# From Intensification to Optimization: Balancing Efficacy, Safety, and Costs in High-Risk Localized Soft Tissue Sarcomas

## TL;DR

This study compares optimized radiotherapy with intensified treatment for soft tissue sarcomas, finding similar survival with fewer side effects and shorter treatment times.

## Contribution

The study introduces a streamlined ultra-hypofractionated radiotherapy protocol as a more practical and safer alternative to intensified treatment regimens.

## Key findings

- The optimized uhpRT protocol achieved comparable survival rates to intensified pembrolizumab treatment.
- uhpRT significantly reduced treatment-related toxicities and shortened treatment duration.
- Outcomes exceeded those of the control arm in the SU2C-SARC032 trial.

## Abstract

Soft tissue sarcomas (STS) are rare, aggressive cancers that require carefully balanced treatment strategies to improve survival without excessive side effects. Standard treatment for high-risk localized STS typically includes preoperative radiotherapy and surgery. Recent trials have explored intensifying treatment by adding immunotherapy (e.g., pembrolizumab), but these approaches often lead to increased toxicity, prolonged treatment times, and higher healthcare demands. In this study, we evaluated an optimized, short-course preoperative ultra-hypofractionated radiotherapy (uhpRT) using real-world data, highlighting differences between outcomes achieved under everyday clinical conditions versus highly standardized trial environments. Comparing our outcomes with those from a recent randomized controlled trial (SU2C-SARC032) that tested intensified therapy with pembrolizumab, our streamlined uhpRT protocol achieved similar survival outcomes while markedly reducing toxicity, treatment duration, and resource utilization. Our results underline the importance of therapeutic optimization, emphasizing efficacy, safety, and real-world applicability over routine intensification.

Background/Objectives: The SU2C-SARC032 randomized controlled trial (RCT) tested pembrolizumab combined with preoperative normofractionated radiotherapy as an intensified treatment for high-risk stage III resectable soft tissue sarcoma (STS), demonstrating a moderate improvement in disease-free survival (DFS) compared to preoperative radiotherapy alone, but accompanied by significantly increased toxicity, prolonged treatment durations, elevated resource source, and limited real-world applicability. To address the gap between highly controlled trial outcomes and routine clinical practice, this comparative analysis evaluated a streamlined ultra-hypofractionated preoperative radiotherapy (uhpRT) protocol using real-world data (RWD) as a potentially more balanced approach. Methods: Prospectively collected observational RWD from 54 consecutive patients with Stage III (T2 N0 M0) high-risk resectable STS treated at a single institution with uhpRT (25 Gy in 5 fractions in one week, no systemic therapy, median interval of 14 days to surgery) were analyzed. Survival endpoints (overall survival [OS], DFS, local disease-free survival [LDFS], distant disease-free survival [DDFS]), toxicity, and treatment duration were compared qualitatively with published outcomes from the SU2C-SARC032 trial’s intensified pembrolizumab arm and control arm. Results: At 2 years, the optimized uhpRT protocol achieved OS (90%), DFS (66%), and DDFS (70%) comparable to the intensified pembrolizumab arm (OS: 88%, DFS: 67%, DDFS (67%)) and clearly exceeded outcomes of the control arm (OS/DFS/DDFS: 85%/52%/52%). Importantly, the uhpRT protocol markedly reduced treatment-related toxicities (0% Grade 3/4 events vs. 56% in the intensified trial arm) and total treatment duration (<1 month vs. 3–11 months). Conclusions: These findings challenge the necessity of broad treatment intensification for high-risk localized STS, strongly supporting the concept of therapeutic optimization. Given substantial real-world variability in treatment practices and feasibility highlighted by recent research, our findings advocate for treatment strategies that prioritize realistic applicability, patient safety, and value-based care principles over pure intensification.