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Radiotherapy and Radiosurgery for Metastatic Spine Disease: What Are the Options, Indications, and Outcomes?

Gerszten, Peter C., MD, MPH*†; Mendel, Ehud, MD; Yamada, Yoshiya, MD§

doi: 10.1097/BRS.0b013e3181b8b6f5
Metastatic Tumors of the Spine
Free

Study Design. Systematic literature review.

Objective. To determine the options, indications, and outcomes for conventional radiotherapy and radiosurgery for metastatic spine disease.

Methods. Three research questions were determined through a consensus among a multidisciplinary panel of spine oncology experts. A systematic review of the literature was conducted regarding radiotherapy and radiosurgery for metastatic spine disease using PubMed, Embase, the Cochrane Evidence Based Medicine Database, and a review of bibliographies of reviewed articles.

Research questions:

  1. What are the clinical outcomes of the current indications for conventional radiotherapy alone and stereotactic radiosurgery for metastatic spine disease?
  2. What are the current dose recommendations and fractionation schedules for conventional spine radiotherapy and stereotactic radiosurgery for metastatic spine disease?
  3. What are the current known patterns of failure and complications after conventional spine radiation and stereotactic radiosurgery for metastatic spine disease?

Results. For conventional radiotherapy, the initial literature search yielded a total of 531 potentially relevant abstracts. Each of these abstracts was reviewed for relevance, and 62 were selected for in-depth review. Forty-nine studies met all the inclusion criteria. References from the articles included in the analysis and review articles were also examined for potential inclusion in the study. For conventional radiotherapy, 3 randomized trials (high-quality evidence), 4 prospective studies (moderate-quality evidence), and over 40 nonprospective data sets (low- or very-low-quality evidence) that included over 5000 patients in the literature were included in this review. Drawing from the same databases, a systematic search for radiosurgery yielded 195 abstracts, of which 29 met all inclusion criteria. They all represented single-institution reports (low- or very-low-quality data). No randomized data are available for spine radiosurgery.

Conclusion. A systematic review of the available evidence suggests that conventional radiotherapy is safe and effective with good symptomatic response and local control, particularly for radiosensitive histologies. A strong recommendation can be made with moderate quality evidence that conventional fractionated radiotherapy is an appropriate initial therapy option for patients with spine metastases in cases in which no relative contraindication exists. A systematic review of the available evidence suggests that radiosurgery is safe and provides an incremental benefit over conventional radiotherapy with more durable symptomatic response and local control independent of histology, even in the setting of prior fractionated radiotherapy. A strong recommendation can be made with low-quality evidence that radiosurgery should be considered over conventional fractionated radiotherapy for the treatment of solid tumor spine metastases in the setting of oligometastatic disease and/or radioresistant histology.

A systematic review of the available evidence found that conventional radiotherapy for spine metastases is safe and effective with good symptomatic response and local control, particularly for radiosensitive histologies. Radiosurgery is safe and provides an incremental benefit over conventional radiotherapy with more durable symptomatic response and local control independent of histology, even in the setting of prior fractionated radiotherapy.

From the Departments of *Neurological Surgery and †Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA; ‡Department of Neurological Surgery, The Ohio State University, Columbus, OH; and §Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY.

The medical device(s)/drug(s) is/are FDA-approved or approved by corresponding national agency for this indication.

No funds were received in support of this work. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.

Address correspondence and reprint requests to Peter C. Gerszten, MD, MPH, Department of Neurological Surgery, Suite B-400, 200 Lothrop St., Pittsburgh, PA 15213; E-mail: gersztenpc@upmc.edu

Approximately 5% to 10% of all cancer patients will develop spine metastases. The majority of these patients will undergo palliative radiation therapy. 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 halting progression of or reversing neurologic compromise.1 The role of radiation therapy for the treatment of metastatic tumors of the spine is well established.2–8

Conventional radiotherapy, defined as radiation delivered in 1 to 2 radiation beams without high precision or highly conformal treatment techniques, is widely accepted as an appropriate treatment modality. However, the effectiveness of conventional radiation has been limited by the spinal cord, which is intolerant of high-dose radiation. In recent years, advances in imaging technology and computerized treatment planning have allowed the safe delivery of high-dose radiation (image-guided intensity-modulated radiation therapy or spinal radiosurgery) to spinal metastases even in close proximity to the spinal cord and other paraspinal dose-sensitive organs. These treatments are often given in 1 to 5 fractions of high-dose radiation (to ensure safe doses) that are able to limit the dose to the spinal cord.

In general, metastatic patients are difficult to study retrospectively because multiple confounding factors are present and difficult to control. They often suffer from a multitude of concurrent clinical problems. Quality of life may be confounded by the effects of chemotherapy or surgery in conjunction with radiation therapy, as well as by the effects of the disease itself. Survival may also be limited and thus long-term follow-up is not typical for this patient population.

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, because conventional external beam radiotherapy lacks the precision to deliver large single-fraction doses of radiation near radiosensitive structures. This often limits the treatment dose to a level far below the optimal therapeutic dose,2,9,10 resulting in less than optimal clinical response. 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.10–18

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.19–24 Studies have previously determined the clinical efficacy of single-fraction therapy for painful bone metastases.25 Both, a Radiation Therapy Oncology Group Phase III trial as well as a meta-analysis found no significant difference in complete and overall pain relief between single-fraction and multifraction palliative radiation therapy for bone metastases.19,25 Most of these trials used 8 Gy in a single fraction. However, none of these trials were specifically evaluating spinal metastases.

The emerging technique of radiosurgery for spine metastases represents a logical extension of the current state-of-the-art radiation therapy. Stereotactic body radiosurgery (SBRS) has emerged as a new treatment option in the multidisciplinary management of metastases located within or adjacent (paraspinal) to vertebral bodies/spinal cord.26 SBRS provides an option to deliver high-dose per fraction radiation, and therefore a high biologic equivalent dose, in 1 to 5 fractions. The aims of SBRS for spinal metastases are to improve on existing rates of clinical response and tumor control, and to reduce the retreatment rate by increasing the biologic equivalent dose.26

Since Hamilton et al27 first described the possibility of linear-accelerator–based spinal stereotactic radiosurgery in 1995, multiple centers have attempted to pursue large fraction conformal radiation delivery to spinal lesions using a variety of technologies.10,13–18,27–35 Researchers have shown the feasibility and clinical efficacy of spinal hypofractionated stereotactic body radiotherapy for metastases. 10,12–18,36 Others have demonstrated the effectiveness of protons for spinal and paraspinal tumors.37 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 3-dimension localization and pretreatment planning, the advent of intensity-modulated radiated therapy, 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 to the spinal cord and cauda equina.

The goals of SBRS parallel those of brain radiosurgery, namely, to improve local control over conventional fractionated radiotherapy and to be effective in previously irradiated lesions with an acceptable safety profile. Therefore, the purpose of this chapter is to provide evidence-based answers to several key questions related to the use of radiosurgery for the treatment of spine metastases. This process will synthesize the best available evidence and use the consensus expert opinion of the Spine Oncology Study Group in offering clinically relevant grades of recommendations for practitioners who treat spine metastases. The grades of recommendation, whether strong or weak, are based on the quality of evidence in conjunction with the balance of the benefits and harms of the intervention.38 Specifically, a focused qualitative systematic review was performed to investigate the 2 pertinent questions regarding the utilization of radiosurgery for spine metastases.

Keeping in mind difficulties regarding the interpretation of data from metastatic patients, a comprehensive survey of the available medical evidence was done to assess the following clinically significant questions:

  1. What are the clinical outcomes of the current indications for conventional radiotherapy alone and stereotactic radiosurgery for metastatic spine disease?
  2. What are the current dose recommendations and fractionation schedules for conventional spine radiotherapy and stereotactic radiosurgery for metastatic spine disease?
  3. What are the current known patterns of failure and complications after conventional spine radiation and stereotactic radiosurgery for metastatic spine disease?
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Materials and Methods

A systematic literature search for conventional radiotherapy of spine metastases was undertaken. The search was limited to data published from 1980 (to limit data to modern treatment techniques) and available in English. References from each paper were also reviewed for relevant articles. Articles were selected for relevance to conventional radiotherapy for bony spine metastases; those which were primarily surgical and without radiation-therapy data were excluded. Surgical data describing cohorts who had radiotherapy without surgery were included if sufficient details regarding radiation and outcomes of those patients were provided. Stereotactic radiosurgery reports were also excluded from this analysis. Case reports or papers describing less than 10 patients were also excluded. Search was performed on PubMed (217 abstracts), Embase (274 abstracts using Emtree terms and 36 using keywords), and the Cochrane Evidence Based Medicine Database (4 abstracts). References from the articles included in the analysis and review articles were also examined for potential inclusion in the study. After cross checking for duplicates, the initial literature search yielded 531 potentially relevant abstracts. Sixty-two abstracts were selected for in-depth review, and 49 studies met all the criteria for inclusion in this article (Table 1). The GRADE criteria set out by Guyatt and coworkers38 was used to critically evaluate the quality of each dataset see “Quality of Evidence” in Table 1).

