title: Dose-effect relationships for adverse events after cranial radiation therapy in long-term childhood cancer survivors.
abstract: OBJECTIVE
  To evaluate the prevalence and severity of clinical adverse events (AEs) and treatment-related risk factors in childhood cancer survivors treated with cranial radiation therapy (CRT), with the aim of assessing dose-effect relationships.
  
  
  METHODS
  The retrospective study cohort consisted of 1362 Dutch childhood cancer survivors, of whom 285 were treated with CRT delivered as brain irradiation (BI), as part of craniospinal irradiation (CSI), and as total body irradiation (TBI). Individual CRT doses were converted into the equivalent dose in 2-Gy fractions (EQD(2)). Survivors had received their diagnoses between 1966 and 1996 and survived at least 5 years after diagnosis. A complete inventory of Common Terminology Criteria for Adverse Events grade 3.0 AEs was available from our hospital-based late-effect follow-up program. We used multivariable logistic and Cox regression analyses to examine the EQD(2) in relation to the prevalence and severity of AEs, correcting for sex, age at diagnosis, follow-up time, and the treatment-related risk factors surgery and chemotherapy.
  
  
  RESULTS
  There was a high prevalence of AEs in the CRT group; over 80% of survivors had more than 1 AE, and almost half had at least 5 AEs, both representing significant increases in number of AEs compared with survivors not treated with CRT. Additionally, the proportion of severe, life-threatening, or disabling AEs was significantly higher in the CRT group. The most frequent AEs were alopecia and cognitive, endocrine, metabolic, and neurologic events. Using the EQD(2), we found significant dose-effect relationships for these and other AEs.
  
  
  CONCLUSIONS
  Our results confirm that CRT increases the prevalence and severity of AEs in childhood cancer survivors. Furthermore, analyzing dose-effect relationships with the cumulative EQD(2) instead of total physical dose connects the knowledge from radiation therapy and radiobiology with the clinical experience.
authors.affiliation: Department of Radiation Oncology, Academic Medical Center, Amsterdam, The Netherlands. i.w.vandijk@amc.uva.nl
authors.forename: Irma W E M
authors.initials: IW
authors.lastname: van Dijk
authors.forename: Mathilde C
authors.initials: MC
authors.lastname: Cardous-Ubbink
authors.forename: Helena J H
authors.initials: HJ
authors.lastname: van der Pal
authors.forename: Richard C
authors.initials: RC
authors.lastname: Heinen
authors.forename: Flora E
authors.initials: FE
authors.lastname: van Leeuwen
authors.forename: Foppe
authors.initials: F
authors.lastname: Oldenburger
authors.forename: Rob M
authors.initials: RM
authors.lastname: van Os
authors.forename: Cécile M
authors.initials: CM
authors.lastname: Ronckers
authors.forename: Antoinette Y N
authors.initials: AY
authors.lastname: Schouten-van Meeteren
authors.forename: Huib N
authors.initials: HN
authors.lastname: Caron
authors.forename: Caro C E
authors.initials: CC
authors.lastname: Koning
authors.forename: Leontien C M
authors.initials: LC
authors.lastname: Kremer
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D016371:Cranial Irradiation / Q000009:adverse effects*; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006258:Head and Neck Neoplasms / Q000453:epidemiology / Q000209:etiology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009381:Neoplasms, Radiation-Induced / Q000453:epidemiology; D016609:Neoplasms, Second Primary / Q000453:epidemiology / Q000209:etiology; D015995:Prevalence; D011832:Radiation Injuries / Q000453:epidemiology; D012044:Regression Analysis; D012189:Retrospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index; D017741:Survivors; D014916:Whole-Body Irradiation / Q000009:adverse effects; D055815:Young Adult