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Radiation Therapy for Childhood Cancer You’ve got to love it, But also hate it! -- Louis S. Constine, MD, FASTRO Professor, Radiation Oncology and Pediatrics Five-Year Survival Rates for Children with Cancer 100 90 80 70 All Cancers ALL 60 AML Bones/Joints Brain/CNS HD 50 NBL NHL 40 Soft Tissue WT 30 20 • Over 250,000 childhood cancer survivors in the US • 1 in 1,000 is a childhood cancer survivor • 1 in 570 is a childhood cancer survivor (ages 20 to 34 yr.) 10 0 '74 - '76 '83 - '85 '92 - '98 Cumulative Cause-Specific Mortality JCO 2001;19:3163-72 Cumulative incidence of chronic physical health conditions among 10,397 young adult survivors of childhood cancer Cumulative Incidence 1 0.9 0.8 Any chronic condition 0.7 0.6 Severe, disabling lifethreatening, or death 0.5 0.4 0.3 0.2 0.1 0 0 5 10 15 20 Years since cancer Oeffinger NEJM 2006 25 30 Factors Contributing to Morbidity Host Factors Genetic BRCA, ATM, p53 polymorphisms Age Gender Race Tumor Factors Cancer-Related Morbidity Health Behaviors Tobacco Diet Alcohol Exercise Sun Premorbid Conditions Treatment Factors Aging Histology Site Biology Response Surgery Chemotherapy Radiation therapy Treatment Events Two Classes of Ionizing Radiation • Electromagnetic – X-rays and g-rays • Particulate – Produced by accelerators and radioactive isotopes How Radiation Works Direct + Indirect Actions Radiation may either: – Directly ionize DNA (via photon-produced electrons) or – Indirectly by first interacting with H2O to produce free radicals Radiation Therapy is Getting Complicated… Tables and Data and Lines, Oh My... Late medical effects of treatment depend on the type of therapy . . . Surgery Radiation Therapy and the specific toxicities/organ interactions of each therapy Chemotherapy Tissues at Risk for Late Toxicity • Bone/soft tissues • Immune system • Cardiovascular • Nervous system • Dental • Neuropsychologic • Endocrine • Ophthalmologic • Gastrointestinal • Pulmonary • Hepatic • Renal • Hematological • Reproductive Being cured of childhood cancer but suffering a broken heart! Radiation Cardiac Injury • • • • • • Manifestations Restrictive cardiomyopathy Premature CAD Myocardial infarction Valvular disease Autonomic dysfunction Conduction defects • • • • • • • • Mantle Field Risk Factors Younger age (< 5 y) Higher dose (> 35 Gy) Higher daily fraction ( 2 Gy) Larger volume of heart in field Anteriorly weighted field Subcarinal shielding Longer time from RT Use of cardiotoxic chemoRx CCSS Cumulative Incidence (95% CI) CHF and MI Cumulative Incidence [%] An NCI-funded Resource Congestive Heart Failure 4 3 2 1 Myocardial Infarction 0 5 10 15 20 Years Since Diagnosis Mulrooney et al., 2009 25 30 CCSS Risk of Congestive Heart Failure Multivariate Analysis An NCI-funded Resource 6 Relative Risk* 5 * 4 2 1 F * M * ≥35 ≤4 3 * * 5-9 * *15-35 10-14 15-20 1-5 ≥250 <250 6-15 0 0 0 Sex P <0.05 Cardiac RT dose (Gy) Anthracycline (mg/m2) * Adjusted for race, BMI, income, education, smoking, treatment era Mulrooney et al., 2009 * Age at Diagnosis (yrs) Risk Riskof ofMyocardial MyocardialInfarction Infarction CCSS Multivariate Analysis Analysis Multivariate An NCI-funded Resource 4 Relative Risk* * >35 3 2 * 15-35 5-9 <250 15-20 1 M ≤4 *F 10-14 0 1-5 0 >250 6-15 0 Sex * Age at Diagnosis (yrs) Cardiac RT dose (Gy) Anthracycline (mg/m2) P <0.05 * Adjusted for race, BMI, income, education, smoking, treatment era Mulrooney et al, 2009 Risk of Valvular Disease CCSS Multivariate Analysis An NCI-funded Resource 6 Relative Risk* 5 * 4 * 3 F * 2 1 M ≤4 * Sex * 5-9 10-14 Age at Diagnosis (yrs) 15-35 * * 15-20 0 * >35 <250 6-15 0 1-5 Cardiac RT dose (Gy) >250 0 Anthracycline (mg/m2) P <0.05 * Adjusted for race, BMI, income, education, smoking, treatment era Mulrooney et al, 2009 Mantle radiation therapy for Hodgkin lymphoma - historic Pulmonary Toxicity Manifestations • Paramediastinal fibrosis • Asymptomatic pulmonary dysfunction – Diffusion – Restriction – Obstruction • Pulmonary fibrosis • Restrictive lung disease • Pneumothorax Risk factors • Higher bleomycin dose • Chest radiation How about a broken thyroid gland? or A cancer in an irradiated thyroid gland? Hypothyroidism • Female sex • Older age (> 15 y) • Higher radiation dose – 30% if 35 - 44 Gy – 50% if > 45 Gy • Time < 5 y from Dx Sklar et al, JCEM 2000 Secondary Thyroid Malignancy After RT Ronckers et al, Rad Res, 166:618, 2006 Now that we are talking about secondary malignancies… Cumulative Incidence of Subsequent Neoplasms 30 year cumulative incidence of any SN = 20.5% SMN = 7.9% NMSC = 9.1% Meningioma = 3.1% Friedman JNCI 2010 Cumulative Incidence of SMNs by Primary Diagnosis • Hodgkin Lymphoma – 18.4% • Ewing Sarcoma – 10.1% • Soft Tissue Sarcoma – 8.8% • Medulloblastoma - 7.8% • Osteosarcoma – 6.0% • Non-Hodgkin Lymphoma – 5.8% • Neuroblastoma – 5.9% • Leukemia – 5.6% • Astrocytoma – 4.7% • Wilms tumor – 4.0% CHILDHOOD CANCER SURVIVOR STUDY Cumulative incidence of SMNs by exposure to radiotherapy Histopathologic Types of Second Malignant Neoplasms (SMN) after Hodgkin Lymphoma Site SIR Years to SMN Breast 37.3 9 - 36 Thyroid 25.1 9 - 23 GI 27.2 10 - 33 Leukemia 21.5 2 - 18 STS 50.4 9 - 18 Bone 53.5 9 - 23 Lymphoma 5.2 1 - 24 CNS 9.7 8 - 29 H&N 12.9 15 - 20 Lung 4.6 11 - 16 Other 1.8 <1 - 25 Breast Cancer Risk by Radiation Dose, Volume after Hodgkin Lymphoma Inskip PD, et al. J Clin Oncol, 2009 De Bruin ML, et al. J Clin Oncol, 2009 Cumulative Incidence of Breast Cancer in Hodgkin Lymphoma Survivors 20% at 45 years of age Bhatia S, et al. J Clin Oncol, 2003 (and N Eng J Med, 1996) Secondary CNS Tumors Meningioma Astrocytoma How about fertility? (effects on ovaries and testes) Ovarian Failure 6 Million 5 4 3 2 1 0 20 weeks gestation Birth Puberty Menopause 2.5 - 5.0 Gy: < 15 years - OK 15-40 years - 30-40% sterility > 40 years - 90% sterility 5 - 8 Gy: < 15 years - variable 15-40 years - 50-70% sterility >40 years - 90% sterility Sperm Recovery After Radiation Therapy Radiation to the brain and hypothalamus-pituitary Brain radiation can affect learning & memory, motor function and sensation Endocrine gland radiation can affect growth, metabolism, and reproduction Neurocognitive Effects of Irradiation Severity and type of effects depend upon • age of child when irradiated • dose of XRT • volume of brain and specific areas treated • other contributing factors (surgery, chemo, pre-existing abnormalities) Neuroimaging Abnormalities • • • • • • Brain atrophy Encephalomalacia Cerebral lacunes Dystrophic calcification Leukoencephalopathy Necrosis/gliosis IQ After Conformal RT for Low Grade Glioma Merchant TE et al. J Clin Oncol 2009; 27:3691-7 Overall Index (Attention Problems) after Conformal Radiation Therapy (CRT) for Pediatric Patients with Different Brain Tumors (Normal Overall Index < 10) Ependymoma Kiehna, E. N. et al. J Clin Oncol; 24:5283-5290 2006 Endocrine Effects of Cranial Irradiation Growth Hormone (GH) Deficiency following XRT is dose related – 18 Gy 0% GH deficient – 24 Gy 20-40% – 30-35 Gy 80-85% – >35Gy 100% Onset: 55% within 1st year, 67% within 5 yrs Peak Growth Hormone (GH) According to Hypothalamic Mean Dose and Time After Start of Irradiation Merchant et al, JCO 29:4776, 2011 Relative Risk (RR) of Death Due to Cerebrovascular Disease vs Radiation Dose Haddy et al, Brain 134:1362, 2011 Hearing Loss Hearing Loss Radiation Dose Chemotherapy CSF Shunting 0 no chemotherapy 10 dBHL 20 30 Dose > 32 Gy (~ 45 Gy) 40 50 0 chemotherapy 60 10 chemotherapy 70 0 12 24 36 48 20 Time (months) dBHL no chemotherapy 30 40 No shunt Shunt Dose < 32 Gy (~18-20 Gy) 50 60 70 0 12 24 Time (months) Merchant, TE et al. Int J Radiat Oncol Biol Phys 2004;58:1194-207 36 48 Dental Abnormalities After ChemoRx • Tooth/root agenesis Adontia Microdontia • Root thinning or shortening • Enamel dysplasia Dental Abnormalities After Radiation • Salivary gland dysfunction • Xerostomia • Dental caries • Periodontal disease How about Muscles and Bones? Fortunately, these effects are mostly historic because we use lower radiation doses, and smaller fields Growth Impairment Risk factors • Younger age (prepubertal) • Higher dose (> 20 Gy) • Higher daily fraction ( 2 Gy) • Larger treatment field • Epiphysis in treatment field Wilm’s Tumor Treated at 10 Mos With Nephrectomy and RT for Wilm’s Tumor, Now 10 Yrs Post Post RT for Ewing’s Sarcoma Radiation to the Kidney and Bladder Radiation cause renal damage and bladder, ureteral fibrosis Resulting sequela: • Hypertension • Hematuria • Incontinence • Hesitancy • Obstruction Renal Complications • Hypertension • Tubular dysfunction Renal tubular acidosis Fanconi’s syndrome Hypophosphatemic rickets • Glomerular injury • Renal insufficiency Bladder Complications • • • • • Hemorrhagic cystitis Bladder fibrosis Dysfunctional voiding Urinary incontinence Bladder carcinoma • Design cancer treatments to reduce the risk of late effects • Develop therapies to protect normal tissues • Monitor childhood cancer patients for late effects • Prescribe corrective therapy • Have regular check-ups so late effects can be prevented or detected in earlier stages • Follow doctor’s advice about medications and other interventions Practice health behaviors that reduce the risk of late effects We are working hard: »To cure children with cancer »To minimize late effects And we are making progress!