Single-fraction versus multifraction spinal stereotactic radiosurgery for spinal metastases from renal cell carcinoma: secondary analysis of Phase I/II trials

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OBJECTIVE

The objective of this study was to compare fractionation schemes and outcomes of patients with renal cell carcinoma (RCC) treated in institutional prospective spinal stereotactic radiosurgery (SSRS) trials who did not previously undergo radiation treatment at the site of the SSRS.

METHODS

Patients enrolled in 2 separate institutional prospective protocols and treated with SSRS between 2002 and 2011 were included. A secondary analysis was performed on patients with previously nonirradiated RCC spinal metastases treated with either single-fraction (SF) or multifraction (MF) SSRS.

RESULTS

SSRS was performed in 47 spinal sites on 43 patients. The median age of the patients was 62 years (range 38–75 years). The most common histological subtype was clear cell (n = 30). Fifteen sites underwent surgery prior to the SSRS, with laminectomy the most common procedure performed (n = 10). All SF SSRS was delivered to a dose of 24 Gy (n = 21) while MF regiments were either 27 Gy in 3 fractions (n = 20) or 30 Gy in 5 fractions (n = 6). The median overall survival duration for the entire cohort was 22.8 months. The median local control (LC) for the entire cohort was 80.6 months with 1-year and 2-year actuarial LC rates of 82% and 68%, respectively. Single-fraction SSRS correlated with improved 1- and 2-year actuarial LC relative to MF SSRS (95% vs 71% and 86% vs 55%, respectively; p = 0.009). On competing risk analysis, SF SSRS showed superior LC to MF SSRS (subhazard ratio [SHR] 6.57, p = 0.014). On multivariate analysis for LC with tumor volume (p = 0.272), number of treated levels (p = 0.819), gross tumor volume (GTV) coverage (p = 0.225), and GTV minimum point dose (p = 0.97) as covariates, MF SSRS remained inferior to SF SSRS (SHR 5.26, p = 0.033)

CONCLUSIONS

SSRS offers durable LC for spinal metastases from RCC. Single-fraction SSRS is associated with improved LC over MF SSRS for previously nonirradiated RCC spinal metastases.

ABBREVIATIONSBED = biological equivalent dose; Dmax = maximum point dose; Dmin = minimum point dose; GTV = gross tumor volume; HR = hazard ratio; IMRT = intensity-modulated radiotherapy; KPS = Karnofsky Performance Scale; LC = local control; MF = multifraction; nBED = normalized BED; RCC = renal cell carcinoma; SF = single fraction; SHR = subhazard ratio; SINS = Spine Instability Neoplastic Score; SSRS = spinal stereotactic radiosurgery.

OBJECTIVE

The objective of this study was to compare fractionation schemes and outcomes of patients with renal cell carcinoma (RCC) treated in institutional prospective spinal stereotactic radiosurgery (SSRS) trials who did not previously undergo radiation treatment at the site of the SSRS.

METHODS

Patients enrolled in 2 separate institutional prospective protocols and treated with SSRS between 2002 and 2011 were included. A secondary analysis was performed on patients with previously nonirradiated RCC spinal metastases treated with either single-fraction (SF) or multifraction (MF) SSRS.

RESULTS

SSRS was performed in 47 spinal sites on 43 patients. The median age of the patients was 62 years (range 38–75 years). The most common histological subtype was clear cell (n = 30). Fifteen sites underwent surgery prior to the SSRS, with laminectomy the most common procedure performed (n = 10). All SF SSRS was delivered to a dose of 24 Gy (n = 21) while MF regiments were either 27 Gy in 3 fractions (n = 20) or 30 Gy in 5 fractions (n = 6). The median overall survival duration for the entire cohort was 22.8 months. The median local control (LC) for the entire cohort was 80.6 months with 1-year and 2-year actuarial LC rates of 82% and 68%, respectively. Single-fraction SSRS correlated with improved 1- and 2-year actuarial LC relative to MF SSRS (95% vs 71% and 86% vs 55%, respectively; p = 0.009). On competing risk analysis, SF SSRS showed superior LC to MF SSRS (subhazard ratio [SHR] 6.57, p = 0.014). On multivariate analysis for LC with tumor volume (p = 0.272), number of treated levels (p = 0.819), gross tumor volume (GTV) coverage (p = 0.225), and GTV minimum point dose (p = 0.97) as covariates, MF SSRS remained inferior to SF SSRS (SHR 5.26, p = 0.033)

CONCLUSIONS

SSRS offers durable LC for spinal metastases from RCC. Single-fraction SSRS is associated with improved LC over MF SSRS for previously nonirradiated RCC spinal metastases.

