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

Bley, Carla Rohrer; Wolf, Friederike; Jorge, Partrik Gonçalves; Grilj, Veljko; Petridis, Ioannis; Petit, Benoît; Böhlen, Till Tobias; Moeckli, Raphaël; Limoli, Charles L.; Bourhis, Jean; Meier, Valeria; Vozenin, Marie-Catherine

doi:10.1158/1078-0432.ccr-22-0262

Cited by 59 publications

(55 citation statements)

References 29 publications

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“…All those evaluations are necessary to critically evaluate its toxicity and efficacy under a more clinically relevant scenario. Dose–volume effects can also have an important impact on FLASH-RT ( 85 ). Furthermore, oxygen content can be crucial in the appearance of FLASH effect ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

Practice-oriented solutions integrating intraoperative electron irradiation and personalized proton therapy for recurrent or unresectable cancers: Proof of concept and potential for dual FLASH effect

Ayestaran¹,

Serrano²,

Cambeiro³

et al. 2022

Front. Oncol.

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BackgroundOligo-recurrent disease has a consolidated evidence of long-term surviving patients due to the use of intense local cancer therapy. The latter combines real-time surgical exploration/resection with high-energy electron beam single dose of irradiation. This results in a very precise radiation dose deposit, which is an essential element of contemporary multidisciplinary individualized oncology.MethodsPatient candidates to proton therapy were evaluated in Multidisciplinary Tumor Board to consider improved treatment options based on the institutional resources and expertise. Proton therapy was delivered by a synchrotron-based pencil beam scanning technology with energy levels from 70.2 to 228.7 MeV, whereas intraoperative electrons were generated in a miniaturized linear accelerator with dose rates ranging from 22 to 36 Gy/min (at Dmax) and energies from 6 to 12 MeV.ResultsIn a period of 24 months, 327 patients were treated with proton therapy: 218 were adults, 97 had recurrent cancer, and 54 required re-irradiation. The specific radiation modalities selected in five cases included an integral strategy to optimize the local disease management by the combination of surgery, intraoperative electron boost, and external pencil beam proton therapy as components of the radiotherapy management. Recurrent cancer was present in four cases (cervix, sarcoma, melanoma, and rectum), and one patient had a primary unresectable locally advanced pancreatic adenocarcinoma. In re-irradiated patients (cervix and rectum), a tentative radical total dose was achieved by integrating beams of electrons (ranging from 10- to 20-Gy single dose) and protons (30 to 54-Gy Relative Biological Effectiveness (RBE), in 10–25 fractions).ConclusionsIndividual case solution strategies combining intraoperative electron radiation therapy and proton therapy for patients with oligo-recurrent or unresectable localized cancer are feasible. The potential of this combination can be clinically explored with electron and proton FLASH beams.

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Section: Discussionmentioning

confidence: 99%

Practice-oriented solutions integrating intraoperative electron irradiation and personalized proton therapy for recurrent or unresectable cancers: Proof of concept and potential for dual FLASH effect

Ayestaran¹,

Serrano²,

Cambeiro³

et al. 2022

Front. Oncol.

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“…Larger animals such as the mini pig, cat, and dog cancer patients have also been assessed using FLASH and CONV RT [ 16 , 59 , 60 , 61 ]. Following irradiation, early effects on skin toxicity as well as late fibrosis were evaluated in the mini pig.…”

Section: In Vivo Studiesmentioning

confidence: 99%

“…Their data showed a dose-modifying factor of at least 20% for single fraction treatment in favor of FLASH for the protection of normal tissue and prevention of fibrosis as endpoints. However, late skin toxicity in a subsequent study with mini pigs was observed with increasing volume, including permanent hyperkeratosis and skin contracture [ 59 ].…”

Section: In Vivo Studiesmentioning

confidence: 99%

“…At 16 months, five of the six cats were still disease free, and after 18 months, three of the six cats were still disease free [ 16 ]. Furthermore, comparison between CONV and FLASH RT in cats showed that 30 Gy at a mean dose rate of 1500 Gy/s led to osteoradionecrosis in three out of seven cats in the FLASH RT arm, resulting in a preliminary termination of the trial [ 59 ]. This potentially important toxicity signal requires further detailed evaluation and explanation.…”

Section: In Vivo Studiesmentioning

confidence: 99%

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Radiobiological Aspects of FLASH Radiotherapy

et al. 2022

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Radiotherapy (RT) is one of the primary treatment modalities for cancer patients. The clinical use of RT requires a balance to be struck between tumor effect and the risk of toxicity. Sparing normal tissue is the cornerstone of reducing toxicity. Advances in physical targeting and dose-shaping technology have helped to achieve this. FLASH RT is a promising, novel treatment technique that seeks to exploit a potential normal tissue-sparing effect of ultra-high dose rate irradiation. A significant body of in vitro and in vivo data has highlighted a decrease in acute and late radiation toxicities, while preserving the radiation effect in tumor cells. The underlying biological mechanisms of FLASH RT, however, remain unclear. Three main mechanisms have been hypothesized to account for this differential FLASH RT effect between the tumor and healthy tissue: the oxygen depletion, the DNA damage, and the immune-mediated hypothesis. These hypotheses and molecular mechanisms have been evaluated both in vitro and in vivo. Furthermore, the effect of ultra-high dose rate radiation with extremely short delivery times on the dynamic tumor microenvironment involving circulating blood cells and immune cells in humans is essentially unknown. Therefore, while there is great interest in FLASH RT as a means of targeting tumors with the promise of an increased therapeutic ratio, evidence of a generalized FLASH effect in humans and data to show that FLASH in humans is safe and at least effective against tumors as standard photon RT is currently lacking. FLASH RT needs further preclinical investigation and well-designed in-human studies before it can be introduced into clinical practice.

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“…Many papers have now been published confirming this effect for different pre-clinical models, and with different irradiation modalities such as electrons, protons or heavy ions [2] , [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] . Based on the (almost) exclusively positive results from pre-clinical studies, a first human patient was already treated using FLASH in 2019 at the University Hospital in Lausanne [11] , [12] , and some first clinical trials in cats (with electrons [13] , [14] ) and in humans (with high-energy protons [15] and electrons [16] ) have been pursued.…”

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confidence: 99%