A Longitudinal Evaluation of Partial Lung Irradiation in Mice by Using a Dedicated Image-Guided Small Animal Irradiator

Purpose

In lung cancer radiation therapy, the dose constraints are determined mostly by healthy lung toxicity. Preclinical microirradiators are a new tool to evaluate treatment strategies closer to clinical irradiation devices. In this study, we quantified local changes in lung density symptomatic of radiation-induced lung fibrosis (RILF) after partial lung irradiation in mice by using a precision image-guided small animal irradiator integrated with micro-computed tomography (CT) imaging.

Methods and Materials

C57BL/6 adult male mice (n=76) were divided into 6 groups: a control group (0 Gy) and groups irradiated with a single fraction of 4, 8, 12, 16, or 20 Gy using 5-mm circular parallel-opposed fields targeting the upper right lung. A Monte Carlo model of the small animal irradiator was used for dose calculations. Following irradiation, all mice were imaged at regular intervals over 39 weeks (10 time points total). Nonrigid deformation was used to register the initial micro-CT scan to all subsequent scans.

Results

Significant differences could be observed between the 3 highest (>10 Gy) and 3 lowest irradiation (<10 Gy) dose levels. A mean difference of 120 ± 10 HU between the 0- and 20-Gy groups was observed at week 39. RILF was found to be spatially limited to the irradiated portion of the lung.

Conclusions

The data suggest that the severity of RILF in partial lung irradiation compared to large field irradiation in mice for the same dose is reduced, and therefore higher doses can be tolerated.

Introduction

Lung cancer remains the most common type of cancer worldwide, and strategies are needed to improve local tumor control (1). The dose-limiting toxicity of radiation therapy with or without drugs is acute stage radiation-induced lung pneumonitis or late stage radiation-induced lung fibrosis (RILF). Advances in radiation dose delivery such as stereotactic body radiation therapy and intensity modulated radiation therapy have been shown to minimize the rate of treatment complications by avoiding radiation to normal lung tissue 2, 3, 4. However, despite recognition of radiation-induced lung injury (RILI) as early as the use of radiation therapy itself, treatment strategies to alleviate lung toxicity have hitherto been largely ineffective (5).

Preclinical small animal models of RILI are a means to evaluate new treatment strategies that would be unethical to investigate in patients and allow for studies with large cohorts, transgenic animals, controlled experimental conditions, and accelerated results due to the shorter lifespans. The use of computed tomography (CT) imaging to noninvasively monitor changes in lung morphology, principally changes in lung density, due to RILI has been successfully applied in both clinical 6, 7, 8, 9 and preclinical studies 10, 11, 12, 13, 14, 15. However, most of these previous preclinical studies were performed using large radiation fields often covering the whole thorax, with relatively coarse clinical resolution CT imaging and limited knowledge of where radiation was delivered. The clinical utility of the results of these studies may be limited due to the radiation dose distributions being highly dissimilar to current radiation therapy practice.

Dedicated precision image-guided small animal irradiation (IR) devices are now available that better mimic clinical radiation therapy, making them potentially better suited to study and quantify RILI 16, 17, 18. These devices provide unparalleled targeting accuracy with registered CT irradiation technology that allows researchers to directly study the response of structures to the known regions of irradiation. Within this context, the focus of this study was to develop advanced methods including deformable registration, image segmentation, and full 3-dimensional (3D) accurate dose calculations for small radiation fields to quantify local changes in lung density following precision irradiation in mice. We aimed to place the results within the context of previous irradiation studies that did not make use of these advanced techniques. We used high-resolution micro-CT to monitor a large cohort of fibrosis-prone C57BL/6 mice for an extended period of 39 weeks of observation, which is longer than that of any previous study.