Radiation-Associated Subsequent Neoplasms: The Childhood Cancer .
Radiation-Associated SubsequentNeoplasms: The Childhood CancerSurvivor StudyLeslie L. Robison, Ph.D.Department of Epidemiology and Cancer ControlSt. Jude Children’s Research HospitalMemphis, TN
Childhood Cancers in the US:Survivorship Statistics Estimate 13,500 newly diagnosed cases annually End of 2013, estimated number surpass 420,000 1 in 750 in the US is a childhood cancer survivor Number of survivors will approach 500,000 by 2020
Proportion SurvivingSurvival of Childhood CancersAges 0-19 years20052000199519901985-891980-841975-79Data Source: SEER 2010Years from DiagnosisRobison and Hudson. Nat Rev Cancer, 2014
Annual Incidence Rate Per 105Age-specific Cancer Incidence 1%Data Source: SEER 2010Age at Cancer DiagnosisRobison and Hudson. Nat Rev Cancer, 2014
Age-specific Cancer IncidenceIncidence Per 105Annual Incidence Rate Per 105Childhood/AdolescentCancerAge at Cancer Diagnosis 1%Data Source: SEER 2010Age at Cancer DiagnosisRobison and Hudson. Nat Rev Cancer, 2014
Childhood Cancer Survivor Study(U24 CA55727) Funded in 199435,923Eligible20,690 (1970-86)15,233 (1987-99)*24,368Participants14,364 (1970-86)10,004 (1987-99)* Retrospective cohort, recentexpansion includes survivorsdiagnosed 1970-1999 31 contributing centers 5-year survival Leukemia, lymphoma, CNS,bone, Wilms, NBL, softtissue sarcoma Detailed treatment data Wide range of outcomes11,889Stored DNA* indicates expansion cohort population,now available to investigators
Childhood Cancer Survivor Study (U24 CA55727)Study DesignCCSS COHORTSelected Cancer DiagnosisConsortium CenterDiagnosed 1970-19995-year Survival 21 yrs. At DiagnosisEnglish- or Spanish-SpeakingSIBLING COHORTRandom SampleQuestionnaire / Interview DataSurvivorsParentsTreatment InformationMedical Record AbstractionRadiation Therapy Records(RT Physics Center)Pathology CenterConfirm Subsequent MalignanciesRepository - Second CancersRepository - Buccal Cell DNALCL for SMN CasesNational Death Index
Participating SitesThe Childhood Cancer Survivor Study
Childhood Cancer Survivor Study (U24 CA55727)Study Participants
Childhood Cancer Survivor Study (U24 CA 55727)Participating CentersSt. Jude Children’s Research HospitalU.T. - M.D. Anderson Cancer CenterUniversity of MinnesotaMayo ClinicChildren’s Hospital of PittsburghChildren’s Hospitals of MinnesotaStanford UniversityChildren’s Hospital of PhiladelphiaDana-Farber Cancer InstituteSt. Louis Children’s HospitalChildren’s National Medical CenterChildren’s Hospital of Los AngelesRoswell Park Cancer CenterUCLA Medical Center/Miller Children’sMemorial Sloan-Kettering Cancer CenterChildren’s Hospital of Orange CountyTexas Children’s HospitalRiley Hospital for Children – Indiana Univ.University of California, San FranciscoUAB/Children’s Hospital of AlabamaSeattle Children’s HospitalUniversity of Michigan – Mott Children’sToronto Hospital for Sick ChildrenChildren’s Medical Center of DallasDenver Children’s HospitalFred Hutchinson Cancer Research CenterNationwide Children’s Hospital, ColumbusNorthwestern UniversityEmory UniversityUniversity of ChicagoCook Children’s Medical Center
Initial Diagnosis (n 24,368)Acute Lymphoid LeukemiaHodgkin LymphomaAstrocytomaWilms TumorNon-Hodgkin LymphomaNeuroblastomaOsteogenic SarcomaRhabdomyosarcomaMedulloblastoma/PNETAcute Myeloid LeukemiaEwing SarcomaOther CNSOther LeukemiaOther BoneDiagnoses Not Included in the CCSS CohortGerm cell 10152025303540Percent of TotalTurcotte et al, manuscript in preparationThe Childhood Cancer Survivor Study
Distribution of Therapy for Initial CancerRadiation ChemotherapyRadiation SurgeryRadiation OnlyRadiation Chemotherapy SurgeryChemotherapy SurgeryChemotherapyOnlyTurcotte et al, manuscript in preparationSurgery OnlyThe Childhood Cancer Survivor Study
All Cause Mortality in 5 Year SurvivorsCumulative Probability8.0Recurrence6.04.0SMNOther ears since diagnosisMertens, et al, JNCI 2008The Childhood Cancer Survivor Study