Table 1

Table 1

Table 1

Table 1

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Data Summary for Conventional Radiotherapy

Overall, only 9 papers presenting prospective data were found,20,45,78–83 of which 3 are randomized trials.78–80 The majority of published literature represents single- or multi-institution retrospective series. A wide range of radiation dose-fraction schedules have been reported in these series, with a mixture of histologies. Given the inherent biases of retrospective data, conclusions from these series must be interpreted as hypothesis generating only.

The vast majority of reported dose-fractionation schedules fall into 2 categories: short course (within 2–5 fractions) and long (>5 fractions). No reports describing treatment more than once a day (i.e., hyperfractionation) were found. Under the umbrella of short-course radiation, 95% were treated by either 8 Gy × 1, 3 Gy × 5 (reirradiation), or 4 Gy × 5. Long-course radiation regimens were 8 Gy × 2, 5 Gy × 3 + 3 Gy × 5 split course, 4 Gy × 7, 3 Gy × 10, or 2 Gy × 20. The most commonly used fractionation schedule was 3 Gy × 10. Short-course radiation was more likely to be prescribed in cases of patients with poor performance status. Thirty-two studies reported survival outcomes (median, 4.3 months; range, 2–20 months). The majority of patients described received dexamethasone in conjunction with radiotherapy.

The most commonly addressed clinical scenario was epidural cord compression. Because of the retrospective nature of the vast majority of the data, functional outcome analysis was problematic. Nonetheless, the most commonly reported outcome was the number of patients who maintained ambulatory status or regained ambulatory status (if not ambulatory before radiotherapy). With similar caveats, pain improvement was addressed in 11 reports. In the retrospective series, no common definition of ambulatory or nonambulatory status was found, and details on how pain was assessed were scant.

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Data Summary for Radiosurgery

Twenty-nine reports of spine radiosurgery treating metastatic spine tumors alone or in combination with benign spinal tumors were identified (Table 2). The quality of evidence of the selected studies was then assigned a score of high, moderate, low, or very low based on the GRADE approach.38 Twenty-one studies met the criteria of low and 8 studies were categorized as very low. The methodologic quality of the studies was overall low. The data were not pooled, but the relevant results were summarized (Table 2).

Table 2

Table 2

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Results

Conventional Radiotherapy for Metastatic Spine Disease

What are the clinical outcomes of the current indications for conventional radiotherapy alone for metastatic spine disease?

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Ambulatory Status.

Data from 3 randomized trials using 3 different fractionation schedules (3000 cGy/10, 3000 cGy/8 split course, 1600 cGy/2 split course) have been reported in a total of 327 patients who presented with epidural spinal cord compression.78,80,81 The patient population represented a mixed group of histologies, with a median overall survival of 3 to 4 months.

Seventy-four percent78 and 67% of patients81 remained ambulatory after radiotherapy alone. Of those deemed nonambulatory at the time of radiation, 19% and 26% of patients regained ambulatory status. In the radiation-only arm of a small randomized study reported by Young et al,80 60% of patients treated with radiation only (3000 cGy/10 fractions split course) remained ambulatory, but only 33% regained ambulant status. Thus, in this prospectively followed patient cohort, less than one-third of nonambulant patients were able to recover ambulation after conventional radiation therapy.

In 2 nonrandomized prospective studies with a total of 423 patients, 82% of patients42 and 75% to 79%20 were reported to be ambulatory, while 60% and 30% of nonambulatory patients regained ambulation after radiation therapy. The high number of patients who regained ambulation in the Maranzano study was thought to be in part due to a large number of favorable histologies in the data set. Seven percent of the patients had also undergone surgical decompression. A prospectively collected data set from Memorial Sloan Kettering Cancer Center reported that 89% of patients remained ambulatory, and 35% recovered the ability to walk after 3000 cGy/10 given in a split course.83 A prospective data set reported by Turner et al found that 81% were ambulant, and only 12.5% regained ambulant status after radiation.82 In the radiation-only arm (3000 cGy/10 fractions) of Patchell’s randomized trial of conventional radiation versus decompressive surgery and conventional radiation, 19% of patients regained ambulation after conventional radiotherapy alone. Only 2 of 35 patients remained ambulatory at 500 days after conventional radiation therapy, compared with 6 of 34 patients who underwent both surgery and radiation (P = 0.024). Patients who received conventional radiotherapy alone were able to walk a median of 54 days. Those who received radiation alone were able to maintain ASIA and Frankel scores a median of 72 days post-treatment. The median survival for this group was 100 days.78

Summarizing the retrospective data, 5125 patient ambulatory outcomes were described, although it is possible that in some cases, patient outcomes were described in different reports by the same authors at different time intervals. Based on the reported data, 4155 patients remained ambulatory after radiation (81%; range, 58%–100%). In the same group of papers, an average of 32% (range, 6%–67%) of patients who were nonambulatory before radiation became ambulatory after radiotherapy alone.

Level 1 evidence shows that 60% to 74% of patients remain ambulatory after conventional radiation in the setting of cord compression, whereas 19% to 33% of nonambulant patients are able to walk after radiation. Prospective series and retrospective data report rates of ambulation somewhat more optimistic than the data from randomized trials, but there is no doubt that conventional radiation is able to provide ambulatory benefit to patients who undergo treatment.

Ambulation status is correlated with survival. However, ambulation status may have less to do with radiation therapy than with the ability of the patient to walk before treatment, or the timing between radiation and the onset of symptoms, as only a minority of patients nonambulant before treatment are able to walk after radiation.

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Pain Palliation.

One randomized trial reported the effects of radiation therapy on pain.79 In this study using 2 unconventional fractionation schedules (3000 cGy/8 or 1600 cGy/2, both split course), 57% of patients reported improvement in pain with a median survival of 4 months. The fractionation schedule was not found to be a significant predictor of pain-related outcomes. A small, randomized trial from UCLA found that 46% of patients experienced pain relief in the radiotherapy-alone arm.80 The median survival for this cohort was 5 months. It appears that approximately half of patients undergoing conventional palliative radiation report pain improvement. The median survival noted for these patients is typical of the advanced stage of disease that this patient cohort represents. Hence, even with short median survival, palliation of pain from spine metastases with conventional radiation therapy can offer important contributions to patient quality of life.

One nonrandomized prospective study reported that 77% of patients reported improvement in pain after radiotherapy.81 The median survival of these patients was 6 months. After split-course radiation (3000 cGy/10), 82% of patients followed prospectively (N = 83) experienced improvement in pain. Another prospective case series of 37 patients treated with a variety of short- or long-course fractionation schedules found that 73% of patients reported reduced pain after radiotherapy alone.82

Of the retrospective series that described pain outcomes,22,39,48,49,45,46,53,54,65,68–70,72,74,76,77,78,81–83 a mean of 70% (range, 57%–100%) of patients were found to have improvement in pain after radiation therapy. However, symptoms like pain are difficult to accurately assess retrospectively, particularly in patients with metastatic disease, who typically have multiple reasons for pain. No uniform method of reporting pain was used. It is not clear whether the responses were reported by patients or were physicians’ assessments. In almost all cases, no validated instrument to measure response to treatment was described. Also the length of follow-up varied from report to report. Despite these shortcomings, the data consistently demonstrates that conventional palliative radiotherapy is an important treatment modality for spine metastases.

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Other.

One prospective report found that 44% of patients recovered sphincter function,81 whereas another report limited to breast-cancer patients reported the improvement in sphincter function after radiation therapy in 67% of the affected patients.45

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What Are the Current Dose Recommendations and Fractionation Schedules for Conventional Spine Radiotherapy?

Finding the optimal dose-fractionation schedule for the treatment of spine metastases with conventional radiation therapy has been a subject of great interest in the medical literature. This has been most commonly assessed in the setting of epidural cord compression.

