This study was designed to determine the radiation tolerance of the spinal cord in swine that receive single-fraction radiosurgery one year following a dose of 30Gy delivered in ten fractions. A companion study(9
) that included identical radiosurgery delivery conditions, determined the spinal cord tolerance to single-fraction radiosurgery alone. Dose-response data for motor neurologic change is nearly identical in both studies with resulting maximum point dose ED50
s of 19.7Gy and 20.0Gy for reirradiation and de novo irradiation, respectively.
Radiation repair kinetics have been studied using uniform dose distributions in the rat(3
), guinea pig(4
) and monkey(2
). Wong, et. al. delivered fractionated irradiation to the cervical spines of 10-12 week-old rats followed by reirradiation with graded single doses 20 weeks later. After a minimum 52-week followup, it was concluded that significant long-term spinal cord recovery occurred and that the initial radiation dose influenced both retreatment tolerance and the latency to response(3
). Knowles performed split-dose studies to investigate reirradiation tolerance of the spinal cord using guinea pigs. One day old guinea pigs received a single 10Gy dose followed one year later by another single dose. The ED50
for paralysis for retreated animals (19.5 Gy) was only slightly lower than animals treated de novo (20.5 Gy) at one year of age(4
). Ang, et. al.(2
) investigated the extent and kinetics of recovery from irradiation injury in rhesus monkeys that varied in age from 7-22 years. The cervical/upper thoracic spinal cord was given 44Gy in daily 2.2Gy fractions and then re-irradiated to doses of 57.2Gy (2.2Gy fractions) after one or two year intervals, or 66Gy (2.2Gy fractions) after two or three year intervals. Fitting the observed myeloparesis data with a model assuming all dose-response curves (single course and reirradiation) were parallel resulted in recovery estimates of 33.6Gy (76%), 37.6Gy (85%), and 44.6Gy (101%) of the initial dose after 1, 2, and 3 years, respectively(2
). Although significant differences in study design and dose distribution prevent direct comparison of the present study with previous studies, all studies have demonstrated that the spinal cord possesses a large capacity for long-term recovery following single or multi-fraction irradiation.
Five cases of re-irradiation myelopathy following spine stereotactic body radiotherapy have been reported with specific dosimetric analysis comparing re-treatment myelopathy cases to controls(8
). Although the SBRT re-irradiation component involved high dose per fraction SBRT ranging from 1 to 3 fractions and thecal sac maximum point dose per fractions ranging from 10.9-14.7Gy, only one case was reported based on conventional radiation followed by single-fraction spinal radiosurgery. This patient received an initial thecal sac dose of 43.2Gy in fifteen fractions based on conventional radiotherapy followed twelve months later by single-fraction radiosurgery with a maximum thecal sac point dose of 14.7Gy. Myelopathy occurred three months following radiosurgery. Although there have been reported single-institution experiences of re-treatment SBRT with a low risk of re-treatment myelopathy,(6
) the experience is still limited. The correlation between human and animal spinal cord tolerance to single-fraction reirradiation has never been rigorously tested but the results of the present study appear to be consistent with clinical practice and more will be learned as human dosimetric data increases(12
The accuracy of spinal cord volumes reported in this study is limited by CT-based contouring. Efforts were made to minimize the errors introduced by CT-contouring but CT-myelogram or CT/MRI fusion would have been preferable. The shape of the dose distribution used in the current study makes the dose-volume histogram relatively insensitive to 1-2 mm shifts in the ventral/dorsal and rostral/caudal directions. A lateral 1mm shift of the spinal cord contour towards the treated isocenter would result in an increase in the maximum spinal cord dose of approximately 1-2% while a 1mm shift in the opposite direction would result in a decrease of the maximum spinal cord dose of 3-4%. The follow-up period of the current study (39-53 weeks) is considered long enough to observe the initial phase of radiation myelopathy as commonly reported for guinea pigs(4
) and pigs(9
) (2-6 months). The latent period observed for the onset of motor deficits in the present study (9-24 weeks) is in good agreement with the companion study(9
), a previous spinal cord tolerance study using pigs(10
) and the case of human myelopathy reported by Sahgal, et. al.(8
) Potentially more cases of radiation myelopathy would have been observed in a longer follow-up period; a previous spinal cord tolerance study(10
) reported two late responding pigs at 65 and 75 weeks following irradiation to doses very close to ED50
. The spinal cords of two pigs (pigs #10 and #12) of the present study were found to have histologic changes including vascular hyalinization accompanied by demyelination and glial scarring 53 weeks following radiosurgery but both pigs maintained normal neurologic status. These pigs received maximum spinal cord doses of 19.2 and 21.3Gy that were close to the study ED50
and may have developed neurologic changes with longer followup.
The histological changes observed in the lateral white matter are very similar to lesions observed in other studies in pigs(10
) and rats(17
). As reported for most species, including humans, focal white matter necrosis is the most common histology underlying radiation myelopathy of the spinal cord(18
). Lesions consist of diffuse demyelination, with focal areas of coalescing necrosis in the higher dose groups. In the current study, the animal showing subtle neurologic signs (#9), had a very small histologic lesion with demyelination, the extent of which is in agreement with the relatively minor character of the motor impairment. No histologic changes were observed in one neurologic responder (pig #8). This animal likely had a focal lesion that occurred between section samples. When comparing histology sections for retreated and de novo irradiated animals, the only difference noted was after prescription doses >20Gy. Although the threshold for induction of neurological damage was the same in both groups, morbidity at higher doses was more severe with gray matter infarction and associated edema. Although a vascular pathology has been suggested to be the basis of most late damage in the spinal cord, it usually does not become manifest as obvious damage to the vasculature such as hemorrhagic infarction. No later signs of vascular gray matter damage have been observed during the one year followup of lower-dosed animals, but a warning is implied that additional vascular damage may occur at longer followup times.
In conclusion, results of the present study are consistent with previous preclinical studies in the rat(3
), guinea pig(4
) and monkey(2
), supporting the observation that the spinal cord possesses a large capacity for recovery following irradiation. Specifically, pigs receiving spinal radiosurgery one year following 30Gy in 10 fractions are not at significantly higher risk of developing motor deficits than pigs that receive radiosurgery alone.