Cancer treatments-related factors for subsequent soft-tissue sarcoma in childhood cancer survivors

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.