Benefits of Spine Radiosurgery

SRS is very effective in providing palliation for spinal tumors, especially radioresistant tumors, either as initial therapy or after the failure of cEBRT. Numerous international investigators have now published outcomes for thousands of patients with spine tumors effectively treated with SRS. These results report excellent local control (85% to 98%), rapid durable symptom relief (pain relief of 65% to 90% with a median time to pain relief of 2 weeks), and minimal toxicity.

A substantial body of data supports a number of benefits of spine SRS over cEBRT including several evidence-based reviews. According to a multidisciplinary spine oncology study group’s recommendations, the current indications for spine SRS can be grouped into three general categories: (1) primary definitive therapy for previously unirradiated tumors, (2) salvage radiosurgery for recurrent or progressive tumors having failed prior cEBRT, and (3) postoperative radiosurgery after surgical intervention with or without spinal stabilization.

When compared to primary cEBRT, the benefits of primary SRS include a shorter treatment time, which minimizes the potential for interruptions in systemic therapy, delivery of a high radiobiologic dose, which may overcome the relative radioresistance that challenged conventional radiotherapy in certain histologies (e.g., melanoma, renal cell carcinoma), and improved tumor control and symptom relief. Tumor control rates of 100% have been published using SRS for previously unirradiated spine metastases. Moreover, long-term radiographic tumor control has been demonstrated to be independent of primary histology with 90% long-term tumor control. In a series of 500 cases, 96% of breast cancer, 96% of melanoma, 94% of renal cell carcinoma, and 93% of lung cancer patients achieved long-term pain improvement greater than 12 months. Patient selection for primary radiosurgery remains an area of ongoing controversy. A recursive partitioning analysis stratifying patients into a three-class system based on time from primary diagnosis (> 30 months) and performance status (Karnofsky Performance Status > 70) has been published. This analysis may serve as a guide for selecting patients with longer overall survival more likely to benefit from the improved tumor and symptom control associated with a primary radiosurgical approach.

Safe dose escalation leads not only to higher rates of pain control than historic controls for cEBRT but also to more durable pain control with a median duration of pain control of greater than 1 year. Other studies demonstrated that quality of life also improved as a result of improved pain control. Finally, the more effective local treatment for spine metastases may translate into longer survival for select patients with oligometastases involving the spine, similar to that seen for brain metastases. Although the cost-effectiveness of radiosurgery has not been as well studied to date, better rates of local control may translate into decreased cost.

Spine Radiosurgery as Primary and Definitive Therapy

One of the most significant applications of SRS to date for malignant spine tumors has been as definitive local treatment. In most series, the use of high-dose radiation has been restricted to tumors that involve the vertebrae alone or with minimal epidural abutment. Tumors with high-grade spinal cord compression have been considered a relative contraindication to SRS. Although radiosensitive tumors (e.g., hematologic malignancies) can be treated with hypofractionated regimens, the greatest utility of SRS is the improved response of radioresistant tumors, even in the setting of prior cEBRT. The response rates for radiation resistant tumors (e.g., renal cell, melanoma, sarcoma) using cEBRT regimens are poor, and most patients eventually demonstrate tumor progression. Large series reporting outcomes after cEBRT for spine metastases without stratifying for radiosensitivity of the tumors often reported good results only because of the large numbers of hematologic malignancies and breast, prostate, and neuroendocrine tumors. However, when stratified by radiosensitivity to cEBRT, marked differences are seen in tumoral responses. In contrast to these poor responses to cEBRT regimens, multiple series reporting outcomes for spine SRS have demonstrated radiographic and clinical responses of greater than 90% with long-term follow-up that are independent of the primary histology.

The largest published series to date reported a prospective cohort series of 500 cases in 393 patients presenting with a variety of primary tumor histologies (e.g., breast, lung, renal, melanoma) and treated with single fraction SRS at all spine levels. The maximum intratumor dose ranged from 12.5 to 25 Gy (mean 20 Gy). Pain and radiographic tumor control were achieved in 86% and 90% of cases, respectively, with a median follow-up time of 21 months. No patient demonstrated new onset postradiation myelopathy or functional radiculopathy.

Yamada and colleagues published a prospective cohort series of 103 patients treated with SRS for radioresistant oligometastatic tumors. The study was a dose escalation trial from 18 to 24 Gy with spinal cord constraints defined as a maximum spinal cord dose of 14 Gy. Local control was 92% at a median follow-up of 16 months. Subgroup analysis demonstrated a dose response; patients receiving 24 Gy had a significantly better local control than those who received less than 24 Gy. Complications were limited to grades 1 and 2 skin and esophageal toxicity. No patient demonstrated new onset postradiation myelopathy or functional radiculopathy.

