title: Risk of subsequent malignant neoplasms in long-term hereditary retinoblastoma survivors after chemotherapy and radiotherapy.
abstract: OBJECTIVE
  Hereditary retinoblastoma (Rb) survivors have increased risk of subsequent malignant neoplasms (SMNs). Previous studies reported elevated radiotherapy (RT) -related SMN risks, but less is known about chemotherapy-related risks.
  
  
  METHODS
  In a long-term follow-up study of 906 5-year hereditary Rb survivors diagnosed from 1914 to 1996 and observed through 2009, treatment-related SMN risks were quantified using cumulative incidence analyses and multivariable Cox proportional hazards regression models with age as the underlying time scale.
  
  
  RESULTS
  Nearly 90% of Rb survivors were treated with RT, and almost 40% received alkylating agent (AA) -containing chemotherapy (predominantly triethylenemelamine). Median follow-up time to first SMN diagnosis was 26.3 years. Overall SMN risk was not significantly elevated among survivors receiving AA plus RT versus RT without chemotherapy (hazard ratio [HR], 1.27; 95% CI, 0.99 to 1.63). AA-related risks were significantly increased for subsequent bone tumors (HR, 1.60; 95% CI, 1.03 to 2.49) and leiomyosarcoma (HR, 2.67; 95% CI, 1.22 to 5.85) but not for melanoma (HR, 0.74; 95% CI, 0.36 to 1.55) or epithelial tumors (HR, 0.89; 95% CI, 0.48 to 1.64). Leiomyosarcoma risk was significantly increased for survivors who received AAs at age < 1 (HR, 5.17; 95% CI, 1.76 to 15.17) but not for those receiving AAs at age ≥ 1 year (HR, 1.75; 95% CI, 0.68 to 4.51). Development of leiomyosarcoma was significantly more common after AA plus RT versus RT (5.8% v 1.6% at age 40 years; P = .01).
  
  
  CONCLUSIONS
  This comprehensive quantification of SMN risk after chemotherapy and RT among hereditary Rb survivors also demonstrates an AA-related contribution to risk. Although triethylenemelamine is no longer prescribed, our findings warrant further follow-up to investigate potential SMN risks associated with current chemotherapies used for Rb.
authors.affiliation: Jeannette R. Wong, Lindsay M. Morton, Margaret A. Tucker, Joshua N. Sampson, and Ruth A. Kleinerman, National Cancer Institute, Bethesda, MD; David H. Abramson, Memorial Sloan-Kettering Cancer Center, New York, NY; and Johanna M. Seddon, Tufts-New England Medical Center, Boston, MA.
authors.forename: Jeannette R
authors.initials: JR
authors.lastname: Wong
authors.affiliation: Jeannette R. Wong, Lindsay M. Morton, Margaret A. Tucker, Joshua N. Sampson, and Ruth A. Kleinerman, National Cancer Institute, Bethesda, MD; David H. Abramson, Memorial Sloan-Kettering Cancer Center, New York, NY; and Johanna M. Seddon, Tufts-New England Medical Center, Boston, MA.
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: Morton
authors.affiliation: Jeannette R. Wong, Lindsay M. Morton, Margaret A. Tucker, Joshua N. Sampson, and Ruth A. Kleinerman, National Cancer Institute, Bethesda, MD; David H. Abramson, Memorial Sloan-Kettering Cancer Center, New York, NY; and Johanna M. Seddon, Tufts-New England Medical Center, Boston, MA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Tucker
authors.affiliation: Jeannette R. Wong, Lindsay M. Morton, Margaret A. Tucker, Joshua N. Sampson, and Ruth A. Kleinerman, National Cancer Institute, Bethesda, MD; David H. Abramson, Memorial Sloan-Kettering Cancer Center, New York, NY; and Johanna M. Seddon, Tufts-New England Medical Center, Boston, MA.
authors.forename: David H
authors.initials: DH
authors.lastname: Abramson
authors.affiliation: Jeannette R. Wong, Lindsay M. Morton, Margaret A. Tucker, Joshua N. Sampson, and Ruth A. Kleinerman, National Cancer Institute, Bethesda, MD; David H. Abramson, Memorial Sloan-Kettering Cancer Center, New York, NY; and Johanna M. Seddon, Tufts-New England Medical Center, Boston, MA.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Seddon
authors.affiliation: Jeannette R. Wong, Lindsay M. Morton, Margaret A. Tucker, Joshua N. Sampson, and Ruth A. Kleinerman, National Cancer Institute, Bethesda, MD; David H. Abramson, Memorial Sloan-Kettering Cancer Center, New York, NY; and Johanna M. Seddon, Tufts-New England Medical Center, Boston, MA.
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Sampson
authors.affiliation: Jeannette R. Wong, Lindsay M. Morton, Margaret A. Tucker, Joshua N. Sampson, and Ruth A. Kleinerman, National Cancer Institute, Bethesda, MD; David H. Abramson, Memorial Sloan-Kettering Cancer Center, New York, NY; and Johanna M. Seddon, Tufts-New England Medical Center, Boston, MA. kleinerr@exchange.nih.gov.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Kleinerman
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008137:Longitudinal Studies; D008297:Male; D016609:Neoplasms, Second Primary / Q000453:epidemiology*; D019572:Retinal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D012175:Retinoblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D012189:Retrospective Studies; D012306:Risk; D015996:Survival Rate; D017741:Survivors; D014265:Triethylenemelamine / Q000009:adverse effects; D014481:United States / Q000453:epidemiology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014265:Triethylenemelamine