title: High risk of symptomatic cardiac events in childhood cancer survivors.
abstract: OBJECTIVE
  To evaluate the long-term risk for validated symptomatic cardiac events (CEs) and associated risk factors in childhood cancer survivors (CCSs).
  
  
  METHODS
  We determined CEs grade 3 or higher: congestive heart failure (CHF), cardiac ischemia, valvular disease, arrhythmia and/or pericarditis (according to Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) in a hospital-based cohort of 1,362 5-year CCSs diagnosed between 1966 and 1996. We calculated both marginal and cause-specific cumulative incidence of CEs and cause-specific cumulative incidence of separate events. We analyzed different risk factors in multivariable Cox regression models.
  
  
  RESULTS
  Overall, 50 CEs, including 27 cases of CHF, were observed in 42 survivors (at a median attained age of 27.1 years). The 30-year cause-specific cumulative incidence of CEs was significantly increased after treatment with both anthracyclines and cardiac irradiation (12.6%; 95% CI, 4.3% to 20.3%), after anthracyclines (7.3%; 95% CI, 3.8% to 10.7%), and after cardiac irradiation (4.0%; 95% CI, 0.5% to 7.4%) compared with other treatments. In the proportional hazards analyses, anthracycline (dose), cardiac irradiation (dose), combination of these treatments, and congenital heart disease were significantly associated with developing a CE. We demonstrated an exponential relationship between the cumulative anthracycline dose, cardiac irradiation dose, and risk of CE.
  
  
  CONCLUSIONS
  CCSs have a high risk of developing symptomatic CEs at an early age. The most common CE was CHF. Survivors treated with both anthracyclines and radiotherapy have the highest risk; after 30 years, one in eight will develop severe heart disease. The use of potentially cardiotoxic treatments should be reconsidered for high-risk groups, and frequent follow-up for high-risk survivors is needed.
authors.affiliation: Emma Children’s Hospital/Academic Medical Centre, Amsterdam, the Netherlands. h.j.vanderpal@amc.uva.nl
authors.forename: Helena J
authors.initials: HJ
authors.lastname: van der Pal
authors.forename: Elvira C
authors.initials: EC
authors.lastname: van Dalen
authors.forename: Evelien
authors.initials: E
authors.lastname: van Delden
authors.forename: Irma W
authors.initials: IW
authors.lastname: van Dijk
authors.forename: Wouter E
authors.initials: WE
authors.lastname: Kok
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Geskus
authors.forename: Elske
authors.initials: E
authors.lastname: Sieswerda
authors.forename: Foppe
authors.initials: F
authors.lastname: Oldenburger
authors.forename: Caro C
authors.initials: CC
authors.lastname: Koning
authors.forename: Flora E
authors.initials: FE
authors.lastname: van Leeuwen
authors.forename: Huib N
authors.initials: HN
authors.lastname: Caron
authors.forename: Leontien C
authors.initials: LC
authors.lastname: Kremer
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology*; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008297:Male; D015999:Multivariate Analysis; D009369:Neoplasms / Q000188:drug therapy* / Q000453:epidemiology / Q000532:radiotherapy*; D009426:Netherlands / Q000453:epidemiology; D018579:Patient Selection; D016016:Proportional Hazards Models; D011832:Radiation Injuries / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology*; D011878:Radiotherapy / Q000009:adverse effects; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D017741:Survivors; D013997:Time Factors; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents