Long-Term Effects of
Cancer Treatment
JOHN CHARLSON, MD
DEPARTMENT OF MEDICINE
DIVISION OF MEDICAL HEMATOLOGY/
ONCOLOGY
MEDICAL COLLEGE OF WISCONSIN
Outline
 Introduction
 Long-term and late effects of breast cancer treatment
 Brief overview of other common cancers
Estimated Number of U.S. Cancer Survivors from 1971 to
2008
Data Source: Howlader N, et al. SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD,
http://seer.cancer.gov/csr/1975_2008/, based on November 2010 SEER data submission, posted to the SEER web site, 2011.
Growing Number of Survivors: Breast Cancer
 2011 – approx. 230,480 new invasive breast cancer
cases in U.S.
 26% of new cancers in U.S. women
 2.6 million breast cancer survivors
Follow-up Issues
 Monitor for relapse
 Late effects of therapy
 Psychosocial effects
 Health promotion
Adverse Effects of Cancer Treatment: Timing
 Survivorship experience is highly individual and is
impacted by short-term, long-term, and late effects
of cancer therapy.
 Definitions


Short-term side effects occur during treatment.
Long-term side effects begin during treatment and continue
after the end of treatment.


Examples: ovarian failure, infertility, neuropathy.
Late effects are symptoms that first appear months or years
after treatment has ended.

Examples: heart failure, osteoporosis, and second cancers.
Late Effects of Breast Cancer Treatment
 Lymphedema
 Cardiac dysfunction
 Premature ovarian failure
 Infertility, bone loss, menopausal symptoms

*Will discuss side effects of endocrine treatments
 Osteoporosis – related to treatment
 Secondary malignancies
 Cognitive dysfunction
 Sexual side effects
Lymphedema
Can be debilitating
mild
moderate
severe
The more lymph
nodes removed and
greater burden of
disease = higher risk
Lymphedema
Lymphedema
 Incidence in breast CA patients – 20% overall
 Up
to 40% with ALND and radiation
 Additional risk factors –
 Older age, obesity
 Symptoms
 Swelling (unilateral arm, breast), numbness,
heaviness, ache, decreased ROM
Lymphedema
 Diagnosis
arm circumference, water displacement
 Sequelae
 pain, disfigurement
 decreased QOL
 impaired healing/infections
 lymphangiosarcoma
 Secondary prevention
 Skin/nail care, avoid shots/medical procedures in
affected arm, avoid dependent position.

Lymphedema Treatment




Decongestive physiotherapy
 Treatment - ROM, massage,
compressive bandages. Daily
for 2-4 weeks.
 Maintenance – compression
garments, skin care,
continued exercise.
Exercise – after treatment phase
 Gradual weight training
beneficial
Medications
 no evidence – diuretics,
pentoxifylline (Trental)
Surgery, laser therapy
 very limited data
Cardiac Disease
 Anthracycline chemotherapy – congestive heart
failure (CHF)



Cumulative, dose dependent
Up to 1% risk for standard breast CA doses
Latency period up to at least 5 yrs in adults



Latency period noted up to 25 years in pediatric patients
Risk factors – HTN, CAD, mediastinal radiation, taxol,
herceptin, young or old age (<18, >65)
Can cause permanent structural damage

87% improve with ACE-I, beta blocker

Tallaj, J Heart Lung Transplant 2005;24:2196
Cardiac Disease
 Trastuzumab
 Class 3 or 4 CHF in 1-4% (adjuvant studies)
 Occurs during treatment - typically reversible
 Radiation
 Mediastinum, left chest
 Children treated for Hodgkin’s lymphoma




7.2x higher risk for fatal cardiovascular events
Adults treated for breast cancer, lymphoma, germ cell tumor
Late effects – pericardial disease, restrictive CM, early CAD,
conduction abnormalities
Onset 5-10 years after treatment
Cardiac Disease
 Other drugs:
 Taxanes


Tyrosine kinase inhibitors (TKIs) e.g. sunitinib, sorafenib


can potentiate CHF risk if given with anthracyclines
CHF and MI risk, present but not well defined yet.
Bevacizumab
Angina
 heart failure
 arterial thromboembolic risk.

Chemotherapy-Induced Ovarian Failure
 Menopause - Definition (NCCN, WHO)
 Permanent cessation of menses, diagnosed after 12 months of
amenorrhea; no other identifiable cause.
 Factors predicting chemo-induced ovarian failure
 Drugs (alkylating agents), doses
 Age – older women more likely amenorrheic

Younger women more likely regain menses
 Half of women <40 y/o will regain menstrual function,
compared to 10% of women > 40 y/o.
Ovarian Failure
 Adverse effects
 Infertility
 Impacts quality of life
Hot flashes
 Vaginal dryness
 Dyspareunia
 Sleep disturbance
 Note: Adjuvant hormone based cancer treatments like tamoxifen
and aromatase inhibitors may contribute to symptoms . . .



