title: Radiation-Related New Primary Solid Cancers in the Childhood Cancer Survivor Study: Comparative Radiation Dose Response and Modification of Treatment Effects.
abstract: OBJECTIVE
  The majority of childhood cancer patients now achieve long-term survival, but the treatments that cured their malignancy often put them at risk of adverse health outcomes years later. New cancers are among the most serious of these late effects. The aims of this review are to compare and contrast radiation dose-response relationships for new solid cancers in a large cohort of childhood cancer survivors and to discuss interactions among treatment and host factors.
  
  
  METHODS
  This review is based on previously published site-specific analyses for subsequent primary cancers of the brain, breast, thyroid gland, bone and soft tissue, salivary glands, and skin among 12,268 5-year childhood cancer survivors in the Childhood Cancer Survivor Study. Analyses included tumor site-specific, individual radiation dose reconstruction based on radiation therapy records. Radiation-related second cancer risks were estimated using conditional logistic or Poisson regression models for excess relative risk (ERR).
  
  
  RESULTS
  Linear dose-response relationships over a wide range of radiation dose (0-50 Gy) were seen for all cancer sites except the thyroid gland. The steepest slopes occurred for sarcoma, meningioma, and nonmelanoma skin cancer (ERR/Gy > 1.00), with glioma and cancers of the breast and salivary glands forming a second group (ERR/Gy = 0.27-0.36). The relative risk for thyroid cancer increased up to 15-20 Gy and then decreased with increasing dose. The risk of thyroid cancer also was positively associated with chemotherapy, but the chemotherapy effect was not seen among those who also received very high doses of radiation to the thyroid. The excess risk of radiation-related breast cancer was sharply reduced among women who received 5 Gy or more to the ovaries.
  
  
  CONCLUSIONS
  The results suggest that the effect of high-dose irradiation is consistent with a linear dose-response for most organs, but they also reveal important organ-specific and host-specific differences in susceptibility and interactions between different aspects of treatment.
authors.affiliation: Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address: inskippeter@gmail.com.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Inskip
authors.affiliation: Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Alice J
authors.initials: AJ
authors.lastname: Sigurdson
authors.affiliation: Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Lene
authors.initials: L
authors.lastname: Veiga
authors.affiliation: Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Parveen
authors.initials: P
authors.lastname: Bhatti
authors.affiliation: Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Cécile
authors.initials: C
authors.lastname: Ronckers
authors.affiliation: Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Preetha
authors.initials: P
authors.lastname: Rajaraman
authors.affiliation: Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; The University of Oran School of Medicine, Algeria.
authors.forename: Houda
authors.initials: H
authors.lastname: Boukheris
authors.affiliation: Department of Radiation Physics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Stovall
authors.affiliation: Department of Radiation Physics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Susan
authors.initials: S
authors.lastname: Smith
authors.affiliation: Department of Laboratory Medicine and Pathology, Children's Hospital and Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Sue
authors.initials: S
authors.lastname: Hammond
authors.affiliation: University of Chicago Department of Pediatrics, Section of Hematology, Oncology and Stem Cell Transplantation, Chicago, Illinois.
authors.forename: Tara O
authors.initials: TO
authors.lastname: Henderson
authors.affiliation: Department of Pediatric Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Tanya C
authors.initials: TC
authors.lastname: Watt
authors.affiliation: Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta/Emory University, Atlanta, Georgia.
authors.forename: Ann C
authors.initials: AC
authors.lastname: Mertens
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Wendy
authors.initials: W
authors.lastname: Leisenring
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Kayla
authors.initials: K
authors.lastname: Stratton
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: John
authors.initials: J
authors.lastname: Whitton
authors.affiliation: Stanford University Medical Center, Stanford, California.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Donaldson
authors.affiliation: Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Armstrong
authors.affiliation: Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Leslie L
authors.initials: LL
authors.lastname: Robison
authors.affiliation: Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Neglia
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000970:Antineoplastic Agents / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D009381:Neoplasms, Radiation-Induced; D016609:Neoplasms, Second Primary / Q000209:etiology*; D011879:Radiotherapy Dosage; D012737:Sex Factors; D017741:Survivors; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents