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Radiosurgery of Spinal Metastases

Standard treatment options for spinal metastases include radiotherapy alone, radionuclide therapy, radiotherapy plus systemic chemotherapy, hormonal therapy, or surgical decompression and/or stabilization followed by radiotherapy.1 The role of radiation therapy in the treatment of metastatic tumors of the spine is well established and is often the initial treatment modality.^1–7 The goals of local radiation therapy in the treatment of spinal tumors have been palliation of pain, prevention of local disease progression and subsequent pathologic fractures, and stoppage of progression or reversal of neurological compromise.⁸ Patients with metastatic spine tumors are often debilitated and at a high risk for surgical morbidity.⁹ For patients with limited life expectancies from their underlying disease, high surgical complication rates with subsequent decrease in quality of life are most unacceptable.

The primary factor that limits radiation dose for local vertebral tumor control with conventional radiotherapy is the relatively low tolerance of the spinal cord to radiation. Conventional external beam radiotherapy lacks the precision to deliver large single-fraction doses of radiation to the spine near radiosensitive structures such as the spinal cord. It is the low tolerance of the spinal cord to radiation that often limits the treatment dose to a level that is far below the optimal therapeutic dose.^2,10,11 Radiotherapy may provide a less than optimal clinical response because the total dose is limited by the tolerance of the spinal cord. Precise confinement of the radiation dose to the treatment volume, as is the case for intracranial radiosurgery, should increase the likelihood of successful tumor control and clinical response at the same time that the risk of spinal cord injury is minimized.^11–19

The idea of single-fraction radiotherapy for symptomatic bone metastases is not new. During the past 2 decades, several clinical trials have compared the relative efficacy of various dose-fractionation schedules in producing pain relief for symptomatic bone metastases.^20–25 Studies have previously determined the clinical efficacy of single-fraction therapy for painful bone metastases.²⁶ Both a Radiation Therapy Oncology Group (RTOG) phase III trial and a meta-analysis found no significant difference in complete and overall pain relief between single-fraction and multifraction palliative radiation therapy for bone metastases.^20,26 Most of these trials used 8 Gy in a single fraction. However, none of these trials were specifically evaluating spinal metastases.

Stereotactic radiosurgery has been shown to be very effective in controlling intracranial metastases, independent of histology.^27–33 Radiosurgery has been demonstrated to be an effective treatment for brain metastases, either with or without whole-brain radiation therapy, with an 85 to 95% control rate. The emerging technique of spine radiosurgery represents a logical extension of the current state-of-the-art radiation therapy. Stereotactic radiosurgery for tumors of the spine has more recently been demonstrated to be accurate, safe, and efficacious.^{11,14,15,17–19,34–39} Since Hamilton et al³⁶ first described the possibility of linear accelerator-based spinal stereotactic radiosurgery in 1995 for spinal metastases, multiple centers have attempted to pursue large fraction conformal radiation delivery to spinal lesions using a variety of technologies.^{11,14–19,34–42} Researchers have shown the feasibility and clinical efficacy of spinal hypofractionated stereotactic body radiotherapy for metastases.^{11,13–19,43} Others have demonstrated the effectiveness of protons for spinal and paraspinal tumors.⁴⁴ There has been a rapid increase in the use of radiosurgery as a treatment alternative for malignant tumors involving the spine. Recent technological developments, including imaging technology for three-dimensional localization and pretreatment planning, the advent of intensity-modulated radiation therapy (IMRT), and a higher degree of accuracy in achieving target dose conformation while sparing normal surrounding tissue, have allowed clinicians to expand radiosurgery applications to treat malignant vertebral body lesions within close proximity of the spinal cord and cauda equina.

Overview of Spine Radiosurgery Treatment for Metastases

The spine radiosurgery procedure can be divided into four distinct components: immobilization and/or fiducial implantation,1 computed tomography (CT) imaging for treatment planning and generation of digitally reconstructed radiographs (DRRs),² treatment planning,³ and dose delivery.⁴ Spine radiosurgery may be performed entirely in an outpatient setting. The patient is placed in a supine position in a conformal alpha cradle during CT imaging as well as during treatment. CT images are acquired using 1.25 mm slices to include the lesion of interest as well as all fiducials or necessary bony landmarks. Planning CT images may be acquired using the addition of intravenous (IV) contrast enhancement. However, contrast is often not necessary for lesions that are completely within the bony elements. In fact, bony windowing is often more helpful for lesion localization and treatment planning than soft tissue windowing for many spinal lesions. For patients with allergies to IV contrast or renal function that precludes contrast, nonenhanced CT imaging is performed with little difficulty in determining precise lesion anatomy.

Each spinal radiosurgical treatment plan is devised jointly by a team comprising a neurosurgeon, a radiation oncologist, and a medical physicist. In each case, the radiosurgical treatment plan is designed based on tumor geometry, proximity to the spinal cord or cauda equina and other critical structures, and location within the spinal column. The lesion is outlined based on CT imaging or from a magnetic resonance (MR) fusion capability. In our series of the first 625 patients with spinal metastases, the mean tumor volume was 46 cc (range 0.20–264.0 cc). This is more than 10 times the average volume of intracranial lesions treated using radiosurgery at our institution, the University of Pittsburgh Medical Center.

Dose Prescriptions

The tumor dose is determined based on the histology of the tumor, spinal cord or cauda equina tolerance, and previous radiation quantity to normal tissue, especially the spinal cord. There is no large experience to date with spine radiosurgery or hypofractionated radiotherapy that has previously developed optimal doses for these treatment techniques. Other centers, employing intensity-modulated, near-simultaneous, CT image-guided stereotactic radiotherapy techniques, have used doses of 6 to 30 Gy in one to five fractions.^{15,16,19,45–47} We initially chose to use a single-fraction radiosurgery technique as opposed to fractionate therapy because of our experience with intracranial radiosurgery principles using the Leksell Gamma Knife (Elekta AB, Stockholm, Sweden). Given the good clinical response as well as the lack of adverse consequences to normal tissue, including the spinal cord, we have continued to employ a single-fraction treatment paradigm for our spine radiosurgery program.

In our series, maximum tumor dose was maintained at 12.5 to 22.5 Gy delivered in a single fraction (mean 20 Gy).⁴⁸ The appropriate dose or fractionation schedule for spine radiosurgery for metastatic tumors has not been determined. At our institution, the tumor dose is prescribed to the 80% isodose line. A maximum tumor dose of 20 Gy, or 16 Gy to the tumor margin, appears to provide a good tumor control with no radiation-induced spinal cord or cauda equina injury. Spine radiosurgery was found to be safe at doses comparable to those used for intracranial radiosurgery without the occurrence of radiation-induced neural injury. In our experience with spinal metastases, there has been no clinically or radiographically identifiable acute or subacute spinal cord damage attributed to the radiation dose with a follow-up period long enough to have seen such events were they to occur.^3,49–54

Dose and fractionation schedules differ by institution. The Memorial Sloan-Kettering group used a maximum dose of 20 Gy delivered in five fractions.^15,47 The Georgetown group used a mean dose of 21 Gy in three fractions.⁵⁵ The MD Anderson group used 30 Gy in five fractions.^12,16 The Henry Ford Hospital group used a 6 to 8 Gy boost after conventional irradiation (25 Gy in 10 fractions).¹⁹ Finally, De Salles et al reported a mean dose of 12 Gy.¹⁷

There is little experience regarding the tolerance of the human spinal cord to single-fraction doses, and the tolerance of the spinal cord to a single dose of radiation has not been well defined.^19,56 Spinal cord tolerance related to IMRT techniques has also not yet been addressed. Therefore, one must still rely on clinical data derived from external beam irradiation series in which the entire thickness of the spinal cord was irradiated. Radiation-induced spinal cord injury, or myelitis, is one of the most dreaded complications related to spine radiosurgery. The true tolerance of the human spinal cord to radiation is not known. The TD 5/5 (the dose at which there is a 5% probability of myelitis necrosis at 5 years from treatment) for 5, 10, and 20 cm lengths of the spinal cord in standard fractionation has been estimated by Emami et al as 5.0, 5.0, and 4.7 Gy, respectively.⁵⁷ These dose levels are estimates based on extrapolations of datasets that date back to 1948. These estimations have been widely adopted in clinical practice. To minimize the risk of spinal cord necrosis, the radiation tolerance with standard fractionation traditionally has been stated to be 45 to 50 Gy. A dose of 45 to 50 Gy in standard fractionation (1.8–2.0 Gy per fraction) is well within the radiation tolerance of the spinal cord (TD 5/5); 8 Gy in a single fraction delivered to a long segment of the spinal cord has been given without reported myelopathy.⁵⁸

