Clinical outcomes and toxicity after proton- versus photon-based spatially fractionated radiotherapy for soft-tissue sarcoma: a retrospective cohort

Introduction Spatially fractionated radiotherapy (SFRT) enables focal dose escalation in bulky/high-grade STS. Proton SFRT, leveraging its Bragg peak, reduces low-dose exposure but may increase proximal skin dose, potentially influencing perioperative wound complications. Comparative data remain limited. Methods We retrospectively reviewed 37 high-grade or bulky STS patients (2009–2023) treated with preoperative SFRT (photon or proton GRID/Lattice) followed by conventional fractionated radiotherapy (CFRT) and surgery. Toxicities (including major wound complications per NCIC criteria) and oncologic outcomes were analyzed using Fisher’s exact tests and Kaplan–Meier. Results Median follow-up was 40 months. Sixteen patients (43.2%) received proton SFRT; all received CFRT (median: 50.4 Gy). Major wound complications 6/16 (37.5%) proton SFRT vs 8/21 (38.1%) photon SFRT patients, with no significant difference (P = 1.000). Acute grade 2-3 (6/16 vs 11/21) and late (3/16 vs 9/21) toxicities did not differ significantly between modalities; no grade 4 or 5 toxicities occurred. Major pathological response (MPR, ≥80% necrosis) was achieved in 12/35 evaluable patients (34.3%) and was not associated with SFRT type (P = 0.489). In exploratory analysis, MPR was associated with longer disease-free survival (median 80 vs. 27 months, P = 0.014). Proton SFRT plans had significantly higher dose heterogeneity (D90/D10 = 0.038 vs 0.093, P = 0.04). Discussion In this largest-to-date retrospective cohort of neoadjuvant proton- versus photon-based SFRT + CFRT for STS, no statistically significant differences in perioperative or skin toxicity were observed, and MPR (≥80% necrosis) occurred in 34.3% of evaluable patients; given the small, non-randomized sample these results should be considered hypothesis-generating.