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Optimizing the Life-long Health of Childhood Cancer Survivors Paul Nathan MD, MSc Paediatric Oncologist/Associate Scientist The Hospital for Sick Children Toronto, Canada Learning objectives 1. Explain why late effects of treatment occur and what influences them 2. Discuss risk-based care and how it impacts long-term follow-up 3. Examine current research and how it influences survivorship The childhood cancer success story % relapse free •More intense therapy 2008: ~80% 90 80 70 60 50 40 30 20 10 0 •Better supportive care •Rationalization of treatment (more in some, less in others) – clinical trials 1960’s: ~10% 1960 1970 1980 1990 Year •Some new treatments e.g. stem cell 2000 2005 transplant, molecularly targeted agents How many survivors are there? 328,652 Mariotto AB, Cancer Epidemiol Biomarkers Prev. 2009 “It’s not over when it’s over” Patricia Ganz, Journal of Oncology Practice 2006 A “small” number of children have a large lifetime impact 10,700 new childhood cancers in US in 2010 1,518,860 new adult cancers in 2010 Bleyer, 1990 Part 1 Why do late effects occur? What is the cost of cure? Based on survivors treated between 1970-86: • By 30 years after their cancer: • 3/4 have at least one chronic health condition • 2/5 have a severe or life threatening condition • 8 times more likely to have a severe or life threatening health condition than their siblings Oeffinger, NEJM, 2006 Armstrong, JCO, 2009 9 Risk of developing late effects 0.8 Any physical late effect Cumulative Incidence 0.7 0.6 0.5 0.4 Severe or life threatening late effect 0.3 0.2 0.1 0 0 5 10 15 20 25 Years Since Diagnosis 30 How much more likely is a cancer survivor to develop a serious health condition? Second cancer: 15 Heart failure: 15 Coronary artery disease: 10 Severe learning difficulties: 11 Ovarian failure – early menopause: 3 ½ Kidney failure/dialysis: 9 *compared to their siblings What is the cost of cure? Survivors are more likely than their siblings to report: • Poor general health (2 ½x) • Poor mental health (2x) • Limitations in activities (e.g. personal care, shopping or housework) (5x) • Inability to attend school or work (6x) 12 But… • Only 10% assess their health as poor • An as yet unknown proportion are “thrivers” • Many survivors are living happy, healthy lives 13 Principles of Survivorship • Late effects are the price of success • Late effects are a moving target • Today’s treatments are the authors of tomorrow’s late effects • Specific exposures do not consistently result in particular late effects • Individual outcomes are difficult to predict • Gene-environment interactions 14 What causes late effects? •Radiation •e.g. brain tumors, bone tumors •Chemotherapy •Surgery Tumor Lifestyle and health behaviors Treatment Child’s attributes/ genetics •Younger age at diagnosis •Gender •Genes (good and bad) Chemotherapy late effects Drug Late effect Adriamycin Heart disease Cyclophosphamide Infertility, secondary leukemia Dexamethasone Reduced bone density, osteonecrosis Bleomycin, busulfan Lung disease Cisplatinum Hearing loss, kidney disease How do genes influence late effects? •Genes are the blueprint for all body processes •4 nucleotides (A,T,C,G) are the template for making proteins •Humans can have minor differences in the code for certain proteins (e.g. replace A with C) •Single nucleotide polymorphism (SNP’s) •This changes the way the proteins work can make them more or less effective •Can change how the body processes chemotherapy increased or decreased toxicity •SNP’s have been shown to impact heart problems, hearing, attention … 17 Does gender make a difference? • Females at slightly higher risk for: • • • • • Lower IQ after ALL therapy Heart disease after anthracyclines Overweight after cranial radiation Hypothyroidism after neck radiation Steroid-induced osteonecrosis • Impact on fertility different in females vs. males Lifestyle • Exercise, diet • Lifestyle habits – smoking, sun tanning, regular medical care • Important and (unlike prior treatment) can be modified by the survivor Part 2 Risk-based care Risk-based care A prescription for lifelong health care focused on ensuring each survivor’s best health outcomes based on their past treatment Cancer survivors – a focus of national and international attention 2003 2006 Risk-based survivor-focused care after the completion of therapy All survivors require a systematic plan for periodic assessment and surveillance aimed at prevention or early diagnosis and management of late effects. Care should be adapted to the risks arising from the cancer, its therapy, genetic predispositions, lifestyle and co-morbid health conditions. 