FLASH Radiotherapy: What Can FLASH's Ultra High Dose Rate Offer to the Treatment of Patients With Sarcoma?

Abstract

FLASH is an emerging treatment paradigm in radiotherapy (RT) that utilizes ultra-high dose rates (UHDR; >40 Gy)/s) of radiation delivery. Developing advances in technology support the delivery of UHDR using electron and proton systems, as well as some ion beam units (e.g. carbon ions), while methods to achieve UHDR with photons are under investigation. The major advantage of FLASH RT is its ability to increase the therapeutic index for RT by shifting the dose response curve for normal tissue toxicity to higher doses. Numerous preclinical studies have been conducted to date on FLASH RT for murine sarcomas, alongside the investigation of its effects on relevant normal tissues of skin, muscle, and bone. The tumor control achieved by FLASH RT of sarcoma models is indistinguishable from that attained by treatment with standard RT to the same total dose. FLASH's high dose rates are able to mitigate the severity or incidence of RT side effects on normal tissues as evaluated by endpoints ranging from functional sparing to histological damage. Large animal studies and clinical trials of canine patients show evidence of skin sparing by FLASH vs. standard RT, but also caution against delivery of high single doses with FLASH that exceed those safely applied with standard RT. Also, a human clinical trial has shown that FLASH RT can be delivered safely to bone metastasis. Thus, data to date support continued investigations of clinical translation of FLASH RT for the treatment of patients with sarcoma. Toward this purpose, hypofractionated irradiation schemes are being investigated for FLASH effects on sarcoma and relevant normal tissues.