Spinal metastases occur in up to 70% of all involved osseous sites, leading to significant morbidity.10 Metastastic involvement of the vertebral column may cause pain, instability, fracture, or neurological compromise. The age-adjusted incidence of renal cell carcinoma (RCC) has increased by nearly 40% in the past 20 years.23 Bone is a common site of metastatic involvement, with 20%–35% of patients with RCC eventually developing bone metastases.4,36,39 The majority of patients with RCC and bone metastases will undergo some form of radiation therapy to palliate pain, prevent disease progression and pathological fracture, and halt or reverse neurological compromise.17 However, for radioresistant tumors, including RCC, conventionally fractionated radiation has been shown to lead to suboptimal local control (LC).21,25,37 With improved progression-free survival and overall survival rates due to the use of targeted therapies in patients with metastatic RCC, addressing bone metastases with modalities that can provide durable LC has become a growing concern.9,12

Spinal stereotactic radiosurgery (SSRS) is a form of stereotactic body radiotherapy by which advanced treatment delivery techniques (such as intensity-modulated radiotherapy [IMRT]) are combined with image guidance and rigid immobilization to deliver a high dose of conformal radiation to the target while minimizing the dose to nearby critical structures such as the spinal cord. Institutional, prospective, single-arm trials have been performed at MD Anderson Cancer Center establishing the safety and efficacy of SSRS for spinal metastases, with 1-year actuarial LC rates of 84% in patients who had not previously undergone radiation therapy at the site of SSRS.15,16

The optimal dose and fractionation for SSRS is debated without Level-1 data to guide therapeutic recommendations.18 This is especially pertinent for radioresistant histologies such as RCC, as it is believed that larger fraction sizes are needed to overcome the intrinsic radioresistance of the tumor cells.5 Single-fraction (SF) SSRS dose escalation to 24 Gy has been correlated with improved LC.38 However, vertebral compression fracture has also been noted to occur in 10%–39% of patients receiving SSRS, with dose escalation correlating with increased risk of fracture.3,28,33 In this study, we performed a secondary analysis of our prospective Phase I/II studies to compare SF SSRS with multifraction (MF) SSRS in patients with previously nonirradiated spinal metastases from RCC.

Methods

Study Population

Between 2002 and 2011, a total of 210 patients were enrolled in 2 Phase I/II trials at MD Anderson Cancer Center (Houston, Texas) evaluating the use of MF SSRS and then SF SSRS in patients with spinal metastases.15,16 The trials were approved by the institutional review board and written informed consent was obtained from trial participants prior to enrollment. Eligibility requirements included diagnosis of cancer, Karnofsky Performance Scale (KPS) score > 40, an MR image identifying spinal or paraspinal metastasis within 4 weeks of enrollment, and no more than 2 metastatic sites in the spine to be irradiated over a single course of treatment. Indications for treatment included oligometastatic disease, failure of prior surgery or conventionally fractionated radiation, residual tumor after surgery, medical inoperability, or refusal of surgery. Exclusion criteria for the clinical trials included spinal cord compression, unstable spine as determined by the multidisciplinary tumor board, cytotoxic chemotherapy within 1 month of enrollment, or external beam radiation therapy to the current site of disease within 3 months prior to enrollment.

Treatment Parameters

All patients underwent image-guided intensity-modulated SSRS with CT guidance using the EXaCT targeting system CT-on-rails or Trilogy treatment delivery system with On-board Imager Cone Beam CT (Varian Medical Systems) as previously described.6,34 Briefly, patients were immobilized in an Elekta BodyFix stereotactic body frame system (Elekta) and aligned using a stereotactic localizer and target positioning frame (Integra Radionics). Treatment planning was performed using IMRT inverse-treatment software (Pinnacle, Philips Medical Systems). Intrathecal injection of contrast medium (Omnipaque, Amersham Health) was used in cases in which MRI alone was not sufficient to clearly delineate the spinal cord. Verification of target positioning and quality assurance procedures for each case were performed by the radiation oncologist and a dedicated radiation physicist, respectively.

The gross tumor volumes (GTVs) were prescribed to receive 30 Gy in 5 fractions prior to transitioning to 27 Gy in 3 fractions on the MF protocol. Patients on the subsequent SF protocol received 18–24 Gy depending on histology. Cord constraint on the MF protocol was 10 Gy maximum point dose (Dmax) for the 5-fraction treatment and 9 Gy for the 3-fraction treatment. Cord constraint on the SF protocol was 0.01 cm3 less than 10 Gy. MF treatments were administered on alternating days.

To compare dosimetric parameters among the various fractionation schemes, the normalized biological equivalent dose (nBED) was calculated. Based on the linear quadratic model of cell survival following radiation therapy, the BED calculation (BED = nd [1 + d/α/β]) allows for the comparison of the effects of different dose fractionation schemes (n = number of fractions, d = dose per fraction).14,29,31 An α/β value of 2 was used for spinal cord effect and 10 was used for tumor effect. The nBED is a normalized BED to 2-Gy equivalents and is calculated by dividing BED by (1 + d/α/β) where both d and α/β are 2 Gy.32

Patients were evaluated during follow-up every 3 months for 2 years, and then every 6 months thereafter with MRI of the spine. For the purposes of this secondary analysis, patients with RCC and no prior history of radiation to the site of SSRS were included. The epidural spinal cord compression scale described by Bilsky et al. was used to grade the degree of epidural extent in the postoperative patients.1 The Spine Instability Neoplastic Score (SINS) was calculated for assessable patients.11 In-field failure was defined as having occurred within 95% of the prescription isodose line while marginal recurrence was defined as having occurred partially or fully in the penumbra, commonly between 20% and 95% of the prescription isodose line.

