Feasibility Trial of Preoperative 5-Day Hypofractionated Radiotherapy for Primary Soft Tissue Sarcoma

The current standard approach to the management of extremity STS is a combination of radiotherapy and limb preserving surgery. Currently guidelines recommend preoperative conventionally fractionated radiotherapy (CFRT) given at 1.8-2.0 Gy/fx, which involves 5-6 weeks of daily treatments. Preoperative hypo-fractionated radiotherapy (HFRT) is an approach that can shorten the duration of treatment. Clinical outcomes with preoperative HFRT in STS have been reported from retrospective case series, prospective institutional registries and phase I-II trials. However, preoperative HFRT has not been compared in a prospective randomized trial to CFRT and due to the rarity of extremity soft tissue sarcoma, attempts to develop such a trial would face feasibility challenges. Therefore, single arm trials of preoperative HFRT will be critical to defining the feasibility, toxicity, efficacy, and potential improvement in access to care associated with this approach.

Radiation therapy combined with wide local excision in the preoperative or postoperative setting optimizes local control for extremity STS. Preoperative radiotherapy confers a higher rate of wound complications but a lower rate of irreversible sequela such as fibrosis and lymphedema compared with postoperative radiotherapy. Resultantly, preoperative radiotherapy is the preferred approach in most cases. Preoperative radiotherapy with CFRT given at 1.8-2.0 Gy/fx, involves 5-6 weeks of daily treatments. The burden of daily travel and time away from work or care giving can be a barrier to utilization of radiotherapy. A recent analysis of the National Cancer Database demonstrated that farther distance to treatment was a negative predictor for receipt of radiotherapy in extremity STS. Sociodemographic factors such as female sex, older age (>70 years), Black race, and noncommercial insurance coverage were also negatively associated with receipt of radiotherapy. The authors summarized that radiotherapy is underutilized in the treatment of STS and that sociodemographic disparities exist in access to radiotherapy. Receipt of radiation therapy and surgery within a high volume (HV) sarcoma center has been associated with improved overall survival, while Black race and non-metropolitan residents were negative predictors for treatment within such centers. To address disparities in access to radiation therapy, the American Society for Radiation Oncology Committee on Health Equity, Diversity, and Inclusion has proposed studying novel HFRT schedules. As validation of this strategy, Kalbasi et al. increased retention of extremity STS patients within a HV sarcoma center by 3-fold with the utilization of preoperative HFRT. Further, the decreased time and travel associated with HFRT, can address an established barrier to clinical trial participation, particularly for those living remote from clinical trial sites. Clinical trial participation is particularly low in rural areas which results in these populations being underrepresented in the clinical research. A survey of South Carolina based medical researchers, identified rural residents as a group that are difficult to find and recruit to clinical trials. In a survey of urban and rural South Carolina residents, there was no difference in reported willingness to participate in clinical trials, but rural residents were more likely to perceive limited access to clinical trial sites. Investigating cancer treatment approaches that decreased the economic and logistical burdens incurred by patients, such as preoperative 5-day HFRT, may increase clinical trial participation by rural South Carolina residents and ultimately address disparities in representation of these populations in cancer research.

HFRT, using >2.2 Gy/fx, has resulted in equivalent oncologic outcomes to CFRT in other tumor sites such as breast, prostate and rectum. For STS, HFRT may confer a radiobiologic advantage in that the linear-quadratic model predicts larger doses per fraction provide better tumor control for tumors with a lower α/β ratio. For liposarcomas and rhabdomyosarcomas, their α/β ratio (~4 Gy) is similar to breast and prostate cancer, malignancies in which HFRT has been widely adopted. While histologic variability certainly exists, most STSs have estimated α/β ratios lower than 10, suggesting increased sensitivity to larger fraction size.

Clinical outcomes with preoperative HFRT in STS have been reported from retrospective case series, prospective institutional registries and phase I-II trials. Comparing oncologic outcomes across these series is hindered by heterogeneous clinicopathological features, surgical techniques, samples sizes, and radiation fractionation schedules. However, the local control and rates of wound complications associated with HFRT and CFRT regimens appear similar as summarized Spalek and Rutkowski.

This study will utilize a 30Gy/5fx preoperative regimen as it has an estimated EQD2 of 50 Gy (based on a α/β ratio=4) and therefore would be expected to closely parallel the biologic effect of CFRT. This preoperative 5-day HFRT regimen was studied in a phase II trial at UCLA and the 2-year rates of acute wound complications were favorable compared to historical controls.