Increased risk of cardiovascular disease
Increased risk of osteoporosis
Hot Flashes
 Thermoregulatory dysfunction caused by estrogen




withdrawal at level of hypothalamus.
Peri-menopausal, post-menopausal
Associated with sleep disturbance
Tamoxifen and Aromatase inhibitors - cause or
exacerbate
Withdrawal of hormone replacement therapy
Treatment for Hot Flashes
 Physical activity, weight loss, smoking cessation.
 Antidepressents: SSRI/SNRI’s can be effective


Paroxetine, fluoxetine, venlafaxine, citalopram,
desvenlafaxine.
Caution w/tamoxifen – some inhibit CYP2D6 – decrease
efficacy of tamoxifen
Paroxetine>fluoxetine>citalopram>venlafaxine
 Gabapentin


300mg tid vs placebo (45% v 29%)
300-600 mg at bedtime
 Clonidine – oral or patch
Vaginal Atrophy
 Symptoms







Vaginal dryness
Pruritis
Discharge
Bleeding
Dyspareunia
Urinary frequency
Recurrent UTIs
 Aromatase inhibitors –
 Tamoxifen –

Weak estrogenic effects in post-menopausal women


decrease estrogen level
no atrophy
Pre-menopausal – anti-estrogenic effects on the vagina.
Treatment for Vaginal Atrophy
 Moisturizer – Replens/bioadhesive polymer
 Lubricant – with intercourse
 Sexual activity
 Low dose vaginal estrogen – if other things fail
 <0.5gm estrogen, <50mcg estradiol
 Vaginal ring, cream
 Caution – may get systemic absorption.
 Minimize dose, schedule.
 Check w/oncologist
Bone Density Loss
 Premature ovarian failure
 more rapid BMD loss first 1-2 years (5% per year)
 Aromatase Inhibitor induced bone loss
 Example –ATAC trial

Bone loss - Arimidex vs tamoxifen
 LS spine/TH – 6/7.2% versus 2.8/0.7%
 Annual fractures – 11% vs 7.7%
 Fracture risk factors
 Low BMD, old age, h/o fragility fracture, chronic steroids, low
BMI, family history, smoking, EtOH abuse
Bone Density Management
 Baseline – BMD test, 25-OH vit D, clinical risk
factors

Additional workup if baseline osteoporosis
 Prevention


Exercise, stop smoking
Calcium 1200mg, vitamin D 600-800IU
 Bisphosphonate – if Tscore <-2.5, or between -1
and -2.5 with risk factors.


Alendronate, risedronate, ibandronate
Zoledronic acid
 Monitor – BMD every 1-2 years
ENDOCRINE THERAPY
MIGHT ADD TO THE
PROBLEM
Tamoxifen
 Tamoxifen – competitive inhibitor of ER

Menopausal symptoms
hot flashes
 irregular menses


Increased VTE risk – 0.19% in P-1 study



Risk factors = chemo, age, incr BMI, immobilization
Ocular toxicity – rare – cataracts, macular edema
Uterine cancer - <1% risk
 Benefits
 40%
risk of recurrence
 40-50% decrease risk of second primary breast cancer

LDL and improves post-menopausal bone loss
Aromatase Inhibitors
 Aromatase inhibitors





decreases estrogen levels by blocking the aromatase
(adrenal CYP-19) enzyme responsible for peripheral
conversion of androgens to estrogen
 Anastrazole (Arimidex), letrozole (Femara), exemestane
(Aromasin)
Hot flashes, other menopausal symptoms
Osteoporosis/fractures
Arthralgias/myalgias
Heart disease
 ASCO – post-menopausal women with ER+ breast
CA should receive an AI
Secondary Malignancies After Breast Cancer Treatment
 Chemotherapy-related
 Treatment related MDS, AML - < 1%
 Alkylating agent (cytoxan) – latency 5-10 yrs
 Topoisomerase II inhibitor (adriamycin) – 1-5 yrs
 Tamoxifen – Uterine cancer
 Relative risk 2-4 - highest in obese, post-menopausal, prior
HRT
P-1 study – 56 uterine malignancy/6700 women
 8 excess cases/10,000 women at 10 years


Annual pelvic exam; if bleeding – U/S, biopsy
 Radiation Therapy – slight risk in sarcomas, lung
cancers (primarily in smokers)
Matesich SM, Semin Oncol 2003;30(6):740
Secondary Malignancies in After Other Cancers
 Hodgkin’s lymphoma
 Mostly solid tumors
Breast
 Thyroid
 Lung
 GI


Occur on average 16 years after treatment
 Small Cell Lung Cancer
 30% rate of second cancers among 2 yr survivors

NSCLC, esophageal CA
Metayer, JCO 2000;18(12):2435, Heyne, JCO 1992;10:1519
Cognitive Dysfunction: “Chemo Brain”
 Mostly studied in breast cancer patients

Series of small studies over the past decade plus
 Affected – verbal memory, attention, visual memory

Difficulty concentrating, trouble recalling events or things just said,
trouble finding the right word
 Changes can persist a year or longer, maybe even 5yrs
 Symptoms improve over time
 Possible mechanisms

vascular injury, oxidative damage, inflammation, autoimmune, direct
injury to neurons
 Contributing factors

fatigue, depression, effect of endocrine treatment
Psychosocial Effects
 Depression/Anxiety
 one third of breast CA patient in first year after diagnosis
 Fatigue
 Sexual Dysfunction
 Changed body image
 Ovarian failure, endocrine meds – libido, dyspareunia
 Other
 Relationships
 Work
 Quality of life
BRIEF OVERVIEW OF
OTHER COMMON
CANCERS
Late Treatment Effects: Colorectal Cancer
 Ostomies
 affect self-image
 sexual relationships
 Chronic, persistent diarrhea
 Rectal cancer  risk for stool incontinence,
decreased rectal compliance


Associated with surgery, increased if RT
Urinary and sexual dysfunction  nerve damage
 Decreased pelvis bone density secondary to pelvic
radiation
Prostate Cancer
 Erectile dysfunction
 prostatectomy and radiation therapy
 Long-term incontinence  low risk with radical
prostatectomy
 Androgen Deprivation Therapy


Used for metastatic or high risk, localized disease
Predisposes to :

obesity, diabetes, cardiovascular disease, decreased bone density
Summary
 Monitoring for late effects of cancer treatment is an
important part of survivorship care
 Individualized based on patient and treatment
factors
 Effective monitoring requires patient education,
communication among providers