Statistical Analysis

Descriptive statistics (mean, median, standard deviation, and proportions) were used to report patient and clinical characteristics. The site of treatment was the unit of analysis. Proportions were compared using Fisher's exact test. The equality of group medians was assessed with a nonparametric test of equality. Cox regression was used to assess LC with covariates having a p value < 0.25 in univariate analysis included in the multivariate analysis. A competing risk regression analysis for LC was performed with death as the competing risk variable. All p values were 2-tailed and were considered significant if they were < 0.05. Statistical analysis was performed with Stata/MP (version 13.1, StataCorp LP).

Results

Of the 210 patients enrolled in the 2 Phase I/II trials, 43 patients with RCC with 47 previously nonirradiated spinal sites were included in this analysis. Detailed patient characteristics are shown in Table 1. The median follow-up for all patients was 23 months, and for those alive it was 72 months. The majority of patients were male (n = 33) with a median age of 62 years (range 38–75 years). The median KPS score was 80 (range 70–100).

TABLE 1.

Patient demographics

VariableValue
No. of patients43
Age (yrs)
  Median62
  Range38–75
Sex
  Male33
  Female10
Ethnicity
  Caucasian35
  Hispanic5
  African American3
KPS score
  1001
  9011
  8021
  7010
Histological subtype
  Clear cell27
  Papillary5
  Sarcomatoid3
  Other8
Sites treated
  139
  24

Treatment characteristics are shown in Table 2. Of the 47 sites, 35 were single-level targets. The most common histological subtype by lesion was clear cell (n = 30). Fifteen sites had undergone surgery prior to the SSRS, with posterior decompression and stabilization the most common procedure performed (n = 10). Lumbar spine (n = 20) and thoracic spine (n = 20) sites were most common. All SF SSRS was delivered to a dose of 24 Gy (n = 21) while MF regimens were either 27 Gy in 3 fractions (n = 20) or 30 Gy in 5 fractions (n = 6). These corresponded to an nBED of 68 Gy2/10, 42.8 Gy2/10, and 40 Gy2/10, respectively (in which “2” = 2 Gy equivalent, and “10” refers to the α/β ratio). Of those with treatment at the level of the spinal cord (n = 35), the median cord Dmax nBED was 22.4 Gy2/2 (range 8.3 Gy2/2–48.8 Gy2/2). Of those with treatment below the level of the spinal cord (n = 12), the median cauda equina Dmax nBED was 49.9 Gy2/2 (range 13.8 Gy2/2–96.7 Gy2/2).

TABLE 2.

Treatment site characteristics

TotalSFMFp ValueTest
Sites472126
Histological subtype
  Clear cell3013170.227Fisher's exact
  Papillary541
  Sarcomatoid303
  Other945
Location
  Cervical4040.251Fisher's exact
  Thoracic20911
  Lumbar20119
  Thoracolumbar junction312
No. of levels
  13518170.338Fisher's exact
  ≥21239
Prior surgery155100.335Fisher's exact
  Posterior decompression1037
  Vertebrectomy110
  Other413
Dose (Gy)
  24, 1 fraction21210NA
  27, 3 fractions20020
  30, 5 fractions606
Bilsky score (no surgery)3216160.109Fisher's exact
  01239
  1a1174
  1b963
Paraspinal disease
  No2712151.0Fisher's exact
  Yes20911
Posterior elements disease
  No3415191.0Fisher's exact
  Yes1367
Tumor volume (cm3)
  Median41.7043.1040.80.863Median
  Mean60.7855.2167.27
  Range7.6–300.17.6–161.114.5–300.1
GTV (median)
  Dmin12.7314.511.40.192Median
  D9821.921.222.10.434Median
  D952423.225.10.297Median
GTV coverage
  Median0.880.920.830.059Median
  Mean0.880.910.85
  Range0.72–1.000.80–0.990.72–1.00
SINS
  Assessable181080.054Fisher's exact
  Stable (0–6)826
  Potentially unstable (7–12)1082

D95 = minimum dose delivered to 95% of the GTV; D98 = minimum dose delivered to 98% of the GTV.

Local Control

The median LC for the entire cohort was 80.6 months. The 1-year and 2-year actuarial LC rates were 82% and 68%, respectively, for the entire cohort. Single-fraction SSRS correlated with improved 1- and 2- year actuarial LC relative to MF SSRS (95% vs 71% and 86% vs 55%, respectively; p = 0.009; Fig. 1). Using a competing risk regression analysis for LC with death as the competing risk variable, MF SSRS had worse LC than SF SSRS on univariate analysis (subhazard ratio [SHR] 6.57, p = 0.014; Table 3). There was no significant difference between the 2 MF SSRS regimens (p = 0.41). On multivariate analysis for LC with tumor volume (p = 0.272), number of treated levels (p = 0.819), GTV coverage (p = 0.225), and GTV minimum point dose (Dmin) (p = 0.97) as covariates, MF SSRS remained worse than SF SSRS (SHR 5.26, p = 0.033; Table 3).

