care programs are developing, established
programs are also disappearing to the point that the
prevalence of outpatient palliative care may not be
changing as many expect.36
Regardless of the specific prevalence figures on local and national scales, the issue of greatest practical
importance is how the capacity of outpatient oncologic
palliative care compares to the need. ASCO’s recommendation for routine palliative care for all US patients
with metastatic cancer or high symptom burden suggests shortages of workforce and clinical capacity.39
With the support of the California HealthCare Foundation, Kerr et al40 assessed the outpatient palliative care
capacity in California, including information about the
presence of outpatient palliative care services from
oncology centers. They estimated a range of need for
palliative care based on estimates of the number of all
deaths in California and the number of deaths from
7 illnesses, including cancer, thus accounting for the
majority of nontraumatic deaths in the state.40 Their estimate suggests that the current capacity for outpatient
palliative care (oncological and nononcological) in California is 24% to 37% of the need, with no type of palliative available in nearly 40% of California counties.40
An international study demonstrated that most oncology palliative care specialists felt their institutions were
unlikely to expand palliative care services due to financial constraints.41
Although the national prevalence and sustainability of outpatient oncological palliative care programs
is not precisely known, interest in the field exists
and there are many exciting areas of innovation and
growth. Six of these areas are reviewed below.
Integration of Care
Setting
Palliative care specialists seek to integrate palliation
within routine oncology care to improve clinical quality.42,43 However, despite widespread calls for integration, no consensus exists about how this is best done.
We do not have a clear vision of what constitutes integration or the added value of various elements of integration.4,44 At a basic level, integration is influenced
by the setting of palliative care. Although stand-alone
palliative care clinics in academic medical centers were
some of the first outpatient palliative care services offered to patients with cancer, palliative care services
are “embedding” into oncology practices.29 Embedded
clinics improve the potential for palliative–oncological
integration and collaboration, and they increase convenience for patients able to avail themselves of “onestop” clinical care. Embedded care requires enhanced
palliative care competencies for nurses and social
Cancer Control 467
workers in these clinics in order to provide interdisciplinary palliative care.45
The precepts of patient-centered care suggest
the need for services available to patients with cancer
throughout the course of their disease and wherever
that patient is living (home, long-term care, rehabilitation facility). Those in outpatient palliative care are recognizing the need for more home-based palliative care
services.46,47 Providing “palliative care everywhere,”
including in the gaps of care between health care transitions and at night and on weekends, is likely to be
necessary to prevent the inefficient utilization of emergency departments and acute care hospitals for preventable symptom-management burdens.48
Although patients who are homebound due to
advanced cancer may also be too disabled to benefit
from chemotherapy, oncologists may be able to extend the care of homebound patients with orally targeted therapies and home-based palliative care. In fact,
home-based palliative care is increasingly recognized
as key for patients who are homebound or nearly so
and have significant symptomatology but do not qualify for home hospice because of a prognosis longer than
6 months, patient refusal of hospice, or the desire to
receive concurrent oncological or other disease-management services (eg, blood transfusions, artificial nutrition) along with palliative care.49 This includes specialty oncology home services that offer monitoring
of home infusion of chemotherapy and other fluids.49
Given resource and workforce limitations, innovative
palliative care programs are collaborating with hospice
organizations or home-based medical and assisted-living services that often have the expertise and capabilities to provide palliative care at home, including in rural and challenging urban settings.49
Timing
Outpatient palliative care allows patients with cancer
to be seen early in the course of their illness.29 Potential benefits of early outpatient oncology palliative care
include aggressive management of adverse events and
symptoms, longitudinal psychosocial support for patients and their caregivers, and the facilitation of conversations on the understanding of illness, prognostic
understanding, and transitions of care as agreed upon
by the health care team.
A growing body of literature suggests that early
outpatient palliative care is beneficial.22-25,29,50 Three
randomized control trials of early, integrated palliative
care plus oncological care compared with standard oncological care alone reported improvements in quality of life, depression, and satisfaction among patients
with advanced cancer and limited prognoses.22-24,50
Temel et al22 found that 151 patients with newly diagnosed non–small-cell lung cancer had a 2.5-month longer survival rate when they were randomized to early
468 Cancer Control
palliative care. Early palliative care has also been associated with reduced health care utilization in studies comparing early palliative care with usual oncology
care and late palliative care (ie, > 90 days or < 90 days
before death).22,25,29
However, the optimal timing of outpatient palliative care involvement to maximize clinical benefit remains unknown. A recent study randomizing patients
with advanced cancer to early in-person outpatient
palliative care consultation plus nursing telephonic
coaching sessions (within 30–60 days of diagnosis) or
late sessions (approximately 4 to 5 months after diagnosis) found no improvements in patient outcomes (eg,
quality of life) or health care utilization.23 However, the
same study found a 15% improvement in rate of survival for patients receiving early palliative care.23 The
results of this study raise questions regarding the optimal timing of palliative care interventions along with
the mechanisms that contribute to increased survival
rates.23 Further complicating the question of timing is
that the benefits of palliative care may differ by cancer
type and prognosis. Additional research is needed to
guide when, along a patient’s cancer journey, palliative
care can have the most reliable and effective impact.
In most referral systems, outpatient oncologists
play a crucial role in deciding on the need for and timing of palliative care referral.51 Although a significant
increase has been seen in the use of palliative care by
oncologists overall, data from a national survey suggest that a minority of oncologists frequently refer their
patients to pain or palliative care specialists.52,53 Furthermore, when referrals do occur, they tend to be late
in the patient’s illness course, typically 30 to 60 days
before death.54 Potential explanations for the lack of
referrals or late referrals include the misperception by
the oncology team members that palliative care means
end-of-life care, concern that referral will cause patients to feel defeated, frightened, or lose hope, limited
access to services, not knowing the appropriate time
to refer, and under-recognition of the patient concerns
that might benefit from palliative care consultation.
One study found significant differences between the
reasons an oncologist referred to palliative care compared with a comprehensive screening system.55
Currently, no national standards for outpatient palliative care referral exist. Identifying reliable markers
and developing standardized screening tools to trigger
timely outpatient palliative care referral would likely
address some barriers to referral and help integrate
palliative care into oncology care. Potential indicators
could include prognosis using validated prognostic
models, index hospitalization for symptom management or loss of function, development of increased
symptom burden, referral of patients with cancers with
historically poor prognoses and/or high symptom burden, or progression after first-line chemotherapy.
October 2015, Vol. 22, No. 4
Primary vs Specialty Palliative Care
The future of comprehensive cancer care includes palliative care beginning at diagnosis and, in particular,
for advanced disease. Given both the need for and benefits of providing palliation in the oncology setting, as
well as the shortages of health care professionals specializing in palliative care, the development of primary
palliative care training and competence among oncologists is key. With mandates from ASCO, CoC, NCCN,
and IOM for palliative care as part of comprehensive
cancer care, outpatient oncology care necessitates that
all health care professionals providing oncology care
have primary palliative care skills as well as access to
palliative care specialists.13-19 All oncologists must learn
to understand basic palliative care concepts and to appropriately utilize palliative care as part of comprehensive, patient- and family-focused care.
A distinction is emerging between primary palliative care and specialty palliative care within oncology care.56 Although both settings pertain to pain and
symptom management and communication, clear delineations exist in skills (Tables 1 and 2).56-59 Primary
palliative care addresses relief of symptoms, including
basic management of pain and symptoms (eg, depression, anxiety) and communication skills (eg, goals of
care inclusive of prognosis, advance care planning,
code status). All oncologists can and must learn palliative care skills. Depending on the clinician’s discipline,
options exist for primary palliative care education.
Nurses, physicians, and social workers may obtain
some palliative care competency through their routine
education and training; however, this is usually insufficient.60 Oncology physician fellowships offer an overview of palliative care, symptom management, and
communication skills. Oncology nurses may receive
education in common symptoms for specific cancers
and management of those symptoms. Other specialized programs, such as End of Life Nursing Education
Consortium and Education in Palliative Care and Endof-life Care for Oncology, focus on the care of patients
with cancer.57,61 Another program for psychologists, social workers, and spiritual care professionals is the Advocating for Clinical Excellence: Transdisciplinary Palliative Care Education.62 In real time, the collaboration
around individual patients between specialty palliative
care teams and oncology teams can create opportunities for cross education. In clinical work together, oncologists can learn primary palliative care concepts
and palliative care specialists can learn about primary
oncology concepts.
Beyond education, new paradigms of primary palliative care in oncology are evolving. One model is an
oncology nurse navigator who employs primary palliative care skills to address patient symptom needs, engage patients in their care through advance care planning, provide emotional support, and communicate
October 2015, Vol. 22, No. 4
Table 1. — Primary and Specialty Palliative Care
in Oncology Care
Primary
Specialty
Basic symptom management
of physical and psychological
symptoms
Cancer-related pain
Depression
Anxiety
Relief of symptoms
Complex symptom management of
refractory symptoms
Complex pain
Complex depression
Existential distress
Communication
Cancer prognosis
Goals of treatment
Communication
Conflict management within the
circle of patients, families, and
health care team
Advance care planning
Ethics (in particular, medical futility)
Adapted from Quill TE, Abernethy AP. Generalist plus specialist
palliative care — creating a more sustainable model. N Engl J Med.
2013;368(13):1173-1175. Copyright ©2013 Massachusetts Medical Society.
Reprinted with permission from Massachusetts Medical Society.
Table 2. — Importance of Palliative Care as
Part of Cancer Care
Goals
Action
Primary Palliative Care Recommendations
The cancer care team should
provide patients and their
families with understandable
information on cancer prognosis, treatment benefits
and harms, palliative care,
psychosocial support, and
estimates of the total and outof-pocket costs of cancer care.
The cancer care team should
collaborate with their patients
to develop a care plan that
reflects their patients’ needs,
values, and preferences,
and considers palliative care
needs and psychosocial
support across the cancer
care continuum.
In the setting of advanced
cancer, the cancer care team
should provide patients with
end-of-life care consistent
with their needs, values, and
preferences.
Professional educational
programs for members of
the cancer care team should
provide comprehensive
and formal training in endof-life communication.
Specialty Palliative Care Recommendation
Members of the cancer care
team should coordinate with
each other and with primary/
geriatrics and specialist care
teams to implement patient care
plans and deliver comprehensive, efficient, and patientcentered care.
Academic institutions and
professional societies should
develop interprofessional
education programs to train
the workforce in team-based
cancer care and promote
coordination with primary/
geriatrics and specialist
care teams.
All individuals caring for patients with cancer should have
appropriate core competencies.
Cancer care delivery organizations should require that
the members of the cancer
care team have the necessary
competencies to deliver
high-quality cancer care, as
demonstrated through
training, certification, or
credentials.
Republished with permission of National Academies Press. From Institute
of Medicine. Delivering High-Quality Cancer Care: Charting a New Course
for a System in Crisis. Washington, DC: The National Academies Press;
2013. Permission conveyed through Copyright Clearance Center, Inc.
Cancer Control 469
with the oncology team about care needs.63 Other palliative care teams have reported on their primary palliative care education for oncologists.64
Even in the setting of primary palliative care by
oncologists, specialist palliative care teams can improve the overall care of patients with cancer.65-72 Specialty palliative care includes the complex management of refractory pain and symptoms, addressing
grief and existential distress, and medical futility, as
well as more advanced communication such as management of conflict among patients, families, and the
health care team. A qualitative review of a small sample of patients with lung cancer who had early intervention specialty palliative care received a range of
services, including psycho/spiritual/emotional support, symptom management, advance care planning,
and promotion of illness understanding.65 Other studies have demonstrated better symptom control and earlier referral to hospice with specialty palliative care.66,67
By reducing and relieving the stress of care, specialty
palliative care saves oncologists time and allows the
oncology team to focus on cancer treatment.68,69 Implementation of specialty palliative care within oncology
varies and can include palliative care teams that have
clinical space in the oncology clinic and are embedded
into care delivery, advanced-practice oncology nurses
or oncologists who provide oncology care on one day
and specialty care on other days, and specialty palliative care clinics within the community.70-72
The relative roles and balance of responsibilities
between primary and specialty palliative care teams in
the outpatient setting remain to be clarified, but they
will need to individualized based on resources, expertise, and access to specialty health care professionals.
Integration of primary and specialty palliative care
is likely to vary depending on whether the oncology
practice is part of an independent practice, hospital, or
large health care system.
Quality and Metrics
The theoretical benefits of outpatient palliative care
services or an informal sense of patient and clinician
satisfaction were historically sufficient to justify support for services. However, increasingly, outpatient palliative care is being challenged to demonstrate its quality objectively, similar to other fields of medicine. This
has ignited a broad conversation about how the quality
of outpatient palliative care can be best measured.
The American Academy of Hospice and Palliative
Medicine and Hospice and Palliative Nurses Association convened a working group to review the existing
literature about quality measures in palliative care and
to select 10 measures considered to be the highest priority because of their scientific validity and clinical utility to promote across the field.73 The majority of quality
metrics prioritized by this initiative pertained to either
470 Cancer Control
hospice or inpatient palliative care, because these are
the settings in which most of the research has been
done.74 An important next step will be to determine
how they should be extrapolated to the outpatient palliative care in oncology centers. Similarly, the National
Quality Forum formally endorsed 13 quality measures
for palliative care in 2012, but the majority of these
pertain to patients in the hospital or hospice settings;
1 measure is specifically tailored to measure the quality of outpatient palliative care at oncology centers.75
The Quality Oncology Practice Initiative is an oncologist-led quality assessment program that has promoted
a unified set of quality measures for oncology since
2011.76 Its list of metrics includes several that pertain
to palliative care, including pain assessment and management, dyspnea assessment, constipation assessment, management of nausea and emesis, provision of
hospice and palliative care, and location of death.77 Although evidence for these activities is abstracted from
oncologist notes, more complete information about the
quality of care that patients with cancer receive could
be determined by also examining the work of palliative care specialists. The American College of Surgeons
CoC set a new standard to be implemented by 2015
stating that all patients with cancer must be screened
at least once for distress and social concerns using a
survey instrument (eg, distress thermometer).18,78 The
role of palliative care specialists in performing or responding to screening has not yet been determined,
but having a robust plan will be critical to respond to
the distress identified.
Traditionally, quality metrics considered for outpatient palliative care are intended for patients being
evaluated by palliative care specialists. However, an
even larger — and unanswered — question is how to
measure and improve the quality of the primary palliative care that oncology teams provide to patients.
In addition to establishing consensus quality metrics for palliative care, methods must be developed to
collect and share standardized data across outpatient
palliative care programs to benchmark and drive improvement. The Palliative Care Quality Network and
the Quality Data Collection Tool provide 2 formats for
the prospective collection and comparison of standardized palliative care data.79,80 Prospective data collection makes it possible to obtain patient-reported outcomes in a standardized way, thus allowing for quality
improvement efforts that target clinical outcomes (eg,
constipation improvement) rather than just processes
of care (eg, treatment of constipation). These organizations also provide opportunities for the collaboration
of coordinated quality improvement projects across
sites that may enable greater gains in quality and safety
than any single program could make alone.79,80
Robust measurement, reporting, and quality improvement are important next steps for outpatient palOctober 2015, Vol. 22, No. 4
liative care to help ensure the best care for our patients
and to continue to earn the confidence of oncology
specialists.
Research
Recognizing its growing importance, prominent
entities such as the IOM, the Patient Centered Outcomes Research Institute, and the National Institutes
of Health have recommended that palliative care
research become a national priority.81 Many unanswered questions warrant research in outpatient
oncology palliative care. The study by Temel et al22
raised a number of key questions, including whether
the benefits seen in patients with non–small-cell lung
cancer can be generalizable to patients with other
cancers, whether their study results can be generalizable to other oncology centers, whether palliative
care focused on those with metastatic disease would
show the same benefit in if provided to those without
metastases, and, of the 7 key elements of palliative
care in their intervention, which one would account
for the most benefit and which ones are true across
different cancers in different settings.
Other important research questions in outpatient
oncology palliative care include which models of care
offer the most effective patient-centered approach to
care and which patient and treatment factors contribute
most to poor quality of life and how these factors can
be modulated to improve patient wellbeing. In 2013,
the National Institute of Nursing Research launched
the Innovative Questions initiative.82 The goal of this
initiative was to initiate a dialogue with the National
Institute of Nursing Research stakeholders to identify
novel scientific questions. Two of the topic areas were
of particular relevance to outpatient oncology palliative care: symptom science and end-of-life/palliative
care. A number of these questions directly related to
outpatient oncology palliative care research (Table 3).82
Investigators, health care systems, and national
organizations are seeking to facilitate research into
these questions. The NPCRC promotes palliative care
research in an era where many palliative care researchers work in isolation with few other collaborators in their institution.83 The NPCRC also helps to develop junior investigators and supports research that
can be rapidly and directly translated into improved
clinical practice.83 The Palliative Care Research Cooperative Group focuses on answering research questions that cannot be easily answered at a single site.84
It provides infrastructure for efficient, multisite palliative care research by offering a network of motivated,
coordinated, investigators/sites that create capacity
for multisite research, as well as methods, tools, and
processes that promote the timely and valid conduct
of robust cooperative group research.84 These 2 organizations support oncology palliative care research
October 2015, Vol. 22, No. 4
Table 3. — Selected Items From the Innovative
Questions Initiative
How do we overcome barriers in underserved, hard-to-reach populations to implement culturally congruent, patient-, and caregivercentered palliative care strategies?
What oncology palliative care interventions/strategies best align
with patient and caregiver goals?
How do type, intensity, complexity, and fluctuation of symptom
burden in oncology patients impact individual and family goals
for care?
What are the best models for community-based oncology
palliative care?
What are the strategies for assessing caregiver preparedness and
self-care abilities for oncology palliative care early in the illness
trajectory?
For symptom management at the end of life, what are the best
minimally invasive methods to monitor functional status,
physiological status, and patient reported outcomes?
What electronic data collection methods can be used by health
care professionals to monitor, evaluate, and improve palliative/endof-life care?
What are the best ways to measure patient reported outcomes
using standardized, widely used instruments or common data
elements?
From National Institute of Nursing Research. The science of compassion: future directions in end-of-life palliative. http://www.ninr.nih.gov/
newsandinformation/iq#.VStKxvldWSr. Accessed September 18, 2015.
and seek to facilitate investigator development in research oriented toward oncology palliative care.83,84
Technology
To comprehensively care for patients across the continuum of oncology care (in hospitals, clinics, home, and
in the community), the future of outpatient palliative
care in the oncology setting will depend on technological innovations. Technology is beginning to address
barriers of space, time, and the limited clinical availability of specialty expertise, and it will be useful as
part of a number of the elements of outpatient palliative care in the oncology setting.
Technology can provide patient education and
support. Beyond how patients and families use social
media, support groups are available online with and
without professional facilitation, and smart phone applications and websites exist to assist patients and families with symptom assessment, advance care planning,
and family caregiver support.85 The applicability and
benefits of a select number of these services have been
evaluated.86-88 Telephonic and video health technology
can provide effective clinical care for patients unable to
travel due to disability or distance.89 Few interventions
have been rigorously evaluated.23 Patient outcomes
electronically reported are the core to some of these
technologies and this will be facilitated by developments in what has been called the “quantified self.”90,91
Key patient documents, including physician orders for
Cancer Control 471
life-sustaining treatment paradigms and advance directives, can be stored and accessed online, improving
care across the continuum of sites over time. Patient
privacy and Health Insurance Portability and Accountability Act concerns must be addressed as clinical care,
patient-reported outcomes, and storage of these data
and other health documents occur electronically and
move online and, thus, outside the physical boundaries
of individual medical centers and across state and national lines. The potential for better care from analysis
and research using “big data” is profound. Technology
can also increase the efficiency of primary palliative
care education and consultation. Educational curricula
can be shared within computerized health systems and
electronic medical records, as well as online. Palliative
care specialists can provide e-consults to treating oncologists at a distance.
Financing
In a fee-for-service system for oncology care, the incentives of individual oncologists and hospitals are
aligned with the provision of multiple treatments and
services (volume-based payment) without respect to
the value of those treatments and services.92 The future
of oncology care likely involves the ongoing development and penetration of more global health care budgets, including for oncology care, in which efficiency
and value (both clinical benefits and cost) are scrutinized and incentivized. ASCO recommends the early
integration of palliative and oncology care as a means
to improve quality and value, thus reducing the rising
costs of oncology care at the end of life.30,93 Although
most research documenting the cost effectiveness of
palliative care has been conducted in the inpatient
setting, outpatient oncology palliative care has demonstrated its role as part of comprehensive oncology
care to improve the efficiency of health care utilization,
thereby helping to control costs.22,25,94,95 Palliative care
in the outpatient oncology setting will continue to be
defined by the historical alignment of quality and cost
in today’s environment of health care reform.
Conclusions
Evidence suggests that palliative care in the outpatient
oncology setting is beneficial. As a result, professional
organizations have issued guidelines and recommendations about the role of palliative care in oncology.13-19
Palliative care is integral to quality comprehensive care
for patients with symptoms from cancer, advanced disease, or other serious illness.58,59 Six areas are at the
forefront of outpatient palliative care for patients with
cancer, including (1) the setting and timing of palliative care integration into the outpatient setting, (2) the
relationship between primary and specialty palliative
care, (3) quality and metrics, (4) research, (5) electronic
and technology innovations, and (6) health care financ472 Cancer Control
ing. Experts in these frontiers have also begun to address the profound challenge of workforce shortages
in specialty palliative care. Through the successful integration of oncology and palliative care, all patients
with cancer should be able to receive standard, comprehensive, integrated care that allows them to live as
long and as well as possible.
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474 Cancer Control
October 2015, Vol. 22, No. 4
Oncologists should collaborate
early with palliative care
specialists to help care for AYA
patients with cancer.
Photo courtesy of Lisa Scholder. Sunlit, 16" × 24".
Palliative Care in Adolescents and Young Adults With Cancer
Kristine A. Donovan, PhD, Dianne Knight, MD, and Gwendolyn P. Quinn, PhD
Background: Cancer survival rates for adolescents and young adults (AYA) have not improved over time
relative to children or adults older than 39 years of age. Palliative care is specialized medical care focused on
the control of symptoms and relief of suffering with the goal of improving quality of life for the patient and
his or her family. To date, the integration of palliative care in AYA patients with cancer remains suboptimal.
Methods: We explore the role of palliative care in the continuum of clinical care for AYA patients with cancer.
Results: Clinical practice guidelines highlight the need for integrating palliative care for all patients with
cancer, including the AYA population. Despite this, a paucity of evidence exists regarding the use of palliative
care with AYA patients with cancer. Graduate clinical education represents an opportunity to promote the
full inclusion and early integration of palliative care in the care of AYA patients with cancer. Advance care
planning is one area where some agreement exists on the unique needs of AYA patients and their families.
Conclusions: In general, palliative care is seen as being synonymous with end-of-life care for patients with
cancer. However, the emerging trend toward standardizing oncology care to meet the unique medical, psychosocial, and supportive care needs of AYA patients with cancer and their families represents an opportunity for
health care professionals to collaborate early with palliative care specialists to control symptoms and relieve
suffering in this vulnerable population.
Introduction
Defined on the basis of age and cancer biology, cancer
in adolescents and young adults (AYA) accounts for approximately 6% of all invasive cancers diagnosed on a
yearly basis.1 Each year, nearly 70,000 AYA patients in
the United States receive a cancer diagnosis.2 The incidence of specific cancers in the AYA population varies
From the Department of Supportive Care Medicine (KAD, DK)
and the Health Outcomes and Behavior Program (KAD, GPQ), H.
Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
Submitted June 15, 2015; accepted July 15, 2015.
Address correspondence to Kristine A. Donovan, PhD, Moffitt
Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612.
E-mail: Kristine.Donovan@Moffitt.org
No significant relationships exist between the authors and the
companies/organizations whose products or services may be
referenced in this article.
October 2015, Vol. 22, No. 4
across the age span, which is typically defined as between 15 and 39 years.3 In the last 30 years, survival
rates for AYA patients have not improved relative to
younger and older age groups, and cancer is the leading cause of disease-related death in this population.4-6
This lack of improvement in survival has been attributed to numerous factors, including the unique biology of AYA cancers, limited access to care, delays in
diagnosis and treatment, lack of consistency in treatment approaches, patient nonadherence to treatment,
and low rates of access to and participation in clinical
trials, as well as the unique medical, psychosocial, and
supportive care needs of this patient population.7-10
Recent study results suggest that implementation of
the Affordable Care Act will positively affect the AYA
population; however, whether the applicable regulations will result in improved rates of cancer survival
Cancer Control 475
remains to be seen.11,12
Although the continuum of AYA development is
different across its age span, many issues have been
identified that distinguish AYA from pediatric and adult
populations.13-16 Such issues include the transition away
from parental dependence toward dependence on
peers and social networks, concerns about future family and life plans, limited access to mental health services and social and peer support networks, and disruptions in school or work life with the associated financial
challenges.13-15 Although the specific needs of individual AYA patients may vary, as a group, these patients
have more in common than not.7
Cancer and its treatment confound the AYA patient’s
ability to establish autonomy and make independent decisions about education, employment, relationships, and
starting a family.13 In a recent review of palliative care in
AYA, Clark and Fasciano17 distinguish AYA patients as a
vulnerable population and highlight the chasm between
pediatric and adult oncology care where the AYA patient
is often lost. This should be alarming to those who care
for AYA patients, because research suggests that, as a
group, AYA patients tend to experience more complex,
more severe, and longer-lasting distress than children or
adults with similar diagnoses.18-20
Palliative Care
Palliative care is specialized medical care for individuals
with serious illnesses. It focuses on control of symptoms
and relief of suffering with the goal of improving quality of life (QOL) for patients and their families. Palliative
care in cancer is appropriate at any age and at any stage
and can be provided along with curative treatment.21
Palliative medicine is a recognized medical specialty in the United States, and current models of palliative care suggest interdisciplinary approaches that
include both the primary oncology team and a specialized palliative care team facilitate optimal patient
and family care.22,23 In 2012, the American Society of
Clinical Oncology issued a provisional clinical opinion calling for the integration of palliative care into
standard oncology care for patients with metastatic
cancer, high symptom burden, or both.21 This opinion derives from expert consensus and the results of
several randomized controlled trials demonstrating
the benefits of integrating palliative care into standard
oncology care, including a trial of early palliative care
in patients with cancer that found an increased survival benefit for those who received palliative care.21,24
Studies also have demonstrated a beneficial effect of
early palliative care on QOL in patients with advanced
cancer.24-26 By referencing the potentially practicechanging data from these studies, the opinion highlights the increasing relevance of palliative care for the
care of all patients with cancer.21 Consistent with the
opinion of the American Society of Clinical Oncology,
476 Cancer Control
many professional organizations now recommend that
patients with cancer be screened for palliative care
needs.21,23,27,28 For example, guidelines from the National Comprehensive Cancer Network recommend
that all patients with cancer be routinely screened and
rescreened at appropriate intervals for palliative care
needs.23 The guidelines also recommend early collaboration with palliative medicine specialists to improve
QOL.23
Cancer Treatment
Despite the focus on symptom control and QOL at any
stage of disease or treatment, palliative care teams
have historically been more often involved in the care
of patients with cancer deemed challenging or at or
near the end of life.7,29 The result is that, among oncology care providers, palliative care is generally synonymous with end-of-life care.29 Thus, integrating palliative care into standard oncology care for AYA, like that
for pediatric and adult patients with cancer, remains
suboptimal.30 To the best of our knowledge, no trial
has integrated early palliative care into the care of AYA
patients with cancer receiving treatment.
Data on symptom burden in AYA patients, especially at the end of life, are limited. Data on AYA patients with cancer are often contained within the adult
and pediatric oncology literature, making it difficult
to discern the potential effects of palliative care in the
vulnerable AYA population.31-33 Nevertheless, data indicate most AYA patients with cancer experience multiple physical and psychological symptoms and often
spend their last days of life within an acute care setting, with end-of-life discussions often occurring only
when death is imminent.34-36
In one of the few studies to date of symptom
burden in AYA patients with advanced cancer, Cohen-Gogo et al35 conducted a retrospective review of
the medical records of 45 AYA patients with cancer
treated in a specific AYA oncology unit who died as a
result of progressive disease during a 2-year period.
Diagnoses of sarcoma or a brain tumor predominated
and accounted for 78% of diagnoses.35 A total of 40%
of patients received palliative chemotherapy during
the last month of life.35 The median time between the
last cycle of chemotherapy and death was 30 days
(range, 2–457 days).35 A total of 24% of patients received radiotherapy in the last month of life, mostly
for pain and symptoms related to tumor volume.35
One-third of patients received artificial nutrition during the last week of life.35 The median number of
physical symptoms was 4 (range, 1–7).35 Pain and dyspnea were the most common symptoms, particularly
among patients with sarcoma, whereas patients with
a brain tumor were more likely to experience paralysis, confusion, or coma.35 With respect to psychological symptoms, during the last month of life, all paOctober 2015, Vol. 22, No. 4
tients reported sadness, anxiety, fear of being alone,
fear of death, fear of pain, and guilt.35 A total of 77%
of patients met with the psychologist on staff at the
AYA unit during their initial anticancer treatment; of
these patients, 83% continued to receive care from the
psychologist during the last month of life.35 In addition, most of the patients admitted to the unit spent
more than 2 weeks in the hospital (median, 16 days;
range, 0–30 days) during the last month of life.35
Although this study provides only general baseline
information about symptoms and patterns of end-oflife care of AYA patients treated in 1 specific AYA unit,
it is noteworthy that in most of the patients, end-of-life
care continued to be an active period of care.35 Many
of the patients experienced substantial physical and
psychological symptoms during the last week of life, a
finding that supports the need for a well-trained, multidisciplinary palliative care team to collaboratively
work with other members of the health care team.35
Data on QOL among AYA patients with advanced
cancer are also scarce, either from descriptive observational studies or randomized controlled trials of interventions aimed at enhancing QOL at any point along
the disease trajectory. In a systematic review of the
literature regarding QOL in AYA patients with cancer,
Quinn et al37 identified 35 studies whose outcomes
were any psychosocial factors affecting QOL in AYA
patients. Most of the studies they reviewed focused on
the post-treatment survivorship period and, broadly
defined, the psychosocial supportive care needs of
AYA cancer “survivors.”37 Only 1 study involved AYA
patients with advanced cancer with an eye toward palliation of symptoms — in this case, at the end of life to
improve QOL.35 In their review, Quinn et al37 note lack
of sufficient QOL measurement tools and lack of evidence-based interventions to improve QOL in AYA at
any point in the cancer care trajectory. They conclude
by commenting on the unique needs of the AYA population and the emerging trend toward standardizing
oncology care for this population (for additional commentary, see Thomas et al38).