Maranzano has reported the results of a study that prospectively evaluated 2 different fractionation schedules: 3000 cGy in 10 fractions versus 500 cGy × 3 + 300 cGy × 5 delivered in a split course.81 Two hundred nine patients were evaluated and the study reported the median survival as 6 months. Of the patients, 82% remained ambulatory and 60% who were not ambulatory regained their ability to walk after radiation therapy. Seven percent of the reported cohort underwent surgery, which confounds the results, but no significant difference in outcome was found for the different fractionation schedules. The same author has reported the results of a prospective randomized trial testing 500 cGy × 3 + 300 cGy × 5 split course versus 800 cGy × 2 split course.79 Two hundred seventy-six patients were enrolled. The study found that 67% of ambulatory patients remained ambulatory, and 26% of nonambulatory patients regained their ambulant status. The median survival was 4 months. Although this study has been heavily criticized for the unusual dose-fractionation schedules it employed, the finding that the dose-fractionation schedule had no significant impact on outcomes is important. Rades reported the results of a prospective study comparing the outcomes for 300 cGy × 10 versus 200 Gy × 20, and found that the dose fractionation did not significantly impact on ambulatory status (75%–79%), or the probability of regaining ambulation (30%).20

The retrospective data suggests that short-course radiation (i.e., given in 1–5 fractions over 1 week) has a less durable response compared with longer fractionation schedules. A retrospective multicenter study that included 1852 patients with mixed histologies treated to either 800 cGy × 1 or 400 cGy × 5 had less local control (65% vs. 85%) compared with those who received longer-course radiation (300 cGy × 10, 250 cGy × 15, 200 cGy × 20).58 Those patients undergoing short-course radiation experience a greater statistically significant likelihood of worsening motor function. In terms of overall survival, the fractionation schedule was not found to be a significant factor in multivariate analysis. The benefit of longer-course radiation was best demonstrated with studies reporting more radioresponsive histologies such as breast and prostate cancer and with median survival greater than 9 months.53,55,56 Studies that found no difference in shorter versus longer fractionation schedules46 recommend short-course radiation, given that the treatment intent is palliation.20,23,79,41,42,44,50 Conversely, those that found a benefit with longer-course radiation recommend that approach with patients expected to have a longer expected survival. This may represent a treatment bias in which patients with more favorable disease are more likely to receive a longer course of treatment. Unfortunately, the available randomized data are not able to provide further clarification, perhaps because the median survival is not sufficiently long, nor the dose-fractionation schedules that were employed sufficiently different to distinguish a difference.

Nonetheless, it is reasonable to consider an abbreviated course of treatment in patients with a poor prognosis, measured in weeks, who will not live long enough to suffer the potential negative consequences of a shorter course of radiation and not benefit from the interruption of their daily routine that 2 to 4 weeks of daily radiation will cause.

What are the current known patterns of failure and complications after conventional spine radiation for metastatic spine disease?

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Local Control.

Local control, defined as the absence of recurrent cord compression in the irradiated field, was reported in 7 retrospective studies that included 885 patients.39,47,49,53,55,56,68, The mean crude rate of local control was 77% (range, 61%–89%). Again there is a probability that in some reports the same patients were reported by the same authors at different times. Likewise, important factors such as dose/fractionation, histology, and the length of follow-up were not controlled. One study39 reported that 80% of postradiation myelograms demonstrated radiographic improvement of epidural disease. Zelefsky et al found that 58% of blocked myelograms returned to normal after radiotherapy for prostate-cancer metastases.68

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The Impact of Histology.

Tumor histology is clearly a prognostic factor in treatment response in both the prospective and retrospective literature. In a prospective trial of 209 evaluable patients, Maranzano found that, although the dose-fractionation schedule had no significant impact, the histology of the lesion was significant.81 For example, 70% of nonambulant breast-cancer patients recovered ambulatory status compared with only 20% of hepatocellular carcinoma patients. Favorable histologies enjoyed a more durable response to treatment (10–16 vs. 1–3 months). In the literature, breast cancer, prostate cancer, myeloma, lymphoma, and leukemia are nearly universally described as favorable (Table 3). In a randomized trial comparing short-course radiotherapy (800 cGy × 2) and split-course radiotherapy (500 cGy × 3, 4-day break, 300 cGy × 5), patients with lymphoma, seminoma, myeloma, prostate cancer, and breast cancer were considered favorable, whereas those with lung cancer, kidney cancer, gastrointestinal cancer, head and neck cancer, melanoma, and sarcoma were considered unfavorable.79 A significant difference in median survival and duration of motor improvement was found for favorable histologies (6 vs. 3 months, P = 0.0001), although the fractionation schedule employed had no significant impact on outcomes.

Table 3

Table 3

Investigators from the University of Nagoya have reported their experience with treating 101 patients with spine metastases with conventional fractionation (93% received 200 cGy × 20).49 With median follow-up in long-term survivors ≤53 month (range, 24–81 months), favorable responders, classified as lymphoma, small-cell lung cancer, prostate cancer, breast cancer, myeloma, and ovarian cancer, had significantly better outcomes (P < 0.001) (83%–87% vs. 64%–66%) in terms of functional ability, neurologic status, and pain relief compared with less favorable histologies. The study reported actuarial outcomes for conventional radiation in terms of favorable and unfavorable histologies. With maximum follow-up approaching 7 years, 10% of radioresistant histologies and 30% of radiosensitive histologies had durable responses at 7 years.

In a prospective evaluation of 300 cGy × 10 versus 200 cGy × 20, patients with epidural cord compression, those with unknown primary non–small-cell lung cancer (NSCLC), and melanoma were grouped as unfavorable, whereas breast cancer, prostate cancer, renal cancer, and other histologies were classified as intermediate. Favorable histology was important, but the dose-fractionation schedule did not impact significantly on the outcome.20

A retrospective evaluation of 922 patients given 3 different fractionation schedules for metastatic spinal cord compression (3000 cGy × 10, 250 cGy × 15, or 200 cGy × 20) found that using these treatment regimens, neither histology (lung, breast, prostate, or other cancer) or dose-fractionation schedule made a difference in local control. Hence 300 cGy × 10 was recommended as the best treatment option.47

In a large multi-institutional retrospective analysis of 1852 patients treated with a variety of fractionation schedules (800 cGy × 1, 400 cGy × 5, 300 cGy × 10, 250 cGy × 15, 200 cGy × 20), representing 12 to 40 Gy total dose in 2 Gy per fraction equivalents, short-course radiation (800 cGy × 1 or 400 cGy × 5) did significantly worse than long-course radiation (P < 0.001). Histology was significant in univariate but not multivariate analysis (P = 0.14).58

In a different study, when the response of specific radioresistant histologies such as renal cell carcinoma was retrospectively assessed, the dose-fractionation schedule was found to have no significant influence on outcome.42 However, follow-up was short (median, 7 months) and the median time to progression was also 7 months, underscoring the difficulty of studying the metastatic patient cohort. Nonetheless, the dose-fractionation schedule did not influence outcome in the setting of unfavorable histologies, suggesting that the biologic impact of conventional fractionation is insufficient for tumor control for these tumor types.

There appears to be near-uniform agreement among investigators to classify lymphomas, myelomas, seminomas, breast cancer, and prostate cancer as radiosensitive or favorable histologies, whereas sarcomas, melanomas, renal cell carcinomas, gastrointestinal carcinomas, and NSCLC are unfavorable or radioresistant (Table 3). Given the limitations of retrospective data, parameters such as improvement in motor function may be an appropriate endpoint to assess radiation response to solid tumor metastases to the spine. Reports of radiation response limited to one specific histology after conventional radiation also seem to corroborate the logic of classifying breast- and prostate-cancer metastases as radiosensitive, with greater than 30% of patients described as having improved motor function, including regaining ambulatory status, whereas patients with NSCLC, renal cell carcinoma, melanoma, and sarcoma achieve improved motor function <30% of the time (Table 2, Table 4).

Table 4

Table 4

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Toxicity.

Metastatic patients often have a myriad of reasons for not feeling well, separate from the effects of spine radiation, because they have in many cases had multiple courses of systemic chemotherapy, radiotherapy, and/or surgical procedures. Each treatment has the potential to induce toxicity that may be related or independent of spine radiation. With multiple potential confounding influences, accurate treatment-related toxicity may be very difficult to report, even in a prospective fashion, but is particularly challenging in retrospective review. Very little data were found in regards to toxicity associated with conventional radiation therapy. When mentioned, it was only in a cursory fashion, stating that no significant toxicity (i.e., myelitis, vertebral body fracture, and severe esophagitis) was noted. In general, conventional radiation for spine metastases confers short-term reversible toxicity such as fatigue, mucositis, or bowel irritation, depending on which segment of the spine is irradiated.