In a review of 172 patients treated with fractionated radiotherapy to the cervical and thoracic spine at the University of California, San Francisco (total dose of 40–70 Gy fractionated over a 2- to 3-week period), Wara et al reported nine cases of radiation-induced myelopathy.⁵⁴ Three out of nine patients had mild cervical cord neurological deficits without any significant long-term symptoms. The length of the spinal cord that was exposed to radiation ranged from 4 to 22 cm. Hatlevoll et al reported a series of 387 patients with bronchial carcinoma treated with a split-course regimen using large single fractions.51 Seventeen patients developed radiation myelitis with an average total dose of 38 Gy. Kim and Fayos reported 7 patients with transverse myelopathy from a group of 109 patients treated with definitive radiotherapy for head and neck cancers to a total dose of 57 to 62 Gy with an average field size of 10 x 10 cm.³ Abbatucci et al reported 8 (of 203) cases of radiation-induced myelopathy with a total radiation dose of 54 to 60 Gy to the cervical and thoracic spine.⁴⁹ McCunniff and Liang reported only 1 case of radiation myelopathy out of 652 patients who had received > 60 Gy using standard fractionation.⁵² Phillips and Buschke reported 3 cases of transverse myelitis in 350 patients treated with tumors to the chest to a total radiation dose of 33.0 to 43.5 Gy.⁵³

For each spine radiosurgery case, the spinal cord or cauda equina is outlined as a critical structure. At the level of the cauda equina, the spinal canal is outlined. Therefore, at the level of the cauda equina, the critical volume is the entire spinal canal and not actual neural tissue. A limit of 8 Gy is set as the maximum spinal cord dose for treatment planning calculations. For the cauda equina, this limit is raised to 10 Gy. A limit of 2 Gy is set as the maximum dose to each of the kidneys. A limit of 8 Gy is set as the maximum dose to the bowel. This becomes important in the treatment of lower thoracic and lumbar vertebral lesions, even more so if the patient has undergone a nephrectomy or received nephrotoxic chemotherapy.

Spine Radiosurgery Indications and Clinical Outcomes

The spine radiosurgery program at the University of Pittsburgh Medical Center began in 2001 with the implementation of extracranial image-guided radiosurgery technology. Our institution’s experience currently represents the largest spine radiosurgery series in the world.^59–62 This new modality was initially introduced into the treatment paradigm for spinal tumors to a subset of the center’s oncology patient population who did not meet the criteria for other forms of therapy, including conventional radiotherapy and the latest in open surgical techniques. The indications for spine radiosurgery at the center have evolved over time and will continue to evolve as clinical experience increases. This is similar to the evolution of indications for intracranial radiosurgery that occurred in the past.

Table 9.1 summarizes the candidate lesions for spine radiosurgery. Table 9.2 lists the current indications for radiosurgery for spinal metastases. Table 9.3 summarizes the characteristics of our first 625 patients treated with a single-fraction radiosurgery technique. Ages ranged from 18 to 85 years (mean 56 years). The most common metastatic tumors (in descending order of frequency) were renal cell, breast, lung, colon, and melanoma. These five histopathologies represent over 60% of our total metastatic cases. Table 9.4 presents the long-term pain improvement and long-term radiographic control rates for the four most common histopathologies.⁴⁸ Figures 9.1 to 9.3 demonstrate several examples of spine radiosurgery used in clinical practice.

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Multidisciplinary Combined Modality Approach for Cancer of the Spinal Cord Spinal Cord Arteriovenous Malformation Radiosurgery Quality Assurance in Spine Radiosurgery Functional Spine Radiosurgery Treatment Delivery Biomechanical Assessment of Spinal Instability and Stabilization

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