Palliative care has not been established in standard
oncological care for AYA patients with cancer. However,
clinical practice guidelines aimed at the care of AYA patients with cancer across the continuum of care — from
diagnosis to survivorship, or end of life — have begun
to reflect the need for integrated palliative care.15 For
example, consistent with the recommendation that oncology care providers collaborate early with palliative
medicine specialists to control symptoms and reduce
suffering in all patients with cancer, guidelines from
the National Comprehensive Cancer Network include
several considerations for palliative care.15 The guidelines note that referral to palliative care is appropriate
when patients are being treated with curative intent,
that palliative care may be initiated at diagnosis (to
October 2015, Vol. 22, No. 4
provide the best possible care for patients), and that
interdisciplinary members of the palliative care team
should have expertise in understanding the psychosocial, emotional, and developmental issues unique to
the AYA cancer population.15 The guidelines also specifically note the importance of creating an AYA team
that includes palliative care as a means of improving
early referrals, research, and patient-centered care.15
Clinical Education
The creation of an AYA team that includes a palliative
care clinician knowledgeable about the unique needs
of AYA patients with cancer highlights a critical fact.
As Wiener et al39 note in their review of factors that
make the provision of palliative care particularly challenging in AYA, a dearth of clinicians exists, both in
medicine and nursing, who have the requisite training and skills in palliative care needed to care for AYA
with cancer. Formal palliative care training is limited in the average US medical school curriculum.39-41
Furthermore, training in adolescent medicine in the
United States has been described by many graduates
of subspecialty medical residency programs as inadequate for clinical practice.39,42,43 Some commentators,
who are aware of the chasm that exists between pediatric and adult oncology care, have suggested that
the key to appropriate symptom palliation among AYA
patients with cancer is to transition the AYA patient to
the adult oncology setting.44 Others have emphasized
the need for specialized AYA multidisciplinary palliative care teams that can work in both pediatric and
adult facilities.45,46 However, the most convincing commentators are those who seek to integrate palliative
care into AYA oncological care by offering educational
strategies for teaching clinicians about palliative care
in the AYA population.
To this end, Wiener et al39 have proposed an educational and conceptual model for education aimed
at palliative care in the AYA population that acknowledges existing contextual barriers, such as the limited
exposure of clinicians-in-training to functional multidisciplinary teams. The model addresses key aspects
of clinician development: knowledge (eg, of human
development), skills (eg, symptom management, ability to work in teams), and attitudes (eg, about patient
dignity).39 Weiner et al39 also advocate for the teaching
of palliative care concepts via educational strategies
and mentorship with the greatest potential to improve
AYA outcomes. With respect to outcomes, their model
highlights social outcomes, such as receiving respect,
feeling understood, and trusting the system, and physical outcomes.39
Advance Care Planning
In comprehensive palliative care, discussions about
end-of-life care are paramount, and advance care planCancer Control 477
ning documents are often used to facilitate these discussions.23 Several advance care planning guides are
available for adults, including Five Wishes (Age With
Dignity, Tallahassee, Florida; https://fivewishesonline.agingwithdignity.org), which is a document that
appoints a legal health care decision-maker at the
end of life and specifies an individual’s desired therapies for medical care (eg, palliative care). Five Wishes largely focuses on the expressed desire of adults
to participate in medical decision-making regarding
treatment at the end of life.
Researchers have begun to explore whether AYA
patients with cancer are similarly motivated to participate in end-of-life discussions and whether they consider these discussions to be beneficial.31,47-52 Evidence
does suggest that AYA patients with cancer are interested in having end-of-life discussions and that the
patients, their families, and their health care professionals all benefit from such discussions.48,51 Although
adult patients with cancer tend to focus on decisionmaking related to their end-of-life care, AYA patients
with cancer appear to be more concerned with how
they want to be treated and remembered than about
decision-making.47
Whether this finding is related to developmental
differences (eg, many adolescent patients may depend
on their parents to make treatment-related decisions
for them) or to a limited understanding of life-support
treatment options and the legal aspects of end-of-life
care is unclear. Regardless, such findings suggest that
advance care planning documents used to facilitate
end-of-life discussions with AYA patients should include developmentally appropriate language and terminology and must also reflect AYA patient values and
beliefs.47 Thus, advance care planning guides developed for adult patients are not suitable for AYA patients
with cancer and their families.
Voicing My Choices (Aging With Dignity; www.
agingwithdignity.org/voicing-my-choices.php) is an advance care planning guide designed for AYA patients
to help them communicate their end-of-life preferences
to family, caregivers, and friends. The guide was developed by investigators at the National Cancer Institute
and National Institute of Mental Health via iterative
formative research using Five Wishes in a population
of patients with cancer and pediatric patients infected
with HIV.47-49,53
Similar to Five Wishes, Voicing My Choices is designed to facilitate communication between AYA and
their families and health care professionals, including
care providers from the fields of medicine, nursing,
social work, chaplaincy, psychiatry, and psychology.
It consists of an introduction followed by 9 sections,
each one a separate module, that addresses topics such
as how patients wish to be supported so they do not
feel alone, who they would want to make their medi478 Cancer Control
cal care decisions if they cannot make them on their
own, and what they wish their friends and family to
know about them. Five Wishes is legally binding. By
contrast, Voicing My Choices is designed to be a legacy document that is not legally binding but that fulfills
the patient’s final wishes. The effectiveness of Voicing
My Choices is predicated on the skills and attitude of
the health care professional.53 The guide brings family
members or a surrogate decision-maker into the discussion.53 However, it has not been systematically evaluated. Thus, although it is likely to enhance and facilitate discussion between the AYA patient and his or her
health care professional, whether the guide serves to
facilitate discussion between the AYA patient and his
or her family is not yet known. These and other issues
are currently being explored in a multi-institutional trial (NCT02108028), so more information about the utility of the guide should be forthcoming.
Conclusions
Cancer survival rates for adolescents and young adults
(AYA) have not improved over time relative to younger
and older age groups.4-6 Palliative care is specialized
medical care that focuses on control of symptoms and
relief of suffering with the goal of improving quality
of life for the patient and his or her family. Palliative
care is appropriate at any age and at any stage of cancer
and can be provided along with curative treatment.21
To date, the integration of palliative care in AYA cancer care remains suboptimal.30 Existing clinical practice guidelines highlight the need for the integration
of palliative care into the care of all patients with cancer, including the AYA population.21,23,27,28 Despite this,
a paucity of evidence exists regarding the use of palliative care in AYA patients with cancer beyond care in
the last few weeks or months of life.35 Graduate clinical education represents an opportunity to promote
the full inclusion and early integration of palliative care
in the care of AYA patients with cancer.39,42,43 Advance
care planning is one area where some agreement exists
on the unique needs of AYA patients and their families.
Although palliative care is generally still synonymous
with end-of-life care in cancer care, the emerging trend
toward standardizing oncology care to meet the unique
medical, psychosocial, and supportive care needs of
AYA patients and their families represents an opportunity for health care professionals to collaborate early
with palliative care specialists to control symptoms and
reduce suffering in this vulnerable population.15,29,37
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47. Wiener L, Ballard E, Brennan T, et al. How I wish to be remembered: the use of an advance care planning document in adolescent and
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48. Wiener L, Zadeh S, Wexler LH, et al. When silence is not golden:
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Cancer Control 479
In conjunction with palliative care,
life expectancy, functional reserve, and the
treatment goals of patients with cancer
should be continually reviewed and
assessed throughout the course of treatment.
Photo courtesy of Lisa Scholder. Duality. 18" × 24".
Palliative Care in Older Patients With Cancer
Lodovico Balducci, MD, Dawn Dolan, PharmD, and Sarah E. Hoffe, MD
Background: In general, cancer is a disease of aging, and palliative care is an essential step in the management of cancer in patients who are older. The goal of this article is to review common symptoms of cancer and
oncology treatment and their management.
Methods: The pertinent medical literature was reviewed.
Results: The scope of palliative care includes personalized cancer treatment. This involves choosing treatment options that best fit the needs of each individual patient. Balancing treatment benefits and risks may
be challenging in older patients, many of whom have limited life expectancies and decreased functional
reserves. The benefits of treatment may diminish, and the risks of such treatment options increase with age.
Thus, the first step toward personalized treatment includes determining physiological age, which is best
estimated with a comprehensive geriatric assessment. Prevention of common complications, which include
neutropenia and mucositis, allows the administration of treatment in full and effective doses. Fatigue is a
chronic symptom related to cancer and its treatment and may lead to functional dependence and an increased risk of death. Fatigue might be prevented by daily exercise even during treatment. Other symptoms
include pain and feelings of memory loss.
Conclusions: The scope of palliative care encompasses more issues that symptom management and, for this
reason, palliative care should be provided once the diagnosis of cancer is established. Determining treatment
goals is essential to improve the treatment experience. Symptom management is similar in older and young
patients, but symptoms in the older population may be associated with more frequent and severe complications.
Many options exist to prevent and ameliorate the complications of oncology treatment in the aged. However,
more studies should be conducted on the long-term care of older patients who have survived cancer.
From the Senior Adult Oncology Program (LB), Pharmacy Service
(DD), and Department of Radiation Therapy (SEH), H. Lee
Moffitt Cancer Center & Research Institute, Tampa, Florida.
Submitted May 14, 2015; accepted August 28, 2015.
Address correspondence to Lodovico Balducci, MD, Moffitt
Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612.
E-mail: Lodovico.Balducci@Moffitt.org
Dr Balducci is a consultant for and receives honorarium from
Teva Pharmaceuticals. He also receives honoraria from Amgen, Astellas Pharma, and Johnson & Johnson. Dr Dolan is a
speaker for and receives honorarium from Eisai. No significant relationship exists between Dr Hoffe and the companies/
organizations whose products or services may be referenced in
this article.
480 Cancer Control
Introduction
The goal of palliative care is to improve the disease experience for all patients, irrespective of the outcome.1 In
addition to symptom management, the scope of palliative care includes emotional, spiritual, and social needs
of patients, their families and friends, and their caregivers. Many palliative care specialists believe that healing is always achievable even when cure is out of reach,
because healing involves patients coming to terms with
their disease and its symptoms and outcome.2
Palliative care in older patients with cancer is important because integrating palliative care into stanOctober 2015, Vol. 22, No. 4
dard oncological care can improve rates of survival and
quality of life as well as reduce the cost of treatment.3
By the year 2020, more than 50% of patients diagnosed
with cancer will be aged 70 years and older.4 In addition, older individuals may present different issues unrelated to cancer than their younger counterparts that
make palliative care both urgent and challenging.4
Table 1. — Comprehensive Geriatric Assessment
Domain
Zubrod performance status
Activities of daily living
Transferring
Bathing
Grooming
Feeding
Dressing
Going to the bathroom
Maintaining continence
Instrumental activities of daily living
Use of transportation
Ability to take medication
Use the phone
Manage finances
Go shopping
Provide one’s own meals
Polymorbidity
Number and severity of medical conditions
(excluding cancer)
Polypharmacy
Number of medications (generally ≥ 5)
Redundancy and duplications
Medications inappropriate for use in the elderly
Risk of drug interactions
Lack of necessary medications
Emotional status
Screening for depression
Memory disorders
Assessment of memory impairment
(common use is Minimental status)
Nutrition
Presence and risk of malnutrition:
Mini Nutritional Assessment
Geriatric
syndromes
Dementia
Severe depression
Delirium during mild infection or with medications
that generally do not cause delirium
Repeated falls
Continuous dizziness
Incontinence
Severe osteoporosis
Assessing Physiological Age
Aging may be defined as a progressive loss of functional reserve in multiple organ systems that eventually
leads to disability and death.5 Thus, social support becomes important to the welfare and survival of persons
who are elderly when they are unable to accomplish
instrumental or basic activities of daily living.
Aging is universal but highly individualized, and
physiological age is poorly reflected in chronological
age.5 Thus, assessing physiological age is paramount to
any medical decisions related to older individuals. In
the case of cancer management, the questions facing
the health care professional may include:
• Will the patient die of cancer or with cancer?
• Is the patient likely to experience consequences of
cancer during his or her lifetime?
• Will the patient tolerate the treatment proposed?
• What might be the long-term consequences of
cancer and its treatment in this patient?
The assessment of physiological age is founded on
the comprehensive geriatric assessment (CGA), which
encompasses medical, emotional, and social domains,
because aging is multidimensional and the assessment
of several domains is necessary to estimate life expectancy and stress tolerance (Table 1).
Several models integrating the CGA with clinical
and laboratory parameters allow estimates of tolerances of surgery, cytotoxic chemotherapy, and life expectancy independent of cancer.6-9 This information may
be used in negotiating and determining the most appropriate treatment for each patient.
Function is assessed in the CGA as a patient’s
ability to perform instrumental and basic activities of
daily living, because they have prognostic value independent of performance status. No consensus exists
concerning the best way to assess polymorbidity and
polypharmacy. Several comorbidity scales that account for the number and the severity of comorbid
conditions are in use.10 The definition of polypharmacy
may include the number of daily drugs, medication redundancy, drugs contraindicated in older individuals,
risk of at least a type 1 drug interaction, and the absence of drugs that may be appropriate.11 Depression,
including subclinical depression, has been associated
with increased risk of mortality if it is left untreated;
depression can be assessed with a number of screening tests.12 Many older individuals may be malnourished or at risk of malnutrition; cancer alone is a cause
October 2015, Vol. 22, No. 4
Element Assessed
Function
of malnutrition.13,14 Both forms of malnutrition can
be estimated with the Mini Nutritional Assessment, a
commonly used tool. Malnutrition is associated with
increased mortality rates, surgery risks, and chemotherapy-related complications.15 A number of simple
tests may be utilized to screen a patient for memory
disorders associated with decreased rates of survival.
Of these, the Minimental status, Montreal Cognitive
Assessment, and Saint Louis University Mental Status
Exam are commonly used tools.16 Assessment of social
support status includes available resources, the need
for a caregiver, and the caregiver’s availability and effectiveness.17 Geriatric syndromes involve several
conditions that become more common with age,
although they are not unique of aging, and purport
decreased life expectancy and increased risk of functional dependence.18
In addition to estimating cancer-independent life
Cancer Control 481
expectancy and risk of treatment-related toxicity, the
CGA helps to determine the existence of unsuspected conditions that could interfere with antineoplastic
treatment, including various diseases, depression, initial memory disorders, inadequate resources, and inadequate caregiver support.19
Many other instruments have been proposed to assess life expectancy and risk of disability but none has
been validated in patients with cancer; however, the
“inflammatory index” has been validated in 2 large cohort studies of aging populations.20 Age-related inflammation may be considered chronic and progressive, and
the concentration of inflammatory markers, such as cytokines and fibrinolytic products, has been associated
with decreased life expectancy and increased risk of disability. The inflammatory index, ie, the sum of the logarithm of interleukin 6 and tumor necrosis factor-α receptor 1 in the circulation, is the most reliable predictor
of long-term mortality.20 It is unclear how cancer-related
inflammation might affect the inflammatory index.
Frailty is a term often used in the geriatric and geriatric oncology literature.21 Frailty can be interpreted
in 2 ways. In one case, it is considered a threshold, a
critical loss of functional reserve beyond which any
stress, even minimal, may have catastrophic consequences. In the other case, it is considered a continuum, a measurement of the degree of aging.
Pharmacology of Aging
Aging is associated with changes of pharmacokinetics
and pharmacodynamics that may affect oncology treatment and the symptoms of cancer (Table 2).22 Reducing
the volume of distribution of hydrosoluble agents may
be related to reduced total body water, reduced concentration of plasma proteins, and reduced mass of red
blood cells, leading to increased area under the curve
and toxicity measures of these hydrosoluble medications. It may be mitigated with the correction of anemia.
CYP450 hepatic reactions are the most common
site of drug interactions. Patients who are elderly are at
increased risk for these interactions due to decreased
activity of these reactions and polypharmacy.
Reduced glomerular filtration rate appears to decrease the excretion of medicaments as well as their active metabolites. For example, although anthracyclines
are excreted with bile, some of these anthracyclines
give rise to active metabolites (daunorubicinol, idarubicinol) excreted from the kidneys. When the glomerular
filtration rate is reduced, compound toxicity, including
myelotoxicity, cardiotoxicity, and mucositis, may be
increased. Morphine and its congeners are partly metabolized to 6-glucuronides that are active and renally
excreted. The increased area under the curve of these
metabolites may partly explain the increased effectiveness and toxicity of opioids in older individuals.
Aging is associated with increased risk for myelo482 Cancer Control
toxicity, mucositis, peripheral neurotoxicity, and cardiotoxicity from cytotoxic agents. Decreased brain volume appears to increase the risk of medication-related
delirium, whereas changes in μ:δ opioid receptors may
partly explain the increased risk of opioid-related complications.23 These complications can include delirium,
constipation, nausea, and vomiting.
Setting Treatment Goals
Setting treatment goals is the first step of personalized
care. The goals of treatment include cure, symptom
Table 2. — Select Pharmacological Changes of Aging
Parameter
Age-Related Change
Pharmacokinetics
Absorption
Uncertain
May be reduced due to decreased absorptive
surface, decreased gastric secretions and
motility, and decreased splanchnic circulation
Volume of
distribution
Decreased for water-soluble agents
Increased for lipid-soluble agents
Hepatic uptake
and metabolism
Decreased hepatic uptake due to decreased
splanchnic circulation and decreased liver weight
Decreased activity of CYP450-dependent
reactions
No apparent change in glucuronidation reactions
Excretion
Renal excretion
Decreased due to reduction of both
glomerular filtration rate and tubular excretion
Biliary excretion
Unchanged
Pharmacodynamics
Organs and
systems
Age-related changes and clinical consequences
Hemopoietic
system
Decreased hemopoietic reserve due to reduced
number and function of hemopoietic precursors
that may lead to increased risk of myelosuppression by cytotoxic drugs
Mucosa
Increased susceptibility to cytotoxic agents to
decreased stem cells and increased proliferation
of cryptal cells
Heart
Decreased number of cardiomyocytes and
increased susceptibility to cardiotoxic drugs
Lungs
Decreased respiratory reserve
Possibly increased susceptibility to cytotoxic
agents
Brain
Decreased brain volume and circulation may lead
to increased susceptibility to medication-related
damage
Possible altered μ:δ receptors may lead to
decreased effectiveness and increased toxicity
of opioids
Peripheral
nervous system
Increased susceptibility to neurotoxic drugs
Kidney
Decreased glomerular filtration rate and tubular
function may lead to increased susceptibility to
nephrotoxic drugs
October 2015, Vol. 22, No. 4
management, prolonging survival, and preserving
lating to the patient. In general, the primary caregiver
quality of life, as well as prolonging active life exof an older patient with cancer is an elderly spouse with
pectancy — that is, maintaining functional indepenhealth conditions of his or her own or an adult child
dence and preventing functional decline in older
who has professional and family responsibilities of his
individuals.24 Loss of independence is universally
or her own (“Aeneas syndrome”).28
recognized as the worst threat to quality of life in
Thus, assessment of the caregiver should be part
older patients.25
of the initial evaluation of an older patient undergoing
Treatment goals may be at odds with each other.
any form of antineoplastic treatment; the health care
For example, adjuvant treatment improves the likeliprofessional can be aided by a social worker to evaluhood of cure for cancers of the breast, lung, large bowate the availability, the capability, and the willingness
el, and bladder, but it may be associated with intoleraof the caregiver. If the results of such an assessment
ble complications. Aromatase inhibitors that represent
prove inadequate, then alternative solutions should be
the hormonal treatment of choice for hormone-sensisought (eg, involvement of other family members or
tive breast cancer can cause severe joint pain and, thus,
other caregivers).
lead to functional decline, as well as vaginal dryness
The caregiver represents a valuable ally for the
and dyspareunia. Approximately 15% of older women
health care team and is likely to make a difference in
decide to forgo a higher likelihood of cancer control
the patient’s experience; however, caregivers may be
because of these complications.26 Peripheral neuropsusceptible to severe emotional and physical stress that
athy is a disabling complication of chemotherapy for
may lead to disease, including depression, disability,
older individuals and may be caused by drugs comand increased mortality.29 This stress may impact the
monly used for adjuvant treatment, such as platinum
family of the caregiver as well as compromise the work
derivatives and taxanes.22 In most cases, the decisions
quality and productivity of the caregiver. By contrast,
of forgo chemotherapy is made following exposure to
caregiving can be a rewarding emotional and spiritual
one of these agents, and, in some cases, the decision
experience that inspires self-worth.30 Thus, the health
may be made due to compelling reasons prior to initicare professional must train and support the caregiver
ating treatment (eg, patients involved in activities that
by providing a realistic outline of the likely course of the
require manual dexterity).
disease and of the difficulties that may emerge, as well
Realistic treatment goals should be established
as potential solutions, by allowing caregivers to express
prior to initiating treatment and revisited during the
concerns and show sympathy for them, and by directing
course of the treatment. Initial goals should be based
caregivers to available resources (eg, support groups).
on patient desires, cancer stage, aggressiveness and reIn each encounter with the health care team, the patient
sponsiveness to treatment, life expectancy, risk of comand caregiver should be recognized as a dyad held toplications, and available resources (Fig). However, it is
gether by the patient’s disease and treatment.
important to remember that the values and desires of
the patient are paramount in situations in which proManagement
longing survival might be achieved at significant perTreatment-Related Complications
sonal cost.
Complications of radiation therapy and systemic canThe role of the caregiver when he or she is unable
cer treatment, including hormonal therapy, cytotoxic
or unwilling to provide necessary care is an unresolved
and vexing problem.27 Caregivers should provide timely
Cancer
Patient
access to health care profesStage
Life expectancy
Treatment
sionals and to emergency
Aggressiveness
Treatment tolerance
Decisions
care, provide assistance at
Responsiveness
Resources
home (eg, symptom management, aid in instrumental
activities of daily living that
the patient is no longer able
Treatment
to perform), and emotionally
Effectiveness
support the patient. In some
Toxicity
instances, the caregiver may
Cost
act as the family spokesperson within the health care
system and may help manage
Fig. — The structure of a medical decision.
conflicts within the family reOctober 2015, Vol. 22, No. 4
Cancer Control 483
chemotherapy, and targeted
Table 3. — Select Complications of Oncology Treatment in Older Patients
therapy, are shown in Table 3.
Osteoporosis is a comComplication
Causes
Possible Prevention/
Treatment
plication of aromatase inhibitors that may be used for the
Osteoporosis
Aromatase inhibitors (breast cancer)
Calcium and vitamin D supplementation
treatment of breast cancer,
Androgen deprivation therapy
Bisphosphonates
(prostate cancer)
and androgen deprivation
Denosumab
treatment (ADT), which may
Myelosuppression Most forms of cytotoxic chemotherapy Dose reductions
be used for prostate cancer;
Select forms of targeted therapy
Prophylactic use of myeloid growth
(palbociclib, idelalisib, rituximab,
factors (cytotoxic chemotherapy alone)
the risk for osteoporosis may
ibrutinib, lenalidomide, TKI [chronic
Blood transfusions
offset the potential benemyeloid leukemia])
Erythropoiesis-stimulating agents
fits.31 For example, in an old(cytotoxic chemotherapy alone)
er woman prone to falls, aroPlatelet transfusions
matase inhibitors may prove
Mucositis
Cytotoxic chemotherapy (fluorouracil, Prophylactic treatment with supermore hazardous than the
methotrexate, anthracycline)
saturated solutions of calcium,
recurrence of breast cancer.
phosphate, and bicarbonates
Cytotoxic chemotherapy in combinaSelect patients with prostate
tion with radiation
Management of mucosal infections
cancer may undergo ADT for
Select targeted agents (everolimus)
Prophylactic positioning of gastric or
a small increase of prostatejejunal tube (for radiation therapy
and chemotherapy combinations)
specific antigen in the serum
IV hydration
after definitive treatment
Diarrhea
Cytotoxic chemotherapy (fluorouracil, Antidiarrheal medications
of the cancer; however, no
methotrexate, irinotecan)
Octreotide for severe/resistant cases
evidence suggests that this
Radiation therapy to the pelvis
IV hydration
practice is beneficial in the
TKIs
Steroids (for check-point inhibitors alone)
absence of disease (based
Anti-EGFR antibodies
on imaging results), whereas
Immune check-point inhibitors
evidence suggests that the
Anti-PD and anti-PD-L1 antibodies
risk of bone fractures inAnti-CTLA-4 antibodies
creases by 50% after 1 year
Cardiomyopathy
Anthracyclines
For anthracyclines, dexrazoxane
of ADT.31
Trastuzumab
Health care professionCTLA-4 = cytotoxic T-lymphocyte-associated protein 4, EGFR = epidermal growth factor receptor,
als must check bone density
IV = intravenous, PD = programmed cell death, PD-L1 = programmed cell death ligand 1, TKI = tyrosine
at the beginning of a pakinase inhibitor.
tient’s treatment; if the value
is normal, then it should be
maintained with adequate intake of calcium and vitapression is managed with dose reduction and delayed
min D. In the presence of osteopenia and osteoporotreatment administration, neutropenia can lead to a desis, then more aggressive treatment with bisphosphocrease in the treatment dose and intensity, which may
nates or denosumab may be indicated. Some studies
result in reduced effectiveness. Myelopoietic growth
have shown that an intensive schedule of intravenous
factors (filgrastim and pegfilgrastim) are effective in
zoledronic acid may prevent osteoporosis and cancer
older individuals.22 Guidelines recommend that parecurrence in postmenopausal women receiving adjutients treated with a chemotherapy dose in an intensity
vant treatment with an aromatase inhibitor.32,33 Thus,
comparable with cyclophosphamide/doxorubicin/vinthe potential benefit of zoledronic acid should be
cristine/prednisone receive prophylactic growth facweighed against its inconvenience, cost, and risk for
tors to prevent neutropenic infections instead of treatosteonecrosis of the jaw.
ment delays or dose reductions.34,35
Myelodepression from cytotoxic chemotherapy is
Several techniques reduce the damage of radiation
more prolonged and more severe in older individuals,
to normal tissues. The most serious complications of
and it may be further aggravated by combination cheradiation damage are seen from combination chemomotherapy/radiotherapy to the chest.22 The risk and
therapy/radiotherapy in the management of cancer
duration of neutropenia and of neutropenic infections
of the upper airways, the esophagus, and the lungs.36
increases with age, and patients aged 65 years or older
Severe mucositis may lead to dysphagia, malnutrition,
are at increased risk for such complications. In addition
and dehydration. Given the limited nutritional and hyto severe and sometimes lethal infections, another risk
dric reserve of the elderly, these complications may be
of neutropenia includes treatment delay, and both may
more severe and lethal for older individuals. The procause decreased therapeutic benefits. When myelodephylactic insertion of a gastric or jejunal tube helps
484 Cancer Control
October 2015, Vol. 22, No. 4
provide the patient with nutrition and fluids throughout treatment. In addition, the prophylactic use of hypersaturated calcium solution may assuage the pain of
mucositis in the upper digestive tract. Laser and light
therapy as well as cryotherapy represent promising
treatment options for oral mucositis. When mucosal infections are present, they must be treated, otherwise
management consists of temporarily discontinuing
oncology treatment and managing pain with opioids.
Even in the absence of radiotherapy, mucositis may
result from cytotoxic chemotherapy, particularly fluorouracil, methotrexate, and doxorubicin. The management is the same as that recommended for combined
chemotherapy/radiotherapy. A keratinocyte-stimulating factor may reduce the risk of mucositis, but it is expensive and cumbersome to administer. Its prophylactic use is not recommended.
Diarrhea is a common complication of the same
drugs that cause mucositis, tyrosine kinase inhibitors, and radiotherapy to the pelvis, although the use
of image-modulated radiation therapy or protons can
reduce the risk of diarrhea. In addition to the use of
antidiarrheal medication, maintaining proper hydration is paramount.37 In some resistant cases, octreotide
may be used. Lactobacillus may be useful in chemotherapy-induced diarrhea and hyperbaric oxygen in
radiation proctitis.36
Diarrhea is also a common complication of immune
check-point inhibitors, such as ipilimumab, nivolumab,
and pembroluzimab.38 In such a case, diarrhea is autoimmune related and may respond to steroids.
Many different medications can cause peripheral
neuropathy, which is common in patients treated with
platinum derivatives (eg, oxaliplatin) and taxanes.22 Peripheral neuropathy may cause symptoms such as loss
of sensation, paresthesias, shooting pain, burning pain,
weakness, and paresis. One prophylaxis for neuropathy is effective, and that is the timely discontinuance of
the offending agents. In some cases, neuropathic pain
may respond to high-dose gabapentin or pregabalin,
but these drugs may cause somnolence and confusion
in older individuals.39 Numbness may be associated with
difficulty performing basic and instrumental activities of
daily living as well as unstable gait and falls.