The more feared complications are often delayed complications such as radiation myelopathy, which may take years to manifest, far beyond the expected survival of typical patients undergoing conventional radiation therapy. Although the actual tolerance of the spinal cord is unknown, a commonly accepted spinal cord dose to give a 5% or less risk of radiation myelopathy at 5 years is 50 Gy to <5 cm of cord, given in standard fractionations.104 Dose-fractionation schedules used for conventional radiation fall below this dose limit. However, one report with 39 long-term survivors with a median follow up of 69 months reported one case of radiation myelopathy in the absence of recurrent disease, 18 months after radiation. No actuarial analysis was provided. This patient had a split course of 800 cGy × 2.105

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Stereotactic Radiosurgery for Metastatic Spine Disease

What are the clinical outcomes of the current indications for radiosurgery for metastatic spine disease?

The current indications for the use of radiosurgery as a treatment modality for metastatic spine disease include pain (palliative benefit) related to a specific involved vertebral body, radiographic tumor progression, as a primary treatment modality, for progressive neurologic deficit, or after open surgical intervention. The evidence to support the use of radiosurgery for each of these indications and associated clinical outcomes will be analyzed separately. The published outcomes of spine radiosurgery can be grouped into 4 general categories, as defined by Sahgal et al26:

  1. Unirradiated patients: spinal metastases in a previously unirradiated volume treated with SBRS.
  2. Reirradiated patients: spinal metastases in a previously irradiated volume now containing new, recurrent, or progressive metastatic disease treated with SBRS.
  3. Postoperative SBRS patients: spinal metastases treated with SBRS after open surgical intervention, with or without spinal stabilization.
  4. Mixed patients: mixed populations involving patients in the previous 3 categories in which outcomes are not separately reported.
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Pain and Quality of Life.

The most frequent indication for the treatment of spinal metastases is pain. Radiation is well known to be effective as a treatment for pain associated with spinal malignancies. Twenty-seven peer-reviewed publications that included clinical outcome after spine radiosurgery were reviewed. Radiosurgery was reported to be highly effective at decreasing pain associated with a symptomatic spine metastasis, regardless of prior treatment with conventional fractionated radiotherapy, with an overall reported improvement rate of approximately 85%. Pain is reported to decrease usually within weeks after treatment, and occasionally within days.

Early prospective small-cohort series reported 85% to 100% improvement rates in pain.13,16–18,27,31,106 For symptomatic spine metastases that had not received prior radiation, Ryu et al98 reported an overall pain-control rate for 1 year of 84% in a series of 61 patients. Yamada et al reported 90% excellent palliation of symptoms with a median follow-up of 12 months.38 Gerszten et al reported a mixed population with an overall pain improvement in 290 of 336 cases (86%), depending on primary histopathology.95 Durable pain improvement was demonstrated in 96% of women with breast cancer, 96% of cases with melanoma, 94% of cases with renal cell carcinoma, and 93% of lung-cancer cases.88,89,90,92 Gibbs et al reported that 84% of symptomatic patients experienced improvement or resolution of symptoms after treatment.97 Jin et al reported 85% pain improvement in a series of 196 patients.94 Excellent pain-control and quality-of-life analysis after spinal radiosurgery has been reported from Georgetown University Hospital.85,96,101 Using visual analog scales for pain assessment and the 12-item Short Form Health Survey (SF-12), in a series of 151 patients radiosurgery was demonstrated to statistically improve pain control and maintain quality of life in 97% of patients with follow-up ≤48 months. Furthermore, the 12-item Short Form Health Survey Physical Component scores demonstrated no significant change throughout the follow-up period.

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Local Control and Radiographic Tumor Progression.

Spine radiosurgery is frequently used to treat radiographic tumor progression after conventional irradiation treatment or after prior surgery. The majority of these lesions have received irradiation with significant spinal cord doses, precluding further conventional irradiation delivery. Currently, spine radiosurgery is often being used as a “salvage” technique for those cases in which further conventional irradiation or open surgery are not appropriate. The ideal lesion should be well circumscribed such that the lesion can be easily outlined (contoured) for treatment planning.

Early prospective small-cohort series reported local control rates of approximately 90%.13,14,16,17,27,31,100 Larger cohort studies have demonstrated similar high local control rates. Degen et al demonstrated a 95% local control rate in 58 lesions.85 Yamada demonstrated 90% local long-term control.99,107 Chang et al reported 84% progression-free incidence in 74 lesions.108 Overall long-term radiographic tumor control for progressive spinal disease in a series of 500 cases was 88%.95 Radiographic tumor control differed based on primary pathology: breast (100%), lung (100%), renal cell (87%), and melanoma (75%). As greater experience is gained, the technique will likely evolve into an initial upfront treatment for spinal metastases in certain cases (e.g., oligometastases). This is similar to the evolution that occurred for the treatment of intracranial metastases using radiosurgery, over the past decade. Finally, Gagnon et al published a matched-pair analysis comparing 18 patients with breast-cancer spine metastases treated with radiosurgery (17 of which had prior irradiation to the lesion) to 18 matched patients who received conventional external beam radiotherapy up front.96 This study concluded that salvage radiosurgery is as efficacious as initial fractionated radiotherapy without added toxicity.

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Primary Treatment Modality.

One option is to use radiosurgery as the sole radiation treatment. This clinical scenario is often encountered in patients undergoing treatment to a symptomatic spine lesion with other significant but asymptomatic spine metastases. The additional asymptomatic lesions may be treated with radiosurgery to avoid further irradiation to the neural elements as well as to avoid further bone-marrow suppression and permit subsequent systemic therapy. The benefits for this approach include a single treatment that is radiobiologically larger than can be delivered with standard radiotherapy, with a minimal radiation dose to adjacent normal tissue.

When used as a primary treatment modality, long-term radiographic tumor control was demonstrated in 90% of cases (in all breast, lung, and renal cell carcinoma metastases, and 75% of melanoma metastases).88,89,90,92 Degen et al85 reported a 100% tumor control rate in lesions that had not previously undergone irradiation. Yamada demonstrated a 90% local long-term control in lesions not previously irradiated.99 Other series report radiographic tumor control rates of 93% and 100%.18,31 Finally, Ryu et al published a dose-escalation trial in which a series of 49 patients with lesions that had not previously undergone fractionated radiotherapy demonstrated good clinical outcomes.98

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Progressive Neurologic Deficit.

Spine radiosurgery may be used to treat patients with progressive neurologic deficits when open surgical intervention is felt to be contraindicated. In most of these particular cases, conventional irradiation has already been delivered to the symptomatic spinal lesion. In an early series, 5 of 12 patients with neurologic symptoms demonstrated improvement.17 Mahan et al reported a series of 8 patients treated for spinal cord compression.87 Gerszten et al reported 36 of 42 patients (86%) with a progressive neurologic deficit before treatment experienced at least some clinical improvement.95 In most of these cases, open surgical decompression was precluded because of medical comorbidities. Yamada reported 90% and 92% palliation of symptoms in patients treated for weakness and paresthesias, respectively.99 Degen reported neurologic deficits improved in 16 patients, unchanged in 24 patients, and worsened in 11 patients in their series.85 In a series from the Henry Ford Hospital, 12 of 16 cases (75%) with neurologic deficit from spinal cord compression were clinically improved or stable improved after spine radiosurgery.18,94,91 High-grade spinal cord compression remains a relative contraindication to radiosurgery, and open surgical decompression should be considered the primary treatment option for these patients.

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After Open Surgery as Adjuvant Therapy.

If a tumor is only partially resected during an open surgery, radiosurgery may be used to treat the residual tumor at a later date. 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 at a later date with radiosurgery, thus further decreasing surgical morbidity. Anterior corpectomy procedures in certain cases can be successfully avoided by posterior decompression and instrumentation alone, followed by radiosurgery to the remaining anterior lesion. With the ability to effectively perform spinal radiosurgery, 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 standard external beam irradiation is permitted. Open surgery for spinal metastases will likely evolve in a similar manner in which malignant intracranial lesions are debulked in such a way as to avoid neurologic deficits and minimize surgical morbidity.

Rock et al specifically evaluated the combination of open surgical procedure followed by adjuvant radiosurgery in a series of 18 patients.98,91 They found this to be a successful treatment paradigm that was associated with a significant chance of stabilizing or improving neurologic function. Local control was 94%. The technique was well tolerated and associated with little to no morbidity. Gerszten et al published a series of 26 patients treated with radiosurgery after vertebral body cement augmentation.109 Local control was 92%. Only 9 patients of a series of 500 cases underwent radiosurgery as adjuvant therapy after open surgery.95

What are the current dose recommendations for spine radiosurgery?

