Abstract 2879: Spatiotemporal fractionation: An innovative concept of fractionated radiotherapy
Authors: Vetrugno Irene , Telarovic Irma , Torelli Nathan , Unkelbach Jan , Pruschy Martin 
Published: March 2024

Abstract
Impressive outcomes in therapeutic radiation oncology have been achieved in the past decade through the development of advanced computer technology and imaging methods, such as intensity modulated radiotherapy. Ideally, radiotherapy treatment delivers a high dose to the tumor while sparing the surrounding healthy tissues and organs at risk from radiation damage. Spatiotemporal Fractionated Radiotherapy has emerged as an innovative technique that delivers different dose distributions to different parts of the tumor in order to achieve high doses to the target while ensuring a low dose-bath in the surrounding normal tissue. Spatiotemporally fractionated regimens showed in silico up to 10 - 15% sparing of normal tissue from radiation damage, while ensuring isoeffective tumor control compared to conventionally fractionated regimens. However, prior to advancing spatiotemporal fractionation to the clinical level, it is important to probe the validity of the main assumption of spatiotemporal fractionation derived from the Biologically Effective Dose (BED) model: two different fractionation schemes that implement a high and a low dose will lead to equivalent clinical effects, regardless of dose-treatment sequence. A tumor growth delay study was performed in a subcutaneous immunocompetent murine tumor model (MC38-tumor cell derived) receiving two different fractionation regimens. Particularly, tumors belonging to the two treatment groups received the same dose combination - a high (12 Gy) and a low (6 Gy) dose fraction separated by 72 hours - with the doses delivered in opposite order in the two treatment groups. The same experimental outline was performed in a subcutaneous immunodeficient murine tumor model derived from the same tumor cells. Tumors were also characterized by immunophenotyping analysis seven days after first irradiation. Even though the two regimens deliver the same physical dose to the tumor - and would be considered equivalent according to the BED model - different tumor growth delays were observed in a time window of 30 days after first irradiation depending on the treatment group. Such differences were observed in the immunocompetent model but not in the immunodeficient model. The immunophenotyping results showed immunostimulatory vs immunosuppressive phenotypes of the tumor microenvironment depending on the order of the treatment doses. An additional tumor growth delay study including immune checkpoint inhibitors confirmed the fundamental role of the immune system with the differential efficacy outcomes of the two regimens. Overall, these intriguing results suggest that a differential radiotherapy-induced immune response to different doses of ionizing radiation plays an important role in the treatment outcome and asks for re-evaluation of the BED model taking scheduling-dependent parameters into consideration.
Citation Format: Irene Vetrugno, Irma Telarovic, Nathan Torelli, Jan Unkelbach, Martin Pruschy. Spatiotemporal fractionation: An innovative concept of fractionated radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2879.