FIG. 1.
FIG. 1.

Actuarial LC for patients treated with SF SSRS (solid line) or MF SSRS (dashed line).

TABLE 3.

Competing risk regression analysis for LC

VariableReferenceUnivariate AnalysisMultivariate Analysis
SHR95% CIp ValueSHR95% CIp Value
MFSF6.571.46–29.550.0145.261.14–24.140.033
Non–clear cellClear cell1.790.65–4.880.257
Prior surgery0.720.23–2.220.569
No. of levels1
  ≥22.440.88–6.760.0881.190.27–5.290.819
Bilsky Class0
  1a0.360.07–1.770.21
  1b1.150.31–4.260.839
Postop treatment0.560.15–2.070.389
Paraspinal disease0.860.31–2.360.771
Tumor volume*1.011–1.010.00210.997–1.010.272
GTV*
  Coverage0.0020.00001–1.0040.050.010.000002–21.520.225
  Dmin0.910.8–1.030.1440.970.86–1.10.97
  D951.070.9–1.270.417
  D981.0010.86–1.160.992

Continuous variable.

The median follow-up duration was not significantly different between the groups (p = 0.9). The 2 cohorts were balanced in terms of histological subtype (p = 0.227), spinal level (p = 0.251), number of levels treated (p = 0.338), paraspinal disease (1.0), posterior element involvement (p = 1.0), tumor volume (p = 0.863), Bilsky class (0.109), and prior surgery (0.335). GTV Dmin (p = 0.192), GTV D95 (p = 0.297), and GTV coverage (p = 0.059) did not significantly differ between the groups (Table 2). With competing risk analysis for LC using death as the competing risk factor, LC did not correlate with histological subtype (p = 0.257), number of levels (p = 0.088), paraspinal disease (0.771), Bilsky score (p = 0.21 for 1a, p = 0.839 for 1b), or prior surgery (p = 0.569). See Table 3 for the competing risk regression analysis.

Overall Survival

The median overall survival for the entire cohort was 22.8 months, with 1- and 2-year actuarial survival rates of 74% and 49%, respectively. The results of the univariate analysis for overall survival are displayed in Table 4. Sex (p = 0.589), KPS score (p = 0.428), histological subtype (p = 0.155), tumor volume (p = 0.47), and SF treatment (p = 0.409) were among factors not correlated with survival. The only factor in this cohort correlating with overall survival was age (hazard ratio [HR] 0.97, p = 0.032).

TABLE 4.

Univariate Cox regression analysis for overall survival

VariableReferenceHR95% CIp Value
Sex (male)1.250.55–2.860.589
KPS score*0.980.95–1.020.428
Age (yrs)*0.970.94–10.032
Non–clear cellClear cell1.620.83–3.160.155
Prior surgery0.980.51–1.890.952
No. of levels1
  ≥21.560.75–3.250.24
Bilsky score0
  1a0.90.37–2.180.81
  1b1.020.37–2.80.972
Postop treatment0.950.43–2.110.893
Paraspinal disease1.450.77–2.730.254
Tumor volume*1.0020.996–1.0090.47
SFMF1.310.69–2.480.409

Continuous variable.

Patterns of Failure

Table 5 includes a comparison of the patterns of failure between the SF cohort and MF cohort. Of the 12 local failures in the MF group, 6 were in field, 4 were epidural marginal, 1 was vertebral body marginal, and 2 were both in field and marginal. Of the 2 local failures in the SF group, 1 was in field and 1 was both in field and epidural marginal.

TABLE 5.

Patterns of failure and toxicity*

TotalSFMFp Value
Sites472126
Pattern of failure
  Total142120.004
  In field716
  Epidural marginal404
  Vertebral body marginal101
  In field and epidural312
Pain flare
  Assessable4020201.0
  Any1376
Vertebral body fracture
  Assessable2413110.11
  Fractures761
  Symptomatic330
  Asymptomatic431

All p values obtained using Fisher's exact test.

Toxicity

Pain flare occurred in 13 of 40 evaluable sites with no difference between SF and MF groups (p = 1.0). Posttreatment fracture occurred in 6 of 13 assessable SF sites and 1 of 11 assessable MF sites (p = 0.11). Of the 7 patients with posttreatment fracture, 3 were symptomatic. Of these 3 patients, 2 received a kyphoplasty and the other died of systemic progression prior to a scheduled kyphoplasty. The mean nBED to the vertebral body was 141 Gy2/2 in those suffering a fracture. A greater proportion of assessable SF sites had an SINS classification of potentially unstable (p = 0.054). One patient had a Grade 3 late radiculopathy (foot drop) in the SF cohort. This patient received 24 Gy in 1 fraction to an L-6 lesion, with the cauda equina receiving a Dmax of 14.7 Gy (nBED = 61.1 Gy2/2).

