Meta-Analysis of Five Fraction Preoperative Radiotherapy for Soft Tissue Sarcoma

Abstract

There is increasing interest in shorter courses of radiation therapy (RT) in the management of soft tissue sarcoma (STS). Studies investigating preoperative ultra-hypofractionated 5-fraction RT for STS are few and often limited to single institution experiences with less than 50 patients. We therefore performed a meta-analysis to determine the efficacy and safety of preoperative 5-fraction RT for STS based on currently published literature, with an analysis evaluating effects of dose delivered. This study level meta-analysis was conducted using Bayesian methods. Statistical estimation for risk of outcome rates were conducted by posterior mean and 95% highest posterior density (HPD) intervals. Studies with two-year local control (LC) and description of major wound complications (MWC) per the CAN-NCIC-SR2 study were included in this meta-analysis, and these served as the primary endpoints. Secondary endpoints included rates of acute and late toxicity. A total of ten studies were identified; seven met inclusion criteria (Kalbasi 2020, Kubicek 2021, Leite 2021, Spalek 2021, Gobo Silva 2021, Bedi 2022, Mayo 2022). Three studies (Kosela-Paterczyk 2014, Kosela-Paterczyk 2021, Potkrajcic 2021) did not include adequate information to accurately determine 2-year LC or MWC. Subgroup analyses were performed for ≥30 Gy vs <30 Gy as the EQD2 of 30 Gy in 5 fractions for an α/β of 3-4 is 50-54 Gy, equivalent to standard preoperative RT fractionation. A total of 208 patients were included from seven studies. Five studies used ≥30 Gy (n = 144) and 2 studies <30 Gy (n = 64). The median follow-up was 29 months (range: 21-57). Primary tumor location was lower extremity in 68%, upper extremity in 22%, and trunk in 10%. In studies with available information, most tumors were intermediate (27%, 46/169) or high grade (67%, 114/169) and 50% (79/158) were >10 cm. Two-year LC for the entire cohort was 96.9% (95% HPD: 0.9374-0.9889) and the rate of MWC was 30.6% (95% HPD: 0.2106-0.4149). Acute grade 2 and 3 dermatitis was seen in 12.7% and 2.2%, respectively. Late grade 2 toxicities included fibrosis (11.1%), stiffness (6.0%), and lymphedema (4.0%) and late grade 3 toxicities included fibrosis (1.8%) and stiffness (0.4%). Grade 4 toxicity was rare and included fibrosis (0.6%) and stiffness (0.6%). There was a trend toward improved LC with ≥ 30 Gy (95% HPD: 0.949-0.997 vs 0.838-0.986). There was no difference in MWC (95% HPD: 0.185-0.420 vs 0.172-0.553) or late toxicity between the two groups. Acute grade 3 dermatitis was seen less frequently with regimens <30 Gy (95% HPD: 0-0 vs 0.009-0.072), however rare overall. Preoperative 5-fraction RT for STS demonstrates excellent 2-year LC with MWC and toxicity similar to standard fractionation preoperative RT. Multi-institutional trials with a universal RT protocol and larger sample size are warranted to assess this novel treatment paradigm.