23 The purpose of risk-based care To PREVENT late effects before they happen To IDENTIFY late effects before they cause problems To MODIFY existing late effects To use the lessons from survivors to influence the care of NEWLY DIAGNOSED PATIENTS 24 http://www.survivorshipguidelines.org For example: 28 yr old woman treated for Hodgkin’s lymphoma at age 14 yr with chemotherapy and chest radiation Every 6 months • Breast exam breast cancer Yearly • Visit to physician with complete check-up • Thyroid examination thyroid cancer • Thyroid function tests hypothyroidism • Mammogram (or breast MRI) breast cancer Every 2 years • Echocardiogram early signs of heart failure 27 Where do survivors get their care? 100.0% 80.0% 100.0% 85.4% 80.0% 60.0% 40.0% 20.0% 60.0% % 0.0% 40.0% 20.0% 14.6% 0.0% Cancer center Primary care facility Cancer center visits and the development of late effects in the years after diagnosis 1 0.9 GRADE Chronic1-5 health conditions, any grade Prevalence or cumulative incidence * 0.8 CCFU Visit to cancer center within past two years 0.7 * 0.6 0.5 0.4 0.3 0.2 0.1 0 0 5 10 15 Interval from cancer diagnosis, years 20 25 The majority of adult survivors of childhood cancer are seen by a family physician in their community not at a cancer center Do survivors seen outside of a cancer center get “risk-based” care? Screening • Women who receive radiation (>20 Gy) to the breast need an annual mammogram (+/- MRI) starting at age 25 (or 8 years off therapy) • Any patient treated with an anthracycline +/- chest radiation needs an echocardiogram every 1, 2 or 5 years Optimal screening practices Mammogram 169/414 (41%) Echocardiogram 511/1810 (28%) Surveillance tests according to care at a cancer centre vs. community Observations Majority of adult survivors of childhood cancer receive care from a primary care physician Primary care physicians less likely to provide guideline recommended screening tests than cancer centers Surveillance for new cancers • ~9% of survivors will develop a new cancer within 30 years of their original diagnosis • A further 7% will develop a new skin cancer (usually in an area of previous radiation) • This risk is 9x greater than the general population • Survivors at risk for a new cancer need regular surveillance! Meadows, JCO; Mertens JCO What can be done to prevent new cancers or detect them early Breast cancer screening Starting at puberty Breast self exam monthly Clinical breast exam yearly Age 25 (or >8 years after radiation) Clinical breast exam every 6 months Mammogram every year (+/- breast MRI) Thyroid cancer: Annual thyroid exam Skin cancer: Sunscreen, sun avoidance, annual skin examination Lung cancer: Smoking cessation programs (peer to peer; direct or internet) 36 Screening in survivors at average risk for a new cancer (USPSTF) Breast Cervix Mammography every 1 to 2 years for Pap smear every 3 years starting at age women aged ≥40 y 21 years Surveillance in survivors at high risk for a new cancer (COG) Breast Colorectal Skin ≥20 Gy radiation therapy to ≥30 Gy radiation therapy Any radiation therapy the chest to the abdomen, pelvis, or spine Annual mammogram Colonoscopy every 5 Annual skin examination starting 8 years after years starting at age 35 of radiated areas radiation or age 25 years, years whichever is last Compliance with recommended screening tests – average risk 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 81% 67% Mammography Pap smears % complying with guidelines Compliance with Recommended Surveillance Tests – high risk 100% 80% 60% 46% 40% 20% 27% 12% 0% Colonoscopy Mammography Skin exam Observation • Survivors are reasonably compliant with population screening but not with high-risk surveillance • Suggests “lack of knowledge” rather than “lack of motivation” Survivor-related barriers to riskbased care • Feel invulnerable to late effects or do not perceive them as serious • Lack of knowledge about treatment received • Lack of awareness of potential late effects/future risks • Other factors: economic (missing work, cost of travel, childcare), culture, spiritual belief Zebrack et al., 2004 Mertens et al., 2004 Survivor care plans Barriers to risk-based care: Physician and health care system-related factors • Lack of capacity for survivor care within cancer treating institutions • Primary care physicians unfamiliar with population • Poor communication between cancer centers and primary care physicians • Lack