The use of spine stereotactic radiosurgery for oligometastatic disease

Jennifer C. HoDepartments of Radiation Oncology,

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Chad TangDepartments of Radiation Oncology,

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Brian J. DeeganDepartments of Radiation Oncology,

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Pamela K. AllenDepartments of Radiation Oncology,

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Eric JonaschGenitourinary Medical Oncology,

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Behrang AminiDiagnostic Radiology,

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Xin A. WangRadiation Physics, and

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Jing LiDepartments of Radiation Oncology,

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Claudio E. TatsuiNeurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas

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Laurence D. RhinesNeurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas

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Paul D. BrownDepartments of Radiation Oncology,

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Amol J. GhiaDepartments of Radiation Oncology,

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OBJECTIVE

The authors investigated the outcomes following spine stereotactic radiosurgery (SSRS) for patients with oligometastatic disease of the spine.

METHODS

The study was a secondary analysis of 38 of 209 patients enrolled in 2 separate institutional Phase I/II prospective protocols and treated with SSRS between 2002 and 2011. Of these 38 patients, 33 (87%) were treated for a solitary spine metastasis, with no other history of metastatic disease. SSRS was prescribed to 24 Gy in 1 fraction (8%), 18 Gy in 1 fraction (18%), 16 Gy in 1 fraction (11%), 27 Gy in 3 fractions (53%), 30 Gy in 5 fractions (8%), or 20 Gy in 5 fractions (3%). Seventeen patients (45%) received prior conventional external beam radiation therapy.

RESULTS

The median overall survival (OS) was 75.7 months, and the 2- and 5-year OS rates were 84% and 60%, respectively. In multivariate analysis, patients who had prior spine surgery and a better Karnofsky Performance Scale score had an improved OS (HR 0.16, 95% CI 0.05–0.52, p < 0.01, and HR 0.33, 95% CI 0.13%–0.84%, p = 0.02, respectively), and those who had undergone prior radiation therapy had a worse OS (HR 3.6, 95% CI 1.2%–10%, p = 0.02). The 1-, 2-, and 5-year local progression-free survival rates were 85%, 82%, and 78%, respectively. The median time to systemic therapy modification was 41 months. Two patients (5%) experienced late Grade 3–4 toxicity.

CONCLUSIONS

Patients with oligometastatic disease of the spine treated with SSRS can experience long-term survival and a long time before needing a modification in systemic therapy. In addition, SSRS leads to excellent local control and minimal late toxicity.

ABBREVIATIONS

CI = confidence interval; CTV = clinical treatment volume; DFS = disease-free survival; Dmax = dose maximum; Dmin = dose minimum; EBRT = external beam radiation therapy; GI = gastrointestinal; GTV = gross tumor volume; HR = hazard ratio; KPS = Karnofsky Performance Scale; OS = overall survival; SSRS = spine stereotactic radiosurgery; STMFS = systemic therapy modification-free survival.

OBJECTIVE

The authors investigated the outcomes following spine stereotactic radiosurgery (SSRS) for patients with oligometastatic disease of the spine.

METHODS

The study was a secondary analysis of 38 of 209 patients enrolled in 2 separate institutional Phase I/II prospective protocols and treated with SSRS between 2002 and 2011. Of these 38 patients, 33 (87%) were treated for a solitary spine metastasis, with no other history of metastatic disease. SSRS was prescribed to 24 Gy in 1 fraction (8%), 18 Gy in 1 fraction (18%), 16 Gy in 1 fraction (11%), 27 Gy in 3 fractions (53%), 30 Gy in 5 fractions (8%), or 20 Gy in 5 fractions (3%). Seventeen patients (45%) received prior conventional external beam radiation therapy.

RESULTS

The median overall survival (OS) was 75.7 months, and the 2- and 5-year OS rates were 84% and 60%, respectively. In multivariate analysis, patients who had prior spine surgery and a better Karnofsky Performance Scale score had an improved OS (HR 0.16, 95% CI 0.05–0.52, p < 0.01, and HR 0.33, 95% CI 0.13%–0.84%, p = 0.02, respectively), and those who had undergone prior radiation therapy had a worse OS (HR 3.6, 95% CI 1.2%–10%, p = 0.02). The 1-, 2-, and 5-year local progression-free survival rates were 85%, 82%, and 78%, respectively. The median time to systemic therapy modification was 41 months. Two patients (5%) experienced late Grade 3–4 toxicity.

CONCLUSIONS

Patients with oligometastatic disease of the spine treated with SSRS can experience long-term survival and a long time before needing a modification in systemic therapy. In addition, SSRS leads to excellent local control and minimal late toxicity.

Spine metastases are the most common site of osseous cancer metastases, with more than 180,000 new cases per year occurring in North America, and in approximately 40% of patients with metastatic cancer with spinal metastases.12,22,32 External beam radiation therapy (EBRT) with conventional fractionation has historically played a large role in the treatment of spine metastases, with a complete response rate for pain of about 13%– 18%.9,15 Because patients with metastatic cancer are living longer, the incidence of spine metastases is expected to increase, creating the need for effective, durable treatment results.

Spine stereotactic radiosurgery (SSRS) is becoming accepted as a method of delivering an ablative dose of radiation therapy in a single or limited number of fractions, with a high degree of conformity allowing for treatment near the spinal cord and other critical structures. It appears to lead to improved tumor control and pain control rates compared with conventionally dosed palliative EBRT, especially for radioresistant histologies, although there has not been any randomized evidence to date.13,23,31 In addition, it has proven to be an effective salvage tool in patients who have progressive spinal metastases who have received prior radiation.11,13,31

In general, patients with oligometastatic disease have been shown to have better prognoses than those with multiple metastatic sites, with some able to attain very long-term survival.26,27 Patients specifically with spine oligometastatic disease may have a more favorable survival compared with patients with synchronous metastatic disease in other sites, and are thus likely to benefit from an ablative rather than a palliative dose of radiation. Moreover, definitive treatment of oligometastatic disease may delay the initiation of or change in systemic therapy. We therefore sought to investigate the long-term outcomes of patients treated with SSRS for oligometastatic disease, including their survival, recurrence patterns, time to systemic therapy modification, and long-term toxicity.

