Neoadjuvant chemotherapy for soft‐tissue sarcoma of the extremities: A post‐hoc Sarculator‐based risk analysis of the EORTC 62961–ESHO 95 randomized trial

BACKGROUND: In the EORTC 62961-ESHO 95 randomized trial (European Organization for Research and Treatment 62961-European Society of Hyperthermia Oncology 95; ClinicalTrials.gov identifier NCT00003052), neoadjuvant chemotherapy (NAC) combined with regional hyperthermia (RHT) improved survival in patients with soft tissue sarcoma (tumor size >5 cm, grade 2 or 3, deep location). This study investigated the survival benefit of NAC + RHT in a subgroup of patients who had extremity soft tissue sarcoma (ESTS) according to risk predictions using the Sarculator nomogram. METHODS: Overall survival (OS) was predicted with the Sarculator nomogram using baseline prognostic parameters. Kaplan-Meier analysis was used to estimate observed OS. A bivariable Cox model including the Sarculator score, treatment, and their interaction was fitted. Hazard ratios for OS were calculated for each decile of the Sarculator risk distribution. RESULTS: Of 143 patients with ESTS, 135 were analyzed (NAC, n = 70; NAC + RHT, n = 65) with a median follow-up of 136 months (interquartile range, 110-183 months). Survival in the NAC + RHT group exceeded Sarculator predictions and improved compared with the group that received NAC alone (hazard ratio, 0.67; 95% confidence interval, 0.39-1.17; p = .081), with an absolute 5-year OS difference of 15.6% (95% confidence interval, 0.0%-31.4%). Risk stratification suggested greater benefit of NAC + RHT as predicted OS decreased. However, the interaction between Sarculator score and treatment was not significant (p = .495). CONCLUSIONS: This analysis of ESTS from a randomized trial confirmed the previously reported OS benefit by adding RHT to NAC. Although patients with higher predicted risk seemed to benefit more from the combined treatment, these findings do not suggest that treatment decisions should be based on risk estimates alone, supporting the use of RHT combined with chemotherapy in patients who have primary ESTS. In a previous clinical trial, adding regional hyperthermia—targeted heating of the tumor area—to standard chemotherapy before surgery improved long‐term survival for patients with high‐risk soft tissue sarcomas. In this study, the authors re‐analyzed data from that trial using the Sarculator, a modern tool that predicts a patient’s individual risk. The authors observed that patients across all risk levels—but within the trial's high‐risk inclusion criteria—tended to live longer when hyperthermia was added to chemotherapy, with the greatest benefit seen in higher risk patients. These results support using hyperthermia as part of treatment for patients who have newly diagnosed extremity sarcomas.