of health insurance or coverage of recommended screening tests Part 3 Current survivorship research What we have and have not researched • Several long term cohort studies • Late Effects Study Group • Childhood Cancer Survivor Study (CCSS) • British Childhood Cancer Survivor Study (BCCSS) • St. Jude Life The Childhood Cancer Survivor Study • Established in 1994 • 26 institutions (25 US, 1 Canada) • National Cancer Institute funded study • • • • 5-year survivors of selected childhood cancers Diagnosed 1970-1986 <21 years at diagnosis Alive, regardless of disease status 46 CCSS – US participants (N=13,277) 47 Topics studied by the CCSS • Specific late effects (heart, fertility, 2nd cancer etc.) • Health care and cancer screening • Survivor knowledge • Psychological outcomes • Insurance, marriage, employment etc. • Physical activity, obesity etc. 48 New CCSS cohort • Can’t always apply knowledge about survivors treated in 70’s/80’s to today’s children • We need to learn about survivors treated more recently • Recruiting 20,700 new survivors treated between 1987-1999 • Increased focus on minorities 49 What we have and have not researched • Modification of therapy during treatment • Elimination of cranial radiation therapy • Dexrazoxane to protect the heart • Hearing protectants (e.g. sodium thiosulfate) What we have and have not researched Single nucleotide polymorphisms (SNP) associated with: • Cisplatinum-induced hearing loss • Obesity after cranial radiation (leptin receptor) • ADD after MTX therapy for ALL • Anthracycline cardiomyopathy Ross et al. Nature Genetics 2009 Ross et al. JCO 2004 Krull et al. J Peds 2007 Blanco et al. Cancer 2008 What we have and have not researched • Few studies of interventions after therapy: • Difficult to target adult survivors since most no longer in “cancer system” • Difficult to test preventive strategies in children • Limited collaboration between oncologists and other researchers What we have and have not researched • St. Jude Consortium for Pediatric Research • Low dose tamoxifen to prevent breast cancer • Physical activity intervention in children on ALL treatment • Beta blockers/ACE inhibitors after anthracyclines • COG Outcomes and Survivorship Committee Part 4 Resources for survivors and their families Provides information and resources for pediatric cancer survivors. 56 Programs include equipment and supplies, support groups, educational literature, and summer camps for childhood cancer survivors. 57 Online information and electronic support groups for pediatric cancer survivors and their caregivers 58 Provides resource guides, quarterly newsletters, referrals, information, and publishes books for pediatric cancer survivors, including ‘Educating the Child with Cancer’. A non-profit organization that offers extensive education, advocacy and public health resources. 61 Answers for Life After Cancer Has a comprehensive website, dedicated to issues that may occur after treatment and offers suggestions to deal with the long-term effects of treatment, tips for healthy living and archived teleconferences/web conferences. Provides web conferences for professionals and families on medical late effects, health insurance, nutrition, sibling concerns and educational late effects. Sponsors survivorship conferences throughout the country. Distributes educational material for parents, young adults and teens addressing issues and concerns that may occur after treatment. Web access to the Late Effects Assessment Tool, a free interactive tool designed to prepare survivors for potential medical issues that may arise after treatment has ended and to offer strategies for maintaining overall health. www.beyondthecure.org Childhood Cancer Ombudsman Program [email protected] Provides help for survivors experiencing problems getting access to appropriate education, medical care, health care cost coverage, and employment. Federation for Children with Special Needs http://www.fcsn.org Federally funded organization providing information on special education rights and laws, conferences, referrals for services, parent training workshops, publications, and advocacy information. National Center for Learning Disabilities http://www.ncld.org Offers extensive resources, referral services, and educational programs related to learning disabilities. US Department of Justice ADA Information Line, Civil Rights Division http://www.usdoj.gov Answers questions about the Americans with Disabilities Act, explains how to file a complaint, and provides dispute resolution information. Questions