Cardiomyopathy is a complication of anthracyclines, anthracenediones, and cyclophosphamide in
high doses. Anthracycline-related cardiomyopathy
may be due to progressive damage of the myocardium
by free radicals, and it may be irreversible.40 It is rare
prior to a total dose of doxorubicin of 300 mg/m2 (and
equivalent doses of other anthracyclines).40 Several approaches may prevent this complication and include
concomitant administration of dexrazoxane to prevent
the formation of free radicals, administration of doxorubicin as a continuous intravenous infusion, or taken
as a low daily dose, and use of liposomal pegylated
October 2015, Vol. 22, No. 4
preparations. Dexrazoxane may enhance other treatment complications, including myelosuppression and
mucositis. According to the results from 1 study, dexrazoxane may diminish the antineoplastic effect of doxorubicin.40 In general, dexrazoxane is recommended
only after at least 2 doses of anthracycline. Administering doxorubicin via continuous infusion may be cumbersome outside of major academic centers, and its effectiveness has been confirmed only in sarcomas and
in myeloma.40 Data are insufficient for recommending
low daily doses of anthracyclines. Pegylated liposomal doxorubicin may be used in lieu of doxorubicin in
patients at high risk of cardiomyopathy, but whether
its effectiveness is comparable with doxorubicin is
unknown.
A different form of cardiac toxicity that is, in most
cases, reversible can be caused by the monoclonal antibody trastuzumab, which causes a condition of frozen myocardium; discontinuing the drug reverses the
effect.41 Risk of cardiac toxicity with trastuzumab also
increases with age, and management consists of suspending the administration of trastuzumab, although
the drug may be safely restarted when myocardial
function has been restored.
Cancer-Related Complications
The most common symptom of cancer in older individuals is fatigue.42 Other important manifestations include pain and malnutrition.
Fatigue: Fatigue is a condition of exhaustion that
does not improve with rest and that interferes with individual functions. The prevalence of fatigue, even in
the absence of cancer, increases with age; in older individuals, fatigue is associated with increased risk of
functional deficiency and death.43 The mechanisms
of fatigue are multiple and not fully understood; they
may include increased concentration of inflammatory
cytokines in the circulation, tissue hypoxia from anemia, hypogonadism-associated ADT, and sarcopenia,
a catabolic condition associated with aging that may
be related to a combination of inflammation, malnutrition, and endocrine senescence.44 Radiotherapy and
cytotoxic chemotherapy may cause fatigue at least in
part through treatment-related anemia.
Management of fatigue is controversial and unsatisfactory.42 There is consensus that exercise prevents
fatigue, but only if the patient is able to follow an exercise program during cancer treatment.45 Correction
of anemia with erythropoiesis-stimulating agents may
improve energy level. Although concern exists that
erythropoiesis-stimulating agents may stimulate tumor
growth, these agents appear safe when the hemoglobin level is not above 12 g/dL and they are used only
in patients receiving cytotoxic chemotherapy.44 Blood
transfusions may also relieve fatigue but only for a limited time.
Cancer Control 485
Pain: The perception of somatic and visceral pain
may decrease with age.46 For example, it is not uncommon in older individuals to experience silent myocardial infarction or silent intestinal perforation. Older individuals may have a higher tolerance of pain, because
they may consider pain an expected consequence of
aging. However, bone pain, in particular, may represent a serious limitation to patient activity and independence.
As in any other individual, the assessment of pain
of older individuals includes:
• Type of pain (eg, dull, aching, burning, spasmodic,
shooting)
• Localization
• Conditions that elicit pain (eg, particular movements, positions)
• Grade of pain on a pain scale
It is important to note that pain may have some
atypical manifestations in older individuals; of these,
delirium is one of the most common manifestations.
Another age-related challenge is assessing pain in
individuals with dementia or in those unable to communicate.46 However, select behavioral manifestations,
including grimaces, grunting, screaming, or withdrawal, may suggest the need to manage pain.
The management of pain depends on many factors, including the type, location, and intensity of the
pain. The most common form of pain is bone pain
from metastases. When the pain is localized to a single
area, local radiotherapy may suffice. If bone metastases are numerous, then relief of pain in one area may
result in the emergence of pain in different areas. Systemic cancer treatment, if effective, represents the most
definitive and lasting treatment of pain. Timely use of
intravenous bisphosphonates or denosumab may mitigate the symptoms and delay the development of pain.
Select radioisotopes are available for the management
of bone pain; of these, radium 223 has been shown to
relieve pain, with minimal marrow damage, in patients
with castrate-resistant prostate cancer.47
Pharmacological management is the mainstay of
acute pain control.48,49 Tapering doses of steroids may
provide temporary relief of bone pain. Nonsteroidal
anti-inflammatory drugs have limited use in older patients due their risks of gastritis and renal insufficiency.
Opioids represent the most beneficial class of drugs,
but their dose should be slowly titrated because the
risk of complications may increase with age.48 Intrathecal administration of opioids may prevent most other
types of complications, but this route of administration
is cumbersome, expensive, and associated with the
risk of spinal infections.48 Administration of opioids
should be complemented by a prophylactic bowel regimen to prevent constipation. Methylnaltrexone relieves
opioid-related constipation without interfering with
analgesic activity.49,50
486 Cancer Control
Malnutrition: Malnutrition is common, especially in most advanced cancer stages.51 In patients with
cancer of the esophagus and upper digestive tract,
malnutrition is often present at diagnosis. Malnutrition is due to a combination of factors, including the
consumption of tissues by the cancer, decreased food
intake, and absorption.52 Anorexia may be prominent
during the last phases of cancer and appears to be mediated by increased concentration of 5HT3 and tryptophan in the brain stem.31
Nutritional support is an essential treatment component for patients with a treatable neoplasm, because
malnutrition increases the risk of complications of
surgery, radiotherapy, and cytotoxic chemotherapy.52
Enteral nutrition is more effective than parenteral nutrition and is preferred in the presence of a functional
gastroenteric tract. Prophylactic insertion of gastric or
jejunal tubes in the presence of an impending obstruction of the esophagus and upper digestive tract and the
aggressive prevention and management of mucositis,
nausea, and vomiting are effective and recommended.
The management of anorexia is not well established.
The effectiveness of cannabinoids is controversial; use
of medroxyprogesterone at a high dose appears to
stimulate the appetite, but it may not increase the lean
body weight of patients. Anamorelin, which is a synthetic analog of the gastric hormone ghrelin, appears
promising in early clinical trials.53
Nutritional support of any type fails to improve the
lean body weight of patients whose neoplasm is advanced and untreatable and does not affect the survival
of such patients. Hyperalimentation may have a detrimental effect on survival. For these patients, nutritional
support is indicated only if it is necessary to maintain
quality of life.
Survivor Care
The survival rates of most cancers have improved for
patients of all ages; however, a consensual definition
of “survivor” is needed.54 Few data relate to elderly patients who have survived cancer. It is well known that
age is a risk factor for developing acute leukemia after cytotoxic chemotherapy, and older cancer survivors
are at increased risk of developing a second cancer
that may be related or unrelated to the original one. At
present, evidence is insufficient to suggest that elderly
patients who are survivors of cancer may benefit from
additional cancer screening.
The main concerns related to elderly cancer survivors include functional dependence and memory
disorders.45 Functional dependence may result from a
combination of factors, including peripheral neuropathy, sarcopenia, and fatigue. Fatigue appears to play
a major role because it is associated with increased
risks of functional dependence and mortality among
older patients. The most effective treatment of fatigue
October 2015, Vol. 22, No. 4
appears to be prevention through regular exercise,
nutritional preservation, correction of anemia, and depression management, beginning at the time oncology
treatment is initiated.
Whether cancer and its treatment are associated
with full-blown dementia is controversial; however,
cognitive function has been shown to decline as a result of treatment, and this decline may cause distress
in patients and their loved ones.45 Distress may be
prevented by anticipating the possibility of cognitive
decline, but reassuring the patient might include performing a neuropsychological evaluation. The fear of
cognitive decline appears to be a major cause of distress, and, thus, normal findings may reassure the patient that decline has not occurred.
Conclusions
The goal of palliative care is to improve the patient experience; thus, palliative care is most effective when
administered together with antineoplastic treatment.
After the evaluation of the disease, life expectancy,
functional reserve, and treatment goals of the patient
should be reviewed and assessed — a process that
should be continually reviewed throughout the course
of treatment. When feasible, common treatment complications, such as neutropenia and neutropenic infections, should be prevented. Management of fatigue,
pain, and malnutrition are paramount to the success of
treatment. More information is needed on the elderly
cancer survivors, particularly as to whether elderly patients should undergo additional cancer screening and
determining the most effective management options
for fatigue and cognitive decline in elderly patients.
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29. Harding R, Gao W, Jackson D, et al. Comparative analysis of informal caregiver burden in advanced cancer, dementia, and acquired brain
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30. Millison MB. Spirituality and the caregiver. Developing an underutilized facet of care. Am J Hosp Care. 1988;5(2):37-44.
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33. Gnant M, Mlineritsch B, Stoeger H, et al. Zoledronic acid combined
with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12.
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36. Lalla RV, Bowen J, Barasch A, et al. MASCC/ISOO clinical practice
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42. Browner IS, Smith TJ. Symptom assessment in elderly cancer patients receiving palliative care. Ann Oncol. 2013;24(suppl 7):vii25-29.
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43. Moreh E, Jacobs JM, Stessman J. Fatigue, function, and mortality
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488 Cancer Control
October 2015, Vol. 22, No. 4
Despite their limited accuracy,
clinician prediction of survival, prognostic
factors, and prognostic models can help
health care professionals estimate survival
and inform clinical decision-making.
Photo courtesy of Lisa Scholder. Dive Forward. 16" × 24".
Prognostication of Survival in Patients With Advanced Cancer:
Predicting the Unpredictable?
David Hui, MD, MSc
Background: Prognosis is a key driver of clinical decision-making. However, available prognostication tools
have limited accuracy and variable levels of validation.
Methods: Principles of survival prediction and literature on clinician prediction of survival, prognostic factors, and prognostic models were reviewed, with a focus on patients with advanced cancer and a survival
rate of a few months or less.
Results: The 4 principles of survival prediction are (a) prognostication is a process instead of an event, (b)
prognostic factors may evolve over the course of the disease, (c) prognostic accuracy for a given prognostic factor/
tool varies by the definition of accuracy, the patient population, and the time frame of prediction, and (d) the
exact timing of death cannot be predicted with certainty. Clinician prediction of survival is the most commonly
used approach to formulate prognosis. However, clinicians often overestimate survival rates with the temporal
question. Other clinician prediction of survival approaches, such as surprise and probabilistic questions, have
higher rates of accuracy. Established prognostic factors in the advanced cancer setting include decreased performance status, delirium, dysphagia, cancer anorexia–cachexia, dyspnea, inflammation, and malnutrition. Novel
prognostic factors, such as phase angle, may improve rates of accuracy. Many prognostic models are available,
including the Palliative Prognostic Score, the Palliative Prognostic Index, and the Glasgow Prognostic Score.
Conclusions: Despite the uncertainty in survival prediction, existing prognostic tools can facilitate clinical
decision-making by providing approximated time frames (months, weeks, or days). Future research should
focus on clarifying and comparing the rates of accuracy for existing prognostic tools, identifying and validating novel prognostic factors, and linking prognostication to decision-making.
From the Department of Palliative Care & Rehabilitation Medicine,
MD Anderson Cancer Center, Houston, Texas.
Submitted April 15, 2015; accepted July 15, 2015.
Address correspondence to David Hui, MD, MSc, Department of
Palliative Care & Rehabilitation Medicine, Unit 1414, MD Anderson
Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.
E-mail: dhui@mdanderson.org
Dr Hui is supported in part by a National Institutes of Health grant
(R21CA186000-01A1) and an American Cancer Society Mentored
Research Scholar Grant in Applied and Clinical Research (MRSG14-1418-01-CCE).
No significant relationship exists between the author and the companies/organizations whose products or services may be referenced
in this article.
October 2015, Vol. 22, No. 4
Introduction
In the last months, weeks, and days of life, patients
with advanced cancer may face numerous decisions regarding their personal affairs and health care, many of
which depend on how long they will live. For example,
patients were less likely to choose chemotherapy at
the end of life if they understood that they had a short
survival rate.1,2 Similarly for health care professionals,
prognosis is a key determinant of clinical decisionmaking because the risk:benefit ratio for many interventions increases as patients approach the last weeks
of life. Chemotherapy given to a patient with months
Cancer Control 489
of life expectancy may result in tumor response, symptom control, and improved survival; however, the same
chemotherapy regimen could cause life-threatening
complications if administered to a patient with a poor
performance status and a short survival rate.3,4 Moreover, palliative resection, total parenteral nutrition, and
insertion of an indwelling pleural catheter are generally appropriate for patients with at least a few months of
life expectancy.5 Moreover, hospice eligibility is based
on a survival of 6 months or less.6 One study showed
that patients were more likely to be referred earlier to
hospice if their health care professionals made an accurate prediction of survival.7
Prognosis-based decision-making depends on an
ability to accurately estimate survival, which has been
a challenge for health care professionals and researchers alike.8 The process of prognostication can be divided
into formulation (foreseeing) and communication (foretelling).9,10 Clinicians may formulate prognosis either
subjectively (ie, clinician prediction of survival based on
intuition) or objectively (ie, actuarial prediction of survival based on prognostic factors and models). Despite
the availability of validated prognostic factors and tools,
most health care professionals rely on clinician prediction of survival to estimate prognosis because clinician
prediction of survival is instantaneous, convenient,
and easy to understand. Although clinician prediction
of survival often incorporates many known prognostic factors in its determination, each may be assigned a
variable weight by different health care professionals.
Coupled with variable knowledge, clinical experience,
and personality, this results in heterogeneous and often
optimistic estimations of life expectancy.11,12
Progress has taken place in the science of prognostication. In this article, some important principles of
survival prediction are discussed and the medical literature on clinician prediction of survival, prognostic factors, and prognostic models are reviewed, focusing on
patients with advanced cancer with a survival rate of
months or less. The implications for clinical decisionmaking and future research directions are also explored.
Principles of Prognostication
Prognostication is a process instead of an event. A
patient’s prognosis may change based on treatment
response, development of acute oncological complications (eg, hypercalcemia, spinal cord compression,
pulmonary embolism), or competing comorbidities
(eg, heart failure). In a study of 352 patients admitted
to acute palliative care units who had a median survival of 10 days, the presence of acute symptomatic
complications, such as pneumonia, peritonitis, metabolic acidosis, and gastrointestinal bleed, was associated with a higher risk of mortality.13 Patients with
a larger number of acute complications also had a
shorter survival.13 Thus, it is important for health care
490 Cancer Control
Table 1. — Differences in Prognostic Factors Between
Patients With Early and Advanced Cancer
Variable
Early Stage
Advanced Stage
Prognosis
Years, decades
Months, weeks, days
Inception cohort
Cancer-site specific
Time of diagnosis
Time of consultation
All cancer groups
Admission/referral
to palliative care
or hospice
Prognostic factors
Clinical: stage,
laboratory studies
Pathological:
histology, grade
Molecular: gene,
microarray
Others: treatments,
resources
Clinical: symptoms,
laboratory studies
Pathological: NA
Molecular: NA
Others: treatments,
resources
Tools
Scores: IPI
Programs:
Adjuvant online
Scores: PaP, PPI
Programs: PPS
Implications
Overall outlook on
life span
Worse prognosis =
more intensive cancer
treatment
New cancer
treatment → changes
in prognostic factors
End-of-life planning
Worse prognosis →
limit cancer treatment
Limited cancer
treatment → same
prognostic factors
IPI = International Prognostic Index, NA = not applicable, PaP = Palliative
Prognostic Score, PPI = Palliative Prognostic Index, PPS = Palliative
Performance Scale.
professionals to revisit prognosis with patients over
time. Sentinel events such as cancer diagnosis, disease progression, and hospitalizations should trigger
a prognostic discussion.
Prognostic factors may vary by the stage of disease. In patients with early stage cancer, prognosis
may be driven by cancer biology such as tumor stage,
histological grade, and mutation status (Table 1). By
contrast, prognostic variables in patients with far advanced disease typically consist of patient-related factors such as performance status, dyspnea, delirium,
and cancer anorexia–cachexia.14 In the last days of
life, distinctive, bedside physical signs may signal that
death is imminent.15,16 Thus, it is important to understand the inception cohort for which the prognostic
factors/models were derived and apply the study findings to the appropriate patient population. Terms used
to describe the inception cohort in the literature, such
as end of life and terminally ill, have been heterogeneously defined.17 A systematic review of the literature
clarified that both of these terms refer to patients with
“months or less of life expectancy,” which represent
the target population of this review.18
Accuracy is an elusive concept in prognostication research. This is because not all prognostic studies consistently report accuracy; and, when reported,
October 2015, Vol. 22, No. 4
different investigators may use different metrics to assess accuracy, the accuracy of a prognostic tool varies
by patient population and the time frame of prediction, and very few studies examining novel prognostic factors have incorporated a comprehensive list of
known prognostic variables for benchmarking and
examined reclassification. Discrimination and calibration are 2 key aspects of accuracy.19-21 Discrimination reflects how well a prognostic tool differentiates
between patients who died and remained alive by a
specific time frame. The Concordance statistic (C-statistic) is often used to examine discrimination, with a
value between 0.5 and 1. For a C-statistic to be significant, the 95% confidence interval should not cross 0.5.
Because the C-statistic is less sensitive to the addition
to a novel prognostic marker to an existing model,
reclassification statistics, such as the reclassification
calibration statistic, net reclassification improvement,
and integrated discrimination improvement should
be used to assess the degree of improvement with
addition of the new factor.22,23 Calibration represents
how well the predicted probability of survival based
on a prognostic model matches the actual outcomes.
A model is considered to have satisfactory calibration (or goodness-of-fit) if the Hosmer–Lemeshow
test gives a P value greater than .05.24,25 Furthermore,
the prognostic accuracy could be estimated with sensitivity, specificity, positive predictive value, negative
predictive value, and overall accuracy. To advance the
science of prognostication, the accuracy of existing
and novel prognostic markers and models need to be
routinely assessed.
It may not be possible to prognosticate with 100%
accuracy (ie, 100% sensitive and 100% specific). Be-
cause death is a probabilistic event, its exact timing
cannot be predicted with certainty.26 With disease progression, the likelihood of acute catastrophic complication increases, such as myocardial infarction, pneumonia, and massive bleeding.13 Some patients may survive
longer than expected, whereas some may die earlier
than expected.27 Thus, health care professionals may
want to avoid providing specific numbers when discussing prognosis, because doing so could be misleading.28 Instead, they can acknowledge the uncertainty,
guide decision-making by providing general time
frames (eg, weeks to months), and advise patients and
families to expect the unexpected.
If we can make decisions based on approximations,
why should we still strive to improve the accuracy of
survival prediction? It is because higher accuracy can
offer health care professionals greater confidence when
communicating with patients and families while also
bringing greater clarity to decision-making.
Clinician Prediction of Survival
Over the last decades, clinician prediction of survival
has evolved from the classic, temporal question, “How
long do I have?” to the surprise and probabilistic questions. Table 2 highlights the question formats and advantages and disadvantages for each approach. The
results of some studies also suggest that how the question about prognosis is asked may impact its rate of accuracy.11,29,30
Temporal Question
With the temporal approach, the health care professional is asked the question, “How long will this patient live?” The answer may be provided as a specific
Table 2. — Three Approaches to Clinician Prediction of Survival
Aspects
Temporal Question11,30
Surprise Question29,32
Probabilistic Question11,30
Question
How long will this patient live?
Would I be surprised if this patient
died in (specific time frame)?
What is the probability of survival within
a specific time frame?
Answer
Specific time frame
Yes or no
0% to 100% (at 10% increments)
Definition of an
accurate response
If estimated time frame was ± 33% of
actual survival
If “no” answer and patient died within
specified time frame
or
If “yes” answer patient remained alive
by specified time frame
If answered ≤ 30% probability and patient
died within specified time frame
or
If answered ≥ 70% probability and patient
remained alive by specified time frame
Accuracy
20%–30%
76%–88% (1-y time frame)
53%–91% (6-mo to 24-h time frames)
Advantage
Simple, quick
Intuitive to provide
Understand
Simple, quick
Intuitive to understand
Simple, quick
Disadvantage
Subjective
Unclear if time frame represents the
average/median, maximal or minimal
May be difficult emotionally to
provide a specific number
Subjective
Time frame dependent
The threshold for “surprise” may vary
by individual
Yes/no answer only
Subjective
Time frame dependent
Probability needs to be interpreted
October 2015, Vol. 22, No. 4
Cancer Control 491
time frame (eg, 3 days, 6 months). This is the most
commonly used approach to estimate the rate of survival. The answer is relative easy to formulate, communicate, and understand. However, it is often not
specified if the answer represents the average, median, maximal, or minimal expected survival, possibly
resulting in confusion among health care professionals and patients. Furthermore, some health care professionals may find it psychologically challenging to
provide a number and communicate with patients an
“expiration date.”
Temporal clinician prediction of survival often results in systematically overestimation and has a 20% to
30% rate of accuracy, defined as a predicted survival
rate of within ± 33% of actual survival.11,12 Christakis
et al31 asked 343 physicians to estimate the survival for
468 patients at the time of hospice referral; the median
survival in this cohort was 24 days. A total of 20% of
predictions were accurate, 63% were overly optimistic, and 17% were overly pessimistic.31 Female patients,
certain medical subspecialties, lack of clinical experience, and a longer duration of the doctor–patient relationship were associated with less accurate predictions.31 Another study that included advanced patients
with cancer with a median survival of 12 days found
that younger patient age was associated with less accurate, temporal clinician prediction of survival.11
Surprise Question
The surprise question poses the following to the health
care professional: “Would I be surprised if this patient
died in (specific time frame)?” The health care professional can answer “no” if he or she would not be surprised that the patient would die within the predefined
period of time and “yes” if he or she felt otherwise.
Rather than a number with infinite possibility, as in the
temporal question, the answer is binominal (yes or no),
which may help to reduce the likelihood of error. However, each health care professional may have a different threshold for “surprise.”
Moss et al29 asked 4 oncologists to estimate the
1-year survival rate of 853 patients with cancer using
this surprise question. The positive predictive value
was 41%, the negative predictive value was 97%, and
the accuracy rate was 88%.29 In other words, the surprise question was helpful in identifying patients who
would live beyond 1 year but less able to identify patients who were going to die within that time frame.
In another study, 42 general practitioners in Italy answered the surprise question for 1-year survival in 231
patients with advanced cancer.32 The positive predictive value was 84%, negative predictive value was 69%,
and accuracy was 76%.32 Most recently, Hamano et al33
examined the prognostic accuracy rate of the surprise
question in 2,361 patients of Japanese descent who
had a median survival of 33 days. With the “7-day” sur492 Cancer Control
prise question, the rates of sensitivity and specificity
were 85% and 68%, respectively, the positive predictive
value was 30%, the negative predictive value was 96%,
and the rate of accuracy was 70%.33 By contrast, the
“30-day” surprise question had sensitivity and specificity rates of 96% and 37%, respectively, and a positive
predictive value of 58%, a negative predictive value of
90%, and a rate of accuracy of 65%.33
The surprise question has been used to identify
patients who have a limited survival and, thus, may
benefit from various services such as palliative care referral and advance care planning discussions; however,
the usefulness of this approach needs to be further validated. One qualitative study examining the use of the
surprise question among general practitioners identified some potential concerns, including its subjective
nature, difficulty in defining a precise time or event
when the health care professional would switch the answer from “yes” to “no,” and disagreement that a “no”
answer represents the ideal time for specific actions
such as advance care planning discussions.34
Probabilistic Question
The third approach to clinician prediction of survival
employs the probabilistic question. Instead of the “surprise” wording, it asks the health care professional to
state the probability of survival within a specific time
frame (at 10% increments from 0% to 100%). The response is considered accurate if the health care professional provided a probability of at least 70% and the
patient was alive by the prespecified time frame, or if
health care professional provided a probability of up to
30% and death occurred within the time frame. By definition, any probability between 40% and 60% is considered inaccurate because the health care professional
expressed ambivalence. The probabilistic approach
has a potential advantage over the surprise question
because it is not dependent on how “surprise” is interpreted.
The probabilistic approach was tested in a cohort
of 151 patients with advanced cancer admitted to an
acute palliative care unit.11 The median survival was
12 days.11 Both physicians and nurses were asked to
provide their estimation of survival from the time of
admission related to the following time frames: 24
hours, 48 hours, 1 week, 2 weeks, 1 month, 3 months,
and 6 months, and the respective accuracy rates were
71%, 66%, 58%, 56%, 67%, 86%, and 96% for physicians and 91%, 86%, 61%, 53%, 60%, 79%, and 88%
for nurses.11 By contrast, the rate of accuracy was significantly lower with the temporal approach (32% for
physicians and 18% for nurses).11 Because the same
group of health care professionals made predictions
in the same cohort of patients, the findings from this
study suggested how we pose the question may yield
answers with different accuracies.11
October 2015, Vol. 22, No. 4
In another study, physicians and nurses provided
daily prognostication in 311 patients from the time of
admission to an acute palliative care unit until death
or discharge using both the probabilistic approach (24and 48-hour time frames) and the temporal approach.30
The rate of accuracy of the probabilistic approach (40%
to 100%) was consistently higher than the temporal approach (10% to 30%) among both professions, although
its rate of accuracy decreased as death approached.30
Nurses were more accurate than physicians with the
probabilistic approach but not with the temporal approach, suggesting that the time of prognostication,
the type of health care professional, and the method of
clinician prediction of survival are all determinants of
the rate of accuracy.30 Finally, the result highlights the
difficulty in identifying patients who are imminently
dying even among experienced palliative care physicians and nurses.27,30
Actuarial Estimation of Survival
Prognostic factors can generally be classified as disease- and patient-related factors. Patient-related factors have a prominent role in prognostication in the
last months or weeks of life. Many tumor-related
markers, such as circulating tumor cells, have been
shown to have prognostic and predictive utility in patients with metastatic disease; however, their role in
patients with only months or weeks of survival need
to be further examined.35 For the purpose of this review, the discussion is focused on the most validated
prognostic factors and models as well as on several
novel prognostic factors.
Prognostic Factors
Among the multiple symptoms with prognostic significance in the advanced cancer setting are the 4 Ds:
decreased performance status, dysphagia and cancer anorexia–cachexia syndrome, delirium, and dyspnea.14,36 Performance status declines in the months
before death, with a steeper deterioration in the weeks
and days preceding death.37,38 Patients with a lower
performance status had a higher likelihood of developing serious adverse events when receiving systematic
therapy.3,4 In a study involving 1,655 patients with advanced cancer, Eastern Cooperative Oncology Group
performance scale, Palliative Performance Scale (PPS),
and Karnofsky Performance Scale were strongly associated with survival, with C-statistics of 0.64, 0.63, and
0.63, respectively.39 A web-based program (Prognostat
[University of Victoria, British Columbia, Canada]) is
available that provides the historical rates of survival
based on PPS, age, sex, and cancer diagnosis; however,
further validation is required.40,41
Cancer anorexia–cachexia is another prognostic
factor seen in patients with advanced cancer and is
associated with elevated inflammatory response and
October 2015, Vol. 22, No. 4
poor nutritional status; loss of appetite is a poor prognostic marker.42 Malnutrition assessed by either subjective global assessment or other nutritional indices has
also been found to be associated with shortened rates
of survival.43-45 A multicenter study showed that a lower
baseline body mass index and higher percentage of
weight loss were both associated with shorten rates of
survival, thus forming the basis for a prognosis-based
staging system for cancer anorexia–cachexia.46 Moreover, decreased lean body mass, a hallmark of anorexia–cachexia, has prognostic significance independent
of the palliative prognostic score.47
Delirium is another syndrome associated with a
shortened rate of survival.13,48 Although delirium is
potentially reversible in some patients, many patients
with cancer develop irreversible or terminal delirium
in the last weeks or days of life.16,49,50 Multiple studies
have also confirmed the prognostic role of dyspnea;
in particular, patients with dyspnea at rest have a
shorter rate of survival than those with episodic dyspnea alone.51,52
Other objective, physiological measures also have
prognostic utility. Phase angle, a marker of cellular
membrane integrity and hydration, is lower in patients
with shorter survival.53,54 A prospective study of 222 patients with advanced cancer and a median survival rate
of 106 days found that phase angle was a significant
prognostic factor independent of Palliative Prognostic
Score (PaP), hypoalbuminemia, and decreased lean
body mass.47 Hand-grip strength and maximal expiratory pressure that assess skeletal muscle and respiratory muscle functions, respectively, were also associated
with survival in patients with advanced cancer.54 These
objective measures show some promise in survival
prediction because they are reproducible, noninvasive,
easy to use, portable, and inexpensive. However, they
need to be further validated before they can be applied
in routine practice.
Several laboratory abnormalities have prognostic
significance in the advanced cancer setting. Markers
of inflammatory response, such as elevated C-reactive
protein, erythrocyte sedimentation rate, leukocytosis, lymphopenia, and neutrophil:lymphocyte ratio
were associated with poor nutritional status and survival.14,44,55 Other markers of decreased survival include
hypoalbuminemia (indicative of malnutrition), hypogonadism (associated with decreased lean body mass
and performance status), hypercalcemia (often related
to tumor progression), hyponatremia, and elevated lactate dehydrogenase.13,56-58 For example, patients with
advanced solid tumors who presented with hypercalcemia have a median survival rate of 2 months.59
Prognostic Models
Multiple prognostic scoring systems have been developed for patients with advanced cancer. These progCancer Control 493
nostic models typically include many of the established
prognostic factors discussed above. Table 3 illustrates
several of the well-validated prognostic models in the
advanced cancer setting, including PaP, the Palliative
Prognostic Index (PPI), and the Glasgow Prognostic
Score.55,60-80 General time frames are provided by risk
score categories for these 3 prognostic models. The
original PaP score does not include delirium, although
the addition of this variable to create the Delirium-PaP
score results in only slight improvement in its performance.81 A modified version of the Glasgow Prognostic Score assigns no points (instead of 1 point) to
hypoalbuminemia alone without an elevated level of
C-reactive protein.82 In all of these models, total score
is calculated based on the number of prognostic factors
(ie, higher score = worse survival) and a probability of
survival by a defined time frame is provided based on
the risk group category.
