Late Effects in Pediatric Cancer Survivors

Late Effects in Pediatric Cancer Survivors LISA K OPP, DO ASSOCIATE PROFESSOR THE UNIVERSITY OF ARIZONA DEPARTMENT OF PEDIATRICS DIVISION OF HEMATOLOGY/ONCOLOGY/BMT

Objectives Review Childhood Cancer and Childhood Cancer Survivor Statistics Recognize some of the common side effects of childhood cancer therapy Be familiar with the resources available for monitoring side effects of childhood cancer therapy Review the most common late effects that you will likely encounter in your office Recognize the modifiable risk factors of childhood cancer therapy

Childhood Cancer Approximately 12,400 children and young adults are diagnosed with cancer each year in the US Cancer remains the leading cause of death among children between 1-19 years of age in the US With the introduction of new treatments over the past 50 years the survival has increased dramatically

Ware, E Childhood and adolescent cancer statistics, 2014, CA: a cancer journal for clinicians

Overall Survival Rate is >80% Ware, E Childhood and adolescent cancer statistics, 2014, CA: a cancer journal for clinicians

Why is this important to the Family Physician? There are over 325,000 survivors in the US = 1 in 570 adults Over 60% of survivors have a long term side effect as a consequence of the therapy they received Childhood cancer survivors will be in your clinic

Childhood Cancer Survivors Previous to the 1990s the only reports on the late effects of therapy consisted of small cohorts of patients These reports did indicate excessive mortality rates in 5-year survivors of childhood cancer survivors In 1994 the Childhood Cancer Survivor Study was began which is a component of the Long Term Survivor Study

Collaborative, multi-institutional study funded by the National Cancer Institute 31 participating centers - coordinated though St. Jude Children s Research Hospital Individuals have survived more than 5 years after diagnosis of cancer during childhood or adolescence Retrospective cohort consisting of 36,000 childhood cancer survivors diagnosed between 1970 and 1999 Approximately 5,000 siblings are also included who serve as matched controls More than 170 publications to date from this data base https://ccss.stjude.org

Childhood Cancer Survivor Cohort Diagnoses: Leukemia Central Nervous System cancers Hodgkin's Lymphoma Non-Hodgkin s Lymphoma Wilms Tumor (Nephroblastoma) Neuroblastoma Soft tissue sarcomas Bone Tumors Late Effects Evaluated: Death Secondary malignancies Organ system problems Impaired growth and development Impaired cognitive function Psychosocial problems Infertility Overall reduction in quality of life

The cumulative incidence of severe, disabling, lift-threatening and fatal events compared to siblings Graded 3 5 as per CTCAE (Common Toxicity Criteria Adverse Events) Median 24 years from diagnosis; Age 35 62 years of age Among survivors 35 years 26% experienced a grade 3 5 Event within 10 years compared to 6% matched siblings Armstrong et. al JCO 2014

Leukemia Central Nervous System Tumors Hodgkin Lymphoma Non-Hodgkin Lymphoma Kidney Tumors Neuroblastoma Soft Tissue Sarcomas Bone Tumors Armstrong et. al JCO 2014

Armstrong et. al JCO 2014

Cross-section study of > 8,000 childhood cancer survivors Assessed prior 2 years medical visits: Were these visits related to prior cancer therapy? Did you receive advice on how to reduce long term effects? Were any screening tests discussed or ordered? Nathan et al. JCO 2008

Nathan et al. JCO 2008

Case Study Suzie is a 27 y/o young lady who is a new patient you are seeing today in clinic CC: new patient came for a preventive care check as she has a new insurance; she has no specific concerns today PMHx History of right pelvic Ewing s sarcoma when she was 16 years old Therapy included: Ifosfamide, Etoposide, Cyclophosphamide, Doxorubicin, and Vincristine; Radiation therapy to right pelvis PSHx tumor biopsy; port-a-cath placement and removal Social History works at CVS as a pharmacy tech; married - no children; does not have time to exercise; nonsmoker; drinks alcohol 1-2 x per month; no substance abuse

Case Study (continued) Physical Exam Vitals: T: 97F R: 16 HR: 85 BP: 140/85 Height: 5 5 Weight: 170 lbs Gen: overweight, A&O x 3 HEENT: EOMI, PERRL, nares patent, mouth clear Lungs: CTAB CVS: RRR, +S1, S2; no murmurs GI: soft, NT/ND, no HSM MKS: limb salvage right femur; slight limp, FROM x 4, Neuro: CN II XII grossly intact; sensation intact

Case (continued) As you ask the last question that you always regret asking prior to walking out the room Do You have anything else I can help you with today? Suzie says oh yeah: She is worried because she has been off her OCP for 1 year and has not gotten pregnant. She is wondering if she should be worried and what she should do about it...

Labs return a few days later.. Labs CBC normal BMP normal HbA1C 6 Lipids LDL 150 HDL 55 Triglycerides 180 https://en.wikipedia.org/wiki/blood_test

Case Study Assessment 30 y/o female with mild hypertension and obesity (history of Ewing s sarcoma) (and possibly infertility) Plan What are her risks due to her chemotherapy? Should you be more concerned about her obesity, mild hypertension, and slightly elevated HbA1C and lipids than you would be with a 27 y/o with no history of cancer? Is her infertility linked at all to her cancer therapy?

