Hypofractionated preoperative radiotherapy for extremity soft tissue sarcoma: Are we racing ahead of the toxicity data?

For patients who have localized, high-risk soft tissue sarcoma of the extremity, combined-modality local treatment with radiation therapy (RT) and surgery offers high rates of local control. When RT is used, preoperative RT is recommended. The current standard of care dosing is 50 Gray (Gy) conventionally fractionated, delivered as 2 Gy per fraction for 25 fractions. Recent interest in shorter courses of preoperative RT has led to several investigations, mostly phase 2 trials, of various ultrahypofractionated and moderately hypofractionated regimens. Those studies demonstrated that, when the preoperative RT dose is estimated to be radiobiologically equivalent to or higher than the 50 Gy conventional standard, local control is commensurate. Major wound complication rates are also acceptable. Differences in toxicities with hypofractionation emerge when the daily fractional dose increases, particularly with regard to delayed wound closure beyond 180 days from surgery and amputations for treatment-related complications. Long-term assessment of bone toxicity is also warranted. A randomized controlled trial of hypofractionation versus the conventionally fractionated standard is needed and must include a composite toxicity co-primary endpoint that includes not only fibrosis, edema, and joint limitation but also delayed wound closure, fracture, and limb loss. Because local control is excellent with the current standard RT and surgery, functional and quality-of-life outcomes are paramount when assessing potential changes in RT approaches. To ensure a patient-centered approach to investigating hypofractionation for soft tissue sarcoma, patient and patient advocate perspectives should be included in clinical trial design and the selection of outcomes measures.