Other prognostic models have been derived from
patients with only months or weeks of survival, including the Objective Prognostic Score, the B12/C-reactive
protein Index, the Japan Palliative Oncology StudyPrognostic Index, the Chuang Prognostic Score, the
Terminal Cancer Prognostic Score, and the Poor Prognosis Indicator.69,70-73,83-86
Despite the plethora of prognostic models, the
one that is the most accurate or superior to clinician
prediction of survival alone remains unclear. In a prospective study of 549 patients with advanced cancer
and a median survival of 22 days, Maltoni et al87 reported that PaP, Delirium-PaP, PPI, and PPS had respective C-indices of 0.72, 0.73, 0.62, and 0.63 and
accuracy rates of 88%, 80%, 72%, and less than 50%.
However, the PPI cutoffs used were different from
earlier studies.87 In a separate study, Stiel et al88 exam-
ined the performance of PPI, PaP, and clinician prediction of survival in 84 patients with cancer. PPI had the
highest correlation coefficient with actual rate of survival (0.68), followed by PaP (0.58) and clinician prediction of survival (0.56).88 Clinician prediction of survival was examined as a categorical variable instead
of as a continuous variable.88 In a large prospective
study in Japan, Baba et al89 examined the feasibility
and accuracy of PaP, Delirium PaP, and PPI in 2,361
patients in both hospital and home settings. Although
PPI was completed more often, PaP and Delirium PaP
scores had higher rates of accuracy than PPI for predicting 21-day survival rates (C-statistic, 0.79–0.89 vs
0.75–0.84; P < .05) and 42-day survival rates (C-statistic, 0.81–0.88 vs 0.75–0.85; P < .05).89
The change in a prognostic score may also be useful for predicting survival, with the understanding that
patients who deteriorate often have a worse prognostic
score over time and vice versa.84,90 In a study of 2,392
patients with advanced cancer, Kao et al90 found that
the median PPI increased from 6 on day 1 to 7 on day
8 (P < .001). The median survival rate was 53 days with
an improvement in PPI score, 36 days with a stable
PPI score, and 22 days with PPI deterioration over the
1-week period.90 The C-statistic for 30-day survival
was 0.63 for a baseline PPI score, 0.64 for a PPI change
score, and 0.71 for the combined baseline and change
in PPI.90 When only patients with a higher baseline PPI
(ie, > 6) were included, the C-statistics for 30-, 60-, and
90-day survival rates were 0.66, 0.64, and 0.63 for the
baseline PPI, respectively, and 0.72, 0.76, and 0.79 for
the magnitude of PPI change between baseline and
day 8.74 The corresponding accuracy rates were 61%,
57%, and 55% for baseline PPI, and 71%, 79%, and
83% for PPI change, respectively.74 By definition, the
Table 3. — Prognostic Models for Patients With Advanced Cancer
Model
Variable
Scoring
Survival Interpretation
Palliative Prognostic
Score60-63
Clinician prediction of survival (0–8.5)
Karnofsky performance scale ≥ 50% (2.5)
Anorexia (1.5)
Dyspnea (1)
Leukocytosis (0–1.5)
Lymphopenia (0–2.5)
Total score 0–17.5 points
Higher score = worse survival
Risk group A (0–5.5 points): months of survival
Risk group B (5.6–11 points): weeks of survival
Risk group C (11.1–17.5 points): days of survival
Palliative Prognostic
Index74-80
Palliative performance scale (0–4)
Delirium (considered absent if caused
by a single medication and potentially
reversible) (4)
Dyspnea at rest (3.5)
Oral intake (0–2.5)
Edema (1)
Total score 0–15 points
Higher score = worse survival
Risk group A (0–4 points): months of survival
Risk group B (4.1–6 points): weeks of survival
Risk group C (6.1–15 points): days of survival
Glasgow Prognostic
Score55,64-68
Albumin < 35 g/L (1)
C-reactive protein > 10 mg/L (1)
Total score 0–2
Higher score = worse survival
Score = 0: months to years of survival
Score = 1: months of survival
Score = 2: weeks to months of survival
494 Cancer Control
October 2015, Vol. 22, No. 4
change score could only be used in patients who remained alive 1 week after the initial assessment, which
may limit its utility to a certain extent; nevertheless, a
change in PPI over only 1 week had prognostic value.74
Further studies are needed to examine the prognostic
utility of change over different time periods and with
different prognostic scores.
Web-Based Programs
Few web-based prognostication programs are available for patients with advanced cancer. Thus, webbased programs should be developed to facilitate the
use of validated prognostic models for clinical decision-making. Existing programs (eg, Prognostat) have
limited use.40,41
Future Directions
Communicating Prognosis
Although it is beyond the scope of this review, how
health care professionals discuss prognoses with patients and families also warrants further research.
Should we give the maximum, minimum, and/or median survival times (as in the temporal approach), the
probability of survival at various time points (as in the
probabilistic question and prognostic models), or general time frames (eg, days, weeks, months)? Given that
the rate of accuracy is below 80% for a vast majority
of prognostic tools, perhaps communicating prognoses using general time frames would provide adequate
information for decision-making while not being misleading. Ultimately, research studies are needed in this
area.
Accuracy Reporting
The discrimination and calibration of prognostic markers (eg, clinician prediction of survival, prognostic factors and models) should be consistently reported using
standardized, predefined, and practical time frames
(eg, 1 week, 1 month, 2 months, 3 months, 6 months)
that would allow comparison across studies.
Clinician Prediction of Survival
How we pose the questions matters. In addition, the
rate of accuracy of clinician prediction of survival varies by clinician factors, patient characteristics, and
time frame of prediction. To date, the surprise question has only been tested with the 1-year, 30-day,
and 7-day survival time frames in advanced patients
with cancer.33 The probabilistic question has been examined with the time frames of 24 hours, 48 hours,
1 week, 2 weeks, 1 month, 3 months, and 6 months;
however, this was only conducted in patients admitted
to palliative care units.11,30 Thus, these rates of clinician prediction of survival must be further validated.
A direct comparison of the accuracy rate of these approaches is also needed.
Prognostic Factors/Models
Existing: Validation of existing prognostic factors/
models is important. Furthermore, comparison of the
performance of these prognostic tools is warranted to
help health care professionals identify the most appropriate model(s) for clinical practice.
Novel: A better understanding of the physiological
and pathological processes in patients with cancer may
help develop novel prognostic markers. Research studies of novel prognostic markers should aim at improving the rate of accuracy of established prognostic model; thus, reclassification statistics should be consistently
reported. The role of serial prognostication should also
be further examined.
Diagnosis of Impending Death
Recognition that a patient has entered the last days of
life presents a unique area for research. Instead of a
prognostic question, this may be a diagnostic issue because the process of dying is irreversible. The results of
some studies have suggested that several bedside clinical signs have very high specificity rates for impending
death; however, further validation is required.15,16
October 2015, Vol. 22, No. 4
Prognostic Factors
Clinical Decision-Making: More studies are needed
to examine how prognostic tools can be used to guide
clinical decisions, such as palliative care referral or
chemotherapy discontinuation.
Clinical Trials: In addition to clinical decisionmaking, prognostic factors and models may be incorporated as eligibility criteria or stratification factors in clinical trials of oncology treatment. Currently, performance
status is commonly included. Some prognostic markers
may have both predictive and prognostic utility.
Conclusions
Clinician prediction of survival remains the most commonly used approach to formulating a prognosis, a fact
that can be attributed to convenience (clinician prediction of survival already incorporates many existing
prognostic factors), and few studies have demonstrated that use of prognostic models can significantly improve rates of accuracy. However, health care professionals often overestimate survival with the temporal
question, and other clinician prediction of survival approaches, such as the surprise question and the probabilistic question, may estimate survival with a defined
time frame and have moderate to high accuracies.
Prognostic factors in the advanced cancer setting include symptoms (eg, decreased performance
status, delirium, dysphagia, cancer anorexia–cachexia, dyspnea), physiological changes (eg, decreased
muscle function, lean body mass), and laboratory abnormalities (eg, increased C-reactive protein, hypoalbuminemia). Multiple prognostic models have been
Cancer Control 495
developed based on these prognostic factors, with the
Palliative Prognostic Score, Palliative Prognostic Index,
and Glasgow Prognostic Score being the most validated. However, the probabilities of survival generated by
these models must be translated into an easy-to-understand format to facilitate clinical decision-making. Finally, research in novel objective prognostic markers
such as phase angle may improve our rates of accuracy
in prognostication.
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Cancer Control 497
Pathology Perspective
Is DOG1 Immunoreactivity Specific to Gastrointestinal
Stromal Tumor?
William Swalchick, MA, Rania Shamekh, MD, and Marilyn M. Bui, MD, PhD
Background: DOG1 is a novel gene on gastrointestinal stromal tumors (GISTs) that encodes the chloride
channel protein anoctamin 1, also known as discovered on GIST-1 (DOG1) protein. DOG1 antibodies are a
sensitive and specific marker against GIST positive for CD117 and CD34 and negative for CD117 and CD34.
DOG1 is also independent of KIT or PDGFRA mutation status and considered specific for GIST when it was
first discovered in 2004.
Methods: The previous 10 years of literature was searched for articles relating to DOG1. We critically reviewed
12 studies that showed DOG1 was positive in 250 cases of 2,360 tested non-GIST neoplasms (10.6%) at different
anatomical sites using monoclonal, polyclonal, or nonspecified antibodies. Criteria for positivity varied
between the studies.
Results: Monoclonal and polyclonal DOG1 antibodies were reactive in various different non-GIST tumor types
spanning 9 organ systems in addition to normal salivary and pancreatic tissues. The tumors included were
renal oncocytoma (100%), renal cell carcinoma chromophobe type (86%), solid pseudopapillary neoplasm of
the pancreas (51%), neoplastic salivary tissue (17%), synovial sarcoma (15%), leiomyoma (10%), pancreatic
adenocarcinoma (7%), and leiomyosarcoma (4%).
Conclusions: By contrast to the original concept that DOG1 antibodies are specific to GIST neoplasms, the
studies reviewed showed that the data suggest DOG1 positivity in select non-GIST tumors. Only in the appropriate
clinical and pathological context is DOG1 positivity specific and helpful in the diagnosis of GIST.
Introduction
A 58-year-old woman who did not smoke was found
to have a 1-cm left upper lobe lingula lung nodule discovered on a screening radiograph as part of a routine
physical examination. The patient denied fever, chills,
sweats, anorexia, or weight loss. She had a past medical history of thyroid nodule. Her family history was
positive for hypertension, heart disease, and lung cancer. She was taking chlorthalidone for hypertension
and ibandronate for osteoporosis as well as multivitamin supplements. Subsequent positron emission tomography showed the hypermetabolic uptake of fluorodeoxyglucose in the nodule with a standard uptake
value of 7, which is suspicious for a neoplasm. She underwent wedge resection of this lung nodule. Gross examination showed a 1-cm, grey-tan, firm nodule 0.5 cm
from the resection margin. Microscopic examination
revealed sheets of oncocytic tumor cells with abundant
From the University of South Florida Morsani College of Medicine
(WS, RS, MMB) and the Departments of Anatomic Pathology and
Sarcoma (MMB), H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
Submitted March 23, 2015; accepted April 28, 2015.
Address correspondence to Marilyn M. Bui, MD, PhD, Moffitt
Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612. E-mail:
Marilyn.Bui@Moffitt.org
No significant relationships exist between the authors and the
companies/organizations whose products or services may be referenced in this article.
498 Cancer Control
pink, granular cytoplasm, ovoid nuclei, small nucleoli
(Fig 1A), and negative surgical margins. Immunohistochemistry was strongly and diffusely positive for
DOG1 (Fig 1B) but negative for CD10, CD34, CD117
(C-kit), CD163, cytokeratin (CK) 7, CK20, CK AE1/AE3,
thyroid transcription factor 1, epithelial membrane antigen, renal cell carcinoma, thyroglobulin, and ERG.
Based on these findings, a preliminary diagnosis
of epithelioid gastrointestinal stromal tumor (GIST)
was made. Magnetic resonance imaging of the abdomen was obtained and was within normal limits. The
patient came to the H. Lee Moffitt Cancer Center & Research Institute (Tampa, FL) for treatment.
After performing a thorough history and physical
examination and reviewing her imaging and pathology
findings, her physician indicated that the findings were
inconsistent with a diagnosis of GIST. Criteria for diagnosing GIST are reviewed in Table 1.1 After our pathological review of the case, the DOG1 immunostain
(SP31 clone, prediluted via a dispenser) was repeated
and it was diffusely but weakly positive (Fig 1C).
Is This Gastrointestinal Stromal Tumor?
To practice evidence-based medicine, it is necessary
to work-up the case in a systemic approach. The steps
include:
1. Clinical and radiological correlation with pathology findings: In this case, the overall hisOctober 2015, Vol. 22, No. 4
A
Table 1. — Diagnostic Criteria of GIST
Site of Involvement
Stomach: 54%
Small intestine and duodenum: 32%
Colon and rectum: 1%
Others: 9%
Histology
Spindle cell tumor, in most
Epitheloid: 20%–25%
Mixed spindle and epithelial cells
Differential
Diagnosis
Smooth muscle tumor
Nerve sheath tumor
Other spindle or epitheloid tumor
Immunophenotype
B
CD117 (C-kit) strongly positive, except in
5% of GIST cases with mutant PDGFRA
CD34 is positive in most cases of
spindle-cell GIST; less consistent in
epitheloid histology
DOG1 is positive in most cases of GIST
(CD117+/DOG1+); often positive in CD117–
GIST (CD117– /DOG1+)
When to Diagnose
GIST?
CD117 positivity in context with correct
clinical and pathological setting
DOG1 more sensitive than CD117 in
detecting GIST of gastric origin, epitheloid
morphology, and GIST harboring
PDGFRA mutation
CD34 alone not used to diagnose GIST
GIST = gastrointestinal stromal tumor.
From Ríos-Moreno MJ, Jaramillo S, Pereira Gallardo S, et al. Gastrointestinal stromal tumors (GISTs): CD117, DOG-1 and PKCθ expression.
Is there any advantage in using several markers? Pathol Res Pract.
2012;208(2):74-81.
C
Fig 1A–C. — (A) Hematoxylin and eosin stain showing an epithelioid neoplasm (× 400). (B) DOG1 (K9 clone) IHC stain showing strong membranous positivity (× 400). (C) DOG1 (SP31 clone) IHC stain showing weak
membranous positivity (× 400). IHC = immunohistochemistry.
tological features are not typical for epithelioid
GIST; however, the immunoreactivity of DOG1
was puzzling.2 Primary GIST of the pleura has
been reported in a single case report2; however,
primary GIST originating in the lung has not
been reported.
2. Review the literature and investigate if DOG1
immunoreactivity is specific for GIST alone and
October 2015, Vol. 22, No. 4
what other tumors are positive for DOG1 and
could be a potential diagnosis: The literature
review revealed an interesting result, and our
findings are included below so other pathologists may find them useful when dealing with
tumors and GISTs positive for DOG1.
3. Conduct judicious ancillary testing to rule in
or out differential diagnoses (eg, carcinoma,
melanoma, granular cell tumor, and epithelial
sarcoma).
4. If in doubt, seek an expert opinion.
After pertinent differential diagnoses were
ruled out, we felt this was not a case of epithelioid GIST, but rather a primary lung tumor that warranted further subtyping. Christopher D.M. Fletcher,
MD, at Brigham & Women’s Hospital (Boston, MA)
was consulted. Other pertinent stains as well as repeat immunostains were negative for DOG1. The
tumor was deemed to be an atypical epithelioid
neoplasm of the lung; however, this entity is not an
established World Health Organization classification but instead is a descriptive diagnosis that reflects the uncertain histogenesis, clinical behavior,
Cancer Control 499
and our current scientific understanding of the lesion. The recommended management is judicious
follow-up. At the time of publication, the patient is
under surveillance.
DOG1 has shown rates of high sensitivity and
specificity in the detection of GISTs, and 74% of
GISTs exhibit a positive DOG1 and CD117 immunoprofile.3 Discovered on GIST-1 (DOG1) protein
antibodies are more sensitive than CD117 antibodies in detecting tumors of gastric origin, epithelioid
tumors, and tumors harboring PDGFRA.4 Although
DOG1 positivity is generally required for the diagnosis of GIST, the results should be interpreted
alongside morphological findings of the tumor and
the clinical picture, as shown in the current case.
From this, we intend to explore the immunoreactivity of DOG1 in non-GIST neoplasms to provide useful information for practicing pathologists and other
health care professionals.
Methods
A search of the English-speaking medical literature
was conducted to identify original articles published
from 2004 to 2015 regarding the use of the DOG1 antibody for the pathological diagnosis on formalin-fixed
and paraffin-embedded human tissue. We reviewed
the relevant studies to examine the results of the
clones of DOG1 antibodies as well as immunoreactive
and tissue types. The clone refers to DOG1 antibodies made by identical immune cells copies of a unique
parent cell (K9, SP31, DOG1.1). These clones were developed from mice and rabbits. Documentation of the
findings, a critical review of the results, and the application of this information in the work-up of the index
case are discussed.
Results
Antibodies
Twelve relevant studies were identified. The DOG1
antibody used in these studies included monoclonal (SP31, K9, DOG1.1), polyclonal, or nonspecified
antibodies. Criteria for positivity varied among the
studies.
DOG1 Expression
DOG1 is expressed in normal salivary acini gland
and pancreatic endocrine tissue (Table 2).5,6
Table 3 summarizes DOG1 expression in 250 cases
out of 2,360 non-GIST neoplasms tested at different
anatomical sites.5,7-17 Of the 2,360 tumors tested, the
average rate of DOG1 positivity was 10.6%.
As illustrated in Fig 2,12,14 DOG1 is 100% positive in cases of renal oncocytoma and chondroblastoma7,9; 60% to 97% positive in acinic cell carcinoma,
chromophobe renal cell carcinoma, fibroadenoma,
adenoid cystic carcinoma, and squamous cell carci500 Cancer Control
noma7,11,12,14; 22% to 53% positive in epithelial-myoepithelial carcinoma, pseudopapillary neoplasm,
neoplastic salivary tissue, endometrial adenocarcinoma, gastric adenocarcinoma, and glomus tumor 5,8,10-14; 7% to 17% positive in cholangiocarcinoma, synovial sarcoma, colonic adenocarcinoma,
leiomyoma, and pancreatic adenocarcinoma8,10-12,14,15;
and 1% to 5% positive in leiomyosarcoma, angiosarcoma, Ewing sarcoma, malignant peripheral nerve
sheath tumor, neuroendocrine tumor, melanoma,
and schwannoma.5,8,10-12,14-16 Reports regarding solid
pseudopapillary neoplasm of the pancreas are conflicting.6,8
Except in cases of renal oncocytoma and chondroblastoma, the tumors mentioned above have
various levels of DOG1 expression. However, of the
2,360 cases, a total of 959 tumors, other than those
listed in Table 3, are nonresponsive to DOG1 immunohistochemistry. The list of these tumors is summarized in Table 4.7-12,14
Discussion
This first clue that this lung tumor may not be GIST
is that primary GIST has never been reported.2 If
this case was the first discovered primary lung GIST,
then molecular confirmation would have been warranted. GIST does not appear to metastasize to the
lung, other than in the setting of many years of treatment with tyrosine kinase inhibitors. To the best of
our knowledge, primary GISTs in the lung have not
been documented in the English literature. The second clue lies in the specificity of DOG1 immunoreactivity in GIST.
DOG1 was shown to be independent of the
KIT/PDGFRA mutation status and was considered
specific for GIST when it was first discovered in
2004.18 In other words, DOG1 should be tested
when the tumor is of gastric origin, has epitheloid
morphology, and in cases harboring the PDGFRA
mutation. Data are emerging regarding the expression of DOG1 in non-GIST tissue. Studies that
have reported higher rates of DOG1 specificity
Table 2. — DOG1 IHC in Non-Neoplastic Non-GISTs
Study
Anti-DOG1
Antibody
Clone Type
Chenevert5
DOG1.1
Ardeleanu6
Polyclonal
Site
Tumor
Type
DOG1
Expression,
n/N (%)
Salivary
gland
Salivary
tissue
109/109 (100)
Pancreas
Endocrine tissue
Adult
11/11 (100)
Fetal
15/15 (100)
Representative of 135 cases.
GIST = gastroinestinal stromal tumor, IHC = immunohistochemistry.
October 2015, Vol. 22, No. 4
100
90
80
DOG1 Specificity, %
70
60
50
40
30
20
roblasto
Chon d
Re n a l o
ncocy to
ma (n =
0
21)
ma (n =
Acinic
9)
cell c ar
C hr o m
cinoma
ophob e
(n = 3 3
r en al c
)
ell c arc
inoma
(n = 37
)
Fibroad
enom a
(n = 11
Adenoid
)
cystic
c arcino
m
a
(n
S qu a m
= 28)
ous c e
ll c arcin
Epitheli
o
m
a
(n = 15
al-myo
)
epitheli
al c ar c
in
o
ma (n=
P s eudo
15)
papilla
r y neop
lasm (n
En dom
= 29)
etrioid
adeno c
arcinom
a
(n
Gastric
= 10)
adeno c
arcinom
a (n = 3
9)
Glomu
s tumo
r (n = 2
Neopla
7)
stic sa
livar y ti
ssue (n
= 8 3)
Cholan
gioc arc
inoma
(n = 6)
S ynovia
l s ar c o
ma (n =
Colonic
115)
adeno c
arcinom
a (n = 3
0)
Leiomy
o
ma (n =
P a n cr e
10 3)
atic ad
eno c ar
cinoma
(n = 11
2)
Leiomy
os ar c o
ma (n =
214)
A ngios
ar c om a
(n = 32
)
Ewing
Malign
s ar c om
a n t p er
a (n = 3
ipher al
4)
n er ve s
heath tu
mor (n
= 3 4)
N e ur o e
ndocrin
e tumo
r (n = 9
9)
Melano
ma (n=
181)
S chw a
nnom a
(n = 8 3
)
10
Non-GIST Neoplasm
Fig 2. — DOG1 tumor specificity rates. GIST = gastrointestinal stromal tumor.
have had small sample sizes, whereas larger studies (> 83 cases) have reported that a small percentage of non-GIST tumors were positive for DOG1
(see Fig 2). 8,10-12,14,16
As shown in Fig 2, neoplastic salivary gland may
show DOG1 expression. As shown in Table 3, the average DOG1 specificity rate for neoplastic salivary
tissue was 17%.5,11,14 DOG1 expression in synovial
sarcoma was reported by 4 different studies to have
various specificity rates.10-12,14 The average rates of
DOG1 specificity for synovial sarcoma was 14.8%.
Gastric adenocarcinoma has 28% positivity for
October 2015, Vol. 22, No. 4
DOG1 compared with 13% for colonic adenocarcinoma
(see Fig 2).12,14 Even though the location of these tumors may overlap with GIST, they rarely overplay
histologically with GIST and do not pose diagnostic
challenges.
Smooth muscle tumors were reported in
5 studies.10-12,14,15 The average rates of DOG1 specificity for leiomyoma and leiomyosarcoma were 10.7%
and 4.2%, respectively (see Fig 2). When the smooth
muscle tumor occurs in the gastrointestinal tract,
it may be diagnostically challenging to be differentiated from GIST. As shown in Fig 2, nerve sheath
Cancer Control 501
Table 3. — DOG1 IHC in Neoplastic Non-GISTs
Study
Anti-DOG1 Antibody
Clone Type
Site
Tumor Type
DOG1 Expression,
n/N (%)a
Zhao7
Hemminger14
Not specified
K9
Kidney
Renal oncocytoma
Chromophobe renal cell carcinoma
21/21 (100)
32/37 (86)
Akpalo9
Wong10
Lopes11
Miettinen12
SP31
K9
Bone
Chondroblastoma
Glomus tumor
Ewing sarcoma
9/9 (100)
6/27 (22)
1/34 (3)
Bergman13
Hemminger 8
Not specified
K9
Pancreas
Pseudopapillary neoplasm
Adenocarcinoma
Neuroendocrine tumor
15/29 (51)
8/112 (7)
2/99 (2)
Chenevert5
Lopes11
Hemminger14
DOG1.1
K9
Head and neck
Salivary gland
Acinic cell carcinoma
Adenoid cystic carcinoma
Epithelial-myoepithelial carcinoma
Neoplastic salivary tissue
32/33 (97)
20/28 (71)
8/15 (53)
14/83 (17)
Lopes11
Wong10
Sah15
Miettinen12
Hemminger14
K9
DOG1.1/K9
Breast
Soft tissue
Fibroadenoma
Synovial sarcoma
Leiomyosarcoma
Angiosarcoma
9/11 (82)
17/115 (15)
9/214 (4)
1/32 (3)
Miettinen12
Sah15
Wong10
Lopes11
K9
Esophagus
Stomach
Liver
Abdomen
Squamous cell carcinoma
Adenocarcinoma
Cholangiocarcinoma
Leiomyoma
9/15 (60)
11/39 (28)
1/6 (17)
11/103 (11)
Miettinen12
Hemminger14
K9
Colon
Adenocarcinoma
4/30 (13)
Hemminger14
Wong10
Lopes11
Miettinen12
K9
Uterus (endometrium)
Central nervous system
Endometrioid adenocarcinoma
Malignant peripheral nerve sheath tumor
Schwannoma
4/10 (40)
1/34 (3)
1/83 (1)
Hemminger14
Gonzalez16
Wong10
Lopes11
Miettinen12
K9/SP31
Skin
Melanoma
3/181 (2)
Tang17
K9
Prostate
Stromal sarcoma
1/1 (100)
Representative of 1,401 cases.
Combined data from multiple studies.
GIST = gastrointestinal stromal tumor, IHC = immunohistochemistry.
a
tumors also have a small rate of DOG1 positivity
(< 5%). In these situations, other markers for GIST, such
as CD117, CD34, or mutational analysis for CD117 and
PDGFR, can be used to help definitively diagnose GIST.
Limitations
The various studies we reviewed used different antibodies and various scoring criteria for DOG1 immunoreactivity. Although no specific practice guideline
exists for the diagnosis of GIST, strong, diffuse, and
membranous DOG1 immunoreactivity was generally
accepted for the diagnosis.4 The heterogeneous result
502 Cancer Control
of DOG1 immunoreactivity by various laboratories
may present a challenge. For example, in our index
case, DOG1 was tested in 3 different laboratories with
2 different antibodies and yielded different results. If
the DOG1 immunostain was negative, then this lung
mass would never have been diagnosed as GIST.
Conclusion
In addition to DOG1 being detected in cases of gastrointestinal stromal tumor, DOG1 positivity can be detected in other non-neoplastic and neoplastic tissue; however, only in the appropriate clinical and pathological
October 2015, Vol. 22, No. 4
Table 4. — IHC Negative for DOG1 in Neoplastic Non-GISTs
Study
Anti-DOG1
Antibody Clone
Type
Tumor Type
Case, n
(N = 959)a
Zhao7
Hemminger14
Not specified
K9
Clear-cell renal cell carcinoma
35
Akpalo9
Lopes11
SP31
K9/DOG1.1
Chondromyxoid fibroma
12
Giant cell tumor
40
Wong10
Lopes11
Miettinen12
Hemminger14
K9
K9/DOG1.1
K9
K9
Dedifferentiated liposarcoma
27
Desmoid tumor
59
Desmoplastic small round cell tumor
16
Endometrial stromal sarcoma
28
Extraskeletal myxoid chondrosarcoma
16
Gastrointestinal ganglioneuroma
3
Inflammatory fibroid polyp
67
Inflammatory myofibroblastic tumor
23
Kaposi sarcoma
24
Neurofibroma
27
Perivascular epithelioid cell tumor/angiomyolipoma
Sarcomatoid carcinoma
8
6
Small cell carcinoma
12
Solitary fibrous tumor
49
Hemminger 8
K9
Serous cystadenoma
28
Lopes
K9/DOG1.1
Mesenchymal tumors other than GIST
Miettinen12
Lopes11
K9
Extramedullary myeloid tumor
5
Mastocytoma, skin
3
11
Neuroblastoma
10
Seminoma testicular
16
Undifferentiated sarcoma
26
Small intestine carcinoid tumor
Undifferentiated sarcomatoid carcinoma
Hemminger 8
Lopes11
K9
K9/DOG1.1
261
6
21
Alveolar soft-part sarcoma
3
Chordoma
5
Clear cell sarcoma
5
Epithelioid sarcoma
8
Granular cell tumor
6
Low-grade fibromyxoid sarcoma
8
Lung adenocarcinoma
5
Perineurioma
4
Pleomorphic undifferentiated sarcoma
77
Prostate adenocarcinoma
10
Combined data from multiple studies.
GIST = gastrointestinal stromal tumor, IHC = immunohistochemistry.
a
context is DOG1 positivity specific and helpful for diagnosing true cases of gastrointestinal stromal tumor.
References
1. Fletcher CD, Bridge JA, Hogendoorn PC, et al, eds. WHO Classification of Tumours of Soft Tissue and Bone. 5th ed. Lyon, France: InternaOctober 2015, Vol. 22, No. 4
tional Agency for Research on Cancer Press; 2013.
2. Long KB, Butrynski JE, Blank SD, et al. Primary extragastrointestinal stromal tumor of the pleura: report of a unique case with genetic confirmation. A J Surg Pathol. 2010;34(6):907-912.