The prescribed dose of radiation to the tumor 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 developed optimal doses for this treatment technique. The appropriate dose or fractionation schedule for spinal radiosurgery for metastatic tumors has not been determined. Spinal radiosurgery was found to be safe at doses comparable to those used for intracranial radiosurgery without the occurrence of radiation-induced neural injury.

Dose and fractionation schedules differ by institution. A range of prescribed doses have been reported and include single-fraction radiosurgery ranging from 8 to 24 Gy or hypofractionated regimens consisting of 4 Gy × 5 fractions, 6 Gy × 5 fractions, 8 Gy × 3 fractions, and 9 Gy × 3 fractions.101 There is currently no evidence to support one regiment over another.26 Many recent larger series are moving to a single-session technique.84,94,95,99 One recent large series101 reported treating lesions with no previous radiation with 26.4 Gy in 3 fractions prescribed to the 75% isodose surface. Previously irradiated lesions were treated to a mean dose of 21 Gy in 3 fractions. Some authors report a multisession treatment for lesions that have been treated with prior irradiation.85 Others continue to prefer treatment delivery in up to 5 fractions.93,97 All dose regimens currently appear to be equally safe and efficacious.

What are the current known patterns of failure and complications after spine radiosurgery for metastatic spine disease?

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Patterns of Failure After Spine Radiosurgery.

Several studies have specifically addressed the patterns of failure encountered after spine radiosurgery. One concern that has been raised regarding radiosurgery for spinal metastases is that adjacent levels are not included in the radiation field. One possibility is that the tumor can progress within the adjacent levels. In our series, there were no cases of tumor progression at the immediate adjacent levels, justifying the treatment of the involved spine only. Ryu et al reported failures occurring in 3 of 49 patients treated for solitary metastases, and no failures in adjacent untreated vertebrae.31 The implication of these findings is that progression in adjacent vertebral bodies is rare, and supports radiosurgery treatment of the involved spinal levels only.26 Chang et al reported their patterns of failure for 74 treated tumors where 23% demonstrated imaging progression.93 Progression occurring in the adjacent vertebrae was rare and occurred in only one case. Gerszten et al reported no case of tumor progression within the immediate adjacent vertebral levels based on 500 cases.95 Based on these data, Sahgal concluded that it is possible that (1) failure in the epidural space may be due to underdosing of the tumor because of strict spinal cord constraints, (2) uninvolved adjacent posterior elements should be included in the target volume, and (3) encompassing one vertebral body above and below the diseased vertebrae is unnecessary.26 Some centers have raised a concern regarding a risk of subsequent vertebral body compression fractures after radiosurgery.

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Safety and Complications of Spine Radiosurgery.

Complications associated with radiosurgery are generally self-limited and mild. Minor and limited toxicities have been reported with spine radiosurgery and include esophagitis,110 mucositis,86 dysphagia,85,86 diarrhea,85,93 paresthesia,85 transient laryngitis,13 and transient radiculitis.13 Radiation-induced spinal cord injury is exceedingly rare, and few cases have been reported in the literature. An early series by Benzil et al reported no radiation-induced spinal cord toxicity.13 Gerszten et al found no spinal cord toxicity with over 60 months of follow-up.95 Ryu et al specifically addressed the partial volume tolerance of the spinal cord and complications of single-dose radiosurgery.84 They reported a single case of radiation-induced cord injury after 13 months of radiosurgery. They concluded that whereas the maximum spinal cord tolerance to single-dose radiation is not known, partial volume tolerance of the human spinal cord is at least 10 Gy to 10% of the spinal cord volume, defined as 6 mm above and below the radiosurgery target. A recent multicenter study102 including 1075 cases reported only 6 patients who developed delayed radiation-induced myelopathy at a mean of 6.3 months (range, 2–9 months) after spinal radiosurgery. Radiation injury to the spinal cord occurred over a spectrum of dose parameters that prevented identification of specific dosimetric factors contributing to this complication. Yamada et al used a maximum dose constraint of 14 Gy to any portion of the spinal cord instead of a dose-volume constraint without any cases of spinal cord toxicity.99

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Discussion

This systematic literature review revealed that, with moderate quality evidence, conventional radiation therapy alone appears to be beneficial for the treatment of spine metastases, particularly in the domains of maintenance of ambulatory function and pain. Conventional radiotherapy is an effective modality of palliation, particularly in the domain of pain management. It appears to be safe and very well tolerated. The literature makes little to no mention of serious toxicity.

The majority of the evidence is low-level retrospective data, with the inherent biases of retrospective series, including nonuniform definitions of outcome measures and follow-up. The metastatic disease population is also an inherently difficult group of patients to study, typically with multiple disease sites, poor health, and quality of life. With limited follow-up and survival, and other probable confounders such as dexamethasone use, the retrospective datasets generally report better outcomes than those found for randomized trials. Despite these obstacles, the overall body of literature is relatively consistent and supports the results of the prospective studies, suggesting that the benefit of conventional radiotherapy is real.

However, given the difficulties of this study population, including multiple confounding variables and relatively short follow-up, in particular nonprospective datasets, one cannot critically comment on treatment-related toxicity. Although the fractionation schedule used with conventional radiation does not appear to make significant differences in outcomes in randomized trials, there may be an advantage to higher cumulative doses with patients with longer expected survival. There is a consistent observation that radiosensitive histologies respond more favorably than those that are deemed radioresistant.

This systematic literature review revealed the relative safety and efficacy of the newer modality of spine radiosurgery. Despite the significant clinical experience and widespread utilization of conventional radiotherapy for spine metastases, there are several theoretical advantages to using a stereotactic radiosurgery technique as a treatment modality for spinal tumors. Early treatment of these lesions before the patient becomes symptomatic and the stability of the spine threatened has obvious advantages.16 Conformal radiosurgery avoids the need to irradiate large segments of the spinal cord. Early stereotactic radiosurgery treatment of spinal lesions may obviate the need for extensive spinal surgeries for decompression and fixation in these already debilitated patients. It may also avoid the need to irradiate large segments of the spinal column, known to have a deleterious effect on bone-marrow reserve in these patients. Avoiding open surgery as well as preserving bone-marrow function facilitates continuous chemotherapy in this patient population. Furthermore, improved local control such as has been the case with intracranial radiosurgery could translate into more effective palliation and potentially longer survival.

An advantage to the patient of using single-fraction radiosurgery is that the treatment can be completed in a single day rather than over the course of several weeks, which is not inconsequential for patients with a limited life expectancy. The technique may be useful to capitalize on possible advantages of radiosensitizers. In addition, cancer patients may have difficulty with access to a radiation-treatment facility for prolonged, daily fractionated therapy. A large single fraction of irradiation may be more radiobiologically advantageous to certain tumors, such as sarcomas, melanomas, and renal cell metastases, compared with prolonged fractionated radiotherapy. Clinical response such as pain or improvement of a neurologic deficit might also be more rapid with a radiosurgery technique. Finally, the procedure is minimally invasive compared with open surgical techniques and can be performed in an outpatient setting.

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Conclusion

Both conventional and stereotactic radiosurgery are important treatment methods for the management of solid tumors metastatic to the spine. Both methods are well tolerated and provide effective tumor control and symptom palliation. Radiosurgery appears to provide higher rates of tumor control, and may be less affected by histology. However, although high-quality evidence is available for conventional radiotherapy, the quality of literature for stereotactic spine radiosurgery is low and very low.

A systematic analysis of the literature shows that there is a small body of moderate-level evidence corroborated by a large body of lower-level evidence supporting the safety and efficacy of conventional fractionated radiotherapy for solid-tumor spine metastases. There is no high level of evidence but a growing body of lower-level evidence supporting the safety and efficacy of radiosurgery for solid tumor spine metastases. Furthermore, there is a remarkable consistency throughout the literature independent of radiosurgery-delivery technology in these reported outcomes. The single greatest limitation of spine radiosurgery is the inability to deliver tumoricidal doses in the setting of significant spinal cord compression. Despite the high precision of current delivery platforms, in the cases of significant epidural disease, a sufficient dose sparing the spinal cord that would avoid radiation-induced injury is currently not possible.