Methods

Patient Population

After institutional review board approval, we reviewed the records of 209 patients who were enrolled in two Phase I/II trials between 2002 and 2011, evaluating single and multifraction SSRS for the treatment of spinal metastases at our institution.4,10,11 Protocol inclusion criteria were a Karnofsky Performance Scale (KPS) score > 40, histopathological confirmation of cancer at our institution, and MRI identifying spinal or paraspinal metastasis < 1 month prior to enrollment. Protocol exclusion criteria were spinal cord compression and unstable spine as determined by multidisciplinary evaluation, cytotoxic chemotherapy within 1 month of enrollment, or EBRT in the prior 3 months to the same site. Before treatment, all patients were presented at a multidisciplinary tumor board to assess appropriate candidacy for the use of SSRS.

We selected 38 patients who had been treated for oligometastatic disease of the spine for this secondary analysis. Patients were included if the spinal metastasis treated with SSRS was the only known site of active progressive disease at the time of treatment. Five patients were included who had a history of previous metastases that had been treated earlier and that were no longer active at the time of SSRS.

Treatment

All patients underwent CT-guided intensity modulated stereotactic body radiation therapy with the CT-on-rails EXaCT targeting system or Trilogy treatment delivery system with On-board Cone Beam CT (Varian Medical Systems), as previously described.4 Patients were immobilized using an Elekta BodyFix stereotactic body frame system (Elekta). Treatment planning was performed using intensity-modulated radiation therapy inverse-treatment planning software (Pinnacle, Philips Medical Systems). Each treatment was monitored by the treating radiation oncologist and a dedicated radiation physicist to verify target positioning and quality assurance, respectively.

SSRS was prescribed to the gross tumor volume (GTV), which was delineated based on the MRI fused with the planning CT. The clinical treatment volume (CTV) included the GTV along with contiguous bone marrow that was at risk. The GTVs were prescribed to receive 20 Gy in 5 fractions or 30 Gy in 5 fractions prior to transitioning to 27 Gy in 3 fractions on the multifraction protocol, which included patients who had received up to 1 previous course of spine radiotherapy to the same region (from prior spine radiation or radiation to another site that had exposed their spinal cord at that level).1 SSRS was not given as a boost in any case. Patients on the subsequent single-fraction protocol, which excluded patients who had undergone spine radiation in the same region, received 16 Gy to 24 Gy, depending on histology. The biologically equivalent maximum dose (Dmax) for cord constraint on the multifraction protocol was 10 Gy for the 5-fraction treatment and 9 Gy for the 3-fraction treatment. Cord constraint on the single-fraction protocol was 0.01 cm3 < 10 Gy. Multifraction treatments were administered on alternating days.

Follow-Up and End Points

Per protocol, patients underwent MRI of the spine with and without contrast and were evaluated at clinic visits 3, 6, 9, 12, 18, and 24 months following treatment, and every 6 months thereafter. Patients also had other surveillance imaging performed, such as CT, PET/CT, and bone scans, ordered at the discretion of their medical oncologist. Patients unable to return for follow-up were contacted annually to obtain information about survival, disease, and treatment status.

End points assessed included overall survival (OS), local control, disease-free survival (DFS), systemic therapy modification-free survival (STMFS), and toxicity. Local recurrences were identified on follow-up spine MRI by the reading radiologist and confirmed by a radiation oncologist after review of the original SSRS treatment plan. The date of systemic therapy modification was the date that patients were initiated on or had a modification in their systemic treatment regimen after SSRS by the treating medical oncologist, usually for progressive disease. Systemic therapy included cytotoxic chemotherapy, targeted agents, hormonal therapy, and radioactive iodine. For patients who underwent systemic therapy that was planned to begin after SSRS, the date of the next modification of systemic treatment was used. Systemic therapy modification due to patient intolerance was not scored. Toxicity was scored using the Common Terminology Criteria for Adverse Events version 4.0. Toxicity was recorded if radiation therapy was a possible cause, but complications believed to be due to progressive tumors were excluded.

Statistical Analysis

All survival rates were calculated from the date of SSRS. For local control and progression-free survival patients were censored at the date of last imaging with either MRI or CT. For OS, patients were censored at the date they were last known to be alive. For DFS and STMFS, patients were censored at the date of last follow-up. For DFS, local failure, out-of-field spine failure, distant nonspine metastasis, and death were scored as events. Local failure status was determined based on the patient's spine MRI, and distant nonspine metastasis was based on various other imaging modalities, most commonly CT or PET/CT.

Data analysis was performed using Stata/MP statistical software (version 14.0, StatCorp). The Fisher's exact test was used to assess measures of association in frequency tables. The equality of group medians was assessed with a nonparametric test for equality. The survival function was performed using Kaplan-Meier estimates. The log-rank test was used to assess the equality of the survivor function across groups. A p value ≤ 0.05 was considered statistically significant. Statistical tests were based on a 2-sided significance level.

The Cox proportional hazard model was used to assess the effect of factors of significance on the survival end points for univariate and multivariate analysis. The estimated hazard ratio (HR) is reported. Multivariate analysis was performed on all factors found to have a p value ≤ 0.25 on univariate analysis. Backward elimination was performed with the least significant factor eliminated in a stepwise manner until the most significant variables were identified.

Results

Patient, Tumor, and Treatment Characteristics

Baseline patient characteristics and treatment characteristics are listed in Table 1. The most common primary histology was renal cell carcinoma (26%), and 42% of patients had radioresistant histology (defined as renal cell, sarcoma, and melanoma). The most common dose and fractionation was 27 Gy in 3 fractions (53%). Seventeen (45%) and 16 (42%) patients had prior radiation therapy and surgery to the same site, respectively. Eleven patients received a prior course of radiation therapy for spinal metastatic disease at the same level and underwent SSRS for progressive disease. Six patients received a previous course of nonspine radiation (such as for the primary cancer) that had exposed their spinal cord at the same level as that in patients receiving subsequent SSRS. Thirty-three patients (87%) had solitary spine metastases, with no prior history of any other metastasis besides the site undergoing SSRS. The other 5 patients (13%) received SSRS for a single spine metastasis as the only site of active/progressive disease, and had a history of a prior metastasis treated with radiation or surgery.

