Cancer treatments-related factors for subsequent soft-tissue sarcoma in childhood cancer survivors.
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BACKGROUND: Previous studies of risk factors for subsequent soft-tissue sarcoma (STS) among childhood cancer survivors had small numbers and were unable to comprehensively investigate the dose-response relationships with radiation from radiotherapy and with cumulative exposure to specific cytotoxics. PATIENTS AND METHODS: We conducted a nested case-control study, encompassing 275 subsequent STS cases and 275 matched controls, within the Pan-European cohort of 69 460 5-year survivors from 12 countries. Odds ratios (ORs) and 95% confidence intervals (CIs) for subsequent STS were calculated for different levels of radiation dose to the STS location (in Gy) and for cumulative doses of specific chemotherapeutic agents (in g/m2). Additionally, excess ORs per Gy (EOR/Gy) or per g/m2 (EOR/g/m2) were calculated to assess dose-response relationships. RESULTS: The OR for subsequent STS was 22-fold [95% CI 6.9-95.4] higher in soft tissue exposed to ≥30 Gy and remained in excess with exposure to 5-9 Gy [OR = 3.8, 95% CI 1.3-12.0] compared with no radiation. The EOR/Gy was 0.86 [95% CI 0.35-2.16], with a particularly high risk observed in survivors of neuroblastoma [EOR/Gy = 5.52, 95% CI 0.71-52.31] or bone sarcoma [EOR/Gy = 4.16, 95% CI 0.40-24.72], and in females [EOR/Gy = 2.35; 95% CI 0.65-8.14]. For patients who had received a cumulative procarbazine dose of ≥6.0 g/m2, the OR was 4.7 [95% CI 1.3-25.1] compared with non-exposure after controlling for radiation. No association was found for other alkylating agents or other specific cytotoxic drugs. CONCLUSION: Although high radiation doses remain the primary risk factor for secondary STS, our findings suggest a possible increase in risk at lower doses (5-9 Gy) and following procarbazine treatment among childhood cancer survivors. These observations warrant further investigation and may merit consideration in treatment planning and long-term follow-up guidelines for cancer survivors.