3. Ríos-Moreno MJ, Jaramillo S, Pereira Gallardo S, et al. Gastrointestinal stromal tumors (GISTs): CD117, DOG-1 and PKCθ expression.
Is there any advantage in using several markers? Pathol Res Pract.
2012;208(2):74-81.
4. Lee CH, Liang CW, Espinosa I. The utility of discovered on gastroCancer Control 503
intestinal stromal tumor 1 (DOG1) antibody in surgical pathology-the GIST
of it. Adv Anat Pathol. 2010;17(3):222-232.
5. Chenevert J, Duvvuri U, Chiosea S, et al. DOG1: a novel marker of salivary acinar and intercalated duct differentiation. Mod Pathol.
2012;25(7):919-929.
6. Ardeleanu C, Arsene D, Hinescu M, et al. Pancreatic expression of
DOG1: a novel gastrointestinal stromal tumor (GIST) biomarker. Appl Immunohistochem Mol Morphol. 2009;17(5):413-418.
7. Zhao W, Tian B, Wu C, et al. DOG1, cyclin D1, CK7, CD117 and
vimentin are useful immunohistochemical markers in distinguishing chromophobe renal cell carcinoma from clear cell renal cell carcinoma and
renal oncocytoma. Pathol Res Pract. 2015;211(4):303-307.
8. Hemminger J, Marsh WL, Iwenofu OH, et al. DOG1 (clone K9) is
seldom expressed and not useful in the evaluation of pancreatic neoplasms. Appl Immunohistochem Mol Morphol. 2012;20(4):397-401.
9. Akpalo H, Lange C, Zustin J. Discovered on gastrointestinal stromal
tumour 1 (DOG1): a useful immunohistochemical marker for diagnosing
chondroblastoma. Histopathology. 2012;60(7):1099-1106.
10. Wong NA, Shelley-Fraser G. Specificity of DOG1 (K9 clone) and
protein kinase C theta (clone 27) as immunohistochemical markers of gastrointestinal stromal tumour. Histopathology. 2010;57(2):250-258.
11. Lopes LF, West RB, Bacchi LM, et al. DOG1 for the diagnosis of
gastrointestinal stromal tumor (GIST): comparison between 2 different antibodies. Appl Immunohistochem Mol Morphol. 2010;18(4):333-337.
12. Miettinen M, Wang ZF, Lasota J. DOG1 antibody in the differential
diagnosis of gastrointestinal stromal tumors: a study of 1840 cases. Am J
Surg Pathol. 2009;33(9):1401-1408.
13. Bergmann F, Andrulis M, Hartwig W, et al. Discovered on gastrointestinal stromal tumor 1 (DOG1) is expressed in pancreatic centroacinar
cells and in solid-pseudopapillary neoplasms--novel evidence for a histogenetic relationship. Hum Pathol. 2011;42(6):817-823.
14. Hemminger J, Iwenofu OH. Discovered on gastrointestinal stromal tumours 1 (DOG1) expression in non-gastrointestinal stromal tumour
(GIST) neoplasms. Histopathology. 2012;61(2):170-177.
15. Sah SP, McCluggage WG. DOG1 immunoreactivity in uterine leiomyosarcomas. J Clin Pathol. 2013;66(1):40-43.
16. Gonzalez RS, Carlson G, Page AJ, et al. Gastrointestinal stromal
tumor markers in cutaneous melanomas: relationship to prognostic factors
and outcome. Am J Clin Pathol. 2011;136(1):74-80.
17. Tang YL, Wong CF, Yap WM, et al. Discovered on gastrointestinal
stromal tumours 1 (DOG1) expression in non-gastrointestinal stromal tumour (non-GIST) neoplasms. Histopathology. 2014;65(5):724-726.
18. West RB, Corless CL, Chen X, et al. The novel marker, DOG1, is
expressed ubiquitously in gastrointestinal stromal tumors irrespective of
KIT or PDGFRA mutation status. Am J Pathol. 2004;165(1):107-113.
504 Cancer Control
October 2015, Vol. 22, No. 4
Case Report
Occurrence of Multiple Tumors in a Patient
Elaine Tan, Mark Friedman, MD, and Domenico Coppola, MD
Summary: An 81-year-old man initially presented
with a right forearm mass that was found to be myxofibrosarcoma. In addition, he was found to have gastric
and intragastric masses identified as neuroendocrine
tumor (NET) and gastrointestinal stromal tumor (GIST;
presenting synchronously), respectively, as well as a
new left upper quadrant mass identified as desmoid tumor in the colon. The patient complained of melena,
which was found to be due to metastatic myxofibrosarcoma in the transverse colon. Several reports have
associated GIST with NET and some reports have associated GIST with sarcomas and NET with sarcomas;
however, this is the first report to document all these
tumors in a single patient. Several factors may have
contributed to the development of these tumors, including growth factors secreted by NET, KIT mutation
of GIST predisposing to additional tumors, immunosuppressed state, or an underlying genetic syndrome.
This case highlights the importance of investigating for
additional malignancies when a primary malignancy is
discovered.
Case Report
An 81-year-old man with a past medical history significant for multifocal lipomas and prostate cancer,
for which he underwent prostatectomy, presented for
removal of a mass on his right forearm. Excision was
performed and pathology revealed high-grade myxofibrosarcoma. The resected tumor was 5 cm in size. Histologically, the tumor was poorly differentiated and involved the surgical resection margins. The tumor was
composed of large epithelioid cells and spindle cells
with scattered multinucleated cells. Nuclear pleomorphism was present, and the surrounding stroma was
myxoid and desmoplastic. The patient underwent wide
resection and radiotherapy.
Positron emission tomography/computed tomography demonstrated a large, hypermetabolic, soft-tisFrom the Departments of Anatomic Pathology (ET, DC) and Gastroenterology (MF), H. Lee Moffitt Cancer Center & Research Institute,
Tampa, Florida.
Submitted July 20, 2015; accepted July 29, 2015.
Address correspondence to Domenico Coppola, MD, Department
of Anatomic Pathology, Moffitt Cancer Center, 12902 Magnolia
Drive, Tampa, FL 33612. E-mail: Domenico.Coppola@Moffitt.org
No significant relationships exist between the other authors and
the companies/organizations whose products or services may be
referenced in this article.
October 2015, Vol. 22, No. 4
sue mass in the subcutaneous fat of the posterior thigh
and a hypermetabolic mass in the left upper quadrant
of the abdomen. Wide excision of the mass of the posterior thigh revealed a 6-cm, metastatic, high-grade
myxofibrosarcoma with positive margins. The patient
underwent radiotherapy.
Later the same year, the patient underwent
esophagogastroduodenoscopy, which revealed a
gastric mass seen at the greater curvature; partial
gastrectomy was performed. Macroscopically, a
5.5 × 3.2 × 3.2 cm well-circumscribed, soft, tan-colored, lobulated gastric mass was identified. The tumor was composed of a monomorphic population of
cells with granular pink cytoplasm and round vesicular nuclei with nucleoli (Fig 1A). Immunohistochemically, the tumor was diffusely positive for cytokeratin
(Fig 1B), chromogranin, and synaptophysin (Fig 1C),
and Ki-67 revealed 4% positivity in 4% of the tumor
(Fig 1D). These findings supported a diagnosis of
well-differentiated, grade 2 neuroendocrine tumor
(NET). One of 4 regional lymph nodes was positive
for metastatic NET.
In addition, a 2.5 × 1.3 × 1.1 cm, well-circumscribed, firm, tan-colored intragastric mass composed
of spindle cells, arranged in intersecting fascicles and
focally exhibiting paranuclear vacuoles (Fig 2A), was
seen. These cells were diffusely positive for CD117
(Fig 2B) and CD34 (Fig 2C) but negative for actin
(Fig 2D) and S100 by immunohistochemistry. The
Ki-67 proliferation index was 1%. Genetic analysis of
the mass revealed a mutation in exon 11 of KIT. Based
on these findings, the diagnosis of gastrointestinal
stromal tumor (GIST) was made.
More than 2 years after the patient originally presented, computed tomography of his abdomen and
pelvis showed a new mass in the left upper quadrant
of his abdomen, so segmental colectomy with primary
colocolostomy was performed. The tumor was 3 cm in
its largest diameter and had negative margins. Gross
examination revealed a white, dense mass invading
the muscularis propria of the large bowel. Microscopically, the tumor was composed of plump, fibroblastic
spindle cells infiltrating the smooth muscle of the muscularis propria (Fig 3A). No necrosis or mitotic activity
was present. The lesion was completely resected. The
lesional cells were immunohistochemically positive for
beta-catenin (Fig 3B) and negative for S100, CD117, acCancer Control 505
A
C
similar to this patient’s primary
high-grade myxofibrosarcoma located in his right forearm and had
infiltrated the colonic wall, including the colonic mucosa (Fig 4).
Discussion
GISTs have been well documented to be associated with the development of synchronous primary
tumors, and this rate of associaB
D
tion can be as high as 11.5% to
33.3%.1 Oftentimes, GIST coexists
with adenocarcinoma of gastric,
colonic, or pancreatic origin, as
well as breast, prostate, and lung
cancers.2,3
In our patient, GIST was
found in association with gastric NET, a finding that has been
reported a handful of times. In
Fig 1A–D. — Gastric neuroendocrine tumor, ×100 magnification. (A) Monotonous population of cells
1 case report, a 69-year-old man
with small round nucleoli exhibiting a “salt and pepper” chromatin pattern. Hematoxylin and eosin stain.
with well-differentiated NET in
(B) Low-molecular-weight cytokeratin IHC. (C) Synaptophysin IHC. (D) Ki-67 proliferative index (≤ 4%) IHC.
the corpus was also found to harIHC = immunohistochemistry.
bor submucosal borderline GIST.4
In
another case, a 65-year-old
A
C
woman with GIST of the gastric
corpus was diagnosed with concomitant, well-differentiated NET
in the same location.5 Although
these 2 cases are examples of
GIST being synchronous to NET,
other cases have described a single tumor type that predated the
occurrence of the second tumor
by years; however, no clear preB
D
disposition of one tumor leading to the other has been established.2,6
GISTs have also been found
in association with sarcomas. Arnogiannaki et al1 reported the
simultaneous occurrence of gastric GIST with uterine leiomyosarcoma. Similarly, Sharma et al7
reported a case of a 50-year-old
Fig 2A–D. — Intragastric gastrointestinal stromal tumor, ×200 magnification (A) Intersecting fascicles
woman with ileal GIST and synof spindle cells with elongated nuclei with blunt ends. Hematoxylin and eosin stain. (B) CD117 IHC.
chronous, high-grade breast
(C) CD34 IHC. (D) Actin IHC. IHC = immunohistochemistry.
sarcoma with heterologous cartilaginous, osseous, and rhabdotin, and desmin. These results supported the diagnosis
myoblastic differentiation. An association with NET
of a desmoid tumor (fibromatosis).
and sarcoma has also been described by Adams et al8
Nine months later, the patient represented with
who reported the occurrence of embryonal rhabdomelena, and subsequent colonoscopy revealed a polmyosarcoma of the cervix and appendiceal carcinoid
ypoid lesion in the transverse colon measuring 3.5 cm
tumor in a 43-year-old woman. However, our patient
in its largest diameter. Histologically, the tumor was
had a unique combination of myxofibrosarcoma, GIST,
506 Cancer Control
October 2015, Vol. 22, No. 4
A
B
Fig 3A–B. — Desmoid tumor. (A) Proliferation of myofibroblasts exhibiting vesicular nuclei and separated by large amount of stroma. Hematoxylin and eosin stain, ×200 magnification. (B) Beta catenin,
×400 magnification.
addition, a primary malignancy may create an immunosuppressed state, thus causing patients to be more susceptible to
developing secondary tumors.10
The presence of genetic mutations could also lead to the simultaneous occurrence of these
tumors, similar to how cancer
syndromes like Li–Fraumeni syndrome, von Hippel–Lindau syndrome, and multiple endocrine
neoplasia syndromes result from
genetic mutations. Exposure to
carcinogenic agents might also
lead to the development of these
synchronous tumors or, possibly,
the synchrony happened by pure
coincidence.3
Conclusion
Gastrointestinal stromal tumors
(GISTs) tend to present with synchronous tumors. When a patient
is diagnosed with a non-GIST
malignancy, the health care professional must consider the possibility of a synchronous or metachronous GIST, among other
types of tumors. More research is
needed on the pathophysiology of
these synchronous and metachronous tumors.
Fig 4. — Metastatic high-grade myxofibrosarcoma. Multinucleated spindle-shaped cells surrounded
by myxoid and desmoplastic stroma infiltrating the wall and mucosa of the colon. Hematoxylin and
eosin stain, ×200 magnification.
NET, and desmoid tumor. To our knowledge, no other
case of this kind has been previously reported in the
English literature.
Several hypotheses have been postulated to explain the development of synchronous and metachronous primary tumors in the same patient. Two studies were unable to establish an immunohistochemical
or molecular profile difference between single GISTs
and GISTs coexisting with other tumors.1,3 The secretion of growth factors from NETs could contribute
to the development of concurrent primary tumors.
Growth factors such as platelet-derived growth factor, transforming growth factor β, and basic fibroblast
growth factor are secreted from NETs and are all tumorigenic.9 GISTs are characterized by the KIT mutation that may predispose them to the development of
other tumors; moreover, impaired KIT expression has
been noted in carcinomas of the breast and colon.1 In
October 2015, Vol. 22, No. 4
References
1. Arnogiannaki N, Martzoukou I, Kountourakis P, et al. Synchronous presentation of
GISTs and other primary neoplasms: a single
center experience. In Vivo. 2010;24(1):109-115.
2. Samaras VD, Foukas PG, Triantafyllou K, et al. Synchronous well
differentiated neuroendocrine tumour and gastrointestinal stromal tumour
of the stomach: a case report. BMC Gastroenterol. 2011;11:27.
3. Liszka L, Zielinska-Pajak E, Pajak J, et al. Coexistence of gastrointestinal stromal tumors with other neoplasms. J Gastroenterol.
2007;42(8):641-649.
4. Maiorana A, Fante R, Maria Cesinaro A, et al. Synchronous occurrence of epithelial and stromal tumors in the stomach: a report of 6 cases.
Arch Pathol Lab Med. 2000;124(5):682-686.
5. Lin YL, Wei CK, Chiang JK, et al. Concomitant gastric carcinoid
and gastrointestinal stromal tumors: a case report. World J Gastroenterol.
2008;14(39):6100-6103.
6. Hung CY, Chen MJ, Shih SC, et al. Gastric carcinoid tumor in a
patient with a past history of gastrointestinal stromal tumor of the stomach.
World J Gastroenterol. 2008;14(44):6884-6887.
7. Sharma M BK, Barad AK, Padu K, et al. Spontaneous Perforation as a First Presentation of Ileal Gastrointestinal Stromal Tumour
(GIST) with Synchronous Breast Sarcoma. J Clin Diagn Res. 2014; 8(5):
ND07- ND09.
8. Adams BN, Brandt JS, Loukeris K, et al. Embryonal rhabdomyosarcoma of the cervix and appendiceal carcinoid tumor. Obstet Gynecol.
2011;117:482-484.
9. Chaudhry A, Funa K, Oberg K. Expression of growth factor peptides and their receptors in neuroendocrine tumors of the digestive system.
Acta Oncol. 1993;32(2):107-114.
10. Habal N, Sims C, Bilchik AJ. Gastrointestinal carcinoid tumors and
second primary malignancies. J Surg Oncol. 2000;75(4):310-316.
Cancer Control 507
Special Report
Association of Cancer Stem Cell Markers With Aggressive
Tumor Features in Papillary Thyroid Carcinoma
Zhenzhen Lin, MD, Xuemian Lu, MD, Weihua Li, MD, Mengli Sun, MD, Mengmeng Peng, MD,
Hong Yang, MD, Liangmiao Chen, MD, Chi Zhang, PhD, Lu Cai, MD, PhD, and Yan Li, MD, PhD
Background: Identifying accurate prognostic molecular markers for papillary thyroid carcinoma (PTC) is
important because many patients with PTC may be erroneously considered to have low-risk tumors. Evidence
is also accumulating to support the existence of cancer stem cells in PTC.
Methods: Thirty controls and 167 patients with PTC were selected to establish a tissue microarray to investigate cancer stem cell marker expression in samples from an established pathological database. The protein
expressions of CD44, CD133, epithelial cell adhesion molecule (EpCAM), CD45, and CD90 were evaluated by
immunohistochemical assay in the tissue microarray.
Results: The protein levels of CD44, CD133, and EpCAM were significantly increased in PTC tissue compared
with tissue from the controls. A positive correlation was found between cancer stem cell markers and tumor,
node, and metastasis staging.
Conclusions: Among a subset of patients with PTC, cancer stem cells detected by immunohistochemistry can
be used as prognostic markers to screen for potential tumor dissemination. Whether these cancer stem cell
markers are potentially therapeutic targets — and, thus, could be used for effective adjuvant treatment strategies — remains to be seen, and more data are needed.
Introduction
Papillary thyroid carcinoma (PTC) is the most common
endocrine malignancy, and an estimated 62,450 new
cases of thyroid cancer will be diagnosed in 2015 in the
United States alone; of these diagnoses, 3 out of 4 cases
will occur in women.1,2 In general, PTC has a favorable
prognosis, the overall 10-year survival rate of patients
with PTC is about 90%, however, approximately 10%
and 20% of patients with stage 1 or 2 PTC, respectively,
have disease recurrence. 2 Tumor recurrence affects the
quality of life of patients; among those who develop local recurrence, some will die from the disease, indicating the existence of more aggressive variants of PTC. Up
to 30% of patients with differentiated thyroid carcinoma
may have tumor recurrence within several decades; 66%
From the Department of Endocrinology (ZL, XL, WL, MS, MP, HY,
LC, CZ), Third Affiliated Hospital, Wenzhou Medical University,
Ruian, Zhejiang, China, Department of Surgery (YL), School of
Medicine, University of Louisville, Louisville, Kentucky, ChineseAmerican Research Institute for Diabetic Complications (XL, CZ,
LC), Ruian Center, Ruian, Zhejiang, China, and Kosair Children’s
Hospital Research Institute (LC), Department of Pediatrics, University of Louisville, Louisville, Kentucky.
Submitted March 13, 2015; accepted July 24, 2015.
Address correspondence to Xuemian Lu, MD, Department of Endocrinology, The Third Affiliated Hospital of Wenzhou Medical
University, Ruian, Zhejiang, China, 325200. E-mail: lu89118@
medmail.com.cn
This project was partly supported by the Science and Technology
Program of Ruian, China (No. 201203074). No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced in this article.
508 Cancer Control
of recurrences occur within the first decade following
initial therapy.3 Therefore, identifying the subpopulation at high-risk for disease recurrence is necessary.
Based on clinical and pathological studies, various
factors, such as age, sex, tumor size, extrathyroidal extension, and distant metastasis, have been investigated
to determine whether an association exists between
them and PTC recurrence; however, the matter is controversial.4 Molecular and cellular events have been
shown to be associated with PTC, and the cancer progenitor/stem cell is considered by some as a common
cellular alteration detected in patients with PTC.5,6 Cancer stem cells, a small subpopulation of cells with stemlike properties, are key factors for tumor initiation and
recurrence.7 Evidence supporting the existence of cancer stem cells in PTC is rapidly accumulating.8-12
Recent research indicates that increased cancer
stem cell–like features play an important role in the
progression of PTC.13 The cancer stem cell theory was
established based on the observation that cancer cell
populations are heterogeneous.14 The identification
and characterization of cancer stem cells in tumors
largely depend on the surface markers shared with
normal stem cells.15 These populations have been identified and isolated using the surface markers CD44 and
CD24 in a human PTC cell line, TPC-1 (BHP10-3).2 Research shows that POU5F1, a stem cell marker, is significantly higher in CD44+ (high levels of CD44) and
CD24 Lin (low levels of CD24) cells, supporting the hypothesis that CD44+CD24–Lin– cells are potential cancer
October 2015, Vol. 22, No. 4
stem cells.2 Further study suggests that CD44+CD24 –
Lin– PTC cells can form thyrospheroids, which are important in vitro features of cancer stem cells; moreover,
data indicate that thyrospheroids can initiate a tumor
in immunodeficient mice.2 Several other potential stem
cell markers have been used by others in thyroid cancer stem cell research, such as CD133 and epithelial
cell adhesion molecule (EpCAM).5,16-18
Although the prognostic influence of cancer stem
cells in PTC is unclear, the use of cancer stem cell
markers may help histopathologically determine the
existence of cancer stem cells in PTC tissue, possibly
impacting patient prognosis. Traditional immunohistological examination consists of single-sectioning
paraffin blocks and is amenable to routine pathology;
however, a wide variety of the staining condition by
traditional assay may limit its utility for detecting cancer stem cell markers in resected PTC samples. Tissue
microarray is a high-throughput technology used for
analyzing molecular markers in oncology. It offers added benefit with respect to decreased technical variability during the staining and interpretation process.
In our study, we established a tissue microarray
process to investigate the expressions of cancer stem
cell markers in tissue samples from a pathological database of patients with PTC. The specimens used in the
tissue microarray consisted of different pathological
stages of PTC and were stained by immunohistochemical assay. The protein expressions of CD44, CD133, EpCAM, CD45, and CD90 were then evaluated for each
pathological stage of PTC. Furthermore, we set forth
to determine the correlation between cancer stem cell
markers and the pathological stages of PTC.
Materials and Methods
Thyroid nodule tissue from 670 patients was collected from a pathological database maintained by the
Third Affiliated Hospital of Wenzhou Medical University (Ruian, Zhejiang, China). All specimens with
a diagnosis of PTC were collected following surgical
excision.
In this retrospective study, we reviewed the database for patients undergoing thyroid nodule resection
between August 2012 and September 2013. This study
was approved by the Institutional Review Board at
Wenzhou Medical University.
Patient Selection
Patients were excluded if they had radiotherapy, chemotherapy, or both, either preoperatively or postoperatively. Patients also met exclusion criteria if they
had certain types of conditions, including autoimmune
disease, cerebrovascular accident, coronary artery disease, viral hepatitis, or another type of cancer. Overall, 167 patients postoperatively diagnosed with PTC,
along with 30 benign, non-PTC controls, met inclusion
October 2015, Vol. 22, No. 4
criteria based on the completeness of their data. Dates
of diagnoses and collection times ranged from August
2012 to September 2013.
Patients were divided into 4 treatment groups according to tumor, node, and metastasis (TNM) staging
per the classification of thyroid cancer by the American Joint Committee on Cancer.19 PTC stage 1 was defined as papillary carcinoma localized to the thyroid
gland. PTC stage 2 was defined as either (a) papillary
carcinoma that has spread distantly in patients younger than 45 years, or (b) papillary carcinoma larger
than 2 cm but no larger than 4 cm, and was limited to
the thyroid gland in patients older than 45 years. PTC
stage 3 was defined as papillary carcinoma occurring
in patients older than 45 years that was larger than
4 cm and was limited to the thyroid or with minimal
extrathyroidal extension, or positive lymph nodes
limited to the pretracheal, paratracheal, or prelaryngeal/Delphian nodes. PTC stage 4 was defined as
papillary carcinoma in patients older than 45 years
that extended beyond the thyroid capsule to the soft
tissues of the neck, cervical lymph node metastases,
or distant metastases.
Of the 167 patients, 139 (83.2%) were women and
28 (16.8%) were men. Of the non-PTC controls with resected thyroid nodules, 26 (86.6%) were women and
4 (13.3%) were men. The mean age of the 167 study
patients was 50.21 ± 11.65 years compared with
48.9 ± 11.34 years for the controls. Of the patients with
PTC, 11 had a family history of diabetes mellitus,
26 had a family history of hypertension, 24 had a history of Hashimoto thyroiditis (chronic lymphocytic
thyroiditis), and 3 were former smokers; by contrast, no
controls had family histories of diabetes mellitus, hypertension, and smoking, and 1 had a history of Hashimoto thyroiditis history. Medical records were also reviewed (Table 1).
Tissue Microarrays
The surgical resection of PTC samples provided ample tissue for paraffin-embedded tissue blocks, and
tissue array was constructed from the paraffin blocks.
Prior to constructing the tissue arrays, the blocks
were categorized into 5 groups: non-PTC (“benign
controls”) and stages 1 to 4. The categorization was
made according to each study patient’s clinical history and diagnosis.
To avoid sample-selection bias, 2 pathologists reviewed the hematoxylin and eosin–stained tissue sections to identify areas of PTC and select the regions in
blocks as donor core tissues. The reviewers were blinded to the study patients’ clinical history. Donor core
tissues with a diameter of 1 mm were obtained from
corresponding regions in the donor paraffin block
and embedded into a recipient block. Cores from archived specimens of normal thyroid tissue adjacent to
Cancer Control 509
Table 1. — Demographics of Study Patient and Control
Groups (N = 197)
Characteristic
Men:women
Papillary
Thyroid
Carcinoma
(n = 167)
Control
(n = 30)
28:139
4:26
50.21 ± 11.65
48.9 ± 11.34
Family history of
diabetes mellitus,
number ratio
11 (167)
0 (30)
Family history of hypertension, number ratio
26 (167)
0 (30)
History of smoking,
number ratio
3 (167)
0 (30)
History of Hashimoto
thyroiditis, number ratio
24 (167)
1 (30)
Thyroid-stimulating
hormone, mU/L
2.02 ± 6.87
1.26 ± 0.85
Total thyroxine 3, nmol/L
1.16 ± 0.26
1.12 ± 0.28
Total thyroxine 4, nmol/L
78.86 ± 36.92
88.61 ± 21.83
Free thyroxine 3, pmol/L
3.09 ± 0.62
2.93 ± 0.45
Age, y
Free thyroxine 4, pmol/L
8.66 ± 4.84
9.13 ± 3.05
Glucose, mmol/L
5.65 ± 1.86
5.39 ± 0.63
Triglycerides, mmol/L
1.95 ± 1.44
1.59 ± 0.71
Total cholesterol, mmol/L
5.09 ± 0.99
5.25 ± 0.97
the thyroid nodule were provided as non-PTC controls.
Single-donor core tissue samples from each specimen
consisting of non-PTC (“benign controls”) and stages 1
to 4 were sampled and designed as 4 rows × 6 columns
per block. The donor cores from all study patients
were embedded in a tissue microarray recipient block.
Nine tissue microarray recipient blocks were prepared
consisting of tissue cores obtained from PTC and nonPTC samples.
Immunohistochemical Assay
Immunohistochemical staining was obtained on the
paraffin-embedded blocks of tissue arrays using the
DAKO EnVision+ System Kit (DAKO, Carpinteria, California). In brief, the sections were deparaffinized and
hydrated. The slides were washed with a Tris buffer,
and peroxidase blocking was performed for 5 minutes. After rewashing, the monoclonal antibodies,
CD44 and EpCAM, and polyclonal antibodies, CD45,
CD90, and CD133, were applied for 60 minutes at
room temperature. The slides were rinsed and incubated with labeled polymer for 30 minutes at room
temperature. The substrate-chromogen solution (diaminobenzidine) was added as a visualization reagent. As a final step, the slides were counterstained
with hematoxylin. A negative control, using the same
experimental procedure as the tested slides, except
for the primary antibody, was included in each run.
510 Cancer Control
Computer Image Analysis
Computer image analysis was performed to quantify the expressions of the cancer stem cell markers in
167 study patients with PTC and 30 benign controls.
Two pathologists performed a pathological reading
to confirm the PTC diagnosis for each tissue microarray slide before the digital image was captured. The
imaging fields were randomly chosen from each core
tissue to ensure sampling objectivity. Five imaging
fields were scanned for each specimen sample. All
digital images were acquired with the Olympus Microscope IX51 (Olympus, Pittsburgh, Pennsylvania)
at 200 magnification using the Spot camera via the
Image-Pro Plus Imaging System (Media Cybernetics,
Warrendale, Pennsylvania) and stored as jpg data files
(resolution was fixed at 200 pixels per inch).
The acquired color images from immunohistochemical staining were defined as standard threshold
according to software specifications. The software
quantified the threshold area represented in these
images. Either the PTC images or normal thyroid images were delineated from the obtained tissues as a
region of interest (ROI) using the set color threshold
subroutine of the image analysis software. Because of
the existence of the duct structure of PTC — in particular, the benign thyroid tissue — the “no tissue” regions were excluded within the ROI to avoid faulty
measurement.
The integrated optical density measured for positive staining was a representation of the mass and a
measurement of the total amount of positive staining
in the delineated regions. Values of integrated optical density were normalized by dividing by the area
of the threshold ROI of the positive staining. Positive expression was represented as the digital values
of the integrated optical density/area, allowing us to
analyze the statistical significance among the study
groups.
Statistic Analysis
Analysis of variance was performed using SPSS16.0
(IBM, New York, New York) to determine the statistical significance of the level of expression of the cancer stem cell markers, if any, between TNM staging and
controls. Spearman rank correlation coefficient was
performed to analyze the correlation between cancer
stem cell markers and TNM staging. Values are reported as mean plus or minus standard deviation. Differences between groups were regarded as statistically
significant when P values were less than .05.
Results
Protein Expressions of CD44, CD133, EpCAM,
CD45, and CD90
The expression pattern of CD44 showed that the
positive staining mainly presented on the cell
October 2015, Vol. 22, No. 4
membrane of PTC cells. Strong staining of CD44
was found in all PTC tissue, but weak and negative
staining were both found in the tissue from the benign controls. Most PTC cells in stages 3 and 4 with
strong CD44 staining also showed cytomorphological
features of poor polarity, which was characterized
by the loss of both apical-basal polarity and wellarranged order of neighboring cells. By contrast,
PTC cells in stages 1 and 2 had cytomorphologic features of well polarity with weaker staining of CD44.