TABLE 1.

Patient and treatment characteristics

VariableValue (%)
Median age in yrs (range)60 (22–88)
Race (%)
  White31 (82)
  Hispanic4 (11)
  Black2 (5)
  Asian1 (3)
Radioresistance (%)
  Radioresistant*16 (42)
  Radiosensitive22 (58)
Primary site (%)
  Renal10 (26)
  Breast7 (18)
  Sarcoma4 (11)
  Lung3 (8)
  Thyroid3 (8)
  Other11 (29)
KPS score (%)
  90–10020 (53)
  70–8018 (47)
Prior spine surgery (%)16 (42)
Prior spine radiation (%)17 (45)
Systemic therapy prior to SSRS (%)3 (8)
  Chemotherapy1 (3)
  Targeted therapy2 (5)
Type of metastasis (%)
  Solitary§33 (87)
  Single5 (13)
Spine location (%)
  Cervical4 (11)
  Lumbar13 (34)
  Sacral1 (3)
  Thoracic20 (53)
Median tumor vol in cm3 (range)28.4 (1.6–98.3)
Fractionation schemes (%)
  24 Gy in 1 fraction3 (8)
  18 Gy in 1 fraction7 (18)
  16 Gy in 1 fraction4 (11)
  27 Gy in 3 fractions20 (53)
  30 Gy in 5 fractions3 (8)
  20 Gy in 5 fractions1 (3)
Median time from cancer diagnosis to SSRS in mos (range)40.8 (0.9–201)

Defined as renal cell carcinoma, melanoma, and sarcoma.

Prior treatment at the same site that underwent SSRS.

Given within 2 months of SSRS.

Only known site of metastatic disease.

Only active metastasis with history of previously treated metastasis.

Three patients (8%) were receiving systemic therapy within the 2 months prior to the date of SSRS. Twenty-five patients (66%) were not receiving any systemic therapy within this time period. Ten patients (26%) were started on a systemic therapy shortly after the completion of SSRS, which was planned prior to SSRS (endocrine therapy, n = 5; targeted agent, n = 2; chemotherapy, n = 2, radioactive iodine, n = 1).

Overall Survival

At a median follow-up of 69 months (range 9–145 months), 21 patients (55%) had died. Among patients still alive at the time of this analysis (n = 17), the median follow-up was 75 months (range 53–145 months). The median OS was 75.7 months (Fig. 1). The 1-, 2-, and 5-year survival rates were 95% (95% CI 81%–99%), 84% (95% CI 68%–93%), and 60% (95% CI 43%–74%), respectively. Patients with a KPS score of 70–80 (compared with 90–100) had a worse OS (HR 3.0, 95% CI 1.2%–7.5%, p = 0.02; Table 2, Fig. 2). Patients who had prior spine surgery had a better OS (HR 0.33, 95% CI 0.12%–0.92%, p = 0.03; Table 2, Fig. 2). Other factors assessed were not significant, including age, sex, tumor volume, radioresistance, spine location, fractionation, and prior radiation. On multivariate analysis, prior radiation (HR 3.6, 95% CI 1.2%–10%, p = 0.02), prior surgery (HR 0.16, 95% CI 0.05%–0.52%, p < 0.01), and higher KPS score (HR 0.33, 95% CI 0.13%–0.84%, p = 0.02) was a significant predictor (Table 3).

FIG. 1.
FIG. 1.

Kaplan-Meier curves demonstrating OS (upper) and local progression-free survival (lower) in all patients.

TABLE 2.

Univariate analysis for OS, local control, DFS, and STMFS

VariableNo.(%)OSLocal ControlDFSSTMFS
HR (95% CI)p ValueHR (95% CI)p ValueHR (95% CI)p ValueHR (95% CI)p Value
Age
  Continuous1.0 (0.99–1.1)0.120.99 (0.95–1.0)0.741.0 (0.97–1.0)0.721.0 (0.97–1.0)0.95
  ≥60 yrs20 (53)1.3 (0.55–3.1)0.560.80 (0.22–2.8)0.720.43 (0.20–0.94)0.030.49 (0.21–1.2)0.10
Sex
  Male15 (39)0.64 (0.26–1.6)0.330.79 (0.22–2.8)0.720.65 (0.31–1.4)0.26
  Female23(61)1.1 (0.48–2.4)0.86
KPS score
  Continuous0.95 (0.91–1.0)0.050.97 (0.90–1.0)0.360.97 (0.93–1.0)0.110.95 (0.91–0.99)0.02
  90–10020 (53)
  70–8018 (47)3.0 (1.2–7.5)0.021.7 (0.46–6.5)0.412.3(1.1–4.7)0.032.9 (1.2–6.8)0.02
Median tumor vol in cm3(range)
  Continuous1.0 (0.99–1.0)0.401.0 (0.98–1.0)0.471.0 (0.99–1.0)0.401.0 (1.0–1.0)0.13
  >2515 (39)1.5 (0.51–4.1)0.482.1 (0.38–11)0.401.1 (0.48–2.5)0.841.3 (0.51–3.2)0.60
Radioresistance*
  Radioresistant16 (42)0.88 (0.36–2.1)0.791.1 (0.32–3.9)0.880.82 (0.39–1.7)0.590.96 (0.43–2.2)0.92
  Radiosensitive22 (58)
Tumor location
  Lumbar/sacral14 (37)1.5 (0.62–3.5)0.382.4 (0.66–8.4)0.181.5 (0.70–3.0)0.322.4 (1.0–5.3)0.04
  Cervical/thoracic24 (63)
Fractionation
  Multiple24 (63)1.6 (0.60–4.2)0.352.4 (0.49–11)0.281.3 (0.59–2.7)0.561.0 (0.44–2.3)0.98
  Single14 (37)
Prior spine radiation
  Yes17(45)1.8 (0.77–4.4)0.172.5 (0.70–9.1)0.161.3 (0.61–2.6)0.531.1 (0.47–2.5)0.86
  No21 (55)
Prior spine surgery
  Yes16 (42)0.33 (0.12–0.92)0.031.2 (0.31–4.5)0.810.71 (0.34–1.5)0.360.85 (0.37–1.9)0.70
  No22 (58)

Defined as renal cell carcinoma, melanoma, and sarcoma.