Chao and associates published a study intended to generate a prognostic index using recursive partitioning analysis for patients undergoing spine radiosurgery for spinal metastases. One hundred seventy-four patients underwent spine SRS with a median dose of 14 Gy typically delivered in a single fraction. Chang and associates reported a phase I/phase II study in a series of 63 spinal metastases patients with 74 lesions. No neuropathy or myelopathy was observed during a median follow-up period of 21 months. There was also no subacute or late grade 3 or 4 toxicity. The actuarial 1-year tumor progression-free incidence was 84% for all tumors. A careful analysis of the patterns of failure in 17 cases revealed two primary mechanisms: (1) tumor recurrence in the bone adjacent to the site of treatment, especially in the pedicles and posterior elements, and (2) tumor recurrence in the epidural space adjacent to the spinal cord. This same group reported a more recent prospective cohort analysis of 55 renal cell carcinoma spinal metastases treated with 27 Gy delivered in three fractions or 30 Gy delivered in five fractions (8 cases were treated with 24 Gy delivered in a single fraction). The actuarial 1-year spine tumor progression-free survival was 82%.

Wowra and coworkers reported treatment of 134 spinal metastases in 102 patients with SRS. The most common tumors were breast cancer (23%), renal cell carcinoma (20%), and gastrointestinal cancers (12%). At a median follow-up of 15 months, 98% of the tumors showed radiographic control based on the criteria of no interval growth. Once again, tumor response was found to be independent of histology. Of the 51 patients with pain, the pretreatment visual analog score was 7, which was reduced to 1 within only 1 week after treatment.

A systematic review of the literature for both cEBRT and SRS for metastatic spine disease was published in 2009. Twenty-nine single institution cases series of spine SRS that had been published to date were carefully examined. Using a Guyatt analysis technique, SRS for metastatic spine disease was determined to be safe and effective with durable symptomatic response and local control for even radioresistant histologies, regardless of prior fractionated radiotherapy. Furthermore, a recommendation was made that SRS should be considered over cEBRT for the treatment of solid tumor spine metastases in the setting of oligometastatic disease or radioresistant histology in which no relative contraindications exist. A similar more recent systematic literature review by Sohn and Chung analyzed a total of 31 studies on spine stereotactic radiosurgery (SRS) for spinal metastases and reported similar conclusions. A clear advantage to the neoadjuvant approach involves the ability to carefully delineate tumor volumes in unviolated tissue planes.

Several clinical series have focused specifically on SRS for primary malignant spine tumors. The results from studies evaluating SRS for the treatment of primary sarcomas suggest that SRS may have a role in the definitive treatment of patients with primary spinal sarcomas who are deemed unresectable and as adjuvant treatment in those undergoing surgery. Radiologic evaluation showed that local control was maintained in 77% of patients at 2 years.

Radiosurgery as a Postsurgical Adjuvant Treatment

In current multimodality treatment paradigms, surgery for malignant spine tumors is reserved as initial therapy to treat patients with high-grade spinal cord or cauda equina compression with or without myelopathy or in cases of significant spinal instability. Although some hematologic malignancies may respond dramatically to cEBRT, the majority of solid tumors do not respond to such conventional radiotherapy techniques and may benefit from surgery to decompress the neural elements and stabilize the spinal column. Furthermore, radiation alone cannot stabilize an unstable spine. Prospective randomized data have established the importance of direct surgical decompression for spine tumor patients with spinal cord compression, with surgery plus postoperative cEBRT improving ambulation rates, bowel/bladder continence, narcotic requirements, and overall survival over conventional radiotherapy alone. Moreover, surgical intervention is integral for the correction of spinal instability and relief of axial load pain from pathologic vertebral compression fractures. Although surgery is very effective for decompressing and stabilizing the spine, radiotherapy is critical for providing local tumor control.

The rationale for using SRS as opposed to cEBRT as an adjuvant to surgical decompression is the predicted improvement in tumor control based on radioresponsiveness. Klekamp and Samii reviewed the local control rates for 106 spinal metastasis cases undergoing decompression followed by cEBRT. The overall local recurrence rates as determined by the Kaplan Meier method were 58% after 6 months, 69% after 1 year, and 96% after 4 years. If patients lived long enough, the tumor recurred locally in essentially all patients. Among the most important predictors of local tumor recurrence was tumor histology. These high rates of tumor recurrence are in stark contrast to results published with decompressive surgery followed by postoperative SRS. Rock and colleagues specifically evaluated the combination of open surgical procedures followed with adjuvant SRS in a prospective cohort series of 18 patients. They found this to be a successful treatment paradigm that was associated with a significant chance of stabilizing or improving neurologic function. Overall local control was achieved in 94%.