Fertility

3,531 survivors and 1,366 female sibling controls Survivors had an increased risk of infertility Most pronounced at early reproductive ages Increasing doses of uterine radiation and alkalyating chemotherapy were strongly associated with infertility Barton et al. Lancet Oncology 2013

Barton et al. Lancet Oncology 2013

Male survivors who wanted to become pregnant - 938 survivors, 174 sibs Prevalence was 46% versus 17.5% in sibs 37% of survivors who met definition of infertility reported at least one pregnancy which resulted in a live birth Wasilewski-Masker et al. Journal of Cancer Survivors 2014

Wasilewski-Masker et al. Journal of Cancer Survivors 2014

10,938 survivors and 3,949 matched siblings Significant decrease in male and female survivors compared to siblings Siring or having a pregnancy Having a livebirth Chemotherapy affected each sex differently regarding risk of infertility Males: higher doses of cyclophosphamide, ifosfamide, and cisplatin Females: highest doses of cyclophosphamide, busulfan, lomostine Chow et al. Lancet Oncology 2016

Chow et al. Lancet Oncology 2016

Case Study Is Suzie at Risk? Therapy included: Ifosfamide and Cyclophosphamide Radiation therapy to right pelvis

Secondary Cancers

Secondary Malignancies are the leading cause of nonrelapse late mortality 20.5% 6 fold increase in secondary malignancies compared with the general population Multifactorial etiology Primary cancer diagnosis Cancer therapy Presence of genetic conditions Meadow et al. JCO 2009

Meadow et al. JCO 2009

Choi et al. IJC 2014

Case Study Is Suzie at Risk? Therapy included: Ifosfamide and Cyclophosphamide Etoposide Doxorubicin Radiation therapy to right pelvis

Cardiovascular Disease

Cardiovascular Disease Almost seven-fold increase of chronic cardiac conditions in survivors compared to sibling controls Cardiomyopathy associated with anthracyclines Atherosclerotic disease Diabetes mellitus Dyslipidemia Obesity Metabolic Syndrome Mody et al. Blood 2008

Cardiotoxic Therapy Chemotherapy Anthracyclines Alkylating agents Vinca alkaloids Antimetabolites Biologic agents Radiation therapy Cardiac radiation dose > 1500cGy

Cumulative Doxorubicin Dose > 450 mg/m 2 ~ 10% heart failure > 500mg/m 2 ~ 20% heart failure Swain, S et al. Cancer 2003

Children s Cancer Survivor Study (CCSS) Cohort Results 14,358 survivors and 3,899 siblings Mean age 27 years Mulrooney, D et al. BMJ 2010

Childhood Cancer Survivors - Netherlands Van der Pal, H. et al JCO 2012

Cardiac Risk Factors - Non-Modifiable Female sex Genetics Pre-existing cardiac disease Young age (< 4 years) Older age (> 40 years) Lipshultz, SE et al NEJM 1995

Cardiac Genetic Risk Factors United States Case control study 170 patients Polymorphisms in the gene CBR3 Predicted and increased risk of cardiomyopathy in those patients exposed to < 250 mg/m 2 of anthracycline Blanco JD et al. JCO 2012

Cardiac Genetic Risk Factors Canada and Netherlands 156 children from Canada treated with anthracyclines 2,997 Single nucleotide polymorphisms (SNP) in 220 drug biotransformation genes were evaluated 9 SNPs were significantly associated with cardiac toxicity Replicated in second cohort of 188 children from across Canada and third cohort 96 children in Netherlands Visscher, H. et al JCO 2012

10,724 5-year survivors 3,159 siblings Reviewed prevalence: Hypertension Diabetes mellitus Dyslipidemia Obesity Armstrong et al. JCO 2013

Prevalence of cardiovascular risk factors (A) hypertension, (B), dyslipidemia, (C), diabetes, (D) obesity, and (E) multiple cardiac risk factors with increasing age. p < 0.01 p = 0.08 Armstrong G T et al. JCO 2013;31:3673-3680

A, B, and C Blue line = RT Radiation Yellow line = no RT Gray line = sibling control Coronary Artery Disease Valvular Disease Arrhythmia D Blue line = RT + Anthracycline Yellow line = Anthracycline Red line = RT alone Dark Blue line = None Gray line = sibling control Heart Failure Armstrong et al. JCO 2013

Behavioral Risk Factors Survivors are more likely to be inactive and less likely to meet physical activity than siblings Miller et al. CCSS PB&C 2013 Ness et al. CCSS Cancer 2009 Hypertension incidence is 7.8% after 15 years of follow up in childhood cancer survivors Armstrong et al. JCO 2013

Monitoring for Cardiotoxicity Cardiac Echocardiogram Monitor left ventricular fractional shortening Circulating biomarkers Cardiac troponin T N-terminal pro-brain natriuretic peptide http://www.qualitycardiaccare.com/test

Case Study Is Suzie at Risk? Therapy included: Doxorubicin Physical Exam Vitals: T: 97F R: 16 HR: 85 BP: 140/85 Height: 5 5 Weight: 170 lbs Gen: overweight, A&O x 3 Labs HbA1C 6 Lipids LDL 150 HDL 55 Triglycerides 180

Summary All Childhood Cancer Survivors are at risk of multiple late effects including Metabolic Syndrome and Cardiovascular Disease Survivors should be monitored closely for these know effects Providers should be aware of potential late effects Providers should educate survivors on modifiable risk factors

Resources http://www.survivorshipguidelines.org

Thank You!