CHILDHOOD CANCER SURVIVORSHIP: The Good News!

1. CHILDHOOD CANCER SURVIVORSHIP: The Good News! ZoAnn E. Dreyer, M.D. Texas Children’s Cancer Center Houston, Texas

2. Surviving! The Face of Childhood Cancer

3. SURVIVAL BY YEAR OF DIAGNOSIS Years5 year survival 1960-69 26% 1970-79 58% 1980-89 65% 1990-99 70% 2014 80%

5. In the year 2010 1 in 250 young adults will be childhood cancer survivors

6. CENTRAL NERVOUS SYSTEM

7. NEUROPSYCHOLOGIC (NP) • NP sequelae most common in leukemia and brain tumor survivors due to XRT and intrathecal chemotherapy • Impairment may be progressive over 3-5 years; slower onset following low dose XRT • Primary risk factors: • Younger age (< 5 years) • Cranial radiation

8. NEUROPSYCHOLOGIC OUTCOME IN A.L.L. • Post cranial XRT: • Diminished IQ and academic achievement • Impairments in attention • Possible relationship to underlying A.D.H.D.

9. NEUROPSYCHOLOGIC OUTCOME IN A.L.L. • Post chemotherapy alone: • Less likely to suffer severe adverse effects • Attention and concentration difficulties most common • Diminished IQ rare CLASSIC NEUROTOXIN = METHOTREXATE

10. Jonah

11. Jonah

12. NEUROENDOCRINE

13. HYPOTHALAMIC-PITUITARY AXIS DAMAGE • Radiation induced: Cranial & Head/Neck • No definite association with chemotherapy • Risk factors: • Dose-dependent: Cumulative/Individual • Age at time of treatment • Time elapsed since treatment (HYPOTHALAMUS MOST SENSITIVE)

14. GROWTH

15. GROWTH HORMONE DEFICIENCY (GHD) • Earliest, most consistent NE disturbance • Associated with lower dose XRT • Cranial XRT (1800 cGy); TBI (900 cGy) • Higher dose XRT increases risk & decreases time to onset • Nearly 100% GHD within five years following >3500 cGy

16. THYROID

17. THYROID DYSFUNCTION • Hypothyroidism: • Most common nonmalignant late effect in thyroid gland • Almost uniformly due to XRT exposure: head, neck, chest, spine

18. THYROID DYSFUNCTION • Primary hypothyroidism seen in: • 40-90% of survivors with XRT to head and neck • 50% of BMT patients who received TBI • Onset 1-6 years post XRT (> 1500 cGy) • Occasionally reversible • Patients receiving > 1000 cGy to thyroid require annual screening

19. Krysia

20. Krysia

21. CARDIAC

22. POTENTIAL CARDIOTOXINS • ANTHRACYCLINES • Doxorubicin • Daunomycin • Idarubicin • Epirubicin • CYCLOPHOSPHAMIDE • RADIOTHERAPY • Chest, Mantle, Spinal, Abdominal

23. ANTHRACYCLINE CARDIOMYOPATHY RISK FACTORS • Cumulative Dose • 1.5% at 350 mg/m2 • 2.6% at 450 mg/m2 • 6.0% at 550 mg/m2 • 50% at 950 mg/m2 • Dose dependent risk at >550 mg/m2 • Asymptomatic cardiac damage unclear

24. ANTHRACYCLINE CARDIOMYOPATHY RISK FACTORS • Age • Very young vs. very old • Dosing Schedule • Individual dosing level • Infusion technique • Prior exposure to radiotherapy • Concurrent exposure to other cardiotoxins

25. RADIATION INDUCED CARDIAC INJURY DELAYED EFFECTS MEDIATED BY VASCULAR DAMAGE AND FIBROSIS • Parietal pericardium - fibrosis, tamponade • Myocardial damage rare • Conduction system defects possible

26. XRT INDUCED CORONARY ARTERY DISEASE • Cofactor for late development of CAD • Proliferation of myofibroblasts with accumulation of lipids reduces vascular lumen • Ischemic effects identical to atherosclerotic disease • Hodgkin’s disease survivors at particular risk for death from CAD and MI

28. GONADAL

29. GONADOTROPIN DEFICIENCY (GND) • Complete or partial GND in 10-20% within 5-10 years following >3500 cGy • Incidence increases with time • Outcome dependent on age at time of tx: • Young child: Amenorrhea, arrested puberty, menstrual irregularity • Adult: Infertility, sexual dysfunction

30. TESTICULAR EFFECTS OF THERAPY • Spermatogonia exquisitely sensitive to XRT • Low dose (150 cGy)=transient depression • High dose(>600 cGy)=permanent depression • Alkylators dose and age dependent Azoospermia cycle dependent in HD: • >5 cycles MOPP / COPP - persistent • >3 cycles MOPP / COPP - transient