Discussion

In this secondary analysis of prospective Phase I/II institutional protocols involving patients treated with SSRS, SF correlated with improved LC over MF regimens in patients with RCC with no prior history of radiation therapy at the site of interest. In the US, the stereotactic body radiotherapy technique is being adopted at an exponential rate.26 Various fractionation schemes have been used without Level 1 data to guide the optimal treatment regimen. At our institution, prospective Phase I/II clinical trials were developed to assess the safety and efficacy of this emerging technology.6,7,15 We have demonstrated excellent durable LC as well as pain relief utilizing SSRS with various fractionation schemes.15,24

Retrospective data have suggested improved LC rates with dose-escalated SF SSRS.20,38 Zelefsky et al.40 reported on 105 extracranial metastastic lesions from RCC treated with hypofractionated (3 or 5 fractions) or SF image-guided IMRT, of which 59 were spinal targets. Similar to the findings in the current study, they showed a statistically significant improvement in LC with dose-escalated SF treatment over hypofractionated treatment (p < 0.001). Their 2-year LC rate of 88% is nearly identical to our 2-year LC rate of 86% for dose-escalated SF SSRS.

In addition, SF SSRS has been correlated with improved LC for sarcoma, another radioresistant histology.13 Improved LC with SF SSRS has correlated with dosimetric factors such as GTV Dmin.2,20 However, SF SSRS has also been correlated with both acute toxicities such as pain flare8,27 and increased late toxicities such as vertebral body compression fractures.3,30,33 No randomized controlled trial exists comparing SF SSRS and MF SSRS to weigh the potential LC benefits of SF against potential toxicities of treatment.

This report serves as the first analysis of patients treated in prospective clinical trials with protocol-defined, rigid extended follow-up who received various SSRS fractionation schemes. All patients had the same histology and no prior radiation therapy at the site of treatment, eliminating a potential selection bias. Relevant clinical and dosimetric factors were balanced between the SF and MF groups. Multivariate analysis utilizing a competing risk regression model showed improved LC with SF SSRS over MF SSRS after controlling for additional potential confounding variables such as tumor volume, number of vertebral body levels involved, GTV coverage, and GTV Dmin.

A separate analysis by Bishop et al. analyzed dosimetric factors correlating with LC in patients receiving SSRS with multiple fractionation schemes.2 That analysis of 332 metastases included this patient cohort, and using a Cox regression analysis revealed a GTV Dmin goal of ≥ 33.4 Gy (BED) as correlating significantly with LC. This corresponds to a GTV Dmin goal of 14 Gy in SF treatment or 21 Gy in 3-fraction treatment.

For radioresistant tumors including RCC, conventionally fractionated radiation has been shown to lead to suboptimal LC.21,25,37 Patients who have spinal metastases from radioresistant tumors such as RCCs have poorer response to radiation treatment, shorter duration of response, and poorer survival, as compared with those with more responsive tumors (e.g., breast cancer).22 The higher BED delivered with stereotactic approaches may account for the improved LC and symptom relief in patients with RCC.15,19,24 Utilizing the linear quadratic model to estimate isoeffect doses for various hypofractionation schemes is controversial and fails to account for the indirect mechanisms of cell death introduced by stereotactic treatment.35 However, delivering dose-escalated SF SSRS with 24 Gy in 1 fraction likely offers a greater BED than delivering MF SSRS with 27 Gy in 3 fractions or 30 Gy in 5 fractions. It is possible that this difference in BED may account for the improved LC observed in this study. Moreover, dose-escalated MF SSRS regimens have the potential to offer LC similar to that of SF SSRS while also reducing the risk of late side effects of therapy such as vertebral body fracture.30 Although we did not see a difference between the 2 multi-fractionated SSRS regimens, possibly due to limited sample sizes, others have demonstrated a difference between low-dose and high-dose hypofractionated SSRS.19 Laufer et al. published a study on a cohort of 186 patients who received separation surgery followed by either SF SSRS or MF SSRS with a variety of dose-fractionation regimens.19 They demonstrated a significant improvement of LC for those receiving dose-escalated hypofractionated SSRS over low-dose hypofractionated SSRS. They did not demonstrate an advantage for dose-escalated SF radiosurgery in terms of LC. In contrast, our report shows a correlation between dose-escalated SF SSRS and LC. Differences in patient populations may account for the differing results as our patient population consisted completely of patients with RCC who had not previously undergone radiation treatment at the site of SSRS, while the patient population in the Laufer et al. study consisted of a more heterogeneous population all treated with separation surgery, of whom nearly 50% received prior external beam radiation.

The incidence of pain flare for SSRS varies widely in the literature from 23% to 68%, with SF treatment regimens showing a greater predilection for flare.8,27 However, in this limited cohort, we did not observe an increased risk of pain flare in those receiving SF SSRS. With the increased dose delivered in SSRS, vertebral compression fracture has been noted to occur in 10%–39% of patients receiving SSRS.3,28 In this limited cohort, there was no correlation between number of fractions and fracture risk, although numerically there were proportionally more fractures in the SF SSRS cohort, consistent with previously published literature.