Prior treatment at the same site that underwent SSRS.

FIG. 2.
FIG. 2.

Kaplan-Meier curves comparing the OS of patients with a KPS score of 90–100 (solid line) versus 70–80 (dashed line; left), and the OS of patients with prior spine surgery (solid line) or no prior spine surgery (dashed line; right).

TABLE 3.

Multivariate analysis

VariableOSLocal Control HR (95% CI)DFSSTMFS
HR (95% CI)p ValueHR (95% CI)p ValueHR (95% CI)p Value
KPS score
  90–1000.33 (0.13–0.84)0.020.37 (0.17–0.81)0.010.21 (0.08–0.57)<0.01
  70–80ReferenceReferenceReference
Prior radiation*3.6 (1.2–10)0.02NS
Prior surgery*0.16 (0.05–0.52)<0.01
Age (yrs)
  ≥60NS0.36 (0.16–0.82)0.020.21 (0.08–0.59)<0.01
  <60ReferenceReference
Spine location
  Lumbar/sacralNS5.6 (2.1–15)<0.01
  Cervical/thoracicReference
Radiation doseNS

NS = nonsignificant; — = variable not included in the multivariate analysis.

Prior treatment at the same site that underwent SSRS.

Spinal Recurrence

The median local progression-free survival was 130.7 months, and the 1-, 2-, and 5-year rates were 85% (95% CI 68%–94%), 82% (95% CI 64%–91%), and 78% (95% CI 59%–89%), respectively (Fig. 1). No variables were identified as predictive of local failure in univariate (Table 2) or multivariate analysis (Table 3).

The patterns of spinal recurrence and the subsequent management strategies are summarized in Table 4. Among the 10 patients (26%) with local progression, 4 underwent surgery, 2 had further surgery and EBRT, 3 had systemic therapy alone, and 1 patient had a repeat course of SSRS (27 Gy in 3 fractions, given 1 year after the initial SSRS). Thirteen patients (34%) experienced out-of-field spine metastases following SSRS at a median of 27.6 months (range 8.5–91.3 months) after SSRS. Three of these 13 patients' subsequent out-of-field spine metastases were located in spinal levels directly adjacent to the site of SSRS and were treated with SSRS in 1 patient, EBRT in 1 patient, and surgery in 1 patient. In the 10 other patients, their distant spine failures were managed with SSRS (n = 5), EBRT (n = 1), surgery followed by SSRS (n = 1), and systemic therapy or best supportive care (n = 3).

TABLE 4.

Patterns of spine failure and salvage therapy

Type of Spine FailureNo. (%)SurgerySurgery + EBRTSurgery + SSRSSSRSEBRTSystemic Therapy Alone
In-field failure10 (26)4213
Out-of-field13 (34)
  Adjacent level3 (8)111
  Distant level10 (26)1513

Disease-Free Survival

The median DFS was 19.0 months. The 1- and 2-year DFS rates were 62% (95% CI 44%–75%) and 44% (95% CI 28%–60%), respectively. Patients with a lower KPS score (70–80 vs 90–100) had a worse DFS (HR 2.3, 95% CI 1.1%–4.7%, p = 0.03; Table 2). Patients aged 60 years or older had a better DFS (HR 0.43, 95% CI 0.20%–0.94%, p = 0.03; Table 2). Seven patients (18%) did not experience any local or distant failure after SSRS, at a median follow-up of 75 months (range 20–119 months). On multivariate analysis, higher KPS score (HR 0.37, 95% CI 0.17%–0.81%, p = 0.01) and older age (HR 0.36, 95% CI 0.16%–0.82%, p = 0.02) were also found to be significant (Table 3).

Systemic Therapy Modification-Free Survival

The median STMFS was 41.2 months (Fig. 3), and the 1- and 2-year rates were 83% (95% CI 67%–92%) and 65% (95% CI 47%–79%), respectively. Patients with a lower KPS score (70–80 vs 90–100) and lumbar or sacral disease (compared with cervical or thoracic) were more likely to experience a modification in systemic therapy (HR 2.9, 95% CI 1.2%–6.8%, p = 0.02, and HR 2.4, 95% CI 1.0%–5.3%, p = 0.04, respectively, Table 2). Twenty-four patients (63%) had a modification in systemic therapy for progressive disease at a median of 29.0 months (range 3.0–144.4 months). Fourteen patients (37%) never had an initiation of or modification in systemic therapy (median follow-up 69 months, range 10–145 months). On multivariate analysis, higher KPS score (HR 0.21, 95% CI 0.08%–0.57%, p < 0.01), older age (HR 0.21, 95% CI 0.08%–0.59%, p < 0.01), and lumbar/sacral spine location (HR 5.6, 95% CI 2.1%–15%, p < 0.01) were found to be significant predictors (Table 3).

FIG. 3.
FIG. 3.

Kaplan-Meier curve showing the STMFS of all patients.

Toxicity

Three patients (8%) experienced acute toxicity: 2 patients had Grade 2 gastrointestinal (GI) toxicity, and 1 patient had Grade 3 GI toxicity. One patient (3%) experienced late Grade 4 GI toxicity. This patient received 18 Gy in 1 fraction to T-8, T-8 laminectomy and vertebrectomy, ERBT (30 Gy in 10 fractions) to T7–9, and finally 16 Gy in 1 fraction to T-7, over the course of 2 years, and developed an esophageal fistula and stricture 29 months after the first instance of SSRS (4 months after the last SSRS). One patient (3%) experienced late Grade 3 myelopathy 12 months after SSRS. Six patients (16%) developed a compression fracture in the area treated with SSRS at a median of 3.8 months (range 0.7–10.2 months). Five of these patients had symptomatic fractures and subsequently underwent vertebral augmentation procedures. The SSRS doses prescribed in these 6 patients who developed fractures were 24 Gy in 1 fraction (n = 3), 18 Gy in 1 fraction (n = 1), and 27 Gy in 3 fractions (n = 2).