Late Mortality Among 5 Year SurvivorsUS FemaleAll Cause Mortality0.95US MaleSMR0.850.90SMNCardiacPulmonary15.27.08.895% CI13.9 – 16.65.9 – 8.26.8 – 11.2Female0.750.80RT-Associated Risk of DeathMale0.70Survival function estimate1.00All-cause Mortality51525Years since diagnosisMertens, et al, JNCI 2008Cause of DeathRR*SMNCardiacPulmonaryOther causes2.93.31.42.095% CI2.12.00.71.3––––4.25.52.93.135* Adjusted for age, sex, year of dx, follow-up, anthracyclinedose, epidodophyllotoxin dose, Bleomycin doseThe Childhood Cancer Survivor Study
Second Neoplasms Among 5 YearSurvivors of Childhood Cancer25N 14,358 five-yearssurvivors of leukemia,lymphoma,neuroblastoma, CNS,bone, soft-tissue andkidney cancerCumulative Incidence2015 21% cumulative incidence ofsecond neoplasm at 30 years 8% cumulative incidence ofsecond malignancy at 30years Highest risks associated withfemale sex, treatment withradiation therapy, older ageat initial cancer diagnosis,earlier treatment era,diagnosis of plasm5(SEER defined)05102030Years from Initial CancerD. Friedman et al, JNCI 2010The Childhood Cancer Survivor Study
Subsequent Neoplasm Among Long-termSurvivors of Childhood CancerCumulative2.94.515.74.22.83.26.38.0Abs. Excess gkinNonHodgkinWilmsNBLSTSarcomaBoneStandardized Incidence RatioIncidence (20 Yrs)876543210The Childhood Cancer Survivor Study
Subsequent Neoplasm Among Long-termSurvivors of Childhood CancerCumulative2.94.515.74.22.83.26.38.0Abs. Excess kinWilmsSTSarcomaBoneStandardized Incidence RatioIncidence (20 Yrs)876543210LeukemiaCNSNBLThe Childhood Cancer Survivor Study
Subsequent Neoplasm Among Long-termSurvivors of Childhood CancerCumulative2.94.515.74.22.83.26.38.0Abs. Excess kinWilmsSTSarcomaBoneStandardized Incidence RatioIncidence (20 Yrs)876543210LeukemiaCNSNBLThe Childhood Cancer Survivor Study
Distribution of Subsequent NeoplasmsOriginal Expanded Cohort (n 3115)LeukemiaLymphomaCNS - GlialCNS - Medullo/PNETCNS - MeningiomaCNS - OtherNMSCBreastBoneSTSThyroidOtherMelanomaTurcotte et al, manuscript in preparationThe Childhood Cancer Survivor Study
Second Neoplasms Occurring 5 yearsIncluding Nonmelanoma Skin Cancer30%RTReceived RT for first cancerCumulative incidence25%20%15%10%No RT5%0%510152025Years since diagnosis30The Childhood Cancer Survivor Study
RT Dose-Risk Relationship for SubsequentNeoplasmsInskip et al, Int J Radiat Oncol Biol Phys 2016The Childhood Cancer Survivor Study
RT Dose-Risk Relationship for SubsequentNeoplasmsInskip et al, Int J Radiat Oncol Biol Phys 2016The Childhood Cancer Survivor Study
Late Occurring Subsequent NeoplasmsSubsequent Neoplasms after 40 years of ageAge (years)Turcotte et al, JCO 2015The Childhood Cancer Survivor Study
Late Occurring Subsequent NeoplasmsSubsequent Neoplasms after 40 years of ageNo Radiation TherapyTurcotte et al, JCO 2015Radiation TherapyThe Childhood Cancer Survivor Study
Distribution of Subsequent Neoplasms(n 3115)LeukemiaLymphomaCNS - GlialCNS - Medullo/PNETCNS - MeningiomaCNS - OtherNMSCBreastBoneSTSThyroidOtherMelanomaTurcotte et al, manuscript in preparationThe Childhood Cancer Survivor Study
Brain Tumors Following Childhood CancerGlioma vs. Meningioma25GliomaMeningioma2015No. Cases10505 to 910 to 1415 to 1920 Time Since First Cancer (years)Neglia et al, JNCI 2006The Childhood Cancer Survivor Study
Brain Tumors Following Childhood CancerRisk by Radiation DoseNeglia et al, JNCI 2006The Childhood Cancer Survivor Study
Distribution of Subsequent Neoplasms(n 3115)LeukemiaLymphomaCNS - GlialCNS - Medullo/PNETCNS - MeningiomaCNS - OtherNMSCBreastBoneSTSThyroidOtherMelanomaTurcotte et al, manuscript in preparationThe Childhood Cancer Survivor Study
Cumulative IncidenceCumulative Incidence of Breast Cancer AmongSurvivors of Pediatric Hodgkin LymphomaHL Chest RTBRCA1BRCA2US PopulationAge (years)Moskowitz et al, J Clin Oncol 2014The Childhood Cancer Survivor Study