As a secondary analysis of prospective clinical trials, these data are not randomized and biases may exist between the 2 primary cohorts of patients. Time bias may exist as patients treated on the MF clinical trial were treated at an earlier time than those treated on the SF clinical trial. Although there were no differences in median follow-up time, tumor volume, number of vertebral body levels, prior surgery, Bilsky degree of epidural disease, or GTV Dmin between the groups, unintended selection bias cannot be ruled out in a nonrandomized study. GTV coverage was nearly significantly improved in the SF treatments, perhaps reflecting the increased experience in treating this cohort; however, multivariate analysis and competing-risks analysis suggested an improvement of LC in the SF treatments independent of GTV coverage. Moreover, the analyzed subset includes only patients with RCC who previously did not receive radiation at the site of SSRS, limiting the generalizability of the results. Although there is a correlation between SF treatment and improved LC for this cohort, it is unclear whether there may be an LC advantage of SF treatment over MF treatment for other tumor histologies or in the setting of prior radiation.

This study verifies the role of SSRS in the management of patients with RCC and spinal metastases. With extended regimented follow-up per the requirements of the prospective clinical trials, there was a correlation between SF treatment and improved LC, with a 2-year actuarial rate of 86%. SSRS provides durable LC with limited toxicity and serves as a viable technique for definitive management of spinal metastases from RCC.

Conclusions

On the basis of this study, SSRS provides excellent long-term LC for spinal metastases from RCC treated in the radiation-naïve setting. Single-fraction SSRS is associated with improved LC compared with MF SSRS and should be considered in the upfront management of these patients. A randomized prospective trial is required to definitively demonstrate an LC advantage for SF SSRS.

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    • Export Citation
  • 18

    Guckenberger MMantel FGerszten PCFlickinger JCSahgal ALétourneau D: Safety and efficacy of stereotactic body radiotherapy as primary treatment for vertebral metastases: a multi-institutional analysis. Radiat Oncol 9:2262014

    • Search Google Scholar
    • Export Citation
  • 19

    Laufer IIorgulescu JBChapman TLis EShi WZhang Z: Local disease control for spinal metastases following “separation surgery” and adjuvant hypofractionated or high-dose single-fraction stereotactic radiosurgery: outcome analysis in 186 patients. J Neurosurg Spine 18:2072142013

    • Search Google Scholar
    • Export Citation
  • 20

    Lovelock DMZhang ZJackson AKeam JBekelman JBilsky M: Correlation of local failure with measures of dose insufficiency in the high-dose single-fraction treatment of bony metastases. Int J Radiat Oncol Biol Phys 77:128212872010

    • Search Google Scholar
    • Export Citation
  • 21

    Maor MHFrias AEOswald MJ: Palliative radiotherapy for brain metastases in renal carcinoma. Cancer 62:191219171988

  • 22

    Maranzano ELatini P: Effectiveness of radiation therapy without surgery in metastatic spinal cord compression: final results from a prospective trial. Int J Radiat Oncol Biol Phys 32:9599671995

    • Search Google Scholar
    • Export Citation
  • 23

    National Cancer Institute: SEER Stat Fact Sheets: Kidney and Renal Pelvis Cancer. (http://seer.cancer.gov/statfacts/html/kidrp.html)[Accessed October 29 2015]

    • Export Citation
  • 24

    Nguyen QNShiu ASRhines LDWang HAllen PKWang XS: Management of spinal metastases from renal cell carcinoma using stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 76:118511922010

    • Search Google Scholar
    • Export Citation
  • 25

    Onufrey VMohiuddin M: Radiation therapy in the treatment of metastatic renal cell carcinoma. Int J Radiat Oncol Biol Phys 11:200720091985

    • Search Google Scholar
    • Export Citation
  • 26

    Pan HSimpson DRMell LKMundt AJLawson JD: A survey of stereotactic body radiotherapy use in the United States. Cancer 117:456645722011

    • Search Google Scholar
    • Export Citation
  • 27

    Pan HYAllen PKWang XSChang ELRhines LDTatsui CE: Incidence and predictive factors of pain flare after spine stereotactic body radiation therapy: secondary analysis of phase 1/2 trials. Int J Radiat Oncol Biol Phys 90:8708762014

    • Search Google Scholar
    • Export Citation
  • 28

    Rose PSLaufer IBoland PJHanover ABilsky MHYamada J: Risk of fracture after single fraction image-guided intensity-modulated radiation therapy to spinal metastases. J Clin Oncol 27:507550792009

    • Search Google Scholar
    • Export Citation
  • 29

    Ryu SJin JYJin RRock JAjlouni MMovsas B: Partial volume tolerance of the spinal cord and complications of single-dose radiosurgery. Cancer 109:6286362007

    • Search Google Scholar
    • Export Citation
  • 30

    Sahgal AAtenafu EGChao SAl-Omair ABoehling NBalagamwala EH: 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 31:342634312013