SRS is being effectively used as a postoperative adjuvant to gain local tumor control after surgery to decompress and instrument patients with high-grade spinal cord compression or spinal instability. There is a growing body of literature to support this algorithm. The theoretic rationale is that one can potentially perform less aggressive tumor resection with the expectation that local tumor control can be achieved with high-dose radiation therapy. This is particularly relevant for radioresistant tumors such as renal cell carcinoma, for which gross total resection or even attempted en bloc resection of the tumor was traditionally thought to be essential for achieving local tumor control. Currently, tumor resection is less aggressive and aimed at epidural decompression and instrumentation to provide stabilization.

The improved tumor control rates associated with spine SRS may afford a new paradigm in malignant spine tumor management where the goal of surgery can be deescalated from gross total resection (often requiring a combined anterior and posterior approach) to limited epidural decompression and instrumented stabilization (“separation surgery”). Using this approach of “separation surgery” with postoperative radiosurgery in 186 patients, Laufer and associates demonstrated a 1-year actuarial local control of 84% and 96% for those completing SRS of 24 to 30 Gy in three fractions. The spinal tumors can be removed away from neural structures allowing for immediate decompression, the spine can be instrumented if necessary, and the residual tumor can be safely treated with SRS at a later date, thus further decreasing surgical morbidity. Anterior corpectomy procedures in certain cases can be successfully avoided by posterior decompression and instrumentation alone followed by SRS to the remaining anterior lesion. With the ability to effectively perform spinal SRS, the current surgical approach to these lesions might change. Given the steep falloff gradient of the target dose with negligible skin dose, such treatments can be given early in the postoperative period as opposed to the usual significant delay before cEBRT is permitted.

One benefit of SRS is the lack of soft tissue injury. Reexploration after SRS often shows no signs of fibrosis, in contradistinction to the situation after cEBRT. On this basis, SRS is offered in the early postoperative period, as early as 1 week after open surgery. Moulding and coworkers reviewed 21 patients who underwent “separation surgery” and posterior segmental instrumentation for radioresistant histologies. The spinal cord and thecal sac contours were established using computed tomography (CT) myelography, which provides for excellent anatomic detail even in the presence of spinal implants. Overall local control was 81% with an estimated 1-year failure rate of 9.5%. The local control was significantly better in the cohort that received 24 Gy compared to patients receiving less than 24 Gy (94% versus 60%, respectively).

Sahgal and associates also analyzed the use of spine SRS for its application in the postoperative patient. In this prospective cohort series, spine SRS in patients with prior cEBRT resulted in equivalent local and pain control when compared with spine SRS in patients with no history of prior radiation. With spine SRS, the area of tumor adjacent to the spinal cord is the area most at risk for local failure, given that the principle of spine SRS is to treat the target region and avoid the uninvolved normal structures. The interface between the tumor and the spinal cord is frequently underdosed relative to the target to keep the dose to the spinal cord within a safe limit. This is most true in cases of repeat irradiation. Therefore, there is potential for microscopic epidural tumor to be exposed to a subtherapeutic dose, and this is certainly also true of gross epidural tumor when it directly abuts the spinal cord. The consequence of failure at this interface is disease progression and tumor recurrence.

Harel and coworkers investigated whether spine SRS results in lower rates of instrumentation failure or higher rates of fusion compared with surgical decompression and stabilization combined with conventional fractionated radiation in patients with spine tumors. Because SRS delivers precise targeting while sparing the surrounding organs or vital structures, spinal arthrodesis (i.e., fusion) should increase. This series demonstrated a trend toward higher fusion rates and a lower incidence of instrumentation failure with radiosurgery compared to conventional fractionated radiotherapy in the setting of spine instrumentation for tumor surgery.

When applying postoperative radiosurgery, continued challenges exist in delineating the interface between the spinal cord and residual tumor, especially in the setting of spinal instrumentation where artifact formation often compromises imaging quality. As a result, this interface is a potential site of underdosing (or even overdosing) in spine SRS. To overcome limitations in image quality, CT myelography and or positron emission tomography (PET)/CT imaging may improve accurate delineation of this interface. However, PET/CT may be falsely positive immediately after surgery. Others have suggested that the extent of surgical resection of epidural disease may improve tumor control following postoperative SRS ( Fig. 116-1 ).

A, Sixty-two-year-old woman discovered to have a marginal recurrence of a T1 chordoma 7 years after initial resection and stabilization followed by radiotherapy. She underwent posterior surgical resection of the recurrent tumor followed by radiosurgery. B–D, The tumor was treated with a prescription dose of 27 Gy in three fractions using volumetric intensity-modulated arc radiotherapy (VMAT) technology.

Radiosurgery in the Setting of Reirradiation

A great advantage of spine SRS is the ability to reirradiate patients after failed cEBRT within spinal cord tolerance. Although cEBRT may provide palliation in many patients with spine tumors, the duration of pain relief may be short lived, and many patients will develop recurrent or persistent symptoms. For tumor recurrence within a previously irradiated field, treatment options are limited. Surgical intervention is limited by concerns of radiation-induced hypoxia and fibrosis, which potentially impairs wound healing, and reirradiation using conventional techniques is limited by concerns of spinal cord tolerance and potential risks of late spinal cord myelopathy. “Salvage” spine SRS combines precise dose delivery, which avoids significant reirradiation of the spinal cord and dose escalation for biologically more resistant metastases that have failed prior radiotherapy.

