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Lung damage following stereotactic irradiation: preclinical modelization and radiopathological aspects

​Annaïg Bertho has defended here thesis​ on 27th November 2019 in Fontenay-aux-Roses, France

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Research Unit > IRSN/PSE-SANTÉ/SERAMED/LRMed

Authors > BERTHO Annaïg

Publication Date > 27/11/2019

Summary

Stereotactic Body Radiation Therapy (SBRT) consists in irradiating small volumes with submillimetric accuracy. The rapid dose decay outside the target volume enables the use of ablative doses, from 6 to 20 Gy per fraction. SBRT is used to treat early stage non-small cells lung cancer as a therapeutic alternative to surgery in inoperable patients. Despite the decrease in irradiated volumes, patients still develop side effects as radiation pneumonitis and lung fibrosis. The lack of radiobiological data for high doses per fraction exposure remains an issue.

The purpose of this thesis work is therefore to acquire, in vivo, original data in pulmonary radiopathology and in vitro, to determine the cellular response to high doses per fraction. The SARRP is a small animal radiation platform allowing lung SBRT modeling, in arc-therapy, in rodents. Effect of the irradiation volume is characterized by 4 different beam collimations (from 1 mm to 10x10mm²), at a dose of 90 Gy. The 3x3 mm² collimator allows the study of early and late effects of the irradiation, with the appearance of radiation-induced pulmonary fibrosis requiring depletion of club cells and reactive proliferation of type II pneumocytes. Dose effect study was conducted using a single dose range (from 20 to 120 Gy, 3x3mm²) and shows that limited lung volumes tolerate very high doses. It also shows that a dose of 60 Gy is necessary to generate pulmonary fibrosis 6 months after irradiation. Study of fractionation effect consists in delivered three fractions of 20, 28, 40 or 50 Gy. Available data showed that a minimum BED3Gy (Biological Effective Dose) of 200 Gy was required to observe radiation-induced pulmonary fibrosis in mice. In vitro, different pulmonary cell lines were irradiated according to 5 fractionation protocols, at variable doses per fraction but constant BED. Analysis of 44 genes shows that irradiation induces the expression of mesenchymal markers as well as collagen by epithelial lines, suggesting an epithelial-mesenchymal transition process. At constant BED, there is no significant effect of dose per fraction in our model.

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