    • Search Google Scholar
    • Export Citation
  • 31

    Sahgal AMa LGibbs IGerszten PCRyu SSoltys S: Spinal cord tolerance for stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 77:5485532010

    • Search Google Scholar
    • Export Citation
  • 32

    Sahgal AWeinberg VMa LChang EChao SMuacevic A: Probabilities of radiation myelopathy specific to stereotactic body radiation therapy to guide safe practice. Int J Radiat Oncol Biol Phys 85:3413472013

    • Search Google Scholar
    • Export Citation
  • 33

    Sahgal AWhyne CMMa LLarson DAFehlings MG: Vertebral compression fracture after stereotactic body radiotherapy for spinal metastases. Lancet Oncol 14:e310e3202013

    • Search Google Scholar
    • Export Citation
  • 34

    Shiu ASChang ELYe JSLii MRhines LDMendel E: Near simultaneous computed tomography image-guided stereotactic spinal radiotherapy: an emerging paradigm for achieving true stereotaxy. Int J Radiat Oncol Biol Phys 57:6056132003

    • Search Google Scholar
    • Export Citation
  • 35

    Song CWCho LCYuan JDusenbery KEGriffin RJLevitt SH: Radiobiology of stereotactic body radiation therapy/stereotactic radiosurgery and the linear-quadratic model. Int J Radiat Oncol Biol Phys 87:18192013

    • Search Google Scholar
    • Export Citation
  • 36

    Woodward EJagdev SMcParland LClark KGregory WNewsham A: Skeletal complications and survival in renal cancer patients with bone metastases. Bone 48:1601662011

    • Search Google Scholar
    • Export Citation
  • 37

    Wrónski MMaor MHDavis BJSawaya RLevin VA: External radiation of brain metastases from renal carcinoma: a retrospective study of 119 patients from the M. D. Anderson Cancer Center. Int J Radiat Oncol Biol Phys 37:7537591997

    • Search Google Scholar
    • Export Citation
  • 38

    Yamada YBilsky MHLovelock DMVenkatraman ESToner SJohnson J: High-dose, single-fraction image-guided intensity-modulated radiotherapy for metastatic spinal lesions. Int J Radiat Oncol Biol Phys 71:4844902008

    • Search Google Scholar
    • Export Citation
  • 39

    Zekri JAhmed NColeman REHancock BW: The skeletal metastatic complications of renal cell carcinoma. Int J Oncol 19:3793822001

  • 40

    Zelefsky MJGreco CMotzer RMagsanoc JMPei XLovelock M: Tumor control outcomes after hypofractionated and single-dose stereotactic image-guided intensity-modulated radiotherapy for extracranial metastases from renal cell carcinoma. Int J Radiat Oncol Biol Phys 82:174417482012

    • Search Google Scholar
    • Export Citation

Disclosures

Dr. Rhines has served as a consultant to Stryker and Globus. Dr. Tannir has served as a consultant to Exelixis and Novartis, is a patent holder for Pfizer, and has received support of non–study-related clinical or research effort from Bristol-Myers Squibb, Exelixis, and Novartis.

Author Contributions

Conception and design: Ghia, Chang, Brown. Acquisition of data: Ghia, Chang, Bishop, Pan, Boehling. Analysis and interpretation of data: Ghia, Allen, Brown. Drafting the article: Ghia. Critically revising the article: all authors. Reviewed submitted version of manuscript: Ghia, Chang, Bishop, Brown, Yang. Approved the final version of the manuscript on behalf of all authors: Ghia. Statistical analysis: Ghia, Allen. Study supervision: Chang, Brown.

Supplemental Information

Previous Presentations

Portions of this work were presented in abstract form at the Asian Society for Neurooncology Annual Meeting, in Istanbul, Turkey, on September 12, 2014.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

INCLUDE WHEN CITING Published online January 22, 2016; DOI: 10.3171/2015.8.SPINE15844.

Correspondence Amol J. Ghia, Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0097, Houston, TX 77030. email: ajghia@mdanderson.org.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Actuarial LC for patients treated with SF SSRS (solid line) or MF SSRS (dashed line).

References

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    Guckenberger MMantel FGerszten PCFlickinger JCSahgal ALétourneau D: Safety and efficacy of stereotactic body radiotherapy as primary treatment for vertebral metastases: a multi-institutional analysis. Radiat Oncol 9:2262014

    • Search Google Scholar
    • Export Citation
  • 19

    Laufer IIorgulescu JBChapman TLis EShi WZhang Z: Local disease control for spinal metastases following “separation surgery” and adjuvant hypofractionated or high-dose single-fraction stereotactic radiosurgery: outcome analysis in 186 patients. J Neurosurg Spine 18:2072142013

    • Search Google Scholar
    • Export Citation
  • 20

    Lovelock DMZhang ZJackson AKeam JBekelman JBilsky M: Correlation of local failure with measures of dose insufficiency in the high-dose single-fraction treatment of bony metastases. Int J Radiat Oncol Biol Phys 77:128212872010