Discussion

Our results represent the largest published series of patients (n = 38) with oligometastatic spinal metastases treated with SSRS and demonstrate that these patients have an excellent long-term OS with limited toxicity. In addition, we showed that these patients did not need a change in systemic therapy for years following SSRS and that a significant portion had excellent survival after SSRS without the need for systemic therapy.

Significant variability exists in the prognosis for patients treated with SSRS. A recent analysis of patients treated with SSRS identified 7 pretreatment variables that grouped patients into 4 survival groups, with a 5-year overall rate of 66% for the excellent survival group compared with 0% for the poor survival group, with 1 of the variables being the SSRS site as the oligometastatic site of disease.28 Our results show that as a group, these patients with oligometastatic spine metastases do have an excellent prognosis with a median survival of 76 months and a 5-year survival rate of 60%. Although all of the patients in this series had a KPS score of at least 70, those with a KPS score of 90–100 had a significantly improved survival compared with those with a score of 70–80, consistent with previously reported data.5,28 In addition, those patients receiving prior surgery had improved survival in our series, which may represent both the advantages of debulking as well as a healthier selected population.

Patients with oligometastatic disease potentially represent a distinct group with a better prognosis than those who develop multiple sites of metastases, and targeted therapy with surgery or ablative radiation may be warranted over the traditional use of only systemic therapy. Several reports of resection of pulmonary, hepatic, or adrenal metastatectomies in select patients have demonstrated excellent long-term survival rates.3,21,29 Stereotactic body radiation therapy is a less-invasive alternative to surgery and appears to offer acceptable local control and survival rates for patients with limited metastatic disease.16,17,30 It is currently the subject of several ongoing clinical trials, examining the value of stereotactic body radiation therapy in oligometastatic disease for various primary sites.

However, the literature on the outcomes of SSRS for oligometastatic spinal disease is limited, and, to our knowledge, ours is the largest series to date. Thibault et al. reviewed patients with renal cell cancer treated with SSRS and showed that patients with oligometastatic disease had an improved survival compared with those with more numerous metastases (1-year survival of 84% vs 53%).30 Gill et al. reported on 20 patients with oligometastatic spinal metastases treated with Cyberknife SSRS to a median dose of 30 Gy in 5 fractions.14 Another report of 4 patients with solitary spine metastases showed excellent survival and control.18 Our study stands out as the highest quality evidence, because it is the largest and a reanalysis of Phase I/II trials. In addition, oligometastatic disease has been variably defined in the literature, which makes comparison between studies challenging. Thibault et al. defined it as fewer than 5 sites of metastatic involvement, while Gill et al. did not define it at all.14,30 Our analysis specifically was more stringently limited to those patients with only 1 site of disease: those who either had solitary spine metastases (in 87% of patients), or those with single spine metastases (13%) who had prior other metastases that were not progressive. Our series also compared favorably to Gill et al. in terms of survival and local control, with 1- and 2-year survival rates of 95% and 84% compared with 80% and 57%, and 1- and 2-year local control rates of 85% and 82%, compared with 80% and 73%.14 The extended long-term OS of our cohort is likely partially due to the fact that the 2 most common primary sites in our study were renal cell and breast, which have a slower natural course and better prognosis than many other primary sites. Our local control rates were acceptable and comparable to larger series, with a median local failure–free survival of 130.7 months, and a 1- and 2-year rate of 85% and 82%, respectively.13,31 Bishop et al. reported that patients with a GTV biologically equivalent minimum dose (Dmin) of at least 33.4 Gy had significantly better local control, recommending that, when possible, the GTV Dmin should be maintained above 14 Gy in 1 fraction and 21 Gy in 3 fractions.1

In addition to excellent survival and acceptable local control, we have shown that these patients with oligometastatic spine disease had extended time intervals before the initiation of or a modification in systemic therapy, with a median time of 41.2 months. Eighteen percent of patients in this series did not develop any subsequent local recurrences or distant metastases at a follow-up of 75 months and never required systemic therapy (except for 1 patient who started leuprolide shortly after SSRS). This supports the notion that in select patients with oligometastatic spinal metastases that are treated definitively with SSRS, close monitoring without the need for the immediate start of systemic therapy could be a reasonable option. However, it cannot be concluded from this study whether systemic therapy should be initiated sooner or later, because it is possible that it could improve DFS in some patients. In addition, many targeted therapies have low toxicity profiles and may not affect quality of life. A thorough discussion between the medical oncologist and patient should take place regarding this decision.

As an alternative to SSRS, en bloc radical resection is a surgical technique with potentially curative intent that can be offered for oligometastatic spinal disease.7,8,20 However, surgical treatment of spine metastases can lead to morbidity and a postoperative complication rate of around 20%–30%.6 In particular, older patients have a higher risk of cardiopulmonary and infectious complications from surgery.19,20 In contrast, SSRS, as an outpatient noninvasive treatment, is generally very well tolerated and carries minimal morbidity and toxicity, with excellent local control rates. Because most patients will ultimately develop further metastases (we reported a median DFS of 19.0 months), SSRS is a practical alternative to en bloc spondilectomy, as it provides durable local control for patients who may ultimately have further progression of disease.

Minimization of late toxicity is especially important after SSRS for these patients with excellent long-term survival. We reported one instance of late Grade 3 myelopathy, and one instance of late Grade 4 GI fistula in a patient who had received multiple courses of radiation and surgery. In addition, 16% of patients developed compression fractures, consistent with previous reports.2,24 There have been variable reports on the dose limitation to the spinal cord using SSRS, with 1 recent analysis reporting a ≤ 5% risk of myelopathy with a 12.4 Gy Dmax,25 or even no reported myelopathy with a Dmax of 14 Gy.33 In general, we limit the spinal cord receiving 10 Gy to 0.01 cm3 or less for single-fraction SSRS.