31. OVARIAN EFFECTS OF THERAPY • Older age increases sensitivity to lower dose XRT • TBI / ovarian XRT: • In pubertal females risk of infertility • In girls < 8 years old may result only in delayed menarche • Sensitivity to alkylator therapy age and dose related

32. PREGNANCY OUTCOME IN LTS • Reports of pregnancy outcome are mixed • Current recommendations are to: - wait minimum of one year post chemo to become pregnant - avoid XS delay in pursuing pregnancy due to risk of premature menopause

33. Dr. Donald J. Fernbach

34. SECOND MALIGNANT NEOPLASMS

35. SECOND MALIGNANT NEOPLASMS (SMN) • Childhood cancer survivors have 10-20X the life time risk of a second cancer compared with age-matched controls • SMN incidence 3-21% within the first 20 years after initial diagnosis • Risk for SMN highly dependent on prior diagnosis, therapy and presence of genetic conditions

36. RISK FACTORS FOR SMN • Prior therapy • Alkylators + XRT • Epipodophyllotoxins • Primary malignancy • Retinoblastoma / Hodgkin’s / Ewings • Familial cancer syndrome • p53 mutation

37. RADIATION RISK FOR SMN • Age dependent • Cranial XRT for leukemia increases risk for later brain tumors • XRT to neck (including scatter radiation) increases risk for later thyroid cancer • XRT to proliferating breast tissue in second decade increases risk of breast cancer

38. SMN IN HODGKIN’S DISEASE: LESG • 1380 children treated 1955 - 1986 • SMN in 88 / 1380 • 56 - solid tumors (36% breast; 20% thyroid) • 26 - leukemias • 6 - non-Hodgkin’s lymphomas (NHL) • 21 - benign tumors • Median time to SMN • Solid tumor, NHL - 14 years • Leukemia - 4 years • Mean cumulative incidence at 15 years - 7%

39. BREAST CANCER FOLLOWING HODGKIN’S DISEASE • History of radiation (+/- chemotherapy) • 16/17 tumors within XRT field • Median age at diagnosis - 31 years (range 16-42 years) • Estimated cumulative probability - 35% at age 40 years • Risk factors: Radiation to mammary tissue Age > 10 years at time of XRT Radiation dose > 2000 cGY

40. SMN IN HODGKIN’S DISEASE: LEUKEMIA • Incidence plateau at 2.8% at 14 years post diagnosis • 24/26 leukemias were AML • Risk factors Alkylator therapy One or more recurrence of HD Stage III/IV HD at diagnosis Older age at diagnosis

41. Sherrell

42. Hello? 911? Just thought I’d call and tell you how I am!

43. THE TEXAS CHILDREN’S CANCER CENTER Long-TermSurvivors Clinic

44. LTS TEAM • Medical Director – ZoAnn Dreyer, MD • Research Director - Fatih Okcu, MD • Dr. Hilary Suzawa; Roz Bryant, PNP • LTS Coordinator - Gaye Hamor • Social Worker; Financial counselor Psychologist; Neuro-psychologist

45. COMPREHENSIVE CARE TEAM Subspecialty Services and Consultation Board Neurology Dermatology Neuropsychology Nephrology Adolescent Medicine Endocrinology Adolescent Gynec Cardiology Orthopedics Radiotherapy Learning Support Ctr Pulmonary

46. LONG-TERM SURVIVOR • Three - five years since diagnosis of primary malignancy • Off therapy for two years • No upper age restriction

47. THE LTS CLINIC VISIT • Review of prior therapy and complications • Organ system testing based on risks • Thorough interval history and exam • Education regarding: • diagnosis and treatment • general health care maintenance • Consultations with social worker& financial counselor

48. COMPREHENSIVE CARE TEAM REFERRALS Approximately 40% of LTS require referral to the Comprehensive Care Team Nearly two thirds of adolescent and young adult survivors have at least one ongoing medical diagnosis

49. MEDICAL ISSUES EMPHASIZE THE NEED FOR ONGOING SURVIVOR CARE • Recent publication in New England Journal of Medicine reported 2/3 of 20,000 survivors surveyed nationally had at least one medical condition; 25% of conditions were serious! • Similar findings reported in our TCCC survivor population 5 years ago

50. TCCC LTS PROGRAM GOALS • Provide comprehensive, integrated care designed to maximize quality of life and long-term survival • Conduct research to predict, prevent and treat late effects • Train future leaders in survivorship • Educate primary care MDs, patients / family members and the public about the importance of survivor care • Collaborate in the continued development of the Passport for care