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Clinically Relevant Questions

  1. What are the clinical outcomes of the current indications for conventional radiotherapy alone and stereotactic radiosurgery for metastatic spine disease?
    1. Conventional radiotherapy. Three randomized trials (high-quality evidence), 4 prospective studies (moderate-quality evidence), and over 40 nonprospective data (low- or very-low-quality evidence) that includes over 5000 patients in the literature suggest the following:
      • i. Approximately 60% to 80% of patients remained ambulatory after conventional radiation therapy for epidural spinal cord compression, and 20% to 60% of patients regained ambulation after conventional radiotherapy.
      • ii. Pain was palliated in 50% to 70% of treated patients.
      • iii. Approximately 70% of patients with sphincter dysfunction were found to have improvement after conventional radiotherapy.
    2. Stereotactic radiosurgery. Twenty-seven single-institution reports were analyzed (low- or very-low-quality data). No randomized data are available.
      • i. Despite the low quality of the available evidence, the reported outcomes are remarkably consistent, with 85% to 100% of reported patients experiencing effective palliation of pain (low- and very–low-quality evidence).
      • ii. Of the patients 57% to 92% experienced improvement of progressive neurologic symptoms after radiosurgery (low- and very–low-quality evidence).
  2. What are the current dose recommendations and fractionation schedules for conventional spine radiotherapy and stereotactic radiosurgery for metastatic spine disease?
    1. Conventional radiation. Three prospective studies (high-quality evidence) testing 3000 cGy/10 fractions, 500 cGy × 5 + 300 cGy × 5 (split course), and 800 cGy × 2, have found that the dose-fractionation schedule had no significant impact on ambulatory status or the probability of regaining ambulation. When short-course radiation (1 week or less in duration) has been compared with longer-course radiation retrospectively, benefit for longer-course radiation was noted only if the follow-up period was sufficiently long (i.e., survival >9 months). Hence, short-course radiation may be better suited for patients with a limited life expectancy (based on low-quality evidence).
    2. Stereotactic radiosurgery. Both hypofractionation (4 Gy × 4, 6 Gy × 5, 8 Gy × 3, 9 Gy × 3) and single dose (16–24 Gy × 1) have been reported with stereotactic radiosurgery. No consensus on dose can be made based on the available evidence (low or very low quality) although significant toxicity does not appear to be associated with any fractionation schedule reported for spine radiosurgery.
  3. What are the current known patterns of failure and complications after conventional spine radiation and stereotactic radiosurgery for metastatic spine disease?
    1. Conventional radiation. Local control rates of 61% to 89% (mean, 77%), defined as the absence of recurrent cord compression after conventional radiotherapy, has been specifically in 7 retrospective studies (low-quality evidence) describing 885 patients. Histology clearly has an impact on response to conventional radiation. Lymphoma, seminoma, myeloma, breast cancer, and prostate cancer are nearly universally categorized as favorable histologies in 1 randomized study (high-quality evidence) and 4 retrospective studies (low-quality evidence).
    2. Stereotactic radiosurgery. Local controls of 75% to 100% have been reported in single-institution reports, and the majority of reported local control rates are approximately 90%. There is a suggestion that certain histologies may do worse (melanoma and renal cell carcinoma) but no high-level evidence is available to confirm this observation.
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Spine Oncology Study Group Recommendations

Conventional radiotherapy is safe and effective with good symptomatic response and local control, particularly for radiosensitive histologies, such as lymphoma, myeloma, and seminoma. A strong recommendation can be made with moderate-quality evidence that conventional fractionated radiotherapy is an appropriate initial therapy option for patients with spine metastases in cases in which no relative contraindications exist. These relative contraindications include, but are not limited to, spinal instability, prior irradiation, radioresistant histology, and/or high-grade spinal cord compression.

Radiosurgery is safe and effective with durable symptomatic response and local control for even radioresistant histologies, regardless of prior fractionated radiotherapy. A strong recommendation can be made with low-quality evidence that radiosurgery should be considered over conventional fractionated radiotherapy for the treatment of solid-tumor spine metastases in the setting of oligometastatic disease and/or radioresistant histology in which no relative contraindications exist.

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Key Points

  • Conventional radiotherapy is safe and effective with good symptomatic response and local control, particularly for radiosensitive histologies, such as lymphoma, myeloma, and seminoma.
  • A strong recommendation can be made with moderate quality evidence that conventional fractionated radiotherapy is an appropriate initial therapy option for patients with spine metastases in cases in which no relative contraindications exist.
  • Radiosurgery is safe and effective with durable symptomatic response and local control for even radioresistant histologies, regardless of prior fractionated radiotherapy.
  • A strong recommendation can be made with low-quality evidence that radiosurgery should be considered over conventional fractionated radiotherapy for the treatment of solid tumor spine metastases in the setting of oligometastatic disease and/or radioresistant histology in which no relative contraindications exist.
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References