Cumulative IncidenceCumulative Incidence of Breast Cancer AmongSurvivors of Pediatric Hodgkin LymphomaHL Chest RTBRCA1BRCA2US PopulationAge (years)Moskowitz et al, J Clin Oncol 2014The Childhood Cancer Survivor Study
Dose-Risk Relationship for Tissue-SpecificRadiation Exposure and Breast Cancer20 Linear dose-response forsecondary breast cancer 11-fold increased risk at40 Gy (compared to no RT)10 Age at RT exposure not arisk factor for breast cancer5 Risk of breast cancermarkedly reduced forwomen with 5 Gy ovarianRTOvarian dose 5 GyRatio15OddsTotalOvarian dose 5 Gy001020304050Dose to breast (Gy)Inskip,et al JCO 2009The Childhood Cancer Survivor Study
Radiation-Associated Risk of Breast Cancerin Childhood Cancer Survivors20Ovarian dose 5 GyOdds ratio15Total105Ovarian dose 5 Gy001020304050Dose to breast (Gy)Inskip,et al JCO 2009The Childhood Cancer Survivor Study
Risk of Secondary Breast Cancer FollowingSpinal Field RadiationMoskowitz et al, Radiat Oncol 2015The Childhood Cancer Survivor Study
Distribution of Subsequent Neoplasms(n 3115)LeukemiaLymphomaCNS - GlialCNS - Medullo/PNETCNS - MeningiomaCNS - OtherNMSCBreastBoneSTSThyroidOtherMelanomaTurcotte et al, manuscript in preparationThe Childhood Cancer Survivor Study
Thyroid Malignancy Among Long-termSurvivors of Childhood CancerDose Response Models of Relative RiskLinearLinear Exponential1 0.5117(dose)1 [1.316(dose)]e[- 0.00189(dose x dose)35Relative Risk3025201510500102030405060Dose in GySigurdson et al, Lancet 2005The Childhood Cancer Survivor Study
Distribution of Subsequent Neoplasms(n 3115)LeukemiaLymphomaCNS - GlialCNS - Medullo/PNETCNS - MeningiomaCNS - OtherNMSCBreastBoneSTSThyroidOtherMelanomaTurcotte et al, manuscript in preparationThe Childhood Cancer Survivor Study
Childhood Cancer Survivor Study6.06.0Subsequent NeoplasmsBCC4.00.02.0Cumulative Incidence [%]4.02.00.0Cumulative Incidence [%]ALL NMSC5.010.015.020.025.0Years Since DiagnosisPerkins et al, JCO 200530.0SCC5.010.015.020.025.030.0Years Since DiagnosisThe Childhood Cancer Survivor Study
8.0Cumulative Incidence of Nonmelanoma Skin Cancer6.0MaleRTRTMale6.04.02.0Cumulative Incidence [%]2.04.0FemaleNo RT0.0No RT0.0IncidenceCumulative[%] [%]Cumulative IncidenceFemale5.010.0 15.0 20.0 25.0Years Since DiagnosisYears Since DiagnosisPerkins et al, JCO 200530.05.010.015.020.025.030.0Years SinceSince DiagnosisYearsDiagnosisThe Childhood Cancer Survivor Study
Radiation-related Risk of Basal Cell CarcinomaWatt et al, JNCI 2011The Childhood Cancer Survivor Study
Race Specific Radiation-Associated Second NeoplasmsLiu et al, JCO 2016The Childhood Cancer Survivor Study
Race Specific Radiation-Associated Second NeoplasmsSt. Jude Lifetime Cohort StudyEhrhardt et al, CEBP 2016The Childhood Cancer Survivor Study
Gaps in Knowledge Regarding Long-termRadiation-Associated Cancer RisksCumulative Incidence1.00Cancer SurvivorPopulationGeneralPopulation.75?.50Advanced Onset ofRadiation-associatedNeoplasm.2510203040506070 Role of lifestylefactorsAge (Years)KnownEmerging Geneticcontributions torisk Radiation enceofRadiationassociatedNeoplasms Newer treatmenttechniques (IMRT,Proton)Unknown
Childhood Cancer Survivor StudyA RESOURCE FOR RESEARCH The Childhood Cancer Survivor Study is anNCI-funded resource to promote and facilitateresearch among long-term survivors of cancerdiagnosed during childhood and adolescence. Investigators interested in potential uses ofthis resource are encouraged to visit:www.stjude.org/ccss
diagnosis of Hodgkin lymphoma. Years from Initial Cancer 5 10 20 30 0 5 10 15 idence 20 25 N 14,358 five-years survivors of leukemia, lymphoma, neuroblastoma, CNS, bone, soft-tissue and kidney cancer Second Neoplasm Second Malignant Neoplasm (SEER defined) D. Friedman et al, JNCI 2010 The Childhood Cancer Survivor Study Second Neoplasms Among .
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