Our study is limited by its small sample size, patient heterogeneity, and potential selection bias. However, to our knowledge, it represents the largest analysis of and the highest level of evidence for patients with oligometastatic spine disease treated with SSRS. Because our data are based on a secondary analysis of Phase I/II clinical trials, we have eliminated some of the biases inherent in retrospective analyses, such as information bias and poor follow-up data. Instead, our rigorous and standardized follow-up, with a median follow-up duration of 69 months, allowed us to carefully assess long-term outcomes.

Conclusions

SSRS for the treatment of oligometastatic spinal metastases is a safe and very effective treatment option with excellent long-term survival, local progression-free survival, and STMFS, and should be offered over palliative radiation regimens for these patients. Further prospective study is warranted to confirm these findings.

References

  • 1

    Bishop AJ, , Tao R, , Rebueno NC, , Christensen EN, , Allen PK, & Wang XA, et al.: Outcomes for spine stereotactic body radiation therapy and an analysis of predictors of local recurrence. Int J Radiat Oncol Biol Phys 92:10161026, 2015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Boehling NS, , Grosshans DR, , Allen PK, , McAleer MF, , Burton AW, & Azeem S, et al.: Vertebral compression fracture risk after stereotactic body radiotherapy for spinal metastases. J Neurosurg Spine 16:379386, 2012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Casiraghi M, , De Pas T, , Maisonneuve P, , Brambilla D, , Ciprandi B, & Galetta D, et al.: A 10-year single-center experience on 708 lung metastasectomies: the evidence of the “international registry of lung metastases”. J Thorac Oncol 6:13731378, 2011

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Chang EL, , Shiu AS, , Lii MF, , Rhines LD, , Mendel E, & Mahajan A, 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 59:12881294, 2004

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Chao ST, , Koyfman SA, , Woody N, , Angelov L, , Soeder SL, & Reddy CA, et al.: Recursive partitioning analysis index is predictive for overall survival in patients undergoing spine stereotactic body radiation therapy for spinal metastases. Int J Radiat Oncol Biol Phys 82:17381743, 2012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Choi D, , Crockard A, , Bunger C, , Harms J, , Kawahara N, & Mazel C, et al.: Review of metastatic spine tumour classification and indications for surgery: the consensus statement of the Global Spine Tumour Study Group. Eur Spine J 19:215222, 2010

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Demura S, , Kawahara N, , Murakami H, , Abdel-Wanis ME, , Kato S, & Yoshioka K, et al.: Total en bloc spondylectomy for spinal metastases in thyroid carcinoma. J Neurosurg Spine 14:172176, 2011

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Fang T, , Dong J, , Zhou X, , McGuire RA Jr, & Li X: Comparison of mini-open anterior corpectomy and posterior total en bloc spondylectomy for solitary metastases of the thoracolumbar spine. J Neurosurg Spine 17:271279, 2012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Foro Arnalot P, , Fontanals AV, , Galcerán JC, , Lynd F, , Latiesas XS, & de Dios NR, et al.: Randomized clinical trial with two palliative radiotherapy regimens in painful bone metastases: 30 Gy in 10 fractions compared with 8 Gy in single fraction. Radiother Oncol 89:150155, 2008

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Garg AK, , Shiu AS, , Yang J, , Wang XS, , Allen P, & Brown BW, et al.: Phase 1/2 trial of single-session stereotactic body radiotherapy for previously unirradiated spinal metastases. Cancer 118:50695077, 2012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Garg AK, , Wang XS, , Shiu AS, , Allen P, , Yang J, & McAleer MF, et al.: Prospective evaluation of spinal reirradiation by using stereotactic body radiation therapy: The University of Texas MD Anderson Cancer Center experience. Cancer 117:35093516, 2011

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Gerszten PC: Spine metastases: from radiotherapy, surgery, to radiosurgery. Neurosurgery 61:Suppl 1 1625, 2014

  • 13

    Gerszten PC, , Burton SA, , Ozhasoglu C, & Welch WC: Radiosurgery for spinal metastases: clinical experience in 500 cases from a single institution. Spine (Phila Pa 1976) 32:193199, 2007

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Gill B, , Oermann E, , Ju A, , Suy S, , Yu X, & Rabin J, et al.: Fiducial-free CyberKnife stereotactic body radiation therapy (SBRT) for single vertebral body metastases: acceptable local control and normal tissue tolerance with 5 fraction approach. Front Oncol 2:39, 2012

    • Search Google Scholar
    • Export Citation
  • 15

    Hartsell WF, , Scott CB, , Bruner DW, , Scarantino CW, , Ivker RA, & Roach M III, et al.: Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 97:798804, 2005

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16

    Inoue T, , Katoh N, , Onimaru R, & Shirato H: Clinical outcomes of stereotactic body radiotherapy for patients with lung tumors in the state of oligorecurrence. Pulm Med 2012:369820, 2012

    • Search Google Scholar
    • Export Citation
  • 17

    Jereczek-Fossa BA, , Piperno G, , Ronchi S, , Catalano G, , Fodor C, & Cambria R, et al.: Linac-based stereotactic body radiotherapy for oligometastatic patients with single abdominal lymph node recurrent cancer. Am J Clin Oncol 37:227233, 2014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    Lee S, , Chun M, & Lee M: Stereotactic body radiotherapy for solitary spine metastasis. Radiat Oncol J 31:260266, 2013

  • 19

    Liang T, , Wan Y, , Zou X, , Peng X, & Liu S: Is surgery for spine metastasis reasonable in patients older than 60 years?. Clin Orthop Relat Res 471:628639, 2013

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Murakami H, , Kawahara N, , Demura S, , Kato S, , Yoshioka K, & Sasagawa T, et al.: Perioperative complications and prognosis for elderly patients with spinal metastases treated by surgical strategy. Orthopedics 33:3, 2010

    • Search Google Scholar
    • Export Citation
  • 21

    Nordlinger B, , Guiguet M, , Vaillant JC, , Balladur P, , Boudjema K, & Bachellier P, et al.: Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Cancer 77:12541262, 1996

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Perrin RG, & Laxton AW: Metastatic spine disease: epidemiology, pathophysiology, and evaluation of patients. Neurosurg Clin N Am 15:365373, 2004

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Ryu S, , Jin R, , Jin JY, , Chen Q, , Rock J, & Anderson J, et al.: Pain control by image-guided radiosurgery for solitary spinal metastasis. J Pain Symptom Manage 35:292298, 2008