The computer quantification of CD44 expression
in control specimens was 56.4 ± 29.88. Compared
with the control specimens, significant increases of
CD44 expression were seen in specimens with stage
1 (241.71 ± 87.25; P < .01), stage 2 (311.98 ± 135.26;
P < .01), stage 3 (354.71 ± 103.42; P < .01), and stage
4 (374.58 ± 51.6; P < .01; Fig 1).
The expression pattern of CD133 showed that the
positive staining mainly presented in the cytosol of
PTC cells. Similar to CD44 expression, strong staining of CD133 was found in all PTC tissue, but weak
and negative staining was found in the tissue from the
benign controls. The PTC cells from stages 3 and 4
tissue samples had poor polarity with strong CD133
staining, whereas the PTC cells from stages 1 and 2
tissue samples had well polarity with weaker staining
of CD133. The computer quantification of CD133 expression in the control specimens was 52.64 ± 37.45.
Compared with the controls, CD133 expression slight-
ly increased in the PTC tissue samples with stage 1
(152.2 ± 52.72; P > .05) but significantly increased in
the PTC tissue samples with stage 2 (201.18 ± 60.33;
P < .01), stage 3 (242.49 ± 66.81; P < .01), and stage 4
(284.81 ± 87.63; P < .01; Fig 2).
EpCAM showed a similar expression pattern as
CD133, in which the positive staining mainly presented in the cytosol of PTC cells. Strong staining of
EpCAM was seen in all PTC malignant tissue samples but weak and negative staining was seen in the
benign controls. The computer quantification of EpCAM expression in control specimens was 48.30 ±
27.07. Compared with the controls, EpCAM expression increased in the stage 1 (157.48 ± 56.48; P > .05)
PTC tissue samples but significantly increased in
the PTC tissue samples with stage 2 (191.33 ± 51.12;
P < .01), stage 3 (201.83 ± 58.20; P < .01), and stage
4 (226.75 ± 81.44; P < .01; Fig 3). The expressions
of CD45 and CD90 showed weak (CD45) and mild
staining (CD90) in the PTC tissue samples from all
4 stages as well as the tissue samples from the benign controls. Analysis of variance did not indicate
a statistical significance among the TNM stages and
controls (Table 2).
Correlation of CD44, CD133, and EpCAM
We further analyzed the correlation between the
3 cancer stem cell markers (CD44, CD133, and EpCAM) and TNM staging. Positive correlations were
B
D
E
C
CD44 Expression (IOD/area)
A
800
F
600
400
200
0
Stage Stage Stage Stage Benign
1
2
3
4 Controls
Fig 1A–F. — Detection of CD44 expressions by immunohistochemistry and computer image analysis of positive staining in the papillary thyroid carcinoma tissue of TNM stages as well as in the tissue of benign controls. (A) Stage 1 tumor. (B) Stage 2 tumor. (C) Stage 3 tumor. (D) Stage 4 tumor.
(E). Benign controls. (F). CD44 expression.
*P < .05 vs benign controls.
IOD = integrated optical density, TNM = tumor, lymph mode, metastasis.
October 2015, Vol. 22, No. 4
Cancer Control 511
B
D
E
C
CD133 Expression (IOD/area)
A
F
500
400
,
,
300
200
100
0
Stage Stage Stage Stage Benign
1
2
3
4 Controls
Fig 2A–F. — Detection of CD133 expression by immunohistochemistry and computer image analysis of positive staining in the papillary thyroid carcinoma tissue of 4 TNM stages and benign controls. (A) Stage 1 tumor. (B) Stage 2 tumor. (C) Stage 3 tumor. (D) Stage 4 tumor. (E). Benign controls.
(F). CD44 expression.
*P < .05 vs benign controls. **P < .05 vs stage 1.
IOD = integrated optical density, TNM = tumor, lymph mode, metastasis.
B
D
E
C
EpCAM Expression (IOD/area)
A
500
F
400
300
200
100
0
Stage Stage Stage Stage Benign
1
2
3
4 Controls
Fig 3A–F. — Detection of EpCAM expressions by immunohistochemistry and computer image analysis of positive staining in the papillary thyroid
carcinoma tissue of TNM stages as well as in the tissue of benign controls. (A) Stage 1 tumor. (B) Stage 2 tumor. (C) Stage 3 tumor. (D) Stage 4 tumor.
(E). Benign controls. (F). CD44 expression.
*P < .05 vs benign controls.
EpCAM = epithelial cell adhesion molecule, IOD = integrated optical density, TNM = tumor, lymph mode, metastasis.
512 Cancer Control
October 2015, Vol. 22, No. 4
Variable
No. of
Patients
Intensity of IOD
(mean ± SD)
P value
CD45
CD90
Age, y
.375
< 45
57
54.43 ± 60.28
1.63 ± 2.07
≥ 45
110
65.14 ± 79.93
1.74 ± 2.34
Sex
.937
Male
28
60.47 ± 66.1
2.38 ± 2.75
Female
139
61.69 ± 75.48
1.57 ± 2.11
TNM stage
CD45:
.745
CD90:
.309
1
101
59.95 ± 71.31
1.76 ± 2.26
2
14
81.30 ± 103.95
1.00 ± 1.24
3
48
60.23 ± 72.06
1.66 ± 2.22
4
4
45.75 ± 37.97
3.36 ± 4.36
30
8.14 ± 7.7
1.41 ± 1.73
Controls
IOD = integrated optical density, SD = standard deviation,
TNM = tumor, lymph mode, metastasis.
found between CD44 and TNM staging (r 2 = 0.5138;
P < .01; Fig 4A), between CD133 and TNM staging
(r 2 = 0.6107; P < .01; Fig 4B), and between EpCAM and
TNM staging (r 2 = 0. 27; P < .01; Fig 4C).
Discussion
The results from this study demonstrate significant increases of expressions of CD44, CD133, and EpCAM in
PTC tissue samples compared with the tissue samples
from the benign controls. The increased amounts of
these cancer stem cell surface markers were moderate
in stage 1 but were the most pronounced in stages 2 to
4 of PTC. To our knowledge, this is the first study to
examine the relationship between cancer stem cell surface markers and TNM staging of PTC.
To date, CD44, CD133, and EpCAM, which were
initially described as surface markers for malignant
600
400
200
0
Benign Stage Stage Stage Stage
Controls 1
2
3
4
500
A
CD133 Expression
CD44 Expression
800
progenitor cells, have been widely explored as reliable markers for isolating cancer stem cells in many
tumor types.20 Interest in these cancer stem cell markers has increased with the observation that the overexpression of cancer stem cell surface markers in tumor
cells is associated with therapeutic failure and tumor
recurrence.21 In PTC, immunohistochemical staining of CD44 has been shown to have a strong membranous expression pattern, which is consistent with
our results.22 In addition, other studies show that the
protein levels of CD44 significantly increase in biopsy
tissue samples of most patients with PTC.22-24 Accordingly, in our study, the overall expression of CD44 was
increased among all patients with PTC.
Research has shown that a CD133-positive subpopulation, such as cancer-initiating cells, can reproduce an original tumor and serially transplant
it for several generations in immunodeficient mice,
whereas CD133-negative cells cannot form tumors.25
Despite CD133 being known as a cancer stem cell
marker in many tumors and tissue, CD133 expression
in PTC was detected at a lower level in PTC cell lines
and in patients with PTC; however, it was detected at
a higher level in patients with anaplastic thyroid carcinoma, which is a highly aggressive neoplasm.26-28
With regard to subcellular compartmentalization,
we found CD133 expression to be predominantly
cytoplasmic, which is consistent with previous observations.28 In our observations, very weak CD133
expression was detected in normal human thyroid
tissue, and a lower level of CD133 expression was detected in patients with stages 1 and 2 PTC. However,
a high level of CD133 expression was detected in patients with stages 3 and 4 stage PTC. Cytomorphological features of stages 3 and 4 PTC showed poor
polarity, which is consist with its aggressive growing
pattern, in which tumor growth was found beyond
the thyroid capsule, including metastasis to the soft
tissues of the neck, cervical lymph node metastases,
and distant metastases.
Although lymphatic spread is the most common form of PTC progression, the existing residual
micrometastatic tumor cells in fact contribute to the
400
300
200
100
0
Benign Stage Stage Stage Stage
Controls 1
2
3
4
400
B
EpCAM Expression
Table 2. — Expressions of CD45 and CD90 in
Study Patients With Papillary Thyroid Carcinoma
C
300
200
100
0
Benign Stage Stage Stage Stage
Controls 1
2
3
4
Fig 4A–C. — Positive correlation of (A) CD44, (B) CD133, and (C) EpCAM expression in TNM staging. EpCAM = epithelial cell adhesion molecule,
TNM = tumor, lymph mode, metastasis.
October 2015, Vol. 22, No. 4
Cancer Control 513
relapse.29 Residual, micrometastatic tumor cells are
undetectable by conventional histopathological examination. Previously, immunohistochemistry using
the monoclonal anti-EpCAM antibody (Ber EP4) for
visualizing disseminated tumor cells in “tumor free”
lymph nodes was performed by others.18 In that study,
positive EpCAM tumor cells were revealed among
“tumor-free” lymph nodes in 12.5% of cases.18 EpCAM
is a 40kDa transmembrane glycoprotein frequently
overexpressed in cancer progenitor cells, which are
cancer-initiating cells in many human malignancies,
including PTC and — although at very lower levels —
in normal epithelia.18,30,31 Thus, the finding of positive
EpCAM expression in tumor cells among “tumor free”
lymph nodes may be clinically significant in relation to
increased risk of local recurrence and distant metastases. However, a follow-up analysis (mean observation,
72 months) indicated no prognostic significance in
cases with positive EpCAM expression because these
patients underwent treatment of radioiodine, which
can eliminate microdisseminated tumor residue.18
Nevertheless, detection of EpCAM is clinical significant. The concept is supported by 2 studies that identified the nucleus localization of EpCAM as an aggressive marker for poor prognosis among patients with
thyroid cancer.17,32 In our study, the pattern of EpCAM
expression showed weak staining in normal human
thyroid tissue and strong staining in PTC tissue, with
the staining increasing from stage 1 to stage 4. We
also found that increased levels of cancer stem cell
markers (CD44, CD133, and EpCAM) were positively
related to the TNM staging of PTC. However, future
studies are needed to define the specificity of cancer
stem cell markers in PTC.
Conclusions
Identification of accurate prognostic molecular markers for papillary thyroid carcinoma (PTC) is important
because most patients with PTC may be erroneously
diagnosed as having low-risk tumors. Our findings
suggest that, compared with traditional histopathological examination, tissue-array based immunohistochemistry for cancer stem cell marker detection can
more accurately evaluate the biological characteristics
of PTC. Thus, locating cancer stem cells in a subset of
patients with PTC may be molecular markers that can
be used as prognostic markers and to screen for tumor
dissemination. However, whether these cancer stem
cells markers are potential therapeutic targets for effective adjuvant treatment strategies requires additional
evaluation.
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514 Cancer Control
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6. Yun JY, Kim YA, Choe JY, et al. Expression of cancer stem cell
markers is more frequent in anaplastic thyroid carcinoma compared to
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7. Rycaj K, Tang DG. Cell-of-origin of cancer versus cancer stem
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8. Klonisch T, Hoang-Vu C, Hombach-Klonisch S. Thyroid stem cells
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Metab. 2011;96(3):610-613.
10. Fierabracci A. Identifying thyroid stem/progenitor cells: advances
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11. Lin RY. Thyroid cancer stem cells. Nat Rev Endocrinol. 2011;7(10):
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13. Hardin H, Guo Z, Shan W, et al. The roles of the epithelial-mesenchymal transition marker PRRX1 and miR-146b-5p in papillary thyroid
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16. Nilubol N, Boufraqech M, Zhang L, et al. Loss of CPSF2 expression is associated with increased thyroid cancer cellular invasion and cancer stem cell population, and more aggressive disease. J Clin Endocrinol
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20. Gires O. Lessons from common markers of tumor-initiating cells in
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21. Colak S, Medema JP. Cancer stem cells--important players in tumor therapy resistance. FEBS J. 2014;281(21):4779-4791.
22. Figge J, del Rosario AD, Gerasimov G, et al. Preferential expression of the cell adhesion molecule CD44 in papillary thyroid carcinoma.
Exp Mol Pathol. 1994;61(13):203-211.
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24. Kim JY, Cho H, Rhee BD, et al. Expression of CD44 and cyclin D1 in
fine needle aspiration cytology of papillary thyroid carcinoma. Acta Cytol.
2002;46(4):679-683.
25. Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445(7123):111-115.
26. Friedman S, Lu M, Schultz A, et al. CD133+ anaplastic thyroid cancer cells initiate tumors in immunodeficient mice and are regulated by thyrotropin. PLoS One. 2009;4(4):e5395.
27. Zito G, Richiusa P, Bommarito A, et al. In vitro identification and
characterization of CD133(pos) cancer stem-like cells in anaplastic thyroid
carcinoma cell lines. PLoS One. 2008;3(10):e3544.
28. Liu J, Brown RE. Immunohistochemical detection of epithelial-mesenchymal transition associated with stemness phenotype in anaplastic
thyroid carcinoma. Int J Clin Exp Pathol. 2010;3(8):755-762.
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October 2015, Vol. 22, No. 4
Special Report
Should Vital Signs Be Routinely Obtained Prior to Intravenous
Chemotherapy? Results From a 2-Center Study
Smitha Menon, MD, Nathan R. Foster, MS, Sherry Looker, RN, Kristine Sorgatz, RN, Pashtoon Murtaza
Kasi, MBBS, Robert R. McWilliams, MD, and Aminah Jatoi, MD
Background: The American Society of Clinical Oncology and the Oncology Nursing Society have issued guidelines stating that the vital signs of patients should be routinely checked on days that intravenous chemotherapy
is administered. This study sought evidence to justify this approach.
Methods: This trial focused on consecutive patients with cancer from 2 institutions and evaluated outcomes
during the first cycle of gemcitabine-based chemotherapy. The primary end point of the study was a visit to
the ED, hospitalization, or death during the first cycle of chemotherapy.
Results: Medical records from 1,158 patients were reviewed, and vital signs were checked in 589 patients on
day 1 and in 486 on day 8. A total of 148 patients (12.8%) were evaluated in the emergency department (ED),
145 (12.5%) were hospitalized, and 11 (0.9%) died during their first cycle of chemotherapy. In multivariate
analyses, which were adjusted for age, sex, cancer type, role of chemotherapy, number of chemotherapy drugs
administered on day 1, and institution, checking vital signs on day 1 was associated with neither higher rates
of ED visits nor with increased hospitalization; however, checking vital signs on day 8 was associated with
higher rates of ED visits (odds ratio [OR]: 3.71; 95% confidence interval [CI]: 2.18–6.22; P < .0001) and higher
rates of hospitalizations (OR: 3.98; 95% CI: 2.34–6.73; P < .0001).
Conclusion: This study suggests a need for additional, evidence-based data to support the routine checking
of vital signs prior to administering cancer chemotherapy.
Introduction
The American Society of Clinical Oncology and the
Oncology Nursing Society have issued joint guidelines
stating that the vital signs (blood pressure, pulse, respiratory rate, and temperature) of patients with cancer should be routinely and consistently checked
on the day that intravenous chemotherapy is administered.1 Yet, to our knowledge, data to justify — or
refute — this recommendation are lacking.
At least 2 factors point to the need to investigate the
value of checking vital signs prior to the administration
of intravenous chemotherapy in patients with cancer.
In the nononcological setting, this issue is an important
focus of ongoing research. Storm-Versloot et al2 performed a meta-analysis of the routine monitoring of vital
signs in hospitalized patients and observed that, among
15 studies (N = 42,565 patients), conclusions were highly
mixed. The investigators noted that studies appeared
From the Division of Hematology/Oncology, Medical College
of Wisconsin, Milwaukee, Wisconsin (SM), and the Divisions of
Biomedical Statistics (NRF) and Medical Oncology (SL, KS, PMK,
RRM, AJ), Mayo Clinic, Rochester, Minnesota.
Submitted July 20, 2015; accepted July 29, 2015.
Address correspondence to Aminah Jatoi, MD, Mayo Clinic, 200
First Street SW, Rochester, Minnesota 55904. E-mail: Jatoi.Aminah@mayo.edu
No significant relationships exist between the other authors and
the companies/organizations whose products or services may be
referenced in this article.
October 2015, Vol. 22, No. 4
flawed and suggested a need for rigorous research “specifically intended to investigate the clinical relevance
of routinely measured vital signs.”2 In addition, health
care professionals are beginning to question the role of
routinely checking vital signs of patients in nononcology settings, a finding that suggests similar questioning
should occur in oncology settings.3-5 In view of a paucity
of data on this topic in the oncology setting, the need to
establish a role for the routine checking of vital signs prior to the administration of chemotherapy is important.
Second, checking vital signs prior to the administration of chemotherapy has enormous, onerous implications. If one assumes that checking vital signs takes
about 5 minutes and if one works in a chemotherapy unit
that treats approximately 150 patients per day, as is currently the case at the Mayo Clinic (Rochester, Minnesota), checking vital signs requires at least 1 full-time staff
member whose only task is to check patient vital signs.
Thus, acquiring evidence to support or refute the importance of this practice offers more than academic interest
and is in keeping with Elshaug et al,6 who describe that
a “groundswell of activity is seeking to identify and reduce the use of health care service that provide little or
no benefit — whether through overuse or misuse.”
Thus, the primary goal of this 2-institution study
was to generate and analyze data to better understand
whether the routine checking of vital signs prior to
the administration of intravenous chemotherapy is
Cancer Control 515
associated with fewer complications — specifically,
with lower rates of emergency department (ED) visits
and hospitalizations.
Methods
Overview
This study was undertaken at the Medical College of
Wisconsin (Milwaukee, Wisconsin) and the Mayo Clinic. The Institutional Review Board of each institution
reviewed and approved the study protocol prior to data
acquisition and analyses. These institutions were chosen because, historically, one routinely checked vital
signs prior to the administration of chemotherapy (the
former) and the other did not.
An ED visit, hospitalization, or death during the
first cycle of chemotherapy was considered a complication, which was the primary end point of the study.
Routine Nursing Assessment
Both institutions incorporated routine clinical assessment prior to the administration of chemotherapy on
days when a prescribing health care professional had
not seen the patient. This prechemotherapy nursing assessment consisted of asking patients about their general well-being and about specific signs and symptoms
such as fever, fatigue, nausea, and vomiting. Concerns
raised during the nursing assessment could conceivably trigger a vital-sign check based on clinical judgment and the temporal incidence and severity of the
signs or symptoms.
Rationale for Focusing on Patients Treated
With Gemcitabine
This study focused on patients with cancer about to receive their first cycle of gemcitabine-based chemotherapy. Pharmacy records were used to identify patients.
The rationale for focusing on gemcitabine-treated patients is as follows: (1) gemcitabine is typically administered on day 8 in the chemotherapy cycle, and this day
often does not entail a visit with a prescribing health
care professional who likely would have checked vital
signs as part of a routine physical examination, (2) this
chemotherapy agent is used to treat a variety of cancers, leading to greater generalizability of findings, and
(3) the adverse events of this agent are characteristic
of those observed with classical, conventional chemotherapy (nausea, vomiting, myelosuppression, diarrhea), a profile that leads to greater generalizability of
findings. We decided to focus on the first cycle of gemcitabine-based chemotherapy alone because the risk
of adverse events generally increases with subsequent
cycles, and this restriction would potentially enhance
the homogeneity of the study population.
Data Abstraction
Consecutive medical records of patients with cancer
516 Cancer Control
treated with gemcitabine were reviewed, starting with
the most recent and proceeding back in time. The following information was abstracted: patient date of
birth, sex, date of administration of the first cycle of
gemcitabine-based chemotherapy, cancer type, whether chemotherapy was given for metastatic disease or
as adjuvant treatment, number of drugs administered
within the regimen, institution of chemotherapy administration, whether vital signs were checked on days
1 and 8 of the chemotherapy cycle (these data were
gathered irrespective of which health care professional
performed the check), ED visit or hospitalization during the first chemotherapy cycle, and death during the
first chemotherapy cycle.
Sample Size and Analyses
In calculating sample size, the study team estimated
that approximately one-third of study patients would
have had their vital signs routinely checked based on
the anticipated patient representation from the Medical College of Wisconsin. Based on prior reported rates
of adverse events in clinical trials, 5% of patients who
had their vital signs checked were estimated to have
a major complication during their first dose of gemcitabine-based chemotherapy. We estimated that this
rate would increase to 10% in the absence of checking
vital signs; this 5% effect size was derived from other
clinical settings in which this increased complication
rate approximates the upper limit of acceptability.7-9
We estimated that a target sample size of 1,015 study
patients would enable us to detect the above with 80%
power, assuming a 2-sided significance level of .05.
Analyses consisted of direct comparisons of complication rates between study patients who did and
did not have their vital signs checked at specific time
points. If chemotherapy was not administered on a
particular day, then the complication data from that
study patient were still included in the analyses relevant to that day. For univariate and multivariate analyses, logistical regression models were constructed to
determine which variables were associated with ED
visits and hospitalizations (in the event of a very low
complication rate [eg, low death rate], this analysis was
not performed). A 2-sided P value of less than .05 was
considered statistically significant. Statistical analyses
were performed using SAS version 9.3 (SAS Institute,
Cary, North Carolina) and JMP software (SAS Institute).
Results
Patient Demographics
We reviewed the medical records of 1,158 study patients. Vital signs were checked for 589 study patients
on day 1 and for 486 study patients on day 8. Based
on whether vital signs had been checked, patient characteristics were similar, although cancer type, number
of drugs administered, and whether patients received
October 2015, Vol. 22, No. 4
adjuvant treatment or treatment for metastatic cancer
differed between groups, at times, based on vital-sign
assessment and institution (Table 1).
Complications and Vital-Sign Checks
A total of 148 study patients (12.8%) were evaluated in the ED, 145 (12.5%) were hospitalized, and
11 (0.9%) died during their first cycle of chemotherapy. Subgroup analyses found no statistically significant differences in these complication rates based on
institution, except for a trend toward a greater number of ED visits in patients from the Medical College
of Wisconsin: 60 visits (15%) compared with 88 visits
(12%; P = .08).
Checking vital signs on day 1 was associated
with a trend toward more ED visits (85 visits [15%])
compared with patients whose vitals signs were not
checked (63 [11%]; P = .09). By contrast, hospitalizations and deaths were not statistically different based
on day 1 vital sign checks. Checking vital signs on
Table 1. — Patient Demographics
Characteristic
Institution
Wisconsina
Median age, y
(range)
62
(42–91)
Mayo
Day 1 Vital Signs Checked?
P
value
63
(22–95)
No
(N = 5690)
Yes
(N = 589)
63
(22–95)
62
(42–91)
.67
P value
Day 8 Vital Signs Checked?
No
(N = 670)
Yes
(N = 486)
62
(22– 95)
62
(42– 91)
.02
P
value
.35
Sex, n (%)
Male
Female
204 (52)
192 (49)
369 (48)
393 (52)
283 (50)
286 (50)
290 (49)
299 (51)
.32
325 (49)
345 (52)
247 (51)
239 (49)
.86
.44
Cancer type,
n (%)
Pancreas
Lung
Breast
Gynecological
Genitourinary
Other
73 (19)
59 (15)
17 (4)
38 (10)
99 (25)
109 (28)
89 (12)
141 (19)
47 (6)
115 (15)
166 (22)
204 (27)
61 (11)
102 (18)
31 (5)
76 (13)
146 (26)
153 (27)
74 (11)
121 (18)
41 (6)
102 (15)
156 (23)
176 (26)
101 (17)
98 (17)
33 (6)
77 (13)
119 (20)
160 (27)
.002
88 (18)
79 (16)
23 (5)
51 (11)
109 (23)
135 (28)
.03
.005
Chemotherapy,
n (%)
Adjuvant
Metastatic
Unspecified
38 (10)
316 (80)
39 (10)
72 (9)
658 (86)
32 (4)
56 (10)
486 (85)
27 (5)
54 (9)
488 (83)
44 (8)
.0006
65 (10)
576 (86)
29 (4)
45 (9)
397 (82)
42 (9)
.14
.01
Drugs given on
day 1, n (%)
1
2
3
4
76 (19)
320 (81)
0
0
196 (26)
499 (66)
65 (9)
2 (0)
143 (25)
384 (68)
41 (7)
1 (0)
129 (22)
435 (74)
24 (4)
1 (0)
< .0001
173 (26)
448 (67)
48 (7)
1 (0)
99 (20)
369 (76)
17 (4)
1 (0)
.09
.008
Drugs given on
day 8, n (%)
0
1
2
3
74 (19)
160 (40)
162 (41)
0
150 (20)
380 (50)
220 (29)
12 (2)
111 (20)
288 (51)
165 (29)
5 (1)
< .0001
a
113 (19)
252 (43)
217 (37)
7 (1)
126 (19)
353 (53)
186 (28)
5 (1)
.02
96 (20)
187 (39)
196 (40)
7 (1)
< .0001
Percentages do not always sum to 100% because of rounding or missing data.
October 2015, Vol. 22, No. 4
Cancer Control 517
day 8 was associated with more patients visiting an ED
(85 [18%] compared with 62 [9%]; P < .0001) and more
patients being hospitalized (81 [17%] compared with
63 [9%]; P = .0002).
Multivariate logistic regression analyses are shown
in Table 2 and show that checking vital signs on
day 1 was neither associated with a higher rate of ED
visits nor an increased rate of hospitalization. However, checking vital signs was associated with a higher
rate of ED visits and higher hospitalization rates when
checked on day 8.
Discussion
This study was undertaken to assess whether or not
checking vital signs on the day of chemotherapy administration is associated with higher complication
rates (eg, ED visits, hospitalizations). Our study findings indicate this was not the case. Rather, the opposite was found: Checking vital signs on the day of
chemotherapy administration appears to be associated with higher rates of ED visits and hospitalizations.
However, these findings do not indicate that checking
vital signs leads to higher rates of complications; rather, patients who appeared ill presumably had their
vital signs checked only because they appeared ill;
these patients were subsequently referred to the ED
or were hospitalized. Thus, the findings of this study
suggest that not checking vital signs routinely prior to
the administration of intravenous chemotherapy does
not have adverse consequences.
The role of routinely checking vital signs is also
being questioned in other areas of clinical medicine.
Historically, checking vital signs was an essential, mandatory component of patient care. However, more recent studies — some of which include the routine monitoring of vital signs in hospitalized patients — have
questioned the value of this practice and suggest that
patients present with other symptoms or signs well before they manifest a concerning change in their vital
signs.2,3 In hospital settings, the concern for compromising patient sleep, as well as escalating health care
costs, has also led to the omission or curtailing of routine vital sign checks.4,5 Although the role of routinely
checking vital signs continues to remain controversial,
emerging trends show that this practice has been discontinued in some circumstances.10,11
A critical distinction should be made between
routinely checking vital signs and checking vital signs
when patients appear ill or when patients are receiving
antineoplastic agents that put them at risk for hypertension. Patients who fall within these latter 2 categories should continue to have vital signs checked. We
acknowledge that patients with cancer who are ill or
asymptomatic but who are receiving a medication such
as bevacizumab should have at least a partial set of vital signs obtained.
518 Cancer Control
Table 2. — Multivariate Logistic Regression Model
End Point
Checking Vital
Signs
OR
(95% CI)a
P value
ED visits
Day 1 (yes vs no)
1.2
(0.72–1.97)
.48
Day 8 (yes vs no)
3.71
(2.18–6.22)
< .0001
Day 1 (yes vs no)
1.32
(0.80–2.14)
.27
Day 8 (yes vs no)
3.98
(2.34–6.73)
< .0001
Hospitalizations
a Analyses were adjusted for adjusted for age, sex, cancer type,
chemotherapy type (adjuvant vs for metastatic disease), and number
of drugs prescribed on day 1 or 8 (day 1 for the day 1 vital signs
predictor and day 8 for the day 8 vital signs predictor), and institution.
CI = confidence interval, ED = emergency department, OR = odds ratio.
Limitations
The retrospective nature of this study makes it impossible to determine why the checking of vital signs occurred or did not outside the routine practice of each
specific institution. On day 1, or close to day 1, patients are likely to see their health care professional,
who has performed an in-depth assessment of their
status. Therefore, one might suggest that nurses can
forgo checking vital signs if a physician had seen the
patient at some very recent time point. Furthermore,
patients with abnormal vital signs during their visit
with their oncologist might have been deflected from
receiving chemotherapy, resulting in a bias toward
seeing normal vital signs on day 1 prior to administering chemotherapy. Of note, the foregoing is speculative, thus emphasizing the limitations of the design
used in this study.
This study might have been underpowered with
respect to determining whether early interventions,
such as hospitalization, based on abnormal vital signs
would have prevented more serious complications. We
were unable to derive such information from a retrospective study.
In addition, the data from the current study are
not derived from a randomized trial. As a result, comparative participant groups might be imbalanced with
respect to institutional practices that could have influenced complication rates or patient predisposition
for chemotherapy toxicity. If a prospective trial were
to be performed, then the focus of that study should
be on asymptomatic patients alone, with the exclusion
of those receiving chemotherapy agents that might increase blood pressure. It would also be important to
balance study arms based on the extent of prior cancer
therapy and other factors that tend to lead to greater
chemotherapy toxicity. One might argue that the great
challenges of performing such a trial add to the importance of the data presented in this paper.
October 2015, Vol. 22, No. 4
Conclusion
Our findings question whether the absence of evidence to support the checking of vital signs should
lead to the conclusion that vital signs should be obtained. At the very least, these study results call for
further evidence-based data to assess this routine, expense-generating clinical practice.
References
1. Neuss MN, Polovich M, McNiff K, et al. 2013 updated American
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administration safety standards including standards for the safe administration and management of oral chemotherapy. J Oncol Pract. 2013;9(2
suppl):5s-13s.
