analysis for LC with tumor volume (p = 0.272), number of treated levels (p = 0.819), gross tumor volume (GTV)

Transcription

1 Clinical article J Neurosurg Spine 24: , 2016 Single-fraction versus multifraction spinal stereotactic radiosurgery for spinal metastases from renal cell carcinoma: secondary analysis of Phase I/II trials Amol J. Ghia, MD, 1 Eric L. Chang, MD, 5 Andrew J. Bishop, MD, 1 Hubert Y. Pan, MD, 1 Nicholas S. Boehling, MD, 1 Behrang Amini, MD, PhD, 4 Pamela K. Allen, PhD, 1 Jing Li, MD, PhD, 1 Laurence D. Rhines, MD, 3 Nizar M. Tannir, MD, 2 Claudio E. Tatsui, MD, 3 Paul D. Brown, MD, 1 and James N. Yang, PhD 1 Departments of 1 Radiation Oncology, 2 Medical Oncology, 3 Neurosurgery, and 4 Radiology, University of Texas MD Anderson Cancer Center, Houston, Texas; and 5 Department of Radiation Oncology, USC Norris Cancer Center, Los Angeles, California 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 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. Key Words metastases; stereotactic body radiotherapy; radiation; fraction; oncology 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 modali- Abbreviations BED = 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. submitted July 14, accepted August 28, include when citing Published online January 22, 2016; DOI: / SPINE AANS, 2016 J Neurosurg Spine Volume 24 May

2 A. J. Ghia et al. ties 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 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 cm 3 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/a/b]) allows for the comparison of the effects of different dose fractionation schemes (n = number of fractions, d = dose per fraction). 14,29,31 An a/b 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/a/b) where both d and a/b 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 < Statistical analysis was performed with Stata/MP (version 13.1, StataCorp LP). 830 J Neurosurg Spine Volume 24 May 2016

3 Single versus multifraction spine SBRT 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 years). The median KPS score was 80 (range ). 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 Gy 2/10, 42.8 Gy 2/10, and 40 Gy 2/10, respectively (in which 2 = 2 Gy equivalent, and 10 refers to the a/b ratio). Of those with treatment at the level of the spinal cord (n = 35), the median cord Dmax nbed was 22.4 Gy 2/2 (range 8.3 Gy 2/ Gy 2/2 ). Of those with treatment below the level of the spinal cord (n = 12), the median cauda equina Dmax nbed was 49.9 Gy 2/2 (range 13.8 Gy 2/ Gy 2/2 ). 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). 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 = for 1b), or prior surgery (p = 0.569). See Table 3 for the competing risk regression analysis. TABLE 1. Patient demographics Variable Value No. of patients 43 Age (yrs) Median 62 Range Sex Male 33 Female 10 Ethnicity Caucasian 35 Hispanic 5 African American 3 KPS score Histological subtype Clear cell 27 Papillary 5 Sarcomatoid 3 Other 8 Sites treated 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). 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. 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 J Neurosurg Spine Volume 24 May

4 A. J. Ghia et al. TABLE 2. Treatment site characteristics Total SF MF p Value Test Sites Histological subtype Clear cell Fisher s exact Papillary Sarcomatoid Other Location Cervical Fisher s exact Thoracic Lumbar Thoracolumbar junction No. of levels Fisher s exact Prior surgery Fisher s exact Posterior decompression Vertebrectomy Other Dose (Gy) 24, 1 fraction NA 27, 3 fractions , 5 fractions Bilsky score (no surgery) Fisher s exact a b Paraspinal disease No Fisher s exact Yes Posterior elements disease No Fisher s exact Yes Tumor volume (cm 3 ) Median Median Mean Range GTV (median) Dmin Median D Median D Median GTV coverage Median Median Mean Range SINS Assessable Fisher s exact Stable (0 6) Potentially unstable (7 12) D95 = minimum dose delivered to 95% of the GTV; D98 = minimum dose delivered to 98% of the GTV. 832 J Neurosurg Spine Volume 24 May 2016

