title: Risk of second malignancies in survivors of retinoblastoma: more than 40 years of follow-up.
abstract: BACKGROUND
  Survivors of hereditary retinoblastoma have an elevated risk of developing second malignancies, but data on the risk in middle-aged retinoblastoma survivors (ie, those with more than 40 years of follow-up) are scarce.
  
  
  METHODS
  Data from the Dutch retinoblastoma registry were used to analyze risks of second malignancies in 668 retinoblastoma survivors, diagnosed from 1945 to 2005 (median age = 24.9 years) and classified as having had hereditary or nonhereditary disease based on the presence of family history, bilateral disease, or a germline RB1 mutation. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) of subsequent cancers in patients with hereditary and nonhereditary disease were estimated by comparison with Dutch sex-, age-, and calendar year-specific rates. Multivariable Cox regression and competing risk analyses were used to determine associations of treatment with risks of second malignancies. All statistical tests were two-sided.
  
  
  RESULTS
  After a median follow-up of 21.9 years, the risk of second malignancies in survivors of hereditary retinoblastoma (SIR = 20.4, 95% confidence interval [CI] = 15.6 to 26.1) far exceeded the risk of survivors of nonhereditary retinoblastoma (SIR = 1.86, 95% CI = 0.96 to 3.24). Among patients with hereditary disease, treatment with radiotherapy was associated with a further increase in the risk of a subsequent cancer (hazard ratio = 2.81, 95% CI = 1.28 to 6.19). After 30 years of follow-up, elevated risks of epithelial cancers (lung, bladder, and breast) were observed among survivors of hereditary retinoblastoma. After 40 years of follow-up, the AER of a second malignancy among survivors of hereditary retinoblastoma had increased to 26.1 excess cases per 1000 person-years. The cumulative incidence of any second malignancy 40 years after retinoblastoma diagnosis was 28.0% (95% CI = 21.0% to 35.0%) for patients with hereditary disease.
  
  
  CONCLUSIONS
  Our analysis of middle-aged hereditary retinoblastoma survivors suggests that these individuals have an excess risk of epithelial cancer. Lifelong follow-up studies are needed to evaluate the full spectrum of subsequent cancer risk in hereditary retinoblastoma survivors.
authors.affiliation: Department of Ophthalmology, VU University Medical Center, de Boelelaan 1117, 1007 MB Amsterdam, the Netherlands. t.marees@vumc.nl
authors.forename: Tamara
authors.initials: T
authors.lastname: Marees
authors.forename: Annette C
authors.initials: AC
authors.lastname: Moll
authors.forename: Saskia M
authors.initials: SM
authors.lastname: Imhof
authors.forename: Michiel R
authors.initials: MR
authors.lastname: de Boer
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ringens
authors.forename: Flora E
authors.initials: FE
authors.lastname: van Leeuwen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology; D002277:Carcinoma / Q000453:epidemiology* / Q000209:etiology; D016001:Confidence Intervals; D015986:Confounding Factors, Epidemiologic; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D015994:Incidence; D008175:Lung Neoplasms / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016609:Neoplasms, Second Primary / Q000453:epidemiology* / Q000209:etiology; D009426:Netherlands / Q000453:epidemiology; D016017:Odds Ratio; D016016:Proportional Hazards Models; D011878:Radiotherapy / Q000009:adverse effects; D012042:Registries; D019572:Retinal Neoplasms / Q000453:epidemiology* / Q000235:genetics / Q000532:radiotherapy; D012175:Retinoblastoma / Q000453:epidemiology* / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics; D018570:Risk Assessment; D012307:Risk Factors; D017741:Survivors / Q000706:statistics & numerical data*; D013997:Time Factors; D001749:Urinary Bladder Neoplasms / Q000453:epidemiology; D055815:Young Adult
chemical_list: D016160:Retinoblastoma Protein