Dose- and Volume-Limiting Late Toxicity of FLASH Radiotherapy in Cats with Squamous Cell Carcinoma of the Nasal Planum and in Mini Pigs

Author:

Rohrer Bley Carla1ORCID,Wolf Friederike1ORCID,Gonçalves Jorge Patrik234,Grilj Veljko234,Petridis Ioannis23,Petit Benoit23,Böhlen Till T.4ORCID,Moeckli Raphael4ORCID,Limoli Charles5,Bourhis Jean2ORCID,Meier Valeria1ORCID,Vozenin Marie-Catherine23ORCID

Affiliation:

1. 1Division of Radiation Oncology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.

2. 2Department of Radiation Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

3. 3Radiation Oncology Laboratory, Department of Radiation Oncology, Lausanne, University Hospital and University of Lausanne, Lausanne, Switzerland.

4. 4Institute of Radiation Physics, Department of Radiology, University Hospital and University of Lausanne, Lausanne, Switzerland.

5. 5Department of Radiation Oncology, School of Medicine, University of California at Irvine, Irvine, California.

Abstract

Abstract Purpose: The FLASH effect is characterized by normal tissue sparing without compromising tumor control. Although demonstrated in various preclinical models, safe translation of FLASH-radiotherapy stands to benefit from larger vertebrate animal models. Based on prior results, we designed a randomized phase III trial to investigate the FLASH effect in cat patients with spontaneous tumors. In parallel, the sparing capacity of FLASH-radiotherapy was studied on mini pigs by using large field irradiation. Experimental Design: Cats with T1-T2, N0 carcinomas of the nasal planum were randomly assigned to two arms of electron irradiation: arm 1 was the standard of care (SoC) and used 10 × 4.8 Gy (90% isodose); arm 2 used 1 × 30 Gy (90% isodose) FLASH. Mini pigs were irradiated using applicators of increasing size and a single surface dose of 31 Gy FLASH. Results: In cats, acute side effects were mild and similar in both arms. The trial was prematurely interrupted due to maxillary bone necrosis, which occurred 9 to 15 months after radiotherapy in 3 of 7 cats treated with FLASH-radiotherapy (43%), as compared with 0 of 9 cats treated with SoC. All cats were tumor-free at 1 year in both arms, with one cat progressing later in each arm. In pigs, no acute toxicity was recorded, but severe late skin necrosis occurred in a volume-dependent manner (7–9 months), which later resolved. Conclusions: The reported outcomes point to the caveats of translating single-high-dose FLASH-radiotherapy and emphasizes the need for caution and further investigations. See related commentary by Maity and Koumenis, p. 3636

Funder

Krebsliga

NIH

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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