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24

    Sahgal A, , Atenafu EG, , Chao S, , Al-Omair A, , Boehling N, & Balagamwala EH, et al.: Vertebral compression fracture after spine stereotactic body radiotherapy: a multi-institutional analysis with a focus on radiation dose and the spinal instability neoplastic score. J Clin Oncol 31:34263431, 2013

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Sahgal A, , Ma L, , Gibbs I, , Gerszten PC, , Ryu S, & Soltys S, et al.: Spinal cord tolerance for stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 77:548553, 2010

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Salama JK, & Milano MT: Radical irradiation of extracranial oligometastases. J Clin Oncol 32:29022912, 2014

  • 27

    Singh D, , Yi WS, , Brasacchio RA, , Muhs AG, , Smudzin T, & Williams JP, et al.: Is there a favorable subset of patients with prostate cancer who develop oligometastases?. Int J Radiat Oncol Biol Phys 58:310, 2004

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Tang C, , Hess K, , Bishop AJ, , Pan HY, , Christensen EN, & Yang JN, et al.: Creation of a prognostic index for spine metastasis to stratify survival in patients treated with spinal stereotactic radiosurgery: secondary analysis of mature prospective trials. Int J Radiat Oncol Biol Phys 93:118125, 2015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Tanvetyanon T, , Robinson LA, , Schell MJ, , Strong VE, , Kapoor R, & Coit DG, et al.: Outcomes of adrenalectomy for isolated synchronous versus metachronous adrenal metastases in non-small-cell lung cancer: a systematic review and pooled analysis. J Clin Oncol 26:11421147, 2008

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    Thibault I, , Al-Omair A, , Masucci GL, , Masson-Côté L, , Lochray F, & Korol R, et al.: Spine stereotactic body radiotherapy for renal cell cancer spinal metastases: analysis of outcomes and risk of vertebral compression fracture. J Neurosurg Spine 21:711718, 2014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31

    Wang XS, , Rhines LD, , Shiu AS, , Yang JN, , Selek U, & Gning I, et al.: Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: a phase 1–2 trial. Lancet Oncol 13:395402, 2012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32

    Witham TF, , Khavkin YA, , Gallia GL, , Wolinsky JP, & Gokaslan ZL: Surgery insight: current management of epidural spinal cord compression from metastatic spine disease. Nat Clin Pract Neurol 2:8794, 116, 2006

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33

    Yamada Y, , Bilsky MH, , Lovelock DM, , Venkatraman ES, , Toner S, & Johnson J, et al.: High-dose, single-fraction image-guided intensity-modulated radiotherapy for metastatic spinal lesions. Int J Radiat Oncol Biol Phys 71:484490, 2008

    • Crossref
    • Search Google Scholar
    • Export Citation

Disclosures

Dr. Rhines is a consultant for Stryker and Globus.

Author Contributions

Conception and design: Ghia, Ho, Brown. Acquisition of data: Ghia, Ho, Tang, Deegan, Jonasch, Amini, Wang, Li, Tatsui, Rhines, Brown. Analysis and interpretation of data: Ghia, Ho, Tang, Allen, Wang, Brown. Drafting the article: Ghia, Ho, Allen. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Ghia. Statistical analysis: Allen. Administrative/technical/material support: all authors. Study supervision: Ghia.

  • Collapse
  • Expand
  • View in gallery

    Kaplan-Meier curves demonstrating OS (upper) and local progression-free survival (lower) in all patients.

  • View in gallery

    Kaplan-Meier curves comparing the OS of patients with a KPS score of 90–100 (solid line) versus 70–80 (dashed line; left), and the OS of patients with prior spine surgery (solid line) or no prior spine surgery (dashed line; right).

  • View in gallery

    Kaplan-Meier curve showing the STMFS of all patients.

  • 1

    Bishop AJ, , Tao R, , Rebueno NC, , Christensen EN, , Allen PK, & Wang XA, et al.: Outcomes for spine stereotactic body radiation therapy and an analysis of predictors of local recurrence. Int J Radiat Oncol Biol Phys 92:10161026, 2015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Boehling NS, , Grosshans DR, , Allen PK, , McAleer MF, , Burton AW, & Azeem S, et al.: Vertebral compression fracture risk after stereotactic body radiotherapy for spinal metastases. J Neurosurg Spine 16:379386, 2012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Casiraghi M, , De Pas T, , Maisonneuve P, , Brambilla D, , Ciprandi B, & Galetta D, et al.: A 10-year single-center experience on 708 lung metastasectomies: the evidence of the “international registry of lung metastases”. J Thorac Oncol 6:13731378, 2011

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Chang EL, , Shiu AS, , Lii MF, , Rhines LD, , Mendel E, & Mahajan A, 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 59:12881294, 2004

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Chao ST, , Koyfman SA, , Woody N, , Angelov L, , Soeder SL, & Reddy CA, et al.: Recursive partitioning analysis index is predictive for overall survival in patients undergoing spine stereotactic body radiation therapy for spinal metastases. Int J Radiat Oncol Biol Phys 82:17381743, 2012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Choi D, , Crockard A, , Bunger C, , Harms J, , Kawahara N, & Mazel C, et al.: Review of metastatic spine tumour classification and indications for surgery: the consensus statement of the Global Spine Tumour Study Group. Eur Spine J 19:215222, 2010

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Demura S, , Kawahara N, , Murakami H, , Abdel-Wanis ME, , Kato S, & Yoshioka K, et al.: Total en bloc spondylectomy for spinal metastases in thyroid carcinoma. J Neurosurg Spine 14:172176, 2011

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Fang T, , Dong J, , Zhou X, , McGuire RA Jr, & Li X: Comparison of mini-open anterior corpectomy and posterior total en bloc spondylectomy for solitary metastases of the thoracolumbar spine. J Neurosurg Spine 17:271279, 2012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Foro Arnalot P, , Fontanals AV, , Galcerán JC, , Lynd F, , Latiesas XS, & de Dios NR, et al.: Randomized clinical trial with two palliative radiotherapy regimens in painful bone metastases: 30 Gy in 10 fractions compared with 8 Gy in single fraction. Radiother Oncol 89:150155, 2008

