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Long-Term Effects of Cancer Treatment

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.

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Long-Term Effects of Cancer Treatment

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  1. Long-Term Effects of Cancer Treatment John Charlson, MD Department of Medicine Division of Medical Hematology/ Oncology Medical College of Wisconsin

  2. Outline Introduction Long-term and late effects of breast cancer treatment Brief overview of other common cancers

  3. 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.

  4. 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

  5. Follow-up Issues Monitor for relapse Late effects of therapy Psychosocial effects Health promotion

  6. 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.

  7. 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

  8. Lymphedema Can be debilitating mild moderate severe The more lymph nodes removed and greater burden of disease = higher risk

  9. Lymphedema

  10. 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

  11. 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.

  12. 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

  13. 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

  14. 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

  15. Cardiac Disease • Other drugs: • Taxanes • can potentiate CHF risk if given with anthracyclines • Tyrosine kinase inhibitors (TKIs) e.g. sunitinib, sorafenib • CHF and MI risk, present but not well defined yet. • Bevacizumab • Angina • heart failure • arterial thromboembolic risk.

  16. 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.

  17. 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

  18. 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

  19. 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 tidvs placebo (45% v 29%) • 300-600 mg at bedtime • Clonidine – oral or patch

  20. Vaginal Atrophy • Symptoms • Vaginal dryness • Pruritis • Discharge • Bleeding • Dyspareunia • Urinary frequency • Recurrent UTIs • Aromatase inhibitors – decrease estrogen level • Tamoxifen – • Weak estrogenic effects in post-menopausal women • no atrophy • Pre-menopausal – anti-estrogenic effects on the vagina.

  21. 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

  22. 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 - Arimidexvstamoxifen • 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

  23. 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

  24. Endocrine Therapy Might Add to the Problem

  25. 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

  26. 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

  27. 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, SeminOncol 2003;30(6):740

  28. 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

  29. 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

  30. 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

  31. Brief Overview of Other Common Cancers

  32. 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

  33. 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

  34. 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

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