The Landmark Series: Neoadjuvant Radiotherapy in Extremity Soft Tissue Sarcoma-The Way to Hypofractionation.

For patients with nonmetastatic soft tissue sarcoma (STS) who are at high risk of local recurrence, the standard of care for limb-conserving local management is combined radiotherapy and surgery. Radiotherapy for STS entails 5 weeks of conventionally fractionated radiotherapy (25 × 2 Gy) preoperatively or 6 or more weeks postoperatively. There is growing interest in the use of preoperative hypofractionated regimes, viz. shorter courses with higher daily doses, for STS. Recent studies have investigated ultrahypofractionation (UHF, ≥ 5 Gy per fraction) and moderate hypofractionation (MHF, > 2 Gy but < 5 Gy per fraction) for STS. Regimens that are designed to be isoeffective for tumor control indeed result in equivalent local relapse-free survival. However, as the daily dose increases, the impacts to normal tissues and potential for toxicities increase owing to differences in fraction-size sensitivity between STS and normal tissues (e.g., skin, subcutaneous tissue, vascular structures, and bone). This article reviews the key studies informing the debate about hypofractionation for STS. We evaluate the current data that reveal relatively small patient cohorts, short follow-up time, and inconsistent toxicity reporting. A randomized, controlled investigation of conventional fractionation, MHF, and UHF is needed. The current phase 2 data confirm that any such study should have co-primary endpoints of both local relapse-free survival as well as immediate- and long-term toxicities because the fundamental question being investigated with significant increase in daily fraction size while maintaining isoeffective total dose (~ 50 Gy equivalent) is: what are the dose impacts to late-responding normal tissues that may result in decrements to physical functioning for patients?