BackgroundModerately hypofractionated, preoperative radiotherapy in patients with soft tissue sarcomas (HYPORT‐STS; ClinicalTrials.gov identifier NCT03819985) investigated a radiobiologically equivalent, moderately hypofractionated course of preoperative radiotherapy (RT) 15 × 2.85 Gy in patients with soft tissue sarcoma (STS). Here, the authors report longer term follow‐up to update local control and report late toxicities, as well as functional and patient‐reported outcomes.MethodsHYPORT‐STS was a single‐center, open‐label, single‐arm, prospective phase 2 clinical trial that enrolled 120 eligible adult patients with localized STS of the extremities or superficial trunk between 2018 and 2021. Patients received a 3‐week course of preoperative RT followed by surgery 4–8 weeks later. End points and follow‐up were analyzed from the date of surgery.ResultsThe median follow‐up was 43 months (interquartile range, 37–52 months), and the 4‐year local recurrence‐free survival rate was 93%. Overall RT‐related late toxicities improved with time from local therapy (p < .001), and few patients had grade ≥2 toxicities (9%; n = 8 of 88) at 2 years. These included: 2% grade ≥2 skin toxicity, 2% fibrosis, 3% lymphedema, and 1% joint stiffness. Four patients (3%) had bone fractures. Both functional outcomes, as measured by the Musculoskeletal Tumor Society Rating Scale (p < .001), and quality of life, as measured by the Functional Assessment of Cancer Therapy‐General (p < .001), improved with time from treatment, and both measures were better in follow‐up at 2 years compared with baseline.ConclusionsLong‐term follow up suggests that moderately hypofractionated preoperative RT for patients with STS is safe and effective. Higher grade late toxicities affect a minority of patients. Late toxicities decrease over time, whereas functional outcomes and health‐related quality of life seem to improve with more time from combined modality treatment.