Melissa M. Hudson, MD Cancer Survivorship Division Childhood Cancer Survivors: Evidence for Accelerated Aging

Overview of Aging Gradual, continuous process of natural change characterized by decline in many body functions –Process begins in early adulthood –Decline varies by time of onset among individuals chronological v. biological age –Factors influencing timing/rate of decline Heredity/genes Lifestyle/health habits Exposures to toxins Health care

Conditions associated with aging: organ dysfunction Hearing loss Heart disease Cognitive decline Dementia Cataracts Far-sightedness Reproductive function Menopause Osteoporosis Loss of muscle mass

Conditions associated with aging: Cancer

1 in 2 men 1 in 3 women ACS Cancer Statistics 2015

Chronic disease in general population 4 of 5 adults age 50 or older suffer from at least one chronic condition –More than half have more than one chronic condition Common chronic diseases: –High blood pressure –High cholesterol –Mental illness –Diabetes –Heart disease –Cancer

Health conditions in 1713 childhood cancer survivors undergoing comprehensive risk-based health testing in St. Jude Lifetime Cohort Age at diagnosis: 6 yrs (range, 0-24) Age at study: 32 yrs (range 18-60) Time from diagnosis: 25 yrs (range 10-47) Hudson et al. JAMA 2013

Normal ovarian reserve AGE FOLLICLE COUNT 25, , Menopause birth 1,000, Menarche

Acute ovarian failure in childhood cancer survivors Follicle Count 25,000 (37) 1,000 (51) Cancer Treatment 6.3% of women studied in CCSS Independent risk factors Increasing doses of abdominal/pelvic radiation >1,000 cGy to ovaries (OR 90.9) Alkylating agent exposure: Procarbazine (OR ) Cytoxan at age > 12 (OR 4.9) High dose alkylators (BMT doses) Chemaitilly et al, J Clin Endocrin Metab, 2006

Premature menopause in childhood cancer survivors Follicle Count 25,000 1,000 Cancer Treatment 8% of women studied in CCSS Approximately 30% treated with abdominal/pelvic radiation plus alkylators Independent risk factors: Advancing age Increasing radiation dose to ovaries Increasing doses of alkylators Diagnosis of Hodgkin lymphoma Sklar et al, J Natl Cancer Inst, 2006

Armstrong et al, J Clin Oncol, % 6.8% 5.0% 0.3% At 45 Years Heart failure in childhood cancer survivors

Congestive Heart Failure Armstrong et al, J Clin Oncol, Rate Ratio RR=34.1 HTN, No Anthracycline RR=8.3 Anthracycline, No HTN RR=88.5 HTN + Anthracycline How much does high blood pressure contribute to development of heart failure Longitudinal evaluation 10,724 survivors, CCSS Hypertension potentiates anthracycline-associated risk for heart failure Multiple traditional CV risk factors increase risk Prevention should be focus of future interventions Relative excess risk due to interaction = 44.5 Chronic health conditions

Breast cancer in Hodgkin lymphoma survivors Bhatia S, et al. J Clin Oncol, 2003 Median time to diagnosis of breast cancer from radiation exposure is 15 to 20 years, with cases being diagnosed as early as 8 years from exposure. Start breast cancer screening at age 25 or 8 years after radiation

Pre-frailty and Frailty are defined by a cluster of five measurements of physical state/abilities – Lean muscle mass – Exhaustion – Energy expenditure – Walking speed – Muscle weakness Frailty as a measure of aging Pre-frail = 2 items Frail = 3+ items

N=1922 (50.3% male) Mean age at diagnosis 8.2±5.6 years Mean age 33.6±8.1 years Mean time since diagnosis 25.5±7.7 years Frailty phenotype differed by sex (females), age (older), and diagnosis CHS: Cardiovascular health study age range years Control participants age range years (mean 29.0±7.5years) Ness KK et al, JCO, 2013 Frailty in childhood cancer survivors

Evidence for accelerated aging? Yes: specific cancer treatments do cause organ dysfunction and can lead to diseases that typically develop in older individuals. Important facts to consider: The results presented reflect outcomes of older treatment approaches that are no longer used. Many changes have been made in cancer treatments to reduce injury to normal organs and tissues.

Advice to cancer survivors: before and during therapy Talk to your care team about cancer treatment effects on health before therapy. Ask about ways to prevent or reduce chances of injury to healthy organs and tissues. Ask about how your health will be monitored during therapy to check for health effects.

Advice to cancer survivors: after therapy Know specific details about your cancer treatment. Know the health risks linked to this treatment. Know about the screening tests recommended to monitor health risks linked to your treatment. Have regular check ups to stay on top of all health issues. Understand how health habits can modify the risk of organ injury and accelerated aging.

Practice health habits that protect against accelerated aging Smoking Sun exposure Diet Physical activity Alcohol intake

Thank you for your attention! Acknowledgements American Lebanese Syrian Associated Charities (ALSAC) NCI Cancer Center Support (CORE) grant CA 21765