- Email: [email protected]
A Phase 2 Study of Post-Operative Stereotactic Body Radiation Therapy (SBRT) for Solid Tumor Spine Metastases
Journal Pre-proof A Phase II Study of Post-Operative Stereotactic Body Radiation Therapy (SBRT) for Solid Tumor Spine Metastases Kristin J. Redmond, M.D., M.P.H., Daniel Sciubba, M.D., Majid Khan, M.D., Chengcheng Gui, B.S., Sheng-fu Larry Lo, M.D., Ziya L. Gokaslan, M.D., Brianne Leaf, B.A., Lawrence Kleinberg, M.D., Jimm Grimm, Ph.D., Xiaobu Ye, M.D., M.S., Michael Lim, M.D. PII:
S0360-3016(19)33892-1
DOI:
https://doi.org/10.1016/j.ijrobp.2019.10.011
Reference:
ROB 25985
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 14 May 2019 Revised Date:
20 September 2019
Accepted Date: 1 October 2019
Please cite this article as: Redmond KJ, Sciubba D, Khan M, Gui C, Lo S-fL, Gokaslan ZL, Leaf B, Kleinberg L, Grimm J, Ye X, Lim M, A Phase II Study of Post-Operative Stereotactic Body Radiation Therapy (SBRT) for Solid Tumor Spine Metastases, International Journal of Radiation Oncology • Biology • Physics (2019), doi: https://doi.org/10.1016/j.ijrobp.2019.10.011. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
A Phase II Study of Post-Operative Stereotactic Body Radiation Therapy (SBRT) for Solid Tumor Spine Metastases
Kristin J. Redmond, M.D., M.P.H.1, Daniel Sciubba, M.D. 2, Majid Khan, M.D.3, Chengcheng Gui, B.S.1 , Sheng-fu Larry Lo, M.D. 2, Ziya L. Gokaslan, M.D. 4, Brianne Leaf, B.A.1, Lawrence Kleinberg, M.D. 1, Jimm Grimm, Ph.D. 1, Xiaobu Ye, M.D.,M.S.2**, Michael Lim, M.D.3**
Corresponding author: Kristin J. Redmond, M.D., M.P.H 401 North Broadway, Suite 1440 Baltimore, MD 21231 Phone: 410-614-1642 Fax: 410-502-1419 Email: [email protected]
Statistical analysis : Xiaobu Ye, M.D., M.S. 600 North Wolfe Street, Meyer 8-181D Baltimore, MD 21287 Phone : 410-614-6261 Email: [email protected]
1. Department of Radiation Oncology and Molecular Radiation Sciences, The John Hopkins University, Baltimore, MD, USA 2. Department Neurological Surgery, The John Hopkins University, Baltimore, MD, USA 3. Department of Radiology, The John Hopkins University, Baltimore, MD, USA
4. Department of Neurological Surgery, The Warren Alpert Medical School of Brown University, Providence, RI, USA
Running Title: Phase II study of post-operative spine SBRT **Drs. Lim and Ye are co-senior authors of this manuscript.
Key words: Post-operative spine stereotactic body radiation therapy (SBRT), solid tumor spine metastases, stereotactic radiosurgery,
Funding: no funding was received to support this clinical trial
Conflict of Interest Statement: Dr. Redmond has research funding from Elekta AB and has received honorarium and travel expenses for a meeting from Accuray. Dr. Kleinberg has research funding from Accuray and Novocure. Dr. Grimm has research funding from Accuray, Novocure and holds a patent for his DVH evaluator software. Dr. Sciubba works as a consultant for Medtronic, Depuy-Synthes, Stryker, Nuvasive, K2M, Globus, Baxter. Dr. Khan works as a consultant for Stryker Medical Corporation, Medwaves, Avecure Corporation. Dr. Lim has research support from Arbor, Aegenus, Altor, BMS, Accuray, DNAtrix, Kyrin-Kyowa; works as a consultant for Tocagen, SQZ Technologies, Stryker, and Baxter. Dr Gokaslan has grants from AO spine.
