QUANTEC: Organ Specific Paper
Radiation Dose–Volume Effects in the Spinal Cord

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Dose–volume data for myelopathy in humans treated with radiotherapy (RT) to the spine is reviewed, along with pertinent preclinical data. Using conventional fractionation of 1.8–2 Gy/fraction to the full-thickness cord, the estimated risk of myelopathy is <1% and <10% at 54 Gy and 61 Gy, respectively, with a calculated strong dependence on dose/fraction (α/β = 0.87 Gy.) Reirradiation data in animals and humans suggest partial repair of RT-induced subclinical damage becoming evident about 6 months post-RT and increasing over the next 2 years. Reports of myelopathy from stereotactic radiosurgery to spinal lesions appear rare (<1%) when the maximum spinal cord dose is limited to the equivalent of 13 Gy in a single fraction or 20 Gy in three fractions. However, long-term data are insufficient to calculate a dose–volume relationship for myelopathy when the partial cord is treated with a hypofractionated regimen.

Section snippets

Clinical Significance

The spinal cord consists of bundles of motor and sensory tracts, surrounded by the thecal sac, which is, in turn, encased by the spinal canal (1). Although the cord proper extends from the base of skull through the top of the lumbar spine, individual nerves continue down the spinal canal to the level of the pelvis. Portions of the spinal cord are often included in radiotherapy (RT) fields for treatment of malignancies involving the neck, thorax, abdomen, and pelvis. In addition, metastatic

Endpoints

Herein, myelopathy is defined as a Grade 2 or higher myelitis, per Common Terminology Criteria for Adverse Events v3.0 (4). Asymptomatic changes in the cord detected radiographically or mild signs/symptoms such as Babinski's sign or L'Hermitte syndrome are not classified as myelopathy for purpose of this analysis. Thus, a diagnosis of myelopathy is based on the appearance of signs/symptoms of sensory or motor deficits, loss of function or pain, now frequently confirmed by magnetic resonance

Challenges Defining Volumes

In conventional external beam RT, the field generally encompasses the entire circumference of the cord, vertebral body, and spinal nerve roots at the treated levels. Thus, precise organ definition is not critical in conventional RT apart from appropriately identifying the level of the involved cord. Delineation of the cord in body radiosurgery is unsettled (6) with various studies contouring the critical organ in the axial plane as the spinal cord, the spinal cord +2–3 mm, the thecal sac and

Preclinical studies

A large number of small-animal studies have explored spinal cord tolerance to de novo radiation and reirradiation, including time-dependent repair of such damage. Several reports suggest regional differences in radiosensitivity across the spinal cord 8, 9. The clinical endpoint in most studies is paralysis, with the spinal cord showing nonspecific white matter necrosis. The pathogenesis of injury is generally believed to be primarily from vascular/endothelial damage, glial cell injury, or both 3

Factors Affecting Risk

Animal studies suggest that the immature spine is slightly more susceptible to radiation-induced complications and the latent period is shorter 13, 57, 58, 59. For example, Ruifrok (57) found that the 50% effect dose in 1-week-old rats was 19.5 Gy vs. 21.5 Gy in adult animals (p < 0.05). The latency to complications increased from about 2 weeks after irradiation in the 1-week-old rats to 6–8 months in the adults (59). Although the ultimate white matter changes were the same in animals

Conventionally fractionated, full-circumference irradiation

Using the data in Table 1, Table 2, Schultheiss 18, 69 estimated the risk of myelopathy as a function of dose using a probability distribution model. In this model, the probability of myelopathy was derived from the data in Table 1, Table 2 adjusted for estimated overall survival (18). A good fit to the combined cervical and thoracic cord data was not possible and separate analyses were performed. For the cervical cord data, values of D50 = 69.4 Gy and α/β = 0.87 Gy were obtained with a Pearson

Special Situations

As discussed in detail previously, hypofractionation via radiosurgery is increasingly employed in the treatment of spinal lesions. Though reports of toxicity are rare, the follow-up time is short and patient numbers small. Caution should be observed in specifying the dose, taking special care to limit the dose to the cord by precise immobilization and image guidance. Predictions based on conventional fractionation should not be applied to such treatments without further careful study. The

Recommended Dose–Volume Limits

With conventional fractionation of 2 Gy per day including the full cord cross-section, a total dose of 50 Gy, 60 Gy, and ∼69 Gy are associated with a 0.2, 6, and 50% rate of myelopathy. For reirradiation of the full cord cross-section at 2 Gy per day after prior conventionally fractionated treatment, cord tolerance appears to increase at least 25% 6 months after the initial course of RT based on animal and human studies. For partial cord irradiation as part of spine radiosurgery, a maximum cord

Future Toxicity Studies

In cases where it is appropriate to irradiate only a partial circumference of the cord (as in irradiation of vertebral body lesions) or spare the interior of the cord (epidural disease), dose tolerance may be increased. SBRT, particularly using intensity-modulated RT techniques, appears well suited for that purpose, as it can be used to deliver concave-shaped RT dose distributions around organs at risk (56). Studies to better understand the importance of the spatial distribution of dose (and,

Toxicity Scoring

We recommend that the Common Terminology Criteria for Adverse Events (version 3) be used to score both acute and late spinal cord injury.

Acknowledgment

Dr. Kirkpatrick has a research grant from Varian Medical Systems, Palo Alto, Ca.

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