Secondary sarcomas in childhood cancer survivors: a report from the Childhood Cancer Survivor Study

Abstract

Background: Childhood cancer survivors are at increased risk for the development of secondary sarcomas. Exposure to radiation therapy is a known risk factor for the development of these sarcomas. Other risk factors for secondary sarcomas have not been well described for childhood cancer survivors. We analyzed a large cohort of childhood cancer survivors to determine the true incidence of secondary sarcomas and to examine factors associated with the risk of developing secondary sarcomas.

Methods: The history of secondary sarcomas in 14,372 participants in the Childhood Cancer Survivor Study was determined from self-reports in three questionnaires. Risk of secondary sarcoma was evaluated by use of standardized incidence ratios (SIRs) and excess absolute risks (EARs) as calculated by use of data from the Surveillance, Epidemiology, and End Results Program. Cox regression models were used to estimate hazard ratios of developing subsequent sarcomas. Hazard ratios were reported as relative risks (RRs).

Results: We identified 108 patients with sarcomas that were diagnosed a median of 11 years after the diagnosis of childhood cancer. The risk of sarcoma was more than ninefold higher among childhood cancer survivors than among the general population (SIR = 9.02, 95% confidence interval [CI] = 7.44 to 10.93). The excess absolute risk of secondary sarcoma was 32.5 per 100,000 person-years (95% CI = 26.1 to 40.3 per 100,000 person-years). Higher standardized incidence ratios and excess absolute risks were associated with young age at primary diagnosis, primary sarcoma diagnosis, and a family history of cancer. In a multivariable model, increased risk of secondary sarcoma was associated with radiation therapy (RR = 3.1, 95% CI = 1.5 to 6.2), with a primary diagnosis of sarcoma (RR = 10.1, 95% CI = 4.7 to 21.8), with a history of other secondary neoplasms (RR = 2.2, 95% CI = 1.1 to 4.5), and with treatment with higher doses of anthracyclines (RR = 2.3, 95% CI = 1.2 to 4.3) or alkylating agents (RR = 2.2, 95% CI = 1.1 to 4.6).

Conclusion: Childhood cancer survivors appear to be at increased risk for secondary sarcomas compared with general population rates.

Fig. 1.

Cumulative incidence curves of all secondary sarcomas in the Childhood Cancer Survivor Study. A) Stratified by exposure to radiation therapy (RT). No history of radiation exposure (No RT) curve: for 10 years, number of survivors at risk = 3840 and cumulative incidence = 0.10% (95% confidence interval [CI] = 0.00% to 0.20%); for 20 years, number of survivors at risk = 2039 and cumulative incidence = 0.24% (95% CI = 0.08% to 0.39%); for 30 years, number of survivors at risk = 238 and cumulative incidence = 0.46% (95% CI = 0.07% to 0.85%). History of radiation exposure (RT) curve: for 10 years, number of survivors at risk = 7775 and cumulative incidence = 0.37% (95% CI = 0.24% to 0.50%); for 20 years, number of survivors at risk = 5072 and cumulative incidence = 0.89% (95% CI = 0.68% to 1.10%); for 30 years, number of survivors at risk = 730 and cumulative incidence = 1.37% (95% CI = 0.97% to 1.78%). B) Stratified by primary diagnoses. Sarcoma curve: for 10 years, number of survivors at risk = 2231 and cumulative incidence = 0.71% (95% CI = 0.37% to 1.04%); for 20 years, number of survivors at risk = 1442 and cumulative incidence = 1.64% (95% CI = 1.12% to 2.16%); for 30 years, number of survivors at risk = 202 and cumulative incidence = 2.18% (95% CI = 1.32% to 3.03%). Hodgkin lymphoma curve: for 10 years, number of survivors at risk = 1758 and cumulative incidence = 0.75% (95% CI = 0.36% to 1.14%); for 20 years, number of survivors at risk = 1157 and cumulative incidence = 1.34% (95% CI = 0.81% to 1.87%); for 30 years, number of survivors at risk = 211 and cumulative incidence = 1.91% (95% CI = 1.01% to 2.80%). Other diagnoses curve: for 10 years, number of survivors at risk = 9283 and cumulative incidence = 0.10% (95% CI = 0.04% to 0.16%); for 20 years, number of survivors at risk = 5401 and cumulative incidence = 0.33% (95% CI = 0.21% to 0.45%); for 30 years, number of survivors at risk = 658 and cumulative incidence = 0.62% (95% CI = 0.31% to 0.92%).