A Phase II Study of Post-Operative Stereotactic Body Radiation Therapy (SBRT) for Solid Tumor Spine Metastases Abstract: Objectives: In patients with spinal instability, cord compression, or neurologic deficits, the standard of care is surgery followed by radiation therapy (RT). Recurrence rates following conventional RT remain high. The purpose of this study is to prospectively examine the efficacy of post-operative SBRT in patients who have undergone surgical intervention for spine metastases. We hypothesize that post-operative SBRT to the spine would be associated with higher local control than historical rates following conventional RT. Methods: 35 adult patients with a KPS ≥40 and spine metastases from solid tumors with no prior overlapping RT and target volumes ≤3 consecutive vertebral levels were enrolled. 33 patients were treated. 2 patients underwent treatment to 2 target volumes for a total of 35 target volumes. All patients received SBRT 30 Gy in 5 fractions. Patients were followed with neurologic exam and CT and/or MRI every 3 months. Neurologic function was assessed at the same time points using the ASIA impairment score. Pain was rated according to the 10 point visual analog scale and MDACC brief pain index. Toxicity was recorded according to NCI CTCAE v4. The primary objective was the rate of radiographic local recurrence at 12 months following completion of SBRT. Results: Patient characteristics: 34.3% had radio-resistant primaries; 71.4% were ASIA E and the remainder ASIA D; the median baseline KPS was 70 (range 50-100). Radiographic and symptomatic local control at 1 year were 90% (95% confidence interval: 76%-98%). The median time to recurrence in these 3 patients was 3.5 months (range 3.4-5.8 months), all had radiosensitive tumors, and all recurrences were epidural. No patients experienced wound dehiscence, hardware failure or spinal cord myelopathy. The median time to return to systemic therapy was 0.5 months (range 0-9.4 months). Conclusions: This prospective study of post-operative spine SBRT demonstrates excellent local control with low toxicity. These data suggest superior rates of local control compared to conventional RT, however a formal comparative study is warranted.
Introduction:
The standard of care in patients with an isolated, symptomatic region of malignant epidural spinal cord compression (MESCC) is decompressive surgery and adjuvant conventional radiation therapy (RT), based on level I data demonstrating improved ambulation following surgery compared to RT alone (1). The goal of surgery is circumferential decompression of the involved level of the spinal cord with stabilization of the vertebral column. RT is typically prescribed following surgery, historically using simple AP/PA field to deliver a total dose of approximately 30 Gy in 10 fractions. Unfortunately, local control and pain control with this approach is poor with rates as low as 30% (2). Given the increasing long term cancer survivorship and the resultant need for more durable local control, SBRT is being utilized as an alternative to low dose conventionally fractionated RT, allowing delivery of a higher biologically equivalent dose in a fewer number of fractions. Numerous retrospective series suggest excellent outcomes following SBRT to both intact and post-operative lesions with local control ranging from 70-100% across tumor histologies (3-25). In addition, a single prospective study comparing 24 Gy in a single fraction using SBRT to 3-dimensional conformal radiation to a total dose of 30 Gy in 10 fractions found significantly lower pain scores following SBRT at 6 months following completion of therapy (12). This improvement in local control compared to conventional RT is vital, given the high risk of deterioration in neurologic function, re-operation, and worsening pain as well as quality of life in patients with progressive spine disease. As a result, the practice of SBRT for spine metastases has been increasing in throughout academic and community practices, and consensus contouring guidelines have been published for both intact and post-operative targets (26-27). Nonetheless, to date, no prospective studies of SBRT to the spine in the post-operative setting have been published. The purpose of this phase II clinical trial is to prospectively evaluate outcomes after SBRT to the spine following surgical intervention for solid tumor metastases.