2. Storm-Versloot MN, Verweij L, Lucas C, et al. Clinical relevance of
routinely measured vital signs in hospitalized patients: a systematic review.
J Nurs Scholarsh. 2014;46(1):39-49.
3. Evans D, Hodgkinson B, Berry J. Vital signs in hospital patients:
a systematic review. Int J Nurs Stud. 2001;38(6):643-650.
4. Fukayama H, Yagiela JA. Monitoring of vital signs during dental
care. Int Dent J. 2006;56(2):102-108.
5. Leinonen T, Leino-Kilpi H. Research in peri-operative nursing care.
J Clin Nurs. 1999;8(2):123-138.
6. Elshaug AG, McWilliams JM, Landon BE. The value of low-value
lists. JAMA. 2013 Feb 27;309(8):775-6.
7. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative
chemoradiotherapy for esophageal or junctional cancer. N Engl J Med.
2012;366(22):2074-2084.
8. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy
in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med.
1996;335(2):91-97.
9. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy
with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med.
2003;348(19):1875-1883.
10. Pellicane AJ. Relationship between nighttime vital sign assessments and acute care transfers in the rehabilitation inpatient. Rehabil
Nurs. 2014;39(6):305-310.
11. Bartick MC, Thai X, Schmidt T, et al. Decrease in as-needed sedative use by limiting nighttime sleep disruptions from hospital staff. J Hosp
Med. 2010;5(3):E20-E24.
October 2015, Vol. 22, No. 4
Cancer Control 519
Special Report
Advancing Cancer Control Through Research and Cancer
Registry Collaborations in the Caribbean
Rishika Banydeen, MPH, Angela M.C. Rose, MSc, Damali Martin, PhD, William Aiken, MD, Cheryl
Alexis, MBBS, MSc, MRCP, Glennis Andall-Brereton, PhD, Kimlin Ashing, PhD, J. Gordon Avery, MB,
ChB, MD, Penny Avery, SRN, Jacqueline Deloumeaux, MD, PhD, Natasha Ekomaye, Owen
Gabriel, MD, Trevor Hassell, MBBS, Lowell Hughes, MBBS, Maisha Hutton, MSc, Shravana Kumar
Jyoti, MD, Penelope Layne, RN/RM, Danièle Luce, PhD, Alan Patrick, MD, Patsy Prussia, MBBS,
Juliette Smith-Ravin, PhD, Jacqueline Veronique-Baudin, PhD, Elizabeth Blackman, MPH, Veronica
Roach, SRN, and Camille Ragin, PhD
Background: Few national registries exist in the Caribbean, resulting in limited cancer statistics being available for the region. Therefore, estimates are frequently based on the extrapolation of mortality data submitted to the World Health Organization. Thus, regional cancer surveillance and research need promoting, and
their synergy must be strengthened. However, differences between countries outweigh similarities, hampering
registration and availability of data.
Methods: The African-Caribbean Cancer Consortium (AC3) is a broad-based resource for education, training,
and research on all aspects of cancer in populations of African descent. The AC3 focuses on capacity building
in cancer registration in the Caribbean through special topics, training sessions, and biannual meetings. We
review the results from selected AC3 workshops, including an inventory of established cancer registries in the
Caribbean region, current cancer surveillance statistics, and a review of data quality. We then describe the
potential for cancer research surveillance activities and the role of policymakers.
Results: Twelve of 30 Caribbean nations have cancer registries. Four of these nations provide high-quality
incidence data, thus covering 14.4% of the population; therefore, regional estimates are challenging. Existing
research and registry collaborations must pave the way and are facilitated by organizations like the AC3.
Conclusions: Improved coverage for cancer registrations could help advance health policy through targeted
research. Capacity building, resource optimization, collaboration, and communication between cancer surveillance and research teams are key to obtaining robust and complete data in the Caribbean.
Introduction
Cancer is increasing in frequency and is a leading
cause of death worldwide. As such, it is a principal
priority for health authorities of many countries.1 An
estimated 14 million new cancer cases occurred in the
world in 2012.2 Lung, female breast, colorectal, pros-
From the Clinical Research and Innovation Unit (RB) and Martinique Cancer Registry (JS-R, JV-B), University Hospital of Martinique,
Fort-de-France, Martinique, French West Indies, Chronic Disease Research Centre (AMCR, NE, PP) and Faculty of Medical Sciences (CA),
University of the West Indies, St Michael, Barbados, West Indies, Epidemiology and Genomics Research Program, Division of Cancer
Control and Population Sciences, National Cancer Institute, National Institute of Health, Bethesda, Maryland (DM), Departments of
Surgery, Radiology, Anaesthesia, and Intensive Care, University of the West Indies, Mona, Kingston, Jamaica, West Indies (WA), Surveillance, Disease Prevention and Control Division, Caribbean Public Health Agency, Port of Spain, Trinidad, West Indies (GA-B), Center
of Community Alliance for Research and Education, Department of Population Science, City of Hope Medical Center, Duarte, California
(KA), University of Medicine and Health Sciences, St Kitts (JGA), and Pink Lily Cancer Care, Nevis Maternal Health Fund (PA), St Kitts
and Nevis, West Indies (JGA), Guadeloupe Cancer Registry, University Hospital of Pointe-à-Pitre, Guadeloupe, West Indies (JD), Oncology Department, Victoria Hospital, Castries Saint Lucia (OG), Healthy Caribbean Coalition, Barbados, West Indies (TH, MH), Hughes
Medical Centre, Anguilla, British West Indies (LH), Health Service Authority Hospital, Georgetown, Cayman Islands, British West Indies
(SKJ), Guyana Cancer Registry, Ministry of Health, Queenstown, Guyana (PL), French National Institute of Health and Medical Research,
Guadeloupe, French West Indies (DL), Tobago Health Studies Office, Scarborough, Trinidad and Tobago (AP), Cancer Prevention and
Control Program, Fox Chase Cancer Center, Temple Health, Philadelphia, Pennsylvania (EB, CR), Dr Elizabeth Quamina National Cancer
Registry of Trinidad and Tobago, Eric Williams Medical Sciences Complex, Mount Hope, Trinidad and Tobago (VR).
Mrs Banydeen, Rose, Layne, and Roach and Drs Aiken, Ashing, Avery, Deloumeaux, Jyoti, Luce, Patrick, Smith-Ravin, Veronique-Baudin, and Ragin are members of the African-Caribbean Cancer Consortium. This work is supported in part by the National Cancer Institute (P30 CA006927) and (R13 CA192672-03 to C.R.). No significant relationships exist between the other authors and the companies/
organizations whose products or services may be referenced in this article.
Submitted December 8, 2014; accepted July 17, 2015.
Address correspondence to Camille Ragin, PhD, Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue,
Philadelphia, PA 19111. E-mail: camille.ragin@fccc.edu
520 Cancer Control
October 2015, Vol. 22, No. 4
tate, and stomach cancers accounted for nearly 50%
of all cases diagnosed and of cancer-related deaths
worldwide.2 The Caribbean, whose location is detailed in Fig 1, is no exception, with malignant neoplasms being the leading cause of mortality for those
living in the Caribbean.3
Although Caribbean nations share the same urgency in the fight against cancer in terms of surveillance and research, important limitations exist in
addressing this issue.4,5 For example, although different countries share many similarities in terms of
environmental, ethnic predominance (most Englishspeaking Caribbean countries comprise majority
African-origin populations), and other common risk
factors, geographical, demographic, and ethnic differences are also present.6 Not all Caribbean countries are islands, and their populations vary in size:
from more than 11 million in Cuba to about 5,000 for
Montserrat.7 Some countries have majority populations of East Indian ethnic origin, and many have an
increasing proportion of their population of mixed
ethnic background.8
Economic differences also exist, with some Ca-
ribbean countries classified as high- (eg, Barbados,
Bahamas), upper-middle (eg, Jamaica, Suriname),
lower-middle (eg, Guyana), or low-income economies (eg, Haiti).9 Although ethnic and environmental
factors influence trends in rates of cancer incidence
and mortality, such factors are generally correlated
with economic development.10,11 Variation in economic development throughout the Caribbean also
means a range of access to and quality of health
care across different countries; in some communities, insufficient or inadequate health insurance, or
geographical remoteness, or estrangement from adequate specialized health infrastructure has resulted
in a higher frequency of cancers with poor prognoses (due to diagnosis and treatment at advanced
stages) and more deaths.12
It is necessary to monitor epidemiological trends
in cancer (eg, through surveillance), particularly in
low-resource countries undergoing demographic
transition with increasingly aging populations like
those in the Caribbean.6,13 This is even more important because high-quality data on cancer are lacking
from low- and medium-resource countries, and, con-
Fig 1. — Map of the Caribbean.
October 2015, Vol. 22, No. 4
Cancer Control 521
sidering the differences between countries across the
Caribbean, generalizations have been difficult.10 In
addition, research is vital for understanding the specific determinants of most cancers, especially those
affecting high-risk populations such as African Caribbean or indigenous populations, such as Amerindians, and to provide better guidance and evaluation
of cancer control policies to develop targeted and efficient programs for cancer prevention and care.6,14,15
Although the distinction between surveillance and
research is important, the synergy between them is
often overlooked. Surveillance is necessary for continued disease monitoring, and its data analysis may
hint at previously unknown insights. By contrast, the
value of research lies in the ability of researchers to
examine what can only be alluded to, but not proved,
using surveillance data. Therefore, surveillance is
often termed hypothesis generating and research hypothesis testing. Collaboration between researchers
using these different methods for generating information on a subject can be powerful, although often
they run along parallel paths.16
However, considering the intra-Caribbean variation, countries in the region cannot be “equal in arms”
against the cancer epidemic. Not all Caribbean countries possess sufficient essential health surveillance
infrastructure to provide efficient cancer registration
and quality cancer data. Where established and efficient cancer surveillance is present, little optimization
of cancer registration exists to help make progress
through cancer research. In addition, knowledge, resources, and collaboration may be too limited to utilize
and address research needs overall, including via cancer registries.14
Several prior regional scientific workshops and
conferences have identified the few existing cancer
surveillance systems of the Caribbean and have highlighted the ongoing scientific collaborations implicating cancer registries.17-19 These workshops advocate
for more dynamic and productive communication between relevant partners while also emphasizing the
growing importance of, and need for, cancer registration to address the increasing cancer burden through
targeted research.17-19
Herein we describe the latest 2013 and 2014
workshops coordinated by the African-Caribbean
Cancer Consortium (AC3), which facilitates and promotes the collaboration between cancer research
and surveillance. We also join the AC3 and other concerned cancer surveillance and research stakeholders
in the Caribbean in calling for the reinforcement of
cancer registration in the Caribbean to expand population-based coverage by cancer registries and obtain
more complete and reliable data for their strategic use
in guiding requisite cancer control interventions and
collaborative research.
522 Cancer Control
Caribbean Nations
The Caribbean region refers to the 15 Caribbean nation members and 5 associate members of the Caribbean Community (CARICOM), in addition to
10 other Caribbean nations (French Martinique,
Guadeloupe, and French Guiana, as well as other
Caribbean islands of the Greater and Lesser Antilles; see Fig 1). 20 The 30 Caribbean nations referred to in this paper include Anguilla, Antigua
and Barbuda, the Bahamas, Barbados, Belize, Bermuda, the British Virgin Islands, the Cayman Islands, Cuba, Dominica, the Dominican Republic,
French Guiana, Grenada, Guadeloupe, Guyana,
Haiti, Jamaica, Martinique, Montserrat, The Netherlands Antilles (Aruba, Bonaire, Curaçao, Saba,
St Eustatius, and the Dutch half of St Martin and
St Maarten), Puerto Rico, St Barthélemy, St Kitts
and Nevis, St Lucia, St Martin (the French half of St
Martin and St Maarten), St Vincent and the Grenadines, Suriname, Trinidad and Tobago, the Turks
and Caicos, and the US Virgin Islands. Although
they predominantly comprise islands in the Caribbean Sea for which the official language is English,
notable exceptions exist. French Guiana, Suriname
and Guyana are on mainland South America while
Belize is on mainland Central America; French Guiana, Haiti, Martinique, Guadeloupe, Saint Barthélemy and Saint Martin are French-speaking, while
the official language of Suriname, Aruba, Bonaire,
Curaçao and Sint Maarten is Dutch, and that of
Cuba, the Dominican Republic, and Puerto Rico
is Spanish.
African-Caribbean Cancer Consortium
The mission of the AC3 is to study viral, genetic, environmental, and lifestyle factors for cancer risk and
outcomes in populations of African descent.21 The
consortium is part of the Epidemiology and Genomics Research Program consortia of the National Cancer
Institute (NCI), which is composed of 3 connected networks of investigators in the United States, Africa, and
the Caribbean region.21 The AC3 has 120 members and
is a broad-based resource for education, training, and
research on the etiology, screening, prevention, treatment, and survivorship related to cancer in populations of African descent.21 Within the AC3, 7 Caribbean
cancer registries are represented (5 are national: Barbados, Guyana, Guadeloupe, Martinique, and Trinidad
and Tobago; 2 are subnational: Cayman Islands and Jamaica).4,17,18,21
Capacity-Building Activities
The AC3 focuses on capacity-building efforts in the
field of cancer registration in the Caribbean by hosting a series of special topics and training sessions during biannual scientific meetings and other supporting
October 2015, Vol. 22, No. 4
initiatives.4,18,19 Five scientific meetings have been conducted to date since 2007. During the 2007 and 2008
AC3 meetings, presentations by cancer registrars provided an overview of the cancer burden in the Caribbean region.17,18 During the 2010 meeting, rationale
for cancer registration, the different types of cancer
registries, and the relevant steps for planning and
implementation of a cancer registry were discussed.4
The 2012 meeting provided another opportunity for
presentations of national cancer registry data from
4 cancer registries in lower–middle-income countries
(Kenya, Guyana, Jamaica, and Trinidad and Tobago).5
Cancer statistics were presented that revealed the reality of cancer burden in these Caribbean countries.5
Cancer registration activities concluded with a satellite
meeting with the NCI.5
To continue what the AC3 has accomplished, the
information learned thus far, and to address current
needs, an AC3 cancer registry workshop was organized in 2013 as a preconference to the annual meeting of the Caribbean Public Health Agency (CARPHA).22,23 The primary purpose of the 1-day meeting
was to amplify, promote, and sustain Caribbean scientific research through collaborations with cancer
registries.22 The objectives of the workshop were to
describe the applications and utilization of cancer
registry data in collaborative research and to discuss the importance of policy decision-making and
its impact on existing or developing national cancer
registries and cancer control.22 The workshop united
existing and aspiring cancer registrars, pathologists,
clinical and biomedical scientists, representatives of
public health organizations, and cancer advocates.22
It also presented opportunities for dialogue and collaboration between English- and French-speaking Caribbean nations.22
This initiative was further reinforced by the 2014
Cancer Surveillance in the Caribbean meeting, a joint
effort of several stakeholders that included the NCI,
the CARPHA, the US Centers for Disease Control and
Prevention, the International Agency for Research on
Cancer (IARC), the Pan American Health Organization
(PAHO), the US Northern Command, and the AC3.24 As
of this publication, the AC3 2014 scientific meeting was
the most recent gathering to discuss strategies in the
way forward toward better cancer registration and collaborative research for the Caribbean region.21,25
Established Cancer Registries
Of the 30 nations and territories in the Caribbean region, 12 have established cancer registries, 6 of which
have existed for more than 30 years (Puerto Rico, Jamaica-Kingston, Cuba, The Netherlands Antilles, Bermuda, and Martinique) and 1 for 20 years (Trinidad
and Tobago), whereas all others have been in operation for 5 to 15 years (Table 1). Of these, 4 cancer regisOctober 2015, Vol. 22, No. 4
Table 1. — Inventory of Established Cancer Registries
in the Caribbean
Country
Type of
Registry
Year of
Establishment
National
1951
3,688,000
Urban
1958
1,453,248
Cuba
National
1964
11,266,000
Netherlands
Antillesb
National
1977
199,929
Bermudac
National
1979
69,000
Martinique
National
1983
404,000
Trinidad and
Tobago
National
1994
1,341,000
Guyana
National
2000
800,000
French Guiana
National
2005
249,000
Guadeloupe
National
2008
466,000
Barbados
National
2010
289,000
Cayman Islands
National
2010
54,000
Puerto Rico
Jamaica
a
Estimated
Midyear
Population12
aThis registration occurs in urban areas alone (Kingston and St Andrew).
bIncludes 6 Dutch-Caribbean islands: Curacao, Aruba, Bonaire, Saba,
St Eustatius, and St Maarten.
restructuring in 2004 and relaunched in 2008.
cUnderwent
tries (Cuba, Jamaica–Kingston, Martinique, and Puerto
Rico), representing 14.4% of the regional population,
have contributed high-quality incidence data published by the World Health Organization (WHO).26
Based on discussions from the workshop,
emerging cancer registries in other countries (eg,
Anguilla, St Kitts and Nevis, St Lucia, the Bahamas
and the Cayman Islands) may be hampered by challenges, including limited training opportunities, limited staff availability and qualifications, inadequate
information technology support, and transportation difficulties for data retrieval. Other challenges
include lack of diagnostic facilities, lack of pathologists, and long reporting delays compounded by
poor verification of data, lack of formal death certification, and lack of support from ministries of health.
The latter is critical to ensure sustainability of cancer
registries and their role in developing and evaluating
cancer control strategies.27-29
Surveillance Estimates and Quality of Data
The Caribbean region ranks fifth worldwide for cancer incidence and fourth for mortality (185.4 and 102.0
per 100,000 per year, respectively; Fig 2).2 However,
disparities exist in the quality of available cancer data,
because 4 Caribbean nations have high-quality national or regional cancer incidence data, whereas 2 nations have complete, high-quality cancer mortality data
(Table 2).2 Furthermore, for countries without existing
Cancer Control 523
Rates, ASR( W ) (per 100,000)
Table 2. — Quality of Cancer Data in the Caribbean
350
Availability
300
Incidence Data
N
High-quality national or regional data
4
Cuba
Martinique
Puerto Rico
Jamaica
National data (rates)
1
Trinidad and Tobago
Regional data (rates)
0
—
Frequency data
0
—
No data a
9
Bahamas
Barbados
Belize
Dominican Republic
Guadeloupe
French Guiana
Guyana
Haiti
Suriname
High-quality complete vital registration
2
Bahamas
Cuba
Medium-quality complete
vital registration
8
Barbados
Belize
Guyana
Guadeloupe
Martinique
French Guiana
Puerto Rico
Trinidad and Tobago
Low-quality complete vital registration
4
Dominican Republic
Haiti
Jamaica
Suriname
Incomplete or sample vital registration
0
—
Other sourcesb
0
—
No data
0
—
250
200
150
100
50
meric a
Nor th A
Oceania
Eur o p e
a
Americ
South
e an
A sia
Caribb
Centr a
l A m er
Afric a
ic a
0
Incidence
Mortality Data
Mortality
Fig 2. — ASR(W) of and mortality from all cancer sites per 100,000 per
year by world region. The Caribbean region is defined as the Bahamas,
Barbados, Cuba, Dominican Republic, Guadeloupe, Martinique, Haiti,
Jamaica, Puerto Rico, and Trinidad and Tobago.
ASR(W) = world age-standardized incidence rate.
Data from reference 2.
cancer registries or those with newly established registries, cancer statistics are typically derived from estimates of the WHO compiled from a combination of
nationally reported mortality data and hospital-based
data.2 Therefore, it is possible that under-reporting is
occurring for some Caribbean nations, thus underlying
the need for indigenous cancer registry data to accurately reflect the burden of cancer in the region.2
Available Research Data
Deeper insight into cancer registration in the Caribbean and its potential perspectives was achieved
through a description of available data provided by
countries to CARPHA. Highlights from these data included the high prevalence of smoking in some countries (although the general belief is that smoking has a
very low prevalence throughout the Caribbean) and a
high prevalence of alcohol intake.30,31 Taken altogether, the data suggest an increased risk for the development of noncommunicable diseases, including cancer,
with these conditions representing the top 10 causes
of death during the last decade in the Caribbean. Although some research on environmental carcinogens
has been documented, such as the prostate case-control study in Guadeloupe, the region still lacks research
524 Cancer Control
Caribbean
Country
Not all cancer data originating from registries and other sources in
some Caribbean islands have been referenced and evaluated by the
International Agency for Research on Cancer.
b
Cancer registries, verbal autopsy, and surveys, among others.
Data from reference 2.
a
in this domain.32 Other gaps in the data include cancer
morbidity and survival rates, clinical management, and
population screening rates for specific cancers (cervical, breast, and colon).
Usefulness of Cancer Surveillance Data in
Research Collaborations
The usefulness of cancer registries in collaborating
with research for population-based case-control studOctober 2015, Vol. 22, No. 4
ies was also described (Fig 3). For example, data from
registries allow researchers to plan or estimate the
number of expected cases, identify the main hospitals
where cases may be found, or identify patients for recruitment into research studies. During the study, data
can be cross-checked with the registry to ensure coverage. Registry data are also useful for checking on
selection bias in research studies. If the registry also
conducts follow-up for cases, then it can provide the
study with additional data on outcomes. Examples of
such collaborative work were illustrated by an ongoing study investigating socioeconomic inequalities in
cancer incidence and mortality in Martinique and Guadeloupe as well as AC3 collaborations involving the
cancer registries in Trinidad and Tobago and Guyana.33
Analyses of data, issuing from these AC3 collaborations, have been conducted or are near completion for
Research
capacity-Building
collaboration
Outcomes
• Number of expected
cases
• Case ascertainment
(identifying patients for
study recruitment)
• Selection bias
• Geographical variation
• Quality of care
• Quality of life
• Barriers to screening
or treatment
• Comorbidities and
survivorship
• Study of risk factors/
specific determinants
• Identifying vulnerable/
at-risk groups
• Cancer control and
management
• Cancer outcomes
• Public health
interventions
• Improve quality of
diagnosis, survivorship,
treatment, and follow-up
What can
be measured
What outcomes can
be achieved
What to consider
for data collection and
reporting
Cancer
Surveillance
prostate, breast, and head and neck cancers.34-39 Such
findings have helped shed insight into the burden of
cancer and differences in outcomes in comparison
with US or global cancer statistics. Furthermore, the
important role played by cancer registries, in terms of
research or public health intervention, was illustrated by the French Caribbean island of Martinique.40-46
There, long-existing, precise registry data have informed analytical studies on several cancers and have
helped assess the environmental and occupational
health risks or evaluation of medical practice and local
screening programs for major sites.40-46
Optimizing fruitful surveillance and research collaboration requires certain legal and ethical environments, as well as specific infrastructure and organization. Of particular importance is a properly defined
and functioning information system. This should not
• Legal/ethical issues
• Infrastructure/
organization
• Functioning information
systems
• Protocols and best
practices
• Feasibility and
sustainability
• Exhaustivity/quality of
data coding/reporting
• Rates and trends
(incidence, mortality)
• Clinical characteristics
• Survival characteristics
• Measuring impact/
outcomes of interventions
introduced through
research study
C
A
N
C
E
R
C
O
N
T
R
O
L
• Health care planning
• Policy decision-making
• Program planning and
evaluation
Fig 3. — Schematic of how surveillance data can be used to drive research studies through collaboration to promote cancer control.
October 2015, Vol. 22, No. 4
Cancer Control 525
necessarily be electronic, but indicators must be well
defined, with appropriate resources for sustaining
data collection and reporting from both public and
private health care sectors. In addition, standard protocols, and best practices, relying on evidence-based
medicine, should be implemented. Several presenters during the workshop provided evidence for using
cancer registries as building blocks for collaborative
research, with particular emphasis on capacity building in developing regions. Surveillance data were also
demonstrated to have use in driving research studies. For example, the purpose of any cancer registry
should include producing more stable and accurate
rates, greater access to data, and the possibility to investigate geographical variability (Fig 3). However, a
registry would also be valuable to investigate the quality of care, possibly by looking at stage at diagnosis,
or whether screening is being performed, as well as
examinations of social issues and barriers to screening and treatment. Although separate research studies
may be required for some of these, by working with
registry teams, the data could be combined to provide
a broader picture. Population-based cancer registries
represent the gold standard, but they can also be used
to examine rates standardized by age, age-specific
incidence, sex ratios, rates in different ethnic groups
and migrants, time trends, and survival.47-49 These data
could then be used in health care planning and monitoring, as well as to inform policies, guide planning,
and, once the knowledge of trends is available, to project treatment outcomes. When they are used to help
validate current cancer mortality data, cancer registry
data can also illuminate areas for research.
Proving the usefulness of the data from a cancer
registry is a powerful way to influence the public and
to help ensure continued future funding. Linking surveillance with research outcomes is another way to
guarantee continued collaboration and, perhaps, registry sustainability. For example, registry data can be
used to evaluate improved outcomes from a range of
research projects: public health interventions, comorbidity investigations, examination of the quality of diagnosis, treatment and follow-up care, epidemiological
research, genetics, community impact, and survivorship, among others.
Policy Decision-Making and Its Impact
A general consensus suggested that the role of policy
makers in institutions and governments is vital, because financial resources are essential to sustain a
registry, especially in the current economic climate.
This must be considered at a time when countries are
grappling with salary payments and consideration of
the sustainability of a registry may not be seen as a
priority. Barbados represents an example of how surveillance might be made more cost effective.50,51 It has
526 Cancer Control
a cancer and a multi–noncommunicable diseases registry, including data on stroke and acute myocardial infarction.50 Having 3 components to a registry can provide economies of scale, where separate registries may
become too expensive. Shared leadership, office space,
and training, combined with administrative, statistical,
and epidemiological support across all registry components, can reduce costs. However, financial challenges
remain because, as is similar across many countries,
cancer registries operate without much publicity and
the work they conduct may be largely unknown.24
Registry funds rarely include a line item for marketing or public advocacy, and, in many Caribbean countries, cancer is a taboo subject not openly discussed,
so a registry rarely gains much public recognition and,
hence, financial security for a cancer registry becomes
even more precarious.24,51
A stepwise approach was proposed by the CARPHA
to improve cancer registration in the region: strengthen existing registries and establish mechanisms to improve reporting (even if merely reporting on the type
of data collected to date), perform situation analyses of
what currently exists, outline a strategic plan in which
strengths and weaknesses are identified, and assist with
data analysis and reporting at least annually.
Discussion
A need exists in the Caribbean for a common, unified
response and for more active regional collaboration in
terms of cancer surveillance and research, which takes
into account territorial specificities (similarities and differences) and implicates both scientific and governmental bodies. However, Caribbean countries vary in their
urgency and capacity to respond to increasing regional
rates of cancer burden.4,5,22,24 Sparse and incomplete
data, aging populations, high-cancer risk prevalence,
low/limited resource settings, as well as high frequencies of cancer-related deaths or cancers with poor prognoses, or the lack of targeted cancer care and prevention strategies, highlight the importance for progress in
cancer surveillance and research.4,5,22 This is even more
true when it comes to building synergy between these
2 fields for targeting efficient cancer control and management strategies in the Caribbean.4,5,22
Conscious of the need to move forward in
the cancer field, different stakeholders in the region have joined their efforts to address challenges and opportunities for cancer surveillance and
research in the Caribbean.4,5,22,24,25 Prior regional
scientific meetings have helped provide better insight on the current state of surveillance infrastructure and collaborative research initiatives and
outcomes.4,5,17,18,22,24,25 Although collaborations between research and surveillance have benefits and
exist in the regional context, they are still mostly
deemed insufficient.4,5,17,18,22,24,25 The state of colOctober 2015, Vol. 22, No. 4
laborative research between registries and medical/
research teams still remains limited and policymakers
are not fully convinced of the need to promote such
endeavors.27
Population-based cancer registries allow a specific
type of surveillance vital for delivering quality national
data to provide a precise description of the degree of
cancer burden in a country. Without such data, knowledge about the degree of cancer burden may be very
limited. Furthermore, it would be difficult, if not impossible, to develop, implement, monitor, and evaluate
cancer strategies for prevention and disease management without cancer registries due to their continuous provision of national data.14,27-29 These data are
important for cancer control and essential to better
guide research.14,27-29
Most Caribbean nations with registries have managed to achieve an infrastructure that encourages collaboration with research; however, major challenges still
exist to sustaining registry activity, addressing confidentiality concerns in a small island setting, maintaining
economic viability and optimizing the quality of their
data due to a combination of poor documentation and
lack of electronic health information systems.22,24 For example, in Barbados, existing challenges include incomplete or poorly documented medical records, limitations
in retrieval of death records, and suboptimal passive
reporting from the private medical sector.22 One of the
fundamentals will be stimulating better awareness of
available tools and resources as well as resource optimization between existing Caribbean research networks,
cancer registries, and international organizations.
Other Caribbean countries, despite acknowledging their need, experience challenges from limited cancer registry expertise or infrastructure, and/or a lack of
support from governmental bodies.22,24 Many of these
countries have important cancer burdens despite their
small geographical and population sizes.2,4,5,17,18,22,24 For
example, in St Lucia, which has had a hospital-based
cancer registry in operation since 1997, almost one-half
of the cases registered in 2002 were identified from
death certificates alone, and cancer has been the leading cause of death on the island since 2006.22 Fully registered cases often lack follow-up information, partly
due to decentralization and duplication of patient records within the public health care sector and partly
because of the number of patients sent overseas for
treatment.22 In addition, despite being operational for
more than 15 years, the St Lucian registry is not perceived as being indispensable.22 Implementation of a
national cancer control program through a multisectoral approach, including more collaboration with international agencies and more experienced registries,
may help address some of these issues.
To help advance the cancer registry agenda, fledgling registries can take advantage of civil society orOctober 2015, Vol. 22, No. 4
ganizations. For example, in the Cayman Islands, the
Cayman Islands Cancer Society has played a significant
role in lobbying for the registry.22 In Barbados, local
civil society organizations have been strong supporters
of the national cancer registry, working in partnership
with them to ensure comprehensive data capture.22,24
The potential role that civil society organizations can
play in reaching communities to build awareness and
create grass roots advocates for registries is important.