    • Search Google Scholar
    • Export Citation
  • 21

    Maor MHFrias AEOswald MJ: Palliative radiotherapy for brain metastases in renal carcinoma. Cancer 62:191219171988

  • 22

    Maranzano ELatini P: Effectiveness of radiation therapy without surgery in metastatic spinal cord compression: final results from a prospective trial. Int J Radiat Oncol Biol Phys 32:9599671995

    • Search Google Scholar
    • Export Citation
  • 23

    National Cancer Institute: SEER Stat Fact Sheets: Kidney and Renal Pelvis Cancer. (http://seer.cancer.gov/statfacts/html/kidrp.html)[Accessed October 29 2015]

    • Export Citation
  • 24

    Nguyen QNShiu ASRhines LDWang HAllen PKWang XS: Management of spinal metastases from renal cell carcinoma using stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 76:118511922010

    • Search Google Scholar
    • Export Citation
  • 25

    Onufrey VMohiuddin M: Radiation therapy in the treatment of metastatic renal cell carcinoma. Int J Radiat Oncol Biol Phys 11:200720091985

    • Search Google Scholar
    • Export Citation
  • 26

    Pan HSimpson DRMell LKMundt AJLawson JD: A survey of stereotactic body radiotherapy use in the United States. Cancer 117:456645722011

    • Search Google Scholar
    • Export Citation
  • 27

    Pan HYAllen PKWang XSChang ELRhines LDTatsui CE: Incidence and predictive factors of pain flare after spine stereotactic body radiation therapy: secondary analysis of phase 1/2 trials. Int J Radiat Oncol Biol Phys 90:8708762014

    • Search Google Scholar
    • Export Citation
  • 28

    Rose PSLaufer IBoland PJHanover ABilsky MHYamada J: Risk of fracture after single fraction image-guided intensity-modulated radiation therapy to spinal metastases. J Clin Oncol 27:507550792009

    • Search Google Scholar
    • Export Citation
  • 29

    Ryu SJin JYJin RRock JAjlouni MMovsas B: Partial volume tolerance of the spinal cord and complications of single-dose radiosurgery. Cancer 109:6286362007

    • Search Google Scholar
    • Export Citation
  • 30

    Sahgal AAtenafu EGChao SAl-Omair ABoehling NBalagamwala EH: 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 31:342634312013

    • Search Google Scholar
    • Export Citation
  • 31

    Sahgal AMa LGibbs IGerszten PCRyu SSoltys S: Spinal cord tolerance for stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 77:5485532010

    • Search Google Scholar
    • Export Citation
  • 32

    Sahgal AWeinberg VMa LChang EChao SMuacevic A: Probabilities of radiation myelopathy specific to stereotactic body radiation therapy to guide safe practice. Int J Radiat Oncol Biol Phys 85:3413472013

    • Search Google Scholar
    • Export Citation
  • 33

    Sahgal AWhyne CMMa LLarson DAFehlings MG: Vertebral compression fracture after stereotactic body radiotherapy for spinal metastases. Lancet Oncol 14:e310e3202013

    • Search Google Scholar
    • Export Citation
  • 34

    Shiu ASChang ELYe JSLii MRhines LDMendel E: Near simultaneous computed tomography image-guided stereotactic spinal radiotherapy: an emerging paradigm for achieving true stereotaxy. Int J Radiat Oncol Biol Phys 57:6056132003

    • Search Google Scholar
    • Export Citation
  • 35

    Song CWCho LCYuan JDusenbery KEGriffin RJLevitt SH: Radiobiology of stereotactic body radiation therapy/stereotactic radiosurgery and the linear-quadratic model. Int J Radiat Oncol Biol Phys 87:18192013

    • Search Google Scholar
    • Export Citation
  • 36

    Woodward EJagdev SMcParland LClark KGregory WNewsham A: Skeletal complications and survival in renal cancer patients with bone metastases. Bone 48:1601662011

    • Search Google Scholar
    • Export Citation
  • 37

    Wrónski MMaor MHDavis BJSawaya RLevin VA: External radiation of brain metastases from renal carcinoma: a retrospective study of 119 patients from the M. D. Anderson Cancer Center. Int J Radiat Oncol Biol Phys 37:7537591997

    • Search Google Scholar
    • Export Citation
  • 38

    Yamada YBilsky MHLovelock DMVenkatraman ESToner SJohnson J: High-dose, single-fraction image-guided intensity-modulated radiotherapy for metastatic spinal lesions. Int J Radiat Oncol Biol Phys 71:4844902008

    • Search Google Scholar
    • Export Citation
  • 39

    Zekri JAhmed NColeman REHancock BW: The skeletal metastatic complications of renal cell carcinoma. Int J Oncol 19:3793822001

  • 40

    Zelefsky MJGreco CMotzer RMagsanoc JMPei XLovelock M: Tumor control outcomes after hypofractionated and single-dose stereotactic image-guided intensity-modulated radiotherapy for extracranial metastases from renal cell carcinoma. Int J Radiat Oncol Biol Phys 82:174417482012

    • Search Google Scholar
    • Export Citation

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