Preclinical Model of Stereotactic Ablative Lung Irradiation Using Arc Delivery in the Mouse: Effect of Beam Size Changes and Dose Effect at Constant Collimation

Abstract

Purpose: Stereotactic body radiation therapy is a therapeutic option offered to high surgical risk patients with lung cancer. Focal lung irradiation in mice is a new preclinical model to help understand the development of lung damage in this context. Here we developed a mouse model of lung stereotactic therapy using arc delivery and monitored the development of lung damage while varying the beam size and dose delivered. Methods and Materials: C57BL/6JRj mice were exposed to 90 Gy focal irradiation on the left lung using 1-mm diameter, 3 Â 3 mm 2 , 7 Â 7 mm 2 , or 10 Â 10 mm 2 beam collimation for beam size effect and using 3 Â 3 mm 2 beam collimation delivering 20 to 120 Gy for dose effect. Long-term lung damage was monitored with microecomputed tomography imaging with anatomopathologic and gene expression measurements in the injured patch and the ipsilateral and contralateral lungs. Results: Both 1-mm diameter and 3 Â 3 mm 2 beam collimation allow long-term studies, but only 3-mm beam collimation generates lung fibrosis when delivering 90 Gy. Dose-effect studies with constant 3-mm beam collimation revealed a dose of 60 Gy as the minimum to obtain lung fibrosis 6 months postexposure. Lung fibrosis development was associated with club cell depletion and increased type II pneumocyte numbers. Lung injury developed with ipsilateral and contralateral consequences such as parenchymal thickening and gene expression modifications. Conclusions: Arc therapy allows long-term studies and dose escalation without lethality. In our dose-delivery conditions, dose-effect studies revealed that 3 Â 3 mm 2 beam collimation to a minimum single dose of 60 Gy enables preclinical models

Preclinical Model of Stereotactic Ablative Lung Irradiation Using Arc Delivery in the Mouse: Is Fractionation Worthwhile?

“…In addition to the probably too early time point (8 weeks) mentioned by the authors, a smaller irradiated volume (beams target the tumor) may explain the lack of effects on normal tissue. We previously observed that using smaller beams (3 × 3 mm-collimated) did not induce lung fibrosis following a single dose of 20 Gy (12). In this study, and even delivering 3 × 20 Gy, a reduced irradiated volume and a probably lower mean lung dose (35) are responsible for the lack of lung fibrosis development, as observed by Soysouvanh et al, using the same beam arrangements and delivering 5 × 20 Gy (21).…”

“…The absence of dose-response effect relative to the parameters measured in this study (morphometrical measures, cell counting and gene expression levels) may suggest the notion of threshold. Only fibrosing schemes were associated with significant club cell depletion, as previously observed following single dose focal lung exposure (12). Club cells play an important role in lung epithelial homeostasis and repair (37).…”

“…The lung has a large reserve capacity and the volume exposed to ionizing radiation is a strong determinant of its functional tolerance (9). Unsurprisingly, the larger the exposed volume is, the lower the possible dose that can be delivered without generating high animal mortality (10)(11)(12). Using 3 × 3 mm beam collimation, which seems to be the most suitable for modeling SBRT in mice (11,(13)(14)(15)(16), the dose delivered in one single fraction can be as high as 120 Gy (and possibly higher) without associated animal mortality (12), providing that the delivery methods include multiple beam entries to avoid life-threatening thoracic skin/muscle lesions.…”

Immunomodulation by radiotherapy in tumour control and normal tissue toxicity

“…Such animal models will allow us to test how RT total dose and dose per fraction, in combination with IO agents, affect anti-tumour efficacy and normal tissue toxicity, and inform clinical trial design to reduce the risk to patients. This is perhaps most important, when testing higher dose per fraction used in stereotactic ablative radiotherapy (SABR) 125 . Animal models such as fibrosis-susceptible mouse strains and other genetic backgrounds 28,81 may also play a role in informing clinical trial design about RT dose per fraction and scheduling questions.…”

Radiobiologie des très fortes doses par fraction : connaissances en 2020 et nouvelles modélisations précliniques

“…Actuellement, trois projets de thèse au LRMed ont utilisé ce modèle d'irradiation pulmonaire en conditions stéréotaxiques, les thèses de Jérémy Lavigne (soutenue le 16 octobre 2017, Lavigne et al, 2019), Frédéric Soysouvanh (soutenue le 24 janvier 2019, Soysouvanh et al, 2020) et Annaïg Bertho (soutenue le 27 novembre 2019, Bertho et al, 2020). Ces trois premières thèses ont permis au LRMed d'acquérir des connaissances précises sur la cinétique de développement des lésions pulmonaires en fonction du collimateur utilisé et de la dose administrée (Bertho et al, 2020), et de débuter la compréhension de certains mécanismes impliqués dans la réponse pulmonaire à l'irradiation focale, comme le rôle de la sénescence cellulaire (Soysouvanh et al, 2020) ou l'implication d'acteurs clés comme HIF-1 alpha (hypoxia-inducible factor-1 alpha, (Lavigne et al, 2019). Un quatrième projet de thèse (Sarah Braga-Cohen) a débuté en octobre 2019 sur ce même modèle, thèse qui sera soutenue fin 2022.…”