Soft tissue sarcomas (STS) are rare, constituting < 1% of adult cancers.1 This category of malignancies consists of more than 60 histopathologic subtypes, the majority of which are managed similarly with respect to primary disease control. These tumors can arise anywhere in the body but commonly occur in the extremities, hip or shoulder girdles, or superficial trunk. They often present with considerable size and bulk and thus pose local therapy challenges because the mainstay of curative management is complete surgical resection, preferably with widely negative margins. The field of STS management has evolved demonstrating that limb-preserving local management affords equivalent oncologic outcomes compared to the historical approach of amputation. Randomized trials have shown that combining radiation therapy (RT) with limb-conserving (conservation) surgery provides superior local control compared to conservation surgery alone and that local control rates with this combined modality approach are 85%-95%.2, 3, 4

The initial studies that established the validity of foregoing amputations used conservation surgery with postoperative 60-66 Gy delivered in 1.8-2 Gy fractions over 6 weeks to the surgical bed with a generous margin (5-7 cm).2,5 These relatively high doses of radiotherapy to large volumes indeed facilitated limb-preservation but were associated with significant permanent complications such as fibrosis, edema, and joint stiffness, and consequent functional limitations in some patients.6 A landmark randomized study by O'Sullivan et al.3 (National Cancer Institute of Canada SR2; NCIC-SR2) thus investigated whether a lower dose of RT could be delivered preoperatively without compromising outcomes. This study established that local control of STS was equivalent for preoperative RT doses of 50 Gy in 2 Gy fractions over 5 weeks compared to the aforementioned higher postoperative 6-week RT dosing.3,7 The investigators also demonstrated that preoperative RT was associated with higher rates of major wound complications after surgery compared to postoperative RT (35% vs 17%, respectively).3,8 While these wound complications can be significant, sometimes requiring re-operation for repair and/or hospitalization for wound management, they are usually temporary in nature and reversible. In contrast, the observed late complications of fibrosis, edema, and joint limitations occurred more frequently with postoperative RT.7,9 These late complications often result in long-term, permanent, and progressive functional impairment. Therefore, when RT is recommended for STS, preoperative RT is often favored over postoperative RT due to the irreversible and function-compromising nature of the late complications that are more common with postoperative RT. Furthermore, preoperative RT is preferred because it can, in some cases, reduce tumor size and thus facilitate surgical resection. This recommendation regarding preference for preoperative RT for localized STS has been incorporated into the American Society for Radiation Oncology (ASTRO) Clinical Practice Guideline10 on radiotherapeutic management of STS as well as the National Comprehensive Cancer Network (NCCN) STS guidelines.11 Additionally, published data regarding hypofractionation for STS almost exclusively reports on its use in the preoperative setting. Therefore, the remainder of this manuscript will focus on altered fractionation for preoperative RT for localized STS of the extremity and superficial trunk.

In 2002, the NCIC-SR2 trial established the standard-of-care dosing regimen for preoperative STS as 50 Gy in 25 daily fractions of 2 Gy/d (25 × 2 Gy) over 5 weeks. Across the field of radiation oncology, there is a recent growing shift toward the use of hypofractionation—delivery of fewer fractions using higher daily doses. This shift is currently well-founded and based on results of randomized studies for malignancies such as breast cancer and rectal cancer, as well as others.12, 13, 14, 15 Naturally, interest has grown as to whether the standard regimen for preoperative RT for STS can also be safely and effectively condensed into shorter hypofractionation schedules that would be equally effective for tumor control without unacceptably increasing toxicity.

Hypofractionation for STS is not a new concept. It was explored in the 1970s, -80s, and -90s but was administered with concurrent chemotherapy.16 However, chemoradiotherapy has not broadly achieved a foothold as standard practice for localized STS and most sarcoma centers administer preoperative RT without chemotherapy. More recently, published studies have emerged investigating new hypofractionated (3-week) and ultrahypofractionated (1 week) preoperative RT regimens without chemotherapy. All of these studies are single-arm phase 2 or cohort studies, most with small patient numbers and relatively short follow-up.

Despite the lack of randomized clinical trial data, there is evidence that ultrahypofractionation is being rapidly adopted into radiation oncology practice in the US.17 In a surveyed cohort of mostly US-based oncologists and orthopedists, more than a fifth of respondents indicated they already considered the ultrahypofractionated regimen standard of care for STS and only 11% endorsed needing a phase 3 trial to change standard of care. Interestingly, almost half of respondents indicated they would accept late toxicity for an ultrahypofractionated regimen that exceeded that observed with 25 × 2 Gy. There are no data regarding whether patients would accept that choice were they presented with the alternatives. Of note, the framing of the questions around late toxicity in the survey referenced a composite of late toxicity endpoints that included fibrosis, edema, and joint limitation. However, there are virtually no data regarding bone and late skin toxicity following hypofractionation regimens for STS, both of which likely deserve closer scrutiny with ultrahypofractionation for STS, as we will discuss in this manuscript.

It is our position that there is insufficient data to revise the standard-of-care (25 × 2 Gy) fractionation for STS using the currently available data. This position is reinforced by the ASTRO and NCCN guidelines’ radiation therapy recommendations.10,11 We assert that not only is a randomized trial needed, but that it must be designed such that late toxicity endpoints are reported contemporaneously with local tumor control. The basis for our position lies in our detailed review of the current published literature relevant to the growing debate about changing the standard-of-care for the preoperative dose-fractionation regimen for STS. In this manuscript we will review these data and specifically seek to contextualize these regimens with respect to differential toxicity concerns for the various reported regimens that are largely radiobiologically equivalent with respect to tumor control.