Hypofractionated accelerated radiation dose-painting (HARD) improves outcomes in unresected soft-tissue sarcoma

Soft tissue sarcomas (STS) are radioresistant with a low α/β, which may have a biologic benefit with hypofractionation. For unresectable STS, the dose escalation required to achieve durable control is often limited by long-term toxicity risk. We sought to compare an isotoxic approach utilizing hypofractionated accelerated radiation dose-painting (HARD) versus standard fractionated radiation therapy (SFT) in patients with unresected STS. We conducted a retrospective analysis of patients with unresected STS who received either HARD (n = 49) or SFT (n = 43) with photon-based therapy between 1990 and 2022. The 2 HARD regimens each use 3 dose levels based on risk of disease burden. The gross disease, intermediate risk, and low-risk clinical target volumes were treated with either 20-22 fractions of 3/2.5/2-2.2 Gy or 28 fractions of 2.5/2.2/1.8 Gy. SFT included patients treated with definitive intent, receiving ≥ 50 Gy in 1.8-2 Gy per fraction. Clinical endpoints included 3-year local control (LC), overall survival (OS), and progression-free survival (PFS), along with treatment-related toxicity. With a median age of 67 and tumor size of 7 cm, most patients were stage IV (37 %), grade 3 (67 %), had no concurrent systemic therapy (70 %), and were lower extremity tumors (24 %). HARD cohort consisted of higher age, stage, recurrent disease, and median BED₄ (p < 0.05), when compared to SFT. With a median follow-up of 35.9 months, HARD demonstrated significant improvement in 3-year LC (96.4 % vs. 48.4 %, p < 0.001), compared to SFT overall, with a median PFS benefit (16 vs. 10 months, p = 0.037) for non-distantly metastatic patients at baseline. On multivariate analysis, HARD was significantly associated with improved LC (HR 0.058, 95 % CI 0.005-0.682, p = 0.024). The HARD regimen found no significant increase in toxicity, with limited acute grade 3 (24 %, all dermatitis) and late grade 3 toxicity (6 %) observed, with no grade 4 or 5 events. HARD regimen significantly improves LC for unresectable STS without a significant increase in toxicity, when compared to a standard fractionated approach, supporting further prospective investigation of this treatment approach.