For patients with sarcoma, radiotherapy (RT) plays an important role in both definitive and palliative disease management. As is the case with most cancer therapies, RT is intended to prevent malignant cells from dividing or spreading. However, RT also demonstrates toxicity to normal cells and tissues, resulting in treatment-related side effects. This relationship between tumor response and normal tissue response is known as the therapeutic index, and an important goal in advancing RT is to find ways to separate the dose response curves for tumor and normal tissues (Fig. 1). The impact of broadening the therapeutic index in RT can result in vast improvements in tumor control, overall survival, and mitigation of toxicities, especially when RT is delivered over the course of several fractionated treatments.1,2 This concept has guided the development of techniques such as intensity-modulated (x-ray/proton) RT (IMXT/IMPT) and stereotactic body RT (SBRT) that allow for more precise delivery of the bulk of the cytotoxic dose to tumors while sparing surrounding normal tissues. In addition to spatial control of RT therapeutic index, biological radiation response modifiers may further improve therapeutic index.3 Finally, therapeutic index can be affected by temporal modulation of RT dose delivery, which is achieved by modulating factors such as the dose rate within a RT fraction, the dose per fraction, or the time between fractions. Increasing the number of fractions and/or the time between fractions or reducing the dose rate (within the range of 0.001-1 Gy/s) for each fraction generally reduces normal tissue toxicity, although the effect on tumor control may depend on tumor type. However, as noted below, the effect of ultra-high dose rates (UHDR, above 40 Gy/s) on therapeutic index has recently received increasing attention.

Despite our ability to target RT with sophisticated techniques, it can still lead to high rates of normal tissue toxicity that significantly affect patient quality of life. For patients with sarcomas, standard fractionation involves delivery of 2 Gy daily fractions, 5 days per week over 5-7 weeks for total doses of ∼50 Gy and ∼60 – 70 Gy in the neoadjuvant (preoperative) and adjuvant (postoperative) settings, respectively.4,5 Normal tissue toxicity at these doses is significant. For example, in patients undergoing preoperative RT for extremity soft tissue sarcoma (STS), 11%-48% will experience wound complications,5, 6, 7 15%-31.5% will experience late complications such as fibrosis, joint stiffness or lymphedema,8,9 and 2%-10% will experience bone fracture.10, 11, 12, 13

In addition to having significant levels of toxicity, standard fractionation schedules may increase the overall cost (opportunity and financial) for RT and reduce access to high level RT expertise.14,15 With advanced RT delivery techniques that improve tumor imaging/targeting and spatial RT dose conformality to maintain therapeutic index, hypofractionated RT schedules (<7-10 fractions) are increasingly common for a range of malignancies including breast, lung, and prostate cancers.16, 17, 18, 19, 20, 21 For patients with sarcoma, hypofractionated schedules can maintain high tumor control rates.22, 23, 24, 25 In one study of 272 patients with STS receiving 5 Gy x 5 fractions pre-operatively, the 3-year overall survival was 72% and the local recurrence rate was 19%.22 Nevertheless, 7% of patients required additional surgery for treatment of RT complications. Another study of neoadjuvant RT using 30 Gy in 5 fractions in patients with STS demonstrated a 2-year local failure rate of only 6%.25 Nonetheless, the toxicity was similar to standard fractionation schedules with a wound complication rate of 32% and a late complication rate of 16%.

While dose and fractionation have received notable attention in RT clinical trials, the dose rate within each fraction has been underexplored. Typical external beam RT is delivered at dose rates of ∼0.003-0.1 Gy/s. Reducing the dose rate to ∼0.001 Gy/s for large fields, such as in total body RT, is used to reduce side effects.26 Early studies in the effects of UHDR RT were performed with the thought that such dose rates might be less effective due to radiochemical depletion of oxygen in tissues. Indeed, reduced cell-killing effects of radiation were observed in cell culture studies, but the potential differences between tumor and normal tissue remained underexplored.27, 28, 29, 30 More recently, studies of UHDR RT using laser-accelerated protons found no dose rate-dependent effects using a variety of in vitro cell culture techniques that included monolayer and 3D/organoid cultures of both cancer and normal cell lines.31, 32, 33 However, compelling evidence from in vivo studies in the past decade suggest that at dose rates >40 Gy/s (termed “FLASH” RT), RT therapeutic index is increased due to a decrease in normal tissue damage with maintenance of similar tumor control, as compared to RT delivered at standard dose rates.34 In this review, we explore the preclinical and clinical evidence for the FLASH effect and discuss the potential clinical significance for FLASH RT in patients with sarcoma.