They also provide a valuable link between potential
community advocates and decision-makers in ministries of health.
Further solutions lie in developing a strategic plan
that includes setting standards for reinforced sustainable population research for the Caribbean. This implies identifying intercountry and intracountry specificities, needs, and priorities as well as existing tools,
resources, and stakeholders. Developing standards
also requires improved use of existing information
systems, the generation of higher-quality cancer data,
the implementation of best practice protocols, and
more efficient communication. Because of the strong
advocacy for surveillance guiding targeted research,
the strategic regional research plan will also need to
stimulate the development of collaborations in the region. Such collaborations, initiated between the various stakeholders/actors in the field of oncology (existing/aspiring cancer registries, research and medical
teams, governmental and institutional policy makers
and other cancer advocates/research teams at the local,
regional and international levels), will create opportunities for dialogue on the rationale and role of cancer
registration, the value, application, and utilization of
cancer registry data in collaborative research, the illustration of the outcomes of cooperative work, and the
importance and impact of policy decision-making.
Capacity building will be imperative to facilitate
research collaboration through linkages between cancer registries, clinical personnel, research teams, and
diverse data sources (eg, histopathology, comorbidity),
because even well-established cancer registries experience underutilization of their data as a research resource.22,24 For example, the French Caribbean islands
of Martinique and Guadeloupe need to promote their
scientific activities to develop collaboration between
these French Caribbean registries and other Caribbean
islands with populations of similar ethnic and environmental patterns.22,24 Another important issue for some
islands is their small population sizes, which make it
difficult to examine less common cancer sites.22 Collaborative studies involving several Caribbean nations
can overcome this limitation; however, differences
in social and cultural contexts, in economic development, and lack of data on ethnicity in the French registries may be significant barriers to implementation
of such collaborative studies.
Cancer Control 527
To overcome some of these barriers, the AC3 has
integrated cancer registries (7 Caribbean and 2 African) as members of their network and has constituted
a broad-based platform for education, training, and
research on all cancer aspects (etiology, screening,
prevention, treatment, and survival) in populations of
African descent. During the 2012, 2013, and 2014 AC3
Caribbean meetings, the desire to see an increase in
indigenous cancer statistics reports from the region
was unanimous and regional analyses of cancer statistics were prioritized as one of its planned activities.5,22,25 Collaborative efforts between the cancer
registries represented within the AC3 are currently in
motion. At the forefront of collaborative research in the
region with 45 published articles, the AC3 has several
initiatives in progress for regional cancer data analyses, foundations for research biospecimen banks, networking, collaborating, standardizing, supporting, and
optimizing existing cancer surveillance and research
opportunities, with the main objective of establishing
a global cancer network within the Caribbean region.21
The 2013 and 2014 AC3 cancer registration meetings
in Barbados and Martinique provided a much-needed
opportunity for networking between research investigators, cancer registrars, and health care professionals, providing insight into the possibility of collaborative opportunities between cancer registries within
the wider Caribbean region.22,25 These meetings also
emphasized the importance of a regional cancer network in the Caribbean to help promote collaborative
research and to obtain more effective and efficient cancer control, as the Caribbean moves toward optimization of these registries for scientific excellence in cancer research.22,25
Existing research–cancer registry collaborations
are paving the way, and organizations like the AC3,
NCI, IARC, and PAHO facilitate and promote such endeavors.4,5,17,18,21,22,24,25 In 2011, heads of state and governmental representatives assembled for a high level
UN meeting on the prevention and control of noncommunicable diseases.52 The meeting culminated with
a political declaration, thus highlighting the need to
reduce risk factors, strengthen national policies and
health systems, build international cooperation, including collaborative partnerships, promote research
and development, as well as implement systems for
monitoring and evaluation to lessen the growing burden of noncommunicable diseases.52
Because cancer is a major noncommunicable disease that impacts morbidity and mortality in the Caribbean, cancer surveillance must be included as a
key component in the global monitoring framework
for noncommunicable disease prevention and control developed as a result of the political declaration
of the United Nations on noncommunicable diseases.
Therefore, Caribbean countries are obligated to collect
528 Cancer Control
reliable data on cancer to facilitate reporting on these
global indicators for noncommunicable diseases.22,24
Research on cancer is also limited in the Caribbean
region and is greatly needed to facilitate a better understanding of this problem in the area, with a view to
improving care and treatment as well as to guide the
implementation of interventions for cancer prevention
and control.4,5,17,18,21,22,24,25
The regional agency, the CARPHA, supports public health surveillance and research in the Englishand Dutch-speaking Caribbean.53 Working with its
23 member states, as well as with international partners, the agency is committed to strengthening the scientific evidence on cancers and other diseases of public health importance as a means of improving public
health in the region.53
The NCI has made significant investments to international cancer research, training, and other programs,
with the goal of reducing the global cancer burden.54 In
2011, these activities were formalized and coordinated
via the creation of the Center for Global Health, which
works to address the complex global challenges of cancer.54 One of the top priorities of the Center for Global
Health is strengthening US national and international
partnerships for collaborations in global health research, cancer research, prevention, and control relevant to developing countries.54
To pursue these goals, the NCI performed several site visits in the Caribbean with the aim of learning about the available infrastructure and priorities
for cancer control planning.24 As a result, the NCI partnered with national, international, and regional stakeholders to plan initiatives to address the issue of cancer
surveillance and registration for the Caribbean.24 The
NCI is also a partner in the global initiative for developing cancer registries in low- and middle-income
countries, which is led by the IARC and implemented
through regional hubs that provide technical and scientific support, deliver tailored training for population-based cancer registration, advocate for cancer
registration, affiliated associations and networks, and
coordinate international research projects.24 Furthermore, the US NCI has partnered with the CARPHA, the
PAHO, other US federal agencies as well as the AC3, to
plan a stakeholder meeting for cancer surveillance to
stimulate the strengthening of cancer registration and
collaborative research in the Caribbean, to encourage
the strategic use of information for national cancer control plans and programs, and to discuss strategies for
moving forward.24 All of these activities will contribute to an overall strategic plan for the development and
strengthening of cancer registration for the region.
Conclusions
Capacity building, resource optimization and sustainment, as well as collaboration and communication beOctober 2015, Vol. 22, No. 4
tween cancer surveillance and research teams, are key
to obtaining robust and complete cancer surveillance
data for the Caribbean region and advancing cancer
control through collaborative research. The motto remains that we must collaborate to grow.
Acknowledgments: The authors would like to
thank the National Cancer Institute, Center for Global
Health and Donald T. Simeon, MSc, PhD, Caribbean
Public Health Agency, for support of the AC3 Cancer
Registry Workshop during the CARPHA 2013 annual
meeting.
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October 2015, Vol. 22, No. 4
Ten Best Readings Relating
to Palliative Care for Oncology
Beller EM, van Driel ML, McGregor L, et al. Palliative
pharmacological sedation for terminally ill adults.
Cochrane Database Syst Rev. 2015;1:CD010206.
Evidence relating to the effectiveness of palliative
sedation in terms of symptom control or quality of
life was insufficient. However, evidence suggests that
death is not hastened by palliative sedation, but these
data come from low-quality studies. Therefore, further
studies are needed to specifically measure the effectiveness and quality of life in sedated people compared
with nonsedated people as well as the potential for
adverse events.
Smith TJ, Temin S, Alesi ER, et al. American Society
of Clinical Oncology provisional clinical opinion:
the integration of palliative care into standard
oncology care. J Clin Oncol. 2012;30(8):880-887.
This provisional clinical opinion addresses the
integration of palliative care services into standard
oncology practices when a patient is diagnosed with
advanced or metastatic cancer.
Nielsen LM, Olesen AE, Branford R, et al. Association between human pain-related genotypes and
variability in opioid analgesia: an updated review.
Pain Pract. 2015;15(6):580-594.
Studies have revealed promising results regarding
use of pharmacogenetics as a diagnostic tool in the experimental setting; however, use of pharmacogenetics is
a more complex task to accomplish in the clinical setting.
Hui D, Bruera E. Models of integration of oncology
and palliative care. Ann Palliat Med. 2015;4(3):89-98.
The aim of this review was to study contemporary
conceptual models and clinical approaches for integrating
oncology with palliative care. The authors suggest that
additional research is needed to advise best practices for
integrating palliative care into various health care settings.
Kamal AH, Gradison M, Maguire JM, et al. Quality
measures for palliative care in patients with cancer:
a systematic review. J Oncol Pract. 2014;10(4):281-287.
These authors review a large group of measures
used for assessing the quality of palliative care in patients with cancer and suggest that oncology-driven
quality and outcomes studies are needed to broaden
the connection between quality-based care and improved patient experiences.
Pereira J, Green E, Molloy S, et al. Population-based
standardized symptom screening: Cancer Care
October 2015, Vol. 22, No. 4
Ontario’s Edmonton Symptom Assessment System
and performance status initiatives. J Oncol Pract.
2014;10(3):212-214.
Early evidence demonstrates the positive impact that
population-based symptom screening has on patient care
in Ontario, Canada. Expansion outside of hospitals and
cancer centers accompanied by increased clinician engagement and education throughout the system is necessary to ensure the long-term success of the program.
Hui D, Dos Santos R, Chisholm G, et al. Bedside
clinical signs associated with impending death in
patients with advanced cancer: preliminary findings
of a prospective, longitudinal cohort study. Cancer.
2015;121(6):960-967.
Five very specific physical signs associated with
death within 3 days of onset in patients with cancer
may aid in the diagnosis of impending death. In this
study, the authors discuss the frequency and onset
of 52 other bedside physical signs and examine their
diagnostic performance.
Bakitas MA, Tosteson TD, Li Z, et al. Early versus
delayed initiation of concurrent palliative oncology
care: patient outcomes in the ENABLE III randomized
controlled trial. J Clin Oncol. 2015;33(13):1438-1445.
Researchers investigated the effect of early compared with delayed palliative care on symptom impact,
quality of life, mood, resource use, and 1-year survival
rates. They suggest that understanding the complex
mechanisms by which palliative care may improve
survival rates remains an important research priority.
Back AL, Park ER, Greer JA, et al. Clinician roles
in early integrated palliative care for patients with
advanced cancer: a qualitative study. J Palliat Med.
2014;17(11):1244-1248.
Focus groups were conducted with palliative care
clinicians who participated in randomized control trials of early palliative care for metastatic lung cancer.
These data have become the foundation for training
programs for clinicians.
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version 1.2014. Featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2014;12(10):1379-1388.
This report summarizes panel discussions from the
National Comprehensive Cancer Network and updates
to its guidelines from 2013 and 2014. The most updated
version of these guidelines can be found at http://www.
nccn.org/professionals/physician_gls/pdf/palliative.pdf.
Cancer Control 531
Peer Reviewers, 2015
Peer review is the indispensable and critical element in the evaluation of all manuscripts being considered for publication in our journal. The oncology professionals who took part in our peer review process last year are listed
below, and we thank them for their invaluable efforts on behalf of Cancer Control.
— The Editor
External Reviewers
Agarwala, Sanjiv S, MD
Temple University School of Medicine
Alsirafy, Samy A, MBBCH, MSc, MD
Cairo University, Egypt
Andersen, Barbara L, PhD
Ohio State University
Asa, Sylvia, MD, PhD
University of Toronto, Canada
Bauman, Jessica R, MD
Massachusetts General Hospital
Cancer Center
Bouvet, Michael, MD
University of California San Diego
Brody, Garry S, MD
University of Southern California
Bush, Shirley H, MBBS
University of Ottawa, Ontario, Canada
Chan, Jennifer A, MD
University of Calgary, Canada
Cui, Juwei, MD, PhD
First Hospital of Jilin University, China
Damato, Bertil E, MD, PhD
University of California, San Francisco
de Vries, Esther, PhD
Erasmus University Medical Center,
The Netherlands
DeCoteau, John, MD
University of Saskatchewan, Canada
Greer, Joseph A, PhD
Massachusetts General Hospital
Cancer Center
Gwak, Ho-Shin, MD, PhD
National Cancer Center Korea
Heegaard, Steffen, MD, DMSc
University of Copenhagen, Denmark
Henderson, Mark A, MD
Oregon Health & Science University
Vergo, Maxwell T, MD
Dartmouth-Hitchcock Medical Center
Köbel, Martin, MD
University of Calgary, Alberta, Canada
Wainstein, Alberto, MD, PhD
Cirurgião Oncologico ONCAD, Brazil
Lawlor, Peter G, MD
University of Ottawa, Canada
Watson, Peter H, MD
BC Cancer Agency,
Vancouver, British Columbia
Ledezma, Rodrigo A, MD
University of Chicago Medical Center
Leland, June, MD
James A. Haley VA Hospital
Linos, Konstantinos, MD
Dartmouth-Hitchcock Medical Center
Lutgendorf, Susan K, PhD
University of Iowa
Mardini, Houssam, MD
University of Kentucky
Maryska Janssen-Heijnen, PhD
VieCuri Medical Centre, The Netherlands
Mehta, Vikas, MD
Louisiana State University Health Shreveport
Edwards, Brenda K, PhD
National Cancer Institute
Egloff, Ann Marie, MD
University of Pittsburgh
Fitzgibbons, Patrick L, MD
St Jude Medical Center, California
Fry, Lucia C, MD, PhD
University of Alabama at Birmingham
Gandhi, Manish J, MD
Mayo Clinic, Rochester
532 Cancer Control
Temple-Oberle, Claire, MD
University of Calgary, Alberta, Canada
Kim, Eric H, MD
Washington University School of Medicine
Done, Susan, PhD
University of Toronto, Canada
Dylewski, Mark, MD
Baptist Health South Florida
Stewart, Jonathan, MD
James A. Haley VA Hospital
Truini, Anna, PhD
Istituto Nazionale per la Ricerca sul
Cancro, Italy
McMullen, Kevin P, MD
Indiana University School of Medicine
Duggan, Máire, MD
University of Calgary,
Alberta, Canada
Roth, Patrick, MD
University Hospital Zurich, Switzerland
Hertz, Daniel L, PharmD, PhD
University of Michigan College of Pharmacy
Demetrick, Douglas J, PhD, MD
University of Calgary, Canada
Disclafani, Mark, MD
Bradenton, Florida
Park, John W, MD
University of California, San Francisco
Mehran, Resa, MD
MD Anderson Cancer Center
Meloni, Maria Franca, MD
University of Milano-Bicocca, Italy
Munkemuller, K, MD, PhD
University of Alabama at Birmingham
Nagahashi, Masayuki, MD
Niigata University Graduate School of
Medical and Dental Sciences, Japan
Neumann, Helmut, MD
University of Erlangen-Nuremberg, Germany
Ozyigit, Gokhan, MD
Hacettepe University, Ankara, Turkey
Patel, Darpan, PhD
University of Texas Health Science Center
Patel, Jai N, PharmD
Levine Cancer Institute
Wiener, Lori, PhD
National Institutes of Health
Wood, Michael, MD
University of North Carolina
Zanagnolo, Vanna, MD
European Institute of Oncology, Milan, Italy
Zhang, David Y, MD, PhD
Mount Sinai School of Medicine
Internal Reviewers
(H. Lee Moffitt Cancer Center
& Research Institute)
Almhanna, Khaldoun, MD
Balducci, Lodovico, MD
Benson, Kaaron, MD
Chinnaiyan, Prakash, MD
Choi, Junsung, MD
Craig, David S, PharmD
Dilling, Thomas J, MD
Djulbegovic, Benjamin, MD
Extermann, Martine, MD
Gray, Jhanelle E, MD
Hulse, Mark, RN
Khoury, Michael, MD
Loftus, Loretta, MD
Magliocco, Anthony M, MD
Morgan, Mary Ann, PhD, ARNP
Portman, Diane, MD
Pow-Sang, Julio M, MD
Sahebjam, Solmaz, MD
Shah, Bijal, MD
Spiess, Phillip, MD
Thirlwell, Sarah, MSc, MSc(A), RN
Toloza, Eric M, MD
Tran, Nam, MD
October 2015, Vol. 22, No. 4
Index for 2015, Volume 22
Vol 22, No 1: Transfusion Medicine
4 Editorial: Transfusion Medicine Issues
Pertaining to Patients With Cancer
102 Pathology Report: Familial Gastrointestinal Stromal Tumor Syndrome: Report of 2 Cases With KIT Exon 11 Mutation
Derek H. Jones, MD, Jamie T. Caracciolo, MD,
Pamela J. Hodul, MD, et al
Kaaron Benson, MD
7 Safety of the Blood Supply
German F. Leparc, MD
109 Tumor Biology: Current and Emerging
Therapies for Bone Metastatic
Castration-Resistant Prostate Cancer
16 Adverse Effects of Transfusion
Jeremy S. Frieling, David Basanta, PhD,
and Conor C. Lynch, PhD
Radhika Dasararaju, MD, and Marisa B. Marques, MD
26 Clinical Effects of Red Blood Cell Storage
Lirong Qu, MD, PhD, and Darrell J. Triulzi, MD
38 Transfusion Indications for Patients
With Cancer
Thomas Watkins, DO, PhD, Maria Katarzyna
Vol 22, No 2: Molecular Biomarkers
133 Editorial: Personalizing the Attack on
Cancer: Zeroing in on Targets
Anthony M. Magliocco, MD
Surowiecka, MD, and Jeffrey McCullough, MD
137 Practical Applications of Digital Pathology
47 Platelet Transfusion for Patients
With Cancer
Craig H. Fletcher, MD, Melkon G. DomBourian, MD, and Peter A. Millward, MD
52 Transfusion Support Issues in
Hematopoietic Stem Cell Transplantation
Claudia S. Cohn, MD, PhD
60 Therapeutic Apheresis for Patients
With Cancer
Laura S. Connelly-Smith, MBBCh, DM, and
Michael L. Linenberger, MD
79 Using HLA Typing to Support Patients
With Cancer
Daryoush Saeed-Vafa, MD, and Anthony M.
Magliocco, MD
142 Molecular Technologies in the Clinical
Diagnostic Laboratory
Victor E. Zota, MD, and Anthony M. Magliocco, MD
152 Molecular Assays in Cytopathology for
Thyroid Cancer
Pablo Valderrabano, MD, Victor E. Zota, MD,
Bryan McIver, MD, PhD, et al
158 Biomarkers in Hematological Malignancies: A Review of Molecular Testing in
Hematopathology
Mohammad Hussaini, MD
Mark K. Fung, MD, PhD, and Kaaron Benson, MD
87
Special Report: Mobilization and
Transplantation Patterns of Autologous Hematopoietic Stem Cells in Multiple
Myeloma and Non-Hodgkin Lymphoma
Luciano J. Costa, MD, PhD, Shaji Kumar, MD,
Stephanie A. Stowell, MPhil, et al
95 Special Report: Functional Health Literacy, Chemotherapy Decisions, and Outcomes Among a Colorectal Cancer Cohort
Evan L. Busch, MPH, Christopher Martin, MSPH,
Darren A. DeWalt, MD, et al
October 2015, Vol. 22, No. 4
167 Circulating Tumor Cells: A Window Into
Tumor Development and Therapeutic
Effectiveness
Gisela Cáceres, PhD, John A. Puskas, PhD,
and Anthony M. Magliocco, MD
177 Surgical and Molecular Pathology of
Barrett Esophagus
Sherma Zibadi, MD, PhD, and Domenico Coppola, MD
186 Molecular Pathology of Soft-Tissue
Neoplasms and Its Role in Clinical Practice
Evita B. Henderson-Jackson, MD, and Marilyn M.
Bui, MD, PhD
Cancer Control 533
Index for 2015, Volume 22
193 Advances in EGFR as a Predictive Marker in Lung Adenocarcinoma
Farah K. Khalil, MD, and Soner Altiok, MD, PhD
261 Editorial: Does Androgen Deprivation Therapy for Prostate Cancer Increase the Risk of Colorectal Cancer?
Anna Martling, MD, PhD
200 Impending Impact of Molecular Pathology on Classifying Adult Diffuse Gliomas
Robert J. Macaulay, MD
206 Overexpression of Vascular Endothelial
Growth Factor A in Invasive Micropapillary Colorectal Carcinoma
Marilin Rosa, MD, Maisoun Abdelbaqi, MD,
Katherine M. Bui, et al
211 Advances in the Molecular Analysis of Breast Cancer: Pathway Toward
Personalized Medicine
Marilin Rosa, MD
220 Use of Immunohistochemical Stains in
Epithelial Lesions of the Breast
Laila Khazai, MD, and Marilin Rosa, MD
226 Special Technologies for Ex Vivo Analysis
of Cancer
Jenny M. Kreahling, PhD, and Soner Altiok, MD, PhD
232 Editorial: Should We Preclude Phase 1
Clinical Trials From Enrolling Elderly
Individuals?
Lodovico Balducci, MD
235 Original Research: Effect of Age on Clinical Outcomes in Phase 1 Trial Participants
Amit Mahipal, MD, Aaron C. Denson, MD,
Benjamin Djulbegovic, MD, PhD, et al
242 Case Report: Primary Enteropathy-Associated T-Cell Lymphoma Type 2: An Emerging Entity?
Nicole M. Grigg-Gutierrez, MD, Rodolfo Estremera-
Marcial, MD, William W. Cáceres, MD, et al
248 Special Report: Cost Effectiveness of Colorectal Cancer Screening Strategies
Shaan S. Patel and Meredith L. Kilgore, PhD
259 Editorial: Colorectal Cancer: The Last Nail in the Coffin for Androgen Deprivation Therapy for Prostate Cancer?
Lodovico Balducci, MD, and Julio M. Pow-Sang, MD
534 Cancer Control
263 Special Report: Risk of Colorectal Cancer by Subsite in a Swedish Prostate Cancer Cohort
Yunxia Lu, MD, PhD, Rickard Ljung, MD, PhD,
Anna Martling, MD, PhD, et al
Vol 22, No 3: Robotic-Assisted Surgery
278 Editorial: Applications and Advances in
Robotic-Assisted Oncological Surgery: Ready to Dock the ‘Bot
Eric M. Toloza, MD, PhD, and Julio M. Pow-Sang, MD
283 Robotic-Assisted Laparoscopic Radical Prostatectomy
Gautum Agarwal, MD, Oscar Valderrama, MD,
Adam M. Luchey, MD, et al
291 Robotic-Assisted Renal Surgery
Justin B. Emtage, MD, Gautum Agarwal, MD, and
Wade J. Sexton, MD
301 Robotic-Assisted Radical Cystectomy
Adam M. Luchey, MD, Gautum Agarwal, MD, and
Michael A. Poch, MD
307 Robotic-Assisted Surgery in Gynecological Oncology
Stephen H. Bush, MD, and Sachin M. Apte, MD
314 Robotic-Assisted Videothoracoscopic
Surgery of the Lung
Frank O. Velez-Cubian, MD, Emily P. Ng, Jacques P. Fontaine, MD, et al
326 Robotic-Assisted Videothoracoscopic
Mediastinal Surgery
David M. Straughan, MD, Jacques P. Fontaine, MD, and Eric M. Toloza, MD, PhD
331 Robotic-Assisted Surgery in the Head
and Neck
Jon Burton, MD, Robert Wong, MD, and
Tapan Padhya, MD
October 2015, Vol. 22, No. 4
Index for 2015, Volume 22
335 Robotic-Assisted Esophageal Surgery
David M. Straughan, MD, Saїd C. Azoury, MD,
Robert D. Bennett, MD, et al
403 Palliative Pharmacotherapy: State-of-the-Art Management of Symptoms in Patients
With Cancer
Eric E. Prommer, MD
340 Robotic Whipple Procedure for Pancreatic Cancer: The Moffitt Cancer Center Pathway
Omar M. Rashid, MD, JD, John E. Mullinax, MD,
Jose M. Pimiento, MD, et al
412 Pharmacological Management of Cancer Related Pain
Eric E. Prommer, MD
352 Robotics in Neurosurgery: Evolution,
Current Challenges, and Compromises
426 Clinical Implications of Opioid
Pharmacogenomics in Patients With Cancer
James J. Doulgeris, MSME, Sabrina A. Gonzalez-
Blohm, MSBE, Andreas K. Filis, MD, et al
Gillian C. Bell, PharmD, Kristine A. Donovan, PhD,
and Howard L. McLeod, PharmD
360 Special Report: Association of Lymphoma-
genesis and the Reactivation of Hepatitis B Virus in Non-Hodgkin Lymphoma
433 Palliative Sedation in Patients With Cancer
Samir Dalia, MD, Yaman Suleiman, MD,
David W. Croy, MD, et al
442 Integrating Psychosocial Care Into
Routine Cancer Care
Marco Maltoni, MD, and Elisabetta Setola, MD
Paul B. Jacobsen, PhD, and Morgan Lee, MA
366 Case Report: Stromal Overgrowth in a Brenner Tumor or Ovarian Fibroma With Minor Sex Cord Elements?
Julia A. Ross, MD, PhD, and Ozlen Saglam, MD
369
Case Report: Recurrent Systemic Anaplastic Lymphoma Kinase–Negative Anaplastic Large Cell Lymphoma Presenting as a Breast Implant–Associated Lesion
Amanda Zimmerman, MD, Frederick L. Locke, MD, Josephine Emole, MD, et al
450 Systematic Review of Palliative Care in the Rural Setting
Marie A. Bakitas, DNSc, CRNP, Ronit Elk, PhD,
Meka Astin, MPH, et al
465 New Frontiers in Outpatient Palliative Care for Patients With Cancer
Michael W. Rabow, MD, Constance Dahlin, ANP-BC, ACHPN, Brook Calton, MD, et al
475 Palliative Care in Adolescents and Young Adults With Cancer
Vol 22, No 4: Perspectives, Progress, and
Opportunities for Palliative Care in Oncology
Kristine A. Donovan, PhD, Dianne Knight, MD,
and Gwendolyn P. Quinn, PhD
480 Palliative Care in Older Patients With Cancer
382 Editorial: Perspectives, Progress, and
Opportunities for Palliative Care in Oncology
Lodovico Balducci, MD, Dawn Dolan, PharmD,
and Sarah A. Hoffe, MD
Diane Portman, MD, and Sarah Thirlwell, MSc, MSc(A), RN
386 Integrating Palliative Care Into Oncology:
A Way Forward
Kavitha Ramchandran, MD, Erika Tribett, MPH,
Brian Dietrich, MD, et al
396 Improving the Quality of Palliative Care Through National and Regional
Collaboration Efforts
Arif H. Kamal, MD, MHS, Krista L. Harrison, PhD,
Marie Bakitas, DNSc, CRNP, et al
October 2015, Vol. 22, No. 4
489 Prognostication of Survival in Patients With
Advanced Cancer: Predicting the
Unpredictable?
David Hui, MD, MSc
498 Pathology Perspective: Is DOG1 Immuno-
reactivity Specific to Gastrointestinal
Stromal Tumor?
William Swalchick, MA, Rania Shamekh, MD,
and Marilyn M. Bui, MD, PhD
Cancer Control 535
Index for 2015, Volume 22
505 Case Report: Occurrence of Multiple Tumors in a Patient
Elaine Tan, Mark Friedman, MD, and
Domenico Coppola, MD
508 Special Report: Association of Cancer Stem Cell Markers With Aggressive Tumor
Features in Papillary Thyroid Carcinoma
Zhenzhen Lin, MD, Xuemian Lu, MD, Weihua Li, MD, et al
515 Special Report: Should Vital Signs Be
Routinely Obtained Prior to Intravenous Chemotherapy? Results From a 2-Center Study
Smitha Menon, MD, Nathan R. Foster, MS,
Sherry Looker, RN, BSN, et al
520 Special Report: Advancing Cancer Control Through Research and Cancer Registry
Collaborations in the Caribbean
Rishika Banydeen, MPH, Angela M.C. Rose, MSc, Damali Martin, PhD, MPH, et al
Vol 22, No 4: Supplement
2 Why a Special Issue on Chronic Lymphocytic
Leukemia
Lodovico Balducci, MD
3 Chronic Lymphocytic Leukemia in the Elderly:
Epidemiology and Proposed Patient-Related Approach
Lodovico Balducci, MD, and Dawn Dolan, PharmD
7 Chronic Lymphocytic Leukemia in the
Elderly, Which Investigations Are Necessary: A Map for the Practicing Oncologist
Javier Pinilla-Ibarz, MD, PhD, and Josephine Emole, MD
17 Management of Chronic Lymphocytic
Leukemia in the Elderly
Jacqueline C. Barrientos, MD
536 Cancer Control
October 2015, Vol. 22, No. 4
Current Perspectives in
Oncology Nursing
February 18-19, 2016
Moffitt Cancer Center
Tampa, Florida
15th Annual Nursing Conference
SPECIAL EVENT
The 21st Annual Rhinehart Reception & Lecture
February 17, 2016
Moffitt Cancer Center
Vincent Stabile Research Building
12902 Magnolia Drive
Tampa, FL 33612
For More Information & Registration
Visit our website at www.MOFFITT.org/Nursing2016
10th
Annual
Business of Biotech
Conference
Friday, March 18, 2016
7:45 a.m. – 3:00 p.m.
Vincent A. Stabile
Research Building
12902 Magnolia Drive,
Tampa, Florida 33612
To register visit
www.moffittip.com/events
SCIENCE. SYNERGY. sUCCESS!
Keynote - Arie Belldegrun, M.D.
Sam Donaldson
President, CEO and founder of Kite Pharma
with a distinguished tenure in the life
sciences field and closely involved with the
founding and advancement of successful
biopharmaceutical companies.
Former ABC news correspondent and
member of the Moffitt Board of
Advisors conducts a conversation with
Dr. Belldegrun about the exciting
immunotherapy field for cancer treatment.
Business of
#MoffittBOB
Biotech
Moffitt Cancer Center