Pulmonary Hilar Stereotactic Body Radiation Therapy in the Rat

Abstract

Stereotactic Body Radiation therapy (SBRT) is an emerging modality of treatment for early stage non-small cell lung carcinoma. Concerns have arisen related to increased toxicities for medial tumors. We have developed a model of high dose, hypofractionated radiotherapy to the pulmonary hilum using the Leksell Gamma-Knife. Sprague-Dawley rats received hypofractionated SBRT to the unilateral lung hilum using a custom immobilization device on the Gamma Knife. Each animal was individually scanned, treatment planned, and treated with either two 4 mm or one 8 mm collimated shots at escalating doses of 20, 40, and 80 Gy to the 50% isodose volume, encompassing the right mainstem bronchus. All animals were carefully followed post-treatment and imaged by plain film and CT. In addition, histopathological analysis of all rats was performed at selected time points. Animals treated with 4 mm collimated shots demonstrated no appreciable changes on plain films or sequential, follow-up CT scans, or histopathologically. Animals irradiated with the 8 mm collimator were less active, gained weight at a reduced rate, and demonstrated histopathological changes in 7/34 animals six months post-irradiation. Cellular atypia and interstitial pneumonitis were found, three of the seven of the animals showed clear bronchial damage and two showed vascular damage. Significant volume and time effects were found. Utilizing a novel Gamma Knife based animal model to study SBRT toxicity, it was found that the bronchus will tolerate small volumes of very high dose radiotherapy. It was postulated that radiation of the surrounding support stroma and normal tissue are important in the etiology of bronchial or hilar damage.

Stereotactic Body Radiotherapy for Lung Tumors at the Pulmonary Hilum

“…However, Timmerman et al reported that the risk of severe toxicity associated with SBRT was elevenfold higher in patients with centrally located lung tumors in comparison to that of patients whose tumors were peripheral [26]. After this landmark report cautioned us against using SBRT to tumors within 2 cm from the main bronchus, a few reports have been published recently which are affirmative for SBRT to the pulmonary hilum [1,12,27]. Joyner et al treated nine patients who had centrally located lung tumors by SBRT with a dose of 36 Gy in three or six fractions (BED 10 ; 57.6 Gy or 46.8 Gy).…”

“…Tinnel et al analyzed the correlation between the risk of interstitial pneumonia and the irradiated lung volume in rodent experiments [27]. They mentioned that the bronchus could tolerate therapy when a small volume was irradiated with a very high dose, such as a single fraction of 80-160 Gy.…”

Pre-clinical research in small animals using radiotherapy technology – a bidirectional translational approach

“…To prevent exposure of the contralateral eye, corresponding collimator conduits are plugged. The device has also been used for irradiation of the unilateral mainstem bronchus in rats as a model for radiation-induced bronchial damage [79]. A stereotactic positioning device for mice [74] is intended for irradiating the rear flank [80] and mammary gland [81] to investigate colorectal and breast cancer models, respectively.…”

Applications of Gamma Knife Radiosurgery for Experimental Investigations in Small Animal Models

“…In their experiment, the mainstream bronchus was irradiated with 4 mm or 8 mm collimators. It was found that the bronchus well tolerated small volume (4 mm) of very high dose of radiotherapy but a bigger volume (8 mm) encompassing the surrounding support stroma and normal tissue produced cellular atypia, interstitial pneumonitis, bronchial and vascular damages (Tinnel et al, 2007). Finally, Belzile et al showed that administration of octreotide, a drug used in acromegaly and other types of digestive pathologies, prior to GKRS acted as a radioprotective agent on rat parotid glands one month after irradiation (Belzile et al, 2009).…”

“…This visual targeting was deemed adequate because the target was the external eye of the animal, but could not be used for internal organ targeting. This device and method are reported elsewhere (Dynlacht et al, 2006;Dynlacht et al, 2008) and the coordinates were finally confirmed by CT scan (Tinnel et al, 2007). Im et al (Im et al, 2006) also created a stereotactic device for rat consisting of a plate with ear plugs, incisor bar and a sliding Y and Z scales.…”