A Phase 2 Study of 5-Day Preoperative Radiotherapy for Patients With High-Risk Primary Soft Tissue Sarcoma

Abstract

Purpose/Objective(s)Preoperative radiation therapy (RT) is an integral component of local control in soft tissue sarcoma (STS), but the conventional 5-week treatment course is burdensome for patients (pts). We conducted a single-institution phase 2 study of 5-day dose-equivalent preoperative RT for high-risk primary STS, which demonstrated acceptable rates of wound complications and 2-year toxicity. Here, we present results with longer follow-up, including additional pts from an expansion cohort.Materials/MethodsThe initial cohort accrued between April 2016 and May 2018 and included 52 pts with histologically confirmed extremity or trunk STS planning to undergo preoperative RT followed by surgery. The primary endpoint of the initial cohort was the rate of grade ≥2 radiation morbidity (fibrosis, lymphedema, or joint stiffness) at 2-years. An expansion cohort opened in October 2018 to compare wound complication rates between preoperative RT alone versus chemoRT and has enrolled an additional 47 pts. Patients received 30 Gy (RT alone) or 25 Gy (chemoRT) over 5 daily fractions to the primary tumor with standard margins. Here we report on pts with primary localized STS who completed preoperative RT and surgery in the initial and expansion cohorts (N = 79; chemoRT excluded). We assessed disease outcomes (local control, distant metastasis, and survival rates) and toxicity (grade ≥2 fibrosis, lymphedema, or joint stiffness) after minimum 2-year follow-up (N = 52). Fibrosis and joint stiffness were graded using RTOG/EORTC criteria, and lymphedema by Stern's scale. We also updated the major wound complication rate (defined per established criteria) after minimum 1-year follow up (N = 60).ResultsOf the 52 pts with minimum 2-year follow-up, predominant histologic subtypes included undifferentiated pleomorphic sarcoma, spindle cell sarcoma or sarcoma NOS (N = 24), myxofibrosarcoma (N = 8), and myxoid liposarcoma (N = 12). Median tumor size was 6.9 cm, and 15 pts had tumors ≥10 cm. At a median follow-up of 3 years, the local recurrence, distant metastasis and all-cause mortality rates were 6.5% (3 of 46 evaluable pts), 20.8% (10 of 48 evaluable pts), and 21.2% (11 of 52). Two of 3 pts (66%) with a local recurrence had undergone R1 resections, compared to 9 of 46 (19.5%) overall. The rate of overall grade ≥2 radiation morbidity in this same group was 13.0% (fibrosis: 5 pts, joint stiffness: 5 pts, lymphedema: 2 pts). Major wound complications were observed in 16 out of 60 (26.7%) evaluable pts.ConclusionLonger follow-up of a phase 2 study of 5-day pre-operative RT for pts with extremity/trunk STS demonstrates excellent local control. Rates of radiation fibrosis, joint stiffness and lymphedema, as well as wound complications, remain acceptable. We have also developed a web-based, interactive user interface for data visualization, which can help providers identify and understand relationships between baseline characteristics and clinical outcomes in our study. Preoperative radiation therapy (RT) is an integral component of local control in soft tissue sarcoma (STS), but the conventional 5-week treatment course is burdensome for patients (pts). We conducted a single-institution phase 2 study of 5-day dose-equivalent preoperative RT for high-risk primary STS, which demonstrated acceptable rates of wound complications and 2-year toxicity. Here, we present results with longer follow-up, including additional pts from an expansion cohort. The initial cohort accrued between April 2016 and May 2018 and included 52 pts with histologically confirmed extremity or trunk STS planning to undergo preoperative RT followed by surgery. The primary endpoint of the initial cohort was the rate of grade ≥2 radiation morbidity (fibrosis, lymphedema, or joint stiffness) at 2-years. An expansion cohort opened in October 2018 to compare wound complication rates between preoperative RT alone versus chemoRT and has enrolled an additional 47 pts. Patients received 30 Gy (RT alone) or 25 Gy (chemoRT) over 5 daily fractions to the primary tumor with standard margins. Here we report on pts with primary localized STS who completed preoperative RT and surgery in the initial and expansion cohorts (N = 79; chemoRT excluded). We assessed disease outcomes (local control, distant metastasis, and survival rates) and toxicity (grade ≥2 fibrosis, lymphedema, or joint stiffness) after minimum 2-year follow-up (N = 52). Fibrosis and joint stiffness were graded using RTOG/EORTC criteria, and lymphedema by Stern's scale. We also updated the major wound complication rate (defined per established criteria) after minimum 1-year follow up (N = 60). Of the 52 pts with minimum 2-year follow-up, predominant histologic subtypes included undifferentiated pleomorphic sarcoma, spindle cell sarcoma or sarcoma NOS (N = 24), myxofibrosarcoma (N = 8), and myxoid liposarcoma (N = 12). Median tumor size was 6.9 cm, and 15 pts had tumors ≥10 cm. At a median follow-up of 3 years, the local recurrence, distant metastasis and all-cause mortality rates were 6.5% (3 of 46 evaluable pts), 20.8% (10 of 48 evaluable pts), and 21.2% (11 of 52). Two of 3 pts (66%) with a local recurrence had undergone R1 resections, compared to 9 of 46 (19.5%) overall. The rate of overall grade ≥2 radiation morbidity in this same group was 13.0% (fibrosis: 5 pts, joint stiffness: 5 pts, lymphedema: 2 pts). Major wound complications were observed in 16 out of 60 (26.7%) evaluable pts. Longer follow-up of a phase 2 study of 5-day pre-operative RT for pts with extremity/trunk STS demonstrates excellent local control. Rates of radiation fibrosis, joint stiffness and lymphedema, as well as wound complications, remain acceptable. We have also developed a web-based, interactive user interface for data visualization, which can help providers identify and understand relationships between baseline characteristics and clinical outcomes in our study.