1. Lu C, Stomper PC, Drislane FW, et al. Suspected spinal cord compression in breast cancer patients: a multidisciplinary risk assessment. Breast Cancer Res Treat 1998;51:121–31.
2. Faul CM, Flickinger JC. The use of radiation in the management of spinal metastases. J Neurooncol 1995;23:149–61.
3. Kim YH, Fayos JV. Radiation tolerance of the cervical spinal cord. Radiology 1981;139:473–8.
4. Markoe A, Schwade J. The Role of Radiation Therapy in the Management of Spine and Spinal Cord Tumors. Rolling Meadows, IL: American Association of Neurological Surgeons; 1994:23–35.
5. Shapiro W, Posner J. Medical vs. Surgical Treatment of Metastatic Spinal Cord Tumors. New York, NY: Raven Press; 1983.
6. Sundaresan N, Krol G, Digiacinto C, et al. Metastatic tumors of the spine. In: Sundaresan B, Schmidek H, Schiller A, et al, eds. Tumors of the Spine. Philadelphia, PA: WB Saunders; 1990:279–304.
7. Sundaresan N, Digiacinto GV, Hughes JE, et al. Treatment of neoplastic spinal cord compression: results of a prospective study. Neurosurgery 1991;29:645–50.
8. Gerszten PC, Welch WC. Current surgical management of metastatic spinal disease. Oncology (Williston Park) 2000;14:1013–24; discussion 1024, 1029–30.
9. Loblaw DA, Laperriere NJ. Emergency treatment of malignant extradural spinal cord compression: an evidence-based guideline. J Clin Oncol 1998;16:1613–24.
10. Ryu SI, Chang SD, Kim DH, et al. Image-guided hypo-fractionated stereotactic radiosurgery to spinal lesions. Neurosurgery 2001;49:838–46.
11. Shiu AS, Chang EL, Ye JS, et al. Near simultaneous computed tomography image-guided stereotactic spinal radiotherapy: an emerging paradigm for achieving true stereotaxy. Int J Radiat Oncol Biol Phys 2003;57:605–13.
12. Amendola BE, Wolf AL, Coy SR, et al. Gamma knife radiosurgery in the treatment of patients with single and multiple brain metastases from carcinoma of the breast. Cancer J 2000;6:88–92.
13. Benzil DL, Saboori M, Mogilner AY, et al. Safety and efficacy of stereotactic radiosurgery for tumors of the spine. J Neurosurg 2004;101(suppl 3):413–8.
14. Bilsky MH, Yamada Y, Yenice KM, et al. Intensity-modulated stereotactic radiotherapy of paraspinal tumors: a preliminary report. Neurosurgery 2004;54:823–30; discussion 830–1.
15. Chang EL, Shiu AS, Lii MF, et al. Phase I clinical evaluation of near-simultaneous computed tomographic image-guided stereotactic body radiotherapy for spinal metastases. Int J Radiat Oncol Biol Phys 2004;59:1288–94.
16. De Salles AA, Pedroso AG, Medin P, et al. Spinal lesions treated with Novalis shaped beam intensity-modulated radiosurgery and stereotactic radiotherapy. J Neurosurg 2004;101(suppl 3):435–40.
17. Milker-Zabel S, Zabel A, Thilmann C, et al. Clinical results of retreatment of vertebral bone metastases by stereotactic conformal radiotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2003;55:162–7.
18. Ryu S, Fang Yin F, Rock J, et al. Image-guided and intensity-modulated radiosurgery for patients with spinal metastasis. Cancer 2003;97:2013–8.
19. Wu JS, Wong R, Johnston M, et al. Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys 2003;55:594–605.
20. Rades D, Fehlauer F, Stalpers LJ, et al. A prospective evaluation of two radiotherapy schedules with 10 versus 20 fractions for the treatment of metastatic spinal cord compression: final results of a multicenter study. Cancer 2004;101:2687–92.
21. Rades D, Stalpers LJ, Veninga T, et al. Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression. J Clin Oncol 2005;23:3366–75.
22. Maranzano E, Latini P, Perrucci E, et al. Short-course radiotherapy (8 Gy × 2) in metastatic spinal cord compression: an effective and feasible treatment. Int J Radiat Oncol Biol Phys 1997;38:1037–44.
23. Rades D, Karstens JH, Alberti W. Role of radiotherapy in the treatment of motor dysfunction due to metastatic spinal cord compression: comparison of three different fractionation schedules. Int J Radiat Oncol Biol Phys 2002;54:1160–4.
24. Hartsell WF, Scott CB, Bruner DW, et al. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 2005;97:798–804.
25. Bruner D, Winter K, Hartsell WF, et al. Prospective health related quality of life valuations (utilities) of 8 Gy in 1 fraction vs 30 Gy in 10 fractions for palliation of painful bone metastases: preliminary results of RTOG 97-14. Int J Radiat Oncol Biol Phys 2004;60:S142.
26. Sahgal A, Ames C, Chou D, et al. Stereotactic body radiotherapy is effective salvage therapy for patients with prior radiation of spinal metastases. Int J Radiat Oncol Biol Phys 2009;74:723–31.
27. Hamilton AJ, Lulu BA, Fosmire H, et al. Preliminary clinical experience with linear accelerator-based spinal stereotactic radiosurgery. Neurosurgery 1995;36:311–9.
28. Chang SD, Adler JR Jr. Current status and optimal use of radiosurgery. Oncology (Williston Park) 2001;15:209–16; discussion 219–21.
29. Gerszten PC, Welch WC. Cyberknife radiosurgery for metastatic spine tumors. Neurosurg Clin N Am 2004;15:491–501.
30. Medin PM, Solberg TD, De Salles AA, et al. Investigations of a minimally invasive method for treatment of spinal malignancies with LINAC stereotactic radiation therapy: accuracy and animal studies. Int J Radiat Oncol Biol Phys 2002;52:1111–22.
31. Ryu S, Rock J, Rosenblum M, et al. Patterns of failure after single-dose radiosurgery for spinal metastasis. J Neurosurg 2004;101(suppl 3):402–5.
32. Yin FF, Ryu S, Ajlouni M, et al. Image-guided procedures for intensity-modulated spinal radiosurgery [Technical note]. J Neurosurg 2004;101(suppl 3):419–24.
33. Colombo F, Pozza F, Chierego G, et al. Linear accelerator radiosurgery of cerebral arteriovenous malformations: an update. Neurosurgery 1994;34:14–20; discussion 20–1.
34. Hitchcock E, Kitchen G, Dalton E, et al. Stereotactic LINAC radiosurgery. Br J Neurosurg 1989;3:305–12.
35. Pirzkall A, Lohr F, Rhein B, et al. Conformal radiotherapy of challenging paraspinal tumors using a multiple arc segment technique. Int J Radiat Oncol Biol Phys 2000;48:1197–204.
36. Song DY, Kavanagh BD, Benedict SH, et al. Stereotactic body radiation therapy. Rationale, techniques, applications, and optimization. Oncology (Williston Park) 2004;18:1419–30; discussion 1430, 1432, 1435–6.
37. Isacsson U, Hagberg H, Johansson KA, et al. Potential advantages of protons over conventional radiation beams for paraspinal tumors. Radiother Oncol 1997;45:63–70.
38. Schunemann HJ, Jaeschke R, Cook DJ, et al. An official ATS statement: grading the quality of evidence and strength of recommendations in ATS guidelines and recommendations. Am J Respir Crit Care Med 2006;174:605–14.
39. Helweg-Larsen S, Johnsen A, Boesen J, et al. Radiologic features compared to clinical findings in a prospective study of 153 patients with metastatic spinal cord compression treated by radiotherapy. Acta Neurochir (Wien) 1997;139:105–11.
40. Spiegel DA, Sampson JH, Richardson WJ, et al. Metastatic melanoma to the spine. Demographics, risk factors, and prognosis in 114 patients. Spine 1995;20:2141–6.
41. Rades D, Dahm-Daphi J, Rudat V, et al. Is short-course radiotherapy with high doses per fraction the appropriate regimen for metastatic spinal cord compression in colorectal cancer patients? Strahlenther Onkol 2006;182:708–12.
42. Rades D, Walz J, Stalpers LJ, et al. Short-course radiotherapy (RT) for metastatic spinal cord compression (MSCC) due to renal cell carcinoma: results of a retrospective multi-center study. Eur Urol 2006;49:846–52; discussion 852.
43. Rades D, Stalpers LJ, Hulshof MC, et al. Effectiveness and toxicity of single-fraction radiotherapy with 1 × 8 Gy for metastatic spinal cord compression. Radiother Oncol 2005;75:70–3.
44. Rades D, Walz J, Schild SE, et al. Do bladder cancer patients with metastatic spinal cord compression benefit from radiotherapy alone? Urology 2007;69:1081–5.
45. Maranzano E, Latini P, Checcaglini F, et al. Radiation therapy of spinal cord compression caused by breast cancer: report of a prospective trial. Int J Radiat Oncol Biol Phys 1992;24:301–6.
46. Maranzano E, Latini P, Beneventi S, et al. Comparison of two different radiotherapy schedules for spinal cord compression in prostate cancer. Tumori 1998;84:472–7.
47. Rades D, Karstens JH, Hoskin PJ, et al. Escalation of radiation dose beyond 30 Gy in 10 fractions for metastatic spinal cord compression. Int J Radiat Oncol Biol Phys 2007;67:525–31.
48. Hoskin PJ, Grover A, Bhana R. Metastatic spinal cord compression: radiotherapy outcome and dose fractionation. Radiother Oncol 2003;68: 175–80.
49. Katagiri H, Takahashi M, Inagaki J, et al. Clinical results of nonsurgical treatment for spinal metastases. Int J Radiat Oncol Biol Phys 1998;42:1127–32.
50. Rades D, Fehlauer F, Veninga T, et al. Functional outcome and survival after radiotherapy of metastatic spinal cord compression in patients with cancer of unknown primary. Int J Radiat Oncol Biol Phys 2007;67:532–7.
51. Bach F, Agerlin N, Sorensen JB, et al. Metastatic spinal cord compression secondary to lung cancer. J Clin Oncol 1992;10:1781–7.
52. Rades D, Stalpers LJ, Schulte R, et al. Defining the appropriate radiotherapy regimen for metastatic spinal cord compression in non–small-cell lung cancer patients. Eur J Cancer 2006;42:1052–6.
53. Rades D, Stalpers LJ, Veninga T, et al. Evaluation of functional outcome and local control after radiotherapy for metastatic spinal cord compression in patients with prostate cancer. J Urol 2006;175:552–6.
54. Kraiwattanapong C, Buranapanitkit B, Kiriratnikom T. Results of radiotherapy in non round cell spinal metastasis. J Med Assoc Thai 2004;87:239–45.