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Garg AK, , Shiu AS, , Yang J, , Wang XS, , Allen P, & Brown BW, et al.: Phase 1/2 trial of single-session stereotactic body radiotherapy for previously unirradiated spinal metastases. Cancer 118:50695077, 2012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Garg AK, , Wang XS, , Shiu AS, , Allen P, , Yang J, & McAleer MF, et al.: Prospective evaluation of spinal reirradiation by using stereotactic body radiation therapy: The University of Texas MD Anderson Cancer Center experience. Cancer 117:35093516, 2011

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Gerszten PC: Spine metastases: from radiotherapy, surgery, to radiosurgery. Neurosurgery 61:Suppl 1 1625, 2014

  • 13

    Gerszten PC, , Burton SA, , Ozhasoglu C, & Welch WC: Radiosurgery for spinal metastases: clinical experience in 500 cases from a single institution. Spine (Phila Pa 1976) 32:193199, 2007

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Gill B, , Oermann E, , Ju A, , Suy S, , Yu X, & Rabin J, et al.: Fiducial-free CyberKnife stereotactic body radiation therapy (SBRT) for single vertebral body metastases: acceptable local control and normal tissue tolerance with 5 fraction approach. Front Oncol 2:39, 2012

    • Search Google Scholar
    • Export Citation
  • 15

    Hartsell WF, , Scott CB, , Bruner DW, , Scarantino CW, , Ivker RA, & Roach M III, et al.: Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 97:798804, 2005

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16

    Inoue T, , Katoh N, , Onimaru R, & Shirato H: Clinical outcomes of stereotactic body radiotherapy for patients with lung tumors in the state of oligorecurrence. Pulm Med 2012:369820, 2012

    • Search Google Scholar
    • Export Citation
  • 17

    Jereczek-Fossa BA, , Piperno G, , Ronchi S, , Catalano G, , Fodor C, & Cambria R, et al.: Linac-based stereotactic body radiotherapy for oligometastatic patients with single abdominal lymph node recurrent cancer. Am J Clin Oncol 37:227233, 2014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    Lee S, , Chun M, & Lee M: Stereotactic body radiotherapy for solitary spine metastasis. Radiat Oncol J 31:260266, 2013

  • 19

    Liang T, , Wan Y, , Zou X, , Peng X, & Liu S: Is surgery for spine metastasis reasonable in patients older than 60 years?. Clin Orthop Relat Res 471:628639, 2013

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Murakami H, , Kawahara N, , Demura S, , Kato S, , Yoshioka K, & Sasagawa T, et al.: Perioperative complications and prognosis for elderly patients with spinal metastases treated by surgical strategy. Orthopedics 33:3, 2010

    • Search Google Scholar
    • Export Citation
  • 21

    Nordlinger B, , Guiguet M, , Vaillant JC, , Balladur P, , Boudjema K, & Bachellier P, et al.: Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Cancer 77:12541262, 1996

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Perrin RG, & Laxton AW: Metastatic spine disease: epidemiology, pathophysiology, and evaluation of patients. Neurosurg Clin N Am 15:365373, 2004

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Ryu S, , Jin R, , Jin JY, , Chen Q, , Rock J, & Anderson J, et al.: Pain control by image-guided radiosurgery for solitary spinal metastasis. J Pain Symptom Manage 35:292298, 2008

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24

    Sahgal A, , Atenafu EG, , Chao S, , Al-Omair A, , Boehling N, & Balagamwala EH, et al.: Vertebral compression fracture after spine stereotactic body radiotherapy: a multi-institutional analysis with a focus on radiation dose and the spinal instability neoplastic score. J Clin Oncol 31:34263431, 2013

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Sahgal A, , Ma L, , Gibbs I, , Gerszten PC, , Ryu S, & Soltys S, et al.: Spinal cord tolerance for stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 77:548553, 2010

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Salama JK, & Milano MT: Radical irradiation of extracranial oligometastases. J Clin Oncol 32:29022912, 2014

  • 27

    Singh D, , Yi WS, , Brasacchio RA, , Muhs AG, , Smudzin T, & Williams JP, et al.: Is there a favorable subset of patients with prostate cancer who develop oligometastases?. Int J Radiat Oncol Biol Phys 58:310, 2004

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Tang C, , Hess K, , Bishop AJ, , Pan HY, , Christensen EN, & Yang JN, et al.: Creation of a prognostic index for spine metastasis to stratify survival in patients treated with spinal stereotactic radiosurgery: secondary analysis of mature prospective trials. Int J Radiat Oncol Biol Phys 93:118125, 2015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Tanvetyanon T, , Robinson LA, , Schell MJ, , Strong VE, , Kapoor R, & Coit DG, et al.: Outcomes of adrenalectomy for isolated synchronous versus metachronous adrenal metastases in non-small-cell lung cancer: a systematic review and pooled analysis. J Clin Oncol 26:11421147, 2008

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    Thibault I, , Al-Omair A, , Masucci GL, , Masson-Côté L, , Lochray F, & Korol R, et al.: Spine stereotactic body radiotherapy for renal cell cancer spinal metastases: analysis of outcomes and risk of vertebral compression fracture. J Neurosurg Spine 21:711718, 2014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31

    Wang XS, , Rhines LD, , Shiu AS, , Yang JN, , Selek U, & Gning I, et al.: Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: a phase 1–2 trial. Lancet Oncol 13:395402, 2012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32

    Witham TF, , Khavkin YA, , Gallia GL, , Wolinsky JP, & Gokaslan ZL: Surgery insight: current management of epidural spinal cord compression from metastatic spine disease. Nat Clin Pract Neurol 2:8794, 116, 2006

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33

    Yamada Y, , Bilsky MH, , Lovelock DM, , Venkatraman ES, , Toner S, & Johnson J, et al.: High-dose, single-fraction image-guided intensity-modulated radiotherapy for metastatic spinal lesions. Int J Radiat Oncol Biol Phys 71:484490, 2008

    • Crossref
    • Search Google Scholar
    • Export Citation

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