SRS is currently most frequently employed in the clinical scenario of tumor recurrence after prior cEBRT determined as either a recurrence of clinical symptoms or radiographic progression of tumor. Spinal cord or cauda equina tolerance precludes the use of further cEBRT delivery, and therefore the more conformal SRS is employed. Several studies have specifically evaluated the clinical outcomes of SRS in the setting of reirradiation. Masucci and colleagues published a review that provides an overview of reirradiation spine SRS and addressed key issues surrounding safe and effective practice. Sahgal and coworkers described the impact of dose hot spots on spinal cord tolerance following SRS by performing a generalized biologically effective dose analysis.

In the largest outcomes experience from the University of Pittsburgh, 344 of the 500 spine metastases cases received prior radiotherapy (69%) with no clinical spinal cord toxicity documented. Other published outcomes series focused only on previously irradiated cohorts have also demonstrated no significant toxicity at a median reirradiation interval of 20 months, with a 93% rate of overall local disease control. Safe reirradiation and dose escalation of “salvage” SRS provide comparable outcomes to primary (de novo) cEBRT, representing a viable minimally invasive salvage treatment for patients who fail primary conventional radiotherapy.

Choi and associates reported on a series of 51 spine metastases treated with SRS that had recurred after cEBRT in close proximity to a previously irradiated spinal cord. Forty-one (80%) of the lesions were treated using a multisession technique in two to five fractions with a median marginal target dose of 20 Gy. Of the 13 failures in this series, 5 recurrences were associated with the epidural space and potentially resulted from target underdosing that resulted from concern for spinal toxicity. The authors concluded that unless the location of the tumor is sufficiently far from the spinal cord, multisession SRS should be employed. Furthermore, patients should be treated in multiple sessions when the single-session plan would have exposed the spinal cord to > 70% of the prescription dose. Interfraction tumor reoxygenation and cell reassortment may increase tumor kill by minimizing hypoxia-associated radiation resistance and cell cycle-specific radiation sensitivity, respectively.

Mahadevan and coworkers also reported on a series of 81 lesions in 60 consecutive patients who were treated with SRS for progressive epidural involvement after previous radiation for spine metastases. Patients were treated with 3 × 8 Gy (24 Gy) when the tumor did not immediately involve the spinal cord or 5 × 5 to 6 Gy (25 to 30 Gy) when the tumor abutted the spinal cord. The cord surface received up to the prescription dose with no hot spots within the spinal cord itself. Overall, 93% of patients had stable or improved disease. No significant spinal cord toxicity was demonstrated. Multisession SRS was demonstrated to be a highly safe and effective technique for this difficult and high-risk clinical scenario.

Damast and colleagues specifically evaluated the causes of local failure (i.e., “in-field recurrence”) after SRS for recurrent spine metastases in a series of 92 patients. Patients were treated with either five 4 Gy fractions or five 6 Gy fractions. Forty-eight percent of patients were treated after decompressive surgery epidural disease. Of all treatment characteristics examined, only the total dose had a significant impact on actuarial local failure incidence. There was no incidence of myelopathy in this group. Therefore, a significant decrease in local failure with a higher total dose was observed without increased risk of myelopathy. Garg and coworkers published a series of 63 spine tumors that were reirradiated with multisession SRS. Doses included 30 Gy in five fractions or 27 Gy in three fractions. Actuarial 1-year radiographic local control for all patients was 76%. Of the tumors that progressed after SRS, 81% were within 5 mm of the spinal cord, thus translating into a failure at the tumor-spinal cord interface. The authors felt that multisession SRS allowed for a higher dose of radiation that translates into greater long-term local tumor control while avoiding the risk of spinal cord toxicity through the use of fractionation.

Finally, Rades and coworkers reported a series of 124 patients who underwent reirradiation with a variety of fractionation schemes. A cumulative biologic effective dose (BED) of less than 120 Gy to the spinal cord resulted in no spinal cord injuries. Wright and colleagues presented a series of 37 patients reirradiated with 20 Gy at 4 Gy per fraction or with 30 Gy at 5 Gy per fraction. The median spinal cord or cauda equina dose was 9.9 Gy, and the cumulative dose was 42 Gy. The median time between initial cEBRT and SRS reirradiation was 13 months. The probability of local control was 60% at a median follow-up of 8 months. No patient experienced radiation-induced myelopathy. The ultimate goal of reirradiation is high-dose single-fraction treatment, which may provide better local control rates that hypofractionated schedules.