Spinal Nerve Tolerance to Single-Session Stereotactic Ablative Radiotherapy (SAbR)

Abstract

SAbR is a rapidly expanding treatment modality utilized for an increasing number of cancers. The radiosensitivity of healthy neural structures is poorly understood in the setting of SAbR and numerous cases of peripheral neuropathy following SAbR have been reported. A better understanding of tolerated dose limits is critical to avoid overestimation, thus prescribing radiation doses that will lead to normal-tissue injury, or underestimation resulting in lower prescription doses that are less likely to ablate tumors. A study is underway using pigs to define the dose-related incidence of neuropathy resulting from single-session SAbR to the spinal nerves and to test the hypothesis that the spinal nerves have the same tolerance as the spinal cord. To date, 20 Yucatan minipigs (out of 25) have been entered in this study. Each animal has received CT and MRI scans for treatment planning followed by single-session SAbR using an image-guided, 6MV accelerator. A 1.5cm length of the left-sided C6, C7, and C8 spinal nerves was targeted. Pigs were distributed into 5 dose groups receiving 16 (7), 18(5), 20(4), 22(2) or 24(2) Gy with corresponding maximum nerve doses of (17.3, 19.5, 21.6, 24.1, 26.2 Gy). The neurologic status of all animals is being followed by electrodiagnostic (EDX) examination (-1, 2, 10, 20, 36 and 52) weeks following SAbR) and daily observation of gait. Current follow-up ranges between 14 and 56 weeks following SAbR. Animals will continue to be evaluated with EDX examinations and gait observation until neurologic deficits occur or the 52-week planned follow-up period is reached. Histopathologic examination of paraffin-embedded sections with luxol fast blue/periodic acid-Schiff’s staining is performed on bilateral spinal nerves and the spinal cord. To date, gait change has been observed in 10 animals that were in the 18 (2/5), 20 (4/4), 22 (2/2), and 24 (2/2) Gy dose groups. Affected animals presented with a limp in their left front limb only and electromyography demonstrated evidence of denervation in C6 and C7 innervated muscles in these animals. Gait change was first observed 9-14 weeks following irradiation. Histopathologic observation of left-sided spinal nerves for pigs in the 18-24 Gy dose groups revealed fibrosis at all dose levels, and degeneration of myelin with less severity in the 18 Gy dose group. Right-sided spinal nerves and spinal cords have all been normal. The neurologic deficits observed to date have occurred at the predicted dose levels and latency periods suggesting that our hypothesis is true, i.e., the dose-response curves for the spinal nerves and spinal cord are the same. This study is not yet complete, additional data is necessary to make firm conclusions. An additional 5 animals will be entered into this study by May 2017 so significance will be achieved.