Abstract
Lung stereotactic body radiation therapy is characterized by a reduction in target volumes and the use of severely hypofractionated schedules. Preclinical modeling became possible thanks to rodent-dedicated irradiation devices allowing accurate beam collimation and focal lung exposure. Given that a great majority of publications use single dose exposures, the question we asked in this study was as follows: in incremented preclinical models, is it worth using fractionated protocols or should we continue focusing solely on volume limitation? The left lungs of C57BL/6JRj mice were exposed to ionizing radiation using arc therapy and 3 × 3 mm beam collimation. Three-fraction schedules delivered over a period of 1 week were used with 20, 28, 40, and 50 Gy doses per fraction. Lung tissue opacification, global histological damage and the numbers of type II pneumocytes and club cells were assessed 6 months post-exposure, together with the gene expression of several lung cells and inflammation markers. Only the administration of 3 × 40 Gy or 3 × 50 Gy generated focal lung fibrosis after 6 months, with tissue opacification visible by cone beam computed tomography, tissue scarring and consolidation, decreased club cell numbers and a reactive increase in the number of type II pneumocytes. A fractionation schedule using an arc-therapy-delivered three fractions/1 week regimen with 3 × 3 mm beam requires 40 Gy per fraction for lung fibrosis to develop within 6 months, a reasonable time lapse given the mouse lifespan. A comparison with previously published laboratory data suggests that, in this focal lung irradiation configuration, administering a Biological Effective Dose ≥ 1000 Gy should be recommended to obtain lung fibrosis within 6 months. The need for such a high dose per fraction challenges the appropriateness of using preclinical highly focused fractionation schedules in mice.
Highlights
Thoracic radiation therapy exposes healthy lung tissue to ionizing radiation, responsible for the development of radiotherapyassociated side effects such as radiation-induced pneumonitis and fibrosis [1,2,3]
With a view to opening up the possibilities for future research, the question we addressed in this study work was as follows: in incremented models of preclinical stereotactic body radiation therapy (SBRT) exposure with reduced target volumes, is it worth using fractionated protocols or should we continue focusing solely on volume limitation? In this study, we show that using a 3 fractions/1 week regimen, a dose per fraction of at least 40 Gy is necessary for the development of lung fibrosis within 6 months, a reasonable time lapse given the mouse lifespan
Lung Fibrosis at 6 Months Is Obtained for 3 × 40 Gy or More
Summary
Thoracic radiation therapy exposes healthy lung tissue to ionizing radiation, responsible for the development of radiotherapyassociated side effects such as radiation-induced pneumonitis and fibrosis [1,2,3]. 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. This highlights the strong volume impact when considering lung response to radiation exposure. Several authors argue in favor of considering that specificities exist in the response to limited lung volume exposure, such as different patterns of serum cytokine changes [16] or specific gene and protein expression following small field exposure compared to large field [17]
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