55. Rades D, Veninga T, Stalpers LJ, et al. Prognostic factors predicting functional outcomes, recurrence-free survival, and overall survival after radiotherapy for metastatic spinal cord compression in breast cancer patients. Int J Radiat Oncol Biol Phys 2006;64:182–8.
56. Rades D, Veninga T, Stalpers LJ, et al. Outcome after radiotherapy alone for metastatic spinal cord compression in patients with oligometastases. J Clin Oncol 2007;25:50–6.
57. Brown PD, Stafford SL, Schild SE, et al. Metastatic spinal cord compression in patients with colorectal cancer. J Neurooncol 1999;44:175–80.
58. Rades D, Fehlauer F, Schulte R, et al. Prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression. J Clin Oncol 2006;24:3388–93.
59. Sorensen S, Borgesen SE, Rohde K, et al. Metastatic epidural spinal cord compression. Results of treatment and survival. Cancer 1990;65:1502–8.
60. Rades D, Stalpers LJ, Veninga T, et al. Spinal reirradiation after short-course RT for metastatic spinal cord compression. Int J Radiat Oncol Biol Phys 2005;63:872–5.
61. Rades D, Lange M, Veninga T, et al. Preliminary results of spinal cord compression recurrence evaluation (score-1) study comparing short-course versus long-course radiotherapy for local control of malignant epidural spinal cord compression. Int J Radiat Oncol Biol Phys 2009;73:228–34.
62. Schiff D, Shaw EG, Cascino TL. Outcome after spinal reirradiation for malignant epidural spinal cord compression. Ann Neurol 1995;37:583–9.
63. Tazi H, Manunta A, Rodriguez A, et al. Spinal cord compression in metastatic prostate cancer. Eur Urol 2003;44:527–32.
64. Aass N, Fossa SD. Pre- and post-treatment daily life function in patients with hormone resistant prostate carcinoma treated with radiotherapy for spinal cord compression. Radiother Oncol 2005;74:259–65.
65. Podd TJ, Carpenter DS, Baughan CA, et al. Spinal cord compression: prognosis and implications for treatment fractionation. Clin Oncol (R Coll Radiol) 1992;4:341–4.
66. Huddart RA, Rajan B, Law M, et al. Spinal cord compression in prostate cancer: treatment outcome and prognostic factors. Radiother Oncol 1997;44:229–36.
67. Kovner F, Spigel S, Rider I, et al. Radiation therapy of metastatic spinal cord compression. Multidisciplinary team diagnosis and treatment. J Neurooncol 1999;42:85–92.
    68. Zelefsky MJ, Scher HI, Krol G, et al. Spinal epidural tumor in patients with prostate cancer. Clinical and radiographic predictors of response to radiation therapy. Cancer 1992;70:2319–25.
    69. Solberg A, Bremnes RM. Metastatic spinal cord compression: diagnostic delay, treatment, and outcome. Anticancer Res 1999;19:677–84.
    70. Smith EM, Hampel N, Ruff RL, et al. Spinal cord compression secondary to prostate carcinoma: treatment and prognosis. J Urol 1993;149:330–3.
    71. Kim RY, Smith JW, Spencer SA, et al. Malignant epidural spinal cord compression associated with a paravertebral mass: its radiotherapeutic outcome on radiosensitivity. Int J Radiat Oncol Biol Phys 1993;27:1079–83.
    72. Merimsky O, Kollender Y, Bokstein F, et al. Radiotherapy for spinal cord compression in patients with soft-tissue sarcoma. Int J Radiat Oncol Biol Phys 2004;58:1468–73.
    73. Rades D, Heidenreich F, Bremer M, et al. Time of developing motor deficits before radiotherapy as a new and relevant prognostic factor in metastatic spinal cord compression: final results of a retrospective analysis. Eur Neurol 2001;45:266–9.
    74. Ampil FL, Mills GM, Burton GV. A retrospective study of metastatic lung cancer compression of the cauda equina. Chest 2001;120:1754–5.
    75. Hill ME, Richards MA, Gregory WM, et al. Spinal cord compression in breast cancer: a review of 70 cases. Br J Cancer 1993;68:969–73.
    76. Tombolini V, Zurlo A, Montagna A, et al. Radiation therapy of spinal metastases: results with different fractionations. Tumori 1994;80:353–6.
    77. Jeremic B, Grujicic D, Cirovic V, et al. Radiotherapy of metastatic spinal cord compression. Acta Oncol 1991;30:985–6.
    78. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomized trial. Lancet 2005;366:643–8.
    79. Maranzano E, Bellavita R, Rossi R, et al. Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized, multicenter trial. J Clin Oncol 2005;23:3358–65.
    80. Young RF, Post EM, King GA. Treatment of spinal epidural metastases. Randomized prospective comparison of laminectomy and radiotherapy. J Neurosurg 1980;53:741–8.
    81. Maranzano E, Latini P. Effectiveness of radiation therapy without surgery in metastatic spinal cord compression: final results from a prospective trial. Int J Radiat Oncol Biol Phys 1995;32:959–67.
    82. Turner S, Marosszeky B, Timms I, et al. Malignant spinal cord compression: a prospective evaluation. Int J Radiat Oncol Biol Phys 1993;26:141–6.
    83. Greenberg HS, Kim JH, Posner JB. Epidural spinal cord compression from metastatic tumor: results with a new treatment protocol. Ann Neurol 1980;8:361–6.
    84. Ryu S, Jin JY, Jin R, et al. Partial volume tolerance of the spinal cord and complications of single-dose radiosurgery. Cancer 2007;109:628–36.
    85. Degen JW, Gagnon GJ, Voyadzis JM, et al. CyberKnife stereotactic radiosurgical treatment of spinal tumors for pain control and quality of life. J Neurosurg Spine 2005;2:540–9.
    86. Yamada Y, Lovelock DM, Yenice KM, et al. Multifractionated image-guided and stereotactic intensity-modulated radiotherapy of paraspinal tumors: a preliminary report. Int J Radiat Oncol Biol Phys 2005;62:53–61.
    87. Mahan SL, Ramsey CR, Scaperoth DD, et al. Evaluation of image-guided helical tomotherapy for the retreatment of spinal metastasis. Int J Radiat Oncol Biol Phys 2005;63:1576–83.
    88. Gerszten PC, Burton SA, Quinn AE, et al. Radiosurgery for the treatment of spinal melanoma metastases. Stereotact Funct Neurosurg 2005;83:213–21.
    89. Gerszten PC, Burton SA, Welch WC, et al. Single-fraction radiosurgery for the treatment of spinal breast metastases. Cancer 2005;104:2244–54.
    90. Gerszten PC, Burton SA, Ozhasoglu C, et al. Stereotactic radiosurgery for spinal metastases from renal cell carcinoma. J Neurosurg Spine 2005;3:288–95.
    91. Rock JP, Ryu S, Shukairy MS, et al. Postoperative radiosurgery for malignant spinal tumors. Neurosurgery 2006;58:891–8; discussion 891–8.
    92. Gerszten PC, Burton SA, Belani CP, et al. Radiosurgery for the treatment of spinal lung metastases. Cancer 2006;107:2653–61.
    93. Chang EL, Shiu AS, Mendel E, et al. Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure. J Neurosurg Spine 2007;7:151–60.
    94. Jin JY, Chen Q, Jin R, et al. Technical and clinical experience with spine radiosurgery: a new technology for management of localized spine metastases. Technol Cancer Res Treat 2007;6:127–33.
    95. Gerszten PC, Burton SA, Ozhasoglu C, et al. Radiosurgery for spinal metastases: clinical experience in 500 cases from a single institution. Spine 2007;32:193–9.
    96. Gagnon GJ, Henderson FC, Gehan EA, et al. Cyberknife radiosurgery for breast cancer spine metastases: a matched-pair analysis. Cancer 2007;110:1796–802.
    97. Gibbs IC, Kamnerdsupaphon P, Ryu MR, et al. Image-guided robotic radiosurgery for spinal metastases. Radiother Oncol 2007;82:185–90.
    98. Ryu S, Jin R, Jin JY, et al. Pain control by image-guided radiosurgery for solitary spinal metastasis. J Pain Symptom Manage 2008;35:292–8.
    99. Yamada Y, Bilsky MH, Lovelock DM, et al. High-dose, single-fraction image-guided intensity-modulated radiotherapy for metastatic spinal lesions. Int J Radiat Oncol Biol Phys 2008;71:484–90.
    100. Kim B, Soisson ET, Duma C, et al. Image-guided helical tomotherapy for treatment of spine tumors. Clin Neurol Neurosurg 2008;110:357–62.
    101. Gagnon GJ, Nasr NM, Liao JJ, et al. Treatment of spinal tumors using cyberknife fractionated stereotactic radiosurgery: pain and quality-of-life assessment after treatment in 200 patients. Neurosurgery 2009;64:297–306; discussion 306–7.
    102. Gibbs IC, Patil C, Gerszten PC, et al. Delayed radiation-induced myelopathy after spinal radiosurgery. Neurosurgery 2009;64:A67–72.
    103. Gilbert RW, Kim JH, Posner JB. Epidural spinal cord compression from metastatic tumor: diagnosis and treatment. Ann Neurol 1978;3:40–51.
    104. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21:109–22.
    105. Maranzano E, Bellavita R, Floridi P, et al. Radiation-induced myelopathy in long-term surviving metastatic spinal cord compression patients after hypofractionated radiotherapy: a clinical and magnetic resonance imaging analysis. Radiother Oncol 2001;60:281–8.
    106. Bilsky MH, Boakye M, Collignon F, et al. Operative management of metastatic and malignant primary subaxial cervical tumors. J Neurosurg Spine 2005;2:256–64.
    107. Yamada Y, Bilsky L, Zatcky J, et al. Single fraction image guided intensity modulated radiotherapy (IG IMRT) for metastatic lesions of the spinal column. Int J Radiat Biol 2005;63:S155.
    108. Chang J, Yenice KM, Narayana A, et al. Accuracy and feasibility of cone-beam computed tomography for stereotactic radiosurgery setup. Med Phys 2007;34:2077–84.
    109. Gerszten PC, Germanwala A, Burton SA, et al. Combination kyphoplasty and spinal radiosurgery: a new treatment paradigm for pathological fractures. J Neurosurg Spine 2005;3:296–301.
    110. Hamilton AJ, Lulu BA. A prototype device for linear accelerator-based extracranial radiosurgery. Acta Neurochir Suppl 1995;63:40–3.
    Keywords:

    outcomes; radiotherapy; radiosurgery; metastatic spine disease

    © 2009 Lippincott Williams & Wilkins, Inc.