Radiosurgery for Spinal Tumors

Benefits of Spine Radiosurgery

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

A substantial body of data, including several evidence-based reviews, supports a number of benefits of spine SRS over cEBRT. According to recommendations from a multidisciplinary spine oncology study group, 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) combination therapy involving surgical intervention (with or without spinal stabilization) followed by postoperative radiosurgery. Recently, the treatment of oligometastatic disease with radiosurgery has also become an important strategy, and can be associated with prolonged progression-free survival and delay in initiating new systemic therapy.

When compared with primary cEBRT, the benefits of primary SRS include a shorter treatment time (one to five fractions with SRS vs. 10–20 fractions for definitive cEBRT treatment), which minimizes the potential for interruptions in systemic therapy, delivery of a high radiobiological dose, which may overcome the relative radioresistance that challenged conventional radiotherapy in certain histologies (e.g., melanoma, renal cell carcinoma), and improved tumor control via a dual cytotoxic mechanism of cytotoxic DNA double-strand breakage, as well as microvascular endothelial dysfunction and apoptosis, resulting in tumor hypoperfusion and cell death. ^, Tumor control rates of 100% using SRS for previously unirradiated spine metastases have been published. 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 (>12 months), whereas out of 387 cases reported on in a multiinstitutional retrospective study, 84% demonstrated local control at 2 years, similar to other published series. ^,

A recently published series by Katsoulakis et al. evaluating 582 patients further demonstrated the durability of high-dose single-fraction SRS. In this series, 30 patients (5.1%) with 32 lesions required some degree of surgical intervention for mechanical pain or instability. At a median time to surgery of 42.5 months, 78% of the surgically obtained tissue demonstrated ablation of tumor on pathological review despite 50% of the patients having radioresistent renal cell pathology, melanoma, or sarcoma at presentation.

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 score >70) was published by Chao et al. A newer, larger series published by the same group evaluated a cohort of 444 patients based on Karnofsky performance status score, controlled systemic disease, and presence of visceral disease, and found that the patients in class 1 demonstrated a median overall survival of 26.7 months, in contrast to only 4.5 months seen in class 3 patients. 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, 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., hematological 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 radioresistant 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 report good results, only because of the large numbers of hematological 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 and outcomes that are independent of the primary histology or volume. Moreover, SRS has largely replaced en bloc the vertebral body resections that were previously favored, even for solitary metastasis, because of its ability to be delivered in a noninvasive outpatient setting with no associated recovery time. ^, Hence, in cases where the tumor is associated with no or minimal spinal cord compression, SRS is offered as definitive first-line therapy.

One of the largest series published 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. Tseng et al. published a series including 145 patients (279 lesions) treated with 24 Gy over two fractions, for which the 1- and 2-year local control rates were 90.3% and 82.4%, respectively.

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 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.

Chang and associates reported a phase I/phase II study in a series of 63 spinal metastasis 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 (eight cases were treated with 24 Gy delivered in a single fraction). The actuarial 1-year spine tumor progression-free survival rate 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 criterion 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 just 1 week after treatment.

A systematic review of the literature for both cEBRT and SRS for metastatic spine disease was published in 2009. Some 29 single-institution case series of spine SRS 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 with no relative contraindications. A similar, more recent, systematic literature review by Sohn and Chung analyzed a total of 31 studies of SRS for spinal metastases and drew similar conclusions. ^{, , , , , ,} A clear advantage to the neoadjuvant approach involves the ability to carefully delineate tumor volumes in unviolated tissue planes. ^,

Importantly, randomized studies are needed to determine if there is a benefit to SRS over conventional radiation. Radiation Therapy Oncology Group (RTOG) 0631 was a phase II/III study comparing 8 Gy in one fraction delivered conventionally to 16 to 18 Gy in one fraction delivered using SRS. Pain was the primary endpoint, and 353 patients were enrolled. There was no difference in pain outcomes. The pain relief from spine SRS was much less than expected in this study. One criticism is that a dose of 16 Gy was used in this study, which was perhaps insufficient. A similar study (Canadian Cancer Trials Group [CCTG] SC.24 ) was performed in Canada, in which 24 Gy in two fractions delivered with SRS ( n = 114) was compared with 20 Gy in five fractions delivered with conventional radiation ( n = 115). Unlike RTOG 0631, 35% of patients who received 24 Gy in two fractions with SRS in the CCTG SC.24 study had a complete pain response, compared with 14% with conventional radiation at 3 months ( P < .001). This difference in pain relief continued at 6 months. Thus, SRS may provide better pain relief when sufficient dose is given.

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. ^{, ,} Radiological evaluation showed that local control was maintained in 77% of patients at 2 years.