Abstract
OBJECTIVE: Radiation-associated sarcomas (RAS) and in-volume recurrent sarcomas (IRS) are significant therapeutic challenges due to prior radiotherapy (RT) exposure and the risks associated with re-irradiation. The aim of this study was to evaluate the safety and efficacy of moderately hypofractionated RT combined with locoregional hyperthermia (HT) in patients with RAS/IRS. METHODS: A prospective, proof-of-concept, single-arm, phase II clinical trial (NCT04398095) was conducted in which 20 patients with locally advanced RAS/IRS of the extremities and trunk wall were enrolled. Treatment consisted of RT at 36 Gy in 12 fractions over three weeks, combined with at least weekly HT sessions. Unresectable tumors received an integrated boost to 42 Gy. The primary endpoint was grade 3 or higher late toxicity according to the Common Terminology Criteria for Adverse Events version 5.0 at 18 months, while secondary endpoints included local control, progression-free survival (PFS), and cancer-specific survival (CSS). RESULTS: Median follow-up was 48.9 months. No patient developed grade ≥ 3 late toxicity. Seven patients (35%) experienced local progression. No local progression was observed in the unresectable group treated with integrated boost. All tumors showed radiologic response (partial or stable disease). We observed up to 10% viable tumor cells in the postoperative specimens of five of the 12 patients who underwent surgery. One- and two-year PFS were 70% and 45%, respectively; CSS was 95% and 90%, respectively. CONCLUSIONS: Moderately hypofractionated RT with HT is a safe approach for RAS/IRS reirradiation. Dose escalation may improve local control and warrants further investigation in larger studies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13014-025-02772-y.