5 Single versus multifraction spine SBRT Fig. 1. Actuarial LC for patients treated with SF SSRS (solid line) or MF SSRS (dashed line). systemic progression prior to a scheduled kyphoplasty. The mean nbed to the vertebral body was 141 Gy 2/2 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 Gy 2/2 ). 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 doseescalated 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 flare 8,27 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 TABLE 3. Competing risk regression analysis for LC Variable Reference Univariate Analysis Multivariate Analysis SHR 95% CI p Value SHR 95% CI p Value MF SF Non clear cell Clear cell Prior surgery No. of levels Bilsky Class 0 1a b Postop treatment Paraspinal disease Tumor volume* GTV* Coverage Dmin D D * Continuous variable. J Neurosurg Spine Volume 24 May

6 A. J. Ghia et al. TABLE 4. Univariate Cox regression analysis for overall survival Variable Reference HR 95% CI p Value Sex (male) KPS score* Age (yrs)* Non clear cell Clear cell Prior surgery No. of levels Bilsky score 0 1a b Postop treatment Paraspinal disease Tumor volume* SF MF * Continuous variable. TABLE 5. Patterns of failure and toxicity* Total SF MF p Value Sites Pattern of failure Total In field Epidural marginal Vertebral body marginal In field and epidural Pain flare Assessable Any Vertebral body fracture Assessable Fractures Symptomatic Asymptomatic * All p values obtained using Fisher s exact test. 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 multifractionated 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 834 J Neurosurg Spine Volume 24 May 2016

7 Single versus multifraction spine SBRT 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. References 1. Bilsky MH, Laufer I, Fourney DR, Groff M, Schmidt MH, Varga PP, et al: Reliability analysis of the epidural spinal cord compression scale. J Neurosurg Spine 13: , 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: , 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: , Brown JE, Coleman RE: Metastatic bone disease: developing strategies to optimize management. Am J Cancer 2: , Brown PD, Brown CA, Pollock BE, Gorman DA, Foote RL: Stereotactic radiosurgery for patients with radioresistant brain metastases. Neurosurgery 62 (Suppl 2): , 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: , Chang EL, Shiu AS, Mendel E, Mathews LA, Mahajan A, Allen PK, et al: Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure. J Neurosurg Spine 7: , Chiang A, Zeng L, Zhang L, Lochray F, Korol R, Loblaw A, et al: Pain flare is a common adverse event in steroid-naïve patients after spine stereotactic body radiation therapy: a prospective clinical trial. Int J Radiat Oncol Biol Phys 86: , Coppin C, Kollmannsberger C, Le L, Porzsolt F, Wilt TJ: Targeted therapy for advanced renal cell cancer (RCC): a Cochrane systematic review of published randomised trials. BJU Int 108: , Ecker RD, Endo T, Wetjen NM, Krauss WE: Diagnosis and treatment of vertebral column metastases. Mayo Clin Proc 80: , Fisher CG, DiPaola CP, Ryken TC, Bilsky MH, Shaffrey CI, Berven SH, et al: A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group. Spine (Phila Pa 1976) 35:E1221 E1229, Flanigan RC, Campbell SC, Clark JI, Picken MM: Metastatic renal cell carcinoma. Curr Treat Options Oncol 4: , Folkert MR, Bilsky MH, Tom AK, Oh JH, Alektiar KM, Laufer I, et al: Outcomes and toxicity for hypofractionated and single-fraction image-guided stereotactic radiosurgery for sarcomas metastasizing to the spine. Int J Radiat Oncol Biol Phys 88: , Fowler JF: Alpha, beta, and surviving fraction. Int J Radiat Oncol Biol Phys 24: , 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: , 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: , Gerszten PC, Mendel E, Yamada Y: Radiotherapy and radiosurgery for metastatic spine disease: what are the options, indications, and outcomes? Spine (Phila Pa 1976) 34 (22 Suppl):S78 S92, Guckenberger M, Mantel F, Gerszten PC, Flickinger JC, Sahgal A, Létourneau D, et al: Safety and efficacy of stereotactic body radiotherapy as primary treatment for vertebral metastases: a multi-institutional analysis. Radiat Oncol 9:226, Laufer I, Iorgulescu JB, Chapman T, Lis E, Shi W, Zhang Z, et al: Local disease control for spinal metastases following separation surgery and adjuvant hypofractionated or highdose single-fraction stereotactic radiosurgery: outcome analysis in 186 patients. J Neurosurg Spine 18: , Lovelock DM, Zhang Z, Jackson A, Keam J, Bekelman J, Bilsky M, et al: 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: , Maor MH, Frias AE, Oswald MJ: Palliative radiotherapy for brain metastases in renal carcinoma. Cancer 62: , Maranzano E, Latini P: Effectiveness of radiation therapy without surgery in metastatic spinal cord compression: final results from a prospective trial. Int J Radiat Oncol Biol Phys 32: , National Cancer Institute: SEER Stat Fact Sheets: Kidney and Renal Pelvis Cancer. ( html/kidrp.html) [Accessed October 29, 2015] 24. Nguyen QN, Shiu AS, Rhines LD, Wang H, Allen PK, Wang XS, et al: Management of spinal metastases from renal cell carcinoma using stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 76: , Onufrey V, Mohiuddin M: Radiation therapy in the treatment of metastatic renal cell carcinoma. Int J Radiat Oncol Biol Phys 11: , Pan H, Simpson DR, Mell LK, Mundt AJ, Lawson JD: A survey of stereotactic body radiotherapy use in the United States. Cancer 117: , Pan HY, Allen PK, Wang XS, Chang EL, Rhines LD, Tatsui J Neurosurg Spine Volume 24 May

8 A. J. Ghia et al. CE, et al: 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: , Rose PS, Laufer I, Boland PJ, Hanover A, Bilsky MH, Yamada J, et al: Risk of fracture after single fraction image-guided intensity-modulated radiation therapy to spinal metastases. J Clin Oncol 27: , Ryu S, Jin JY, Jin R, Rock J, Ajlouni M, Movsas B, et al: Partial volume tolerance of the spinal cord and complications of single-dose radiosurgery. Cancer 109: , 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: , 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: , Sahgal A, Weinberg V, Ma L, Chang E, Chao S, Muacevic A, et al: Probabilities of radiation myelopathy specific to stereotactic body radiation therapy to guide safe practice. Int J Radiat Oncol Biol Phys 85: , Sahgal A, Whyne CM, Ma L, Larson DA, Fehlings MG: Vertebral compression fracture after stereotactic body radiotherapy for spinal metastases. Lancet Oncol 14:e310 e320, Shiu AS, Chang EL, Ye JS, Lii M, Rhines LD, Mendel E, et al: Near simultaneous computed tomography image-guided stereotactic spinal radiotherapy: an emerging paradigm for achieving true stereotaxy. Int J Radiat Oncol Biol Phys 57: , Song CW, Cho LC, Yuan J, Dusenbery KE, Griffin RJ, Levitt SH: Radiobiology of stereotactic body radiation therapy/stereotactic radiosurgery and the linear-quadratic model. Int J Radiat Oncol Biol Phys 87:18 19, Woodward E, Jagdev S, McParland L, Clark K, Gregory W, Newsham A, et al: Skeletal complications and survival in renal cancer patients with bone metastases. Bone 48: , Wrónski M, Maor MH, Davis BJ, Sawaya R, Levin 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: , Yamada Y, Bilsky MH, Lovelock DM, Venkatraman ES, Toner S, Johnson J, et al: High-dose, single-fraction imageguided intensity-modulated radiotherapy for metastatic spinal lesions. Int J Radiat Oncol Biol Phys 71: , Zekri J, Ahmed N, Coleman RE, Hancock BW: The skeletal metastatic complications of renal cell carcinoma. Int J Oncol 19: , Zelefsky MJ, Greco C, Motzer R, Magsanoc JM, Pei X, Lovelock M, et al: 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: , 2012 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 studyrelated 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, Correspondence Amol J. Ghia, Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0097, Houston, TX ajghia@mdanderson.org. 836 J Neurosurg Spine Volume 24 May 2016