Methods:
Patient selection: Patients age 12 years or older were eligible for enrollment in this single institution study which was registered on clinicaltrials.gov (***) and had approval of the institutional review board. All patients had histologically proven solid tumor malignancy with metastasis to the spine. Patients were required to have radiographic evidence of spinal metastasis and must have undergone surgical resection (gross
total, subtotal, or biopsy) of the spinal lesion(s) no more than 16 weeks prior to SBRT treatment. The extent of epidural involvement was defined according to the Bilsky grading scale (28). High-grade was defined as Bilsky grade 2 or 3, low grade as Bilsky grade 1a, 1b, or 1c and no epidural disease as Bilsky grade 0. SBRT targets involved at maximum 3 consecutive vertebral levels, although multiple targets per patient were permitted. Patients were required to have a minimum KPS of at least 40. There was no limitation to the number of sites of metastases, but for categorization for data analyses, oligometastatic disease was defined as no more than 5 total sites of involvement and diffuse spine disease was defined as greater that 3 vertebral levels of involvement prior to SBRT. Renal cell carcinoma, sarcoma, melanoma, thyroid carcinoma and hepatocellular carcinoma were considered radio-resistant histologies. Patients were excluded if they had prior RT or SBRT to involved level of the spine, if their spine disease was from leukemia, lymphoma or myeloma, or if they had uncontrolled intercurrent illness. Delineation of target volumes and objects at risk: All patients underwent CT simulation utilizing immobilization for a reproducible radiosurgery setup. Intravenous contrast was administered for the CT in cases of extensive paraspinal extension. Patients underwent high resolution MRI simulation including at minimum T1 with gadolinium, T2 and STIR axial and sagittal sequences. In cases of significant metal artifact on MRI due to spinal instrumentation, patients underwent CT myelogram. For the sake of RT planning, the following datasets were fused using the treatment planning software: 1) CT simulation; 2) CT myelogram (if performed); 3) pre-operative diagnostic scan; 4) MRI simulation. Target delineation was according to the consensus contouring guidelines for post-operative patients (26). Although the guidelines were not published until several years after initiation of this study, …***these guidelines reflect the institutional practice for years prior to the submission and publication of the manuscript. The spinal cord planning risk volume (PRV) was defined as the true spinal cord according to CT myelogram or T2 weighted MRI plus a 2 mm radial expansion or the thecal sac without expansion for patients with targets below the conus. Figure 1 shows the pre-operative sagittal (1A) and axial (1B) MRIs and post-operative CT myelogram with contours (1C) for both the PTV and thecal sac for an example patient. The normal tissue dose constraints are outlined in Table 1. Note that for the constraints specified as to a 0.1 cc volume, this was applied as a maximum point dose in the majority of patients. The 0.1 cc volume was specified in the protocol to allow the treating physicians flexibility in clinical decision making if allowing slightly higher doses to a pixel or very small volume resulted in what was deemed to be clinically meaningful improvements in CTV and PTV coverage.
Radiation prescription, dosimetry, and treatment: Patients were treated to a total dose of 30 Gy in 6 Gy per fraction. Patients were required to receive at least 2 fractions the first week. Goal PTV coverage was >90% receiving >90% of prescription dose but coverage was compromised to meet normal tissue constraints. Figure 1D shows an example treatment plan. Patients were treated using a linear accelerator with nominal beam energy of 6 MV. Cone beam CT guidance and/or orthogonal imaging was utilized for precise patient setup. All patients who initiated protocol treatment were followed per the study calendar.
Evaluation of local control and toxicity: Patients were followed with CT and/or MRI of the treated region every 3 months for at least 2 years following completion of SBRT. Bilsky grading (12) was performed by a board certified neuroradiologist based on the 1) immediately pre-operative MRI; 2) post-operative CT myelogram or MRI; and 3) first MRI post-SBRT, which was performed at approximately 3 months following treatment. Follow-up evaluations were performed every 3 months and included neurologic evaluation by the American Spinal Injury Association (ASIA) Impairment Scale (29), and pain evaluation by the 10 point visual analog scale (30) and MD Anderson Cancer Center (MDACC) Brief Pain Inventory Short Form (31). Toxicity was recorded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) Version 4 as well as the RTOG/EORTC acute and late common toxicity assessments for CNS and spinal cord.
Patients were considered to have symptomatic progression if: 1) there was radiographic evidence of progression on CT and/or MRI based on direct comparisons by at least 2 members of the team of the most recently obtained radiographic images compared to the immediate pretreatment images AND 2) the patient had progressive symptoms defined as worsening neurologic function attributable to tumor growth at the level treated according to the ASIA Impairment Scale OR worsening pain attributable to tumor growth at the treated level according to the MDACC brief pain inventory (short form) defined as a new score ≥5 at the treated level of spine.
Statistical methods:
The primary objective of this phase II trial was radiographic local recurrence at 12 months following completion of SBRT. Radiographic local recurrence was defined as progressive disease on CT and/or MRI in the treatment volume or at the margin of the treatment field when compared to imaging studies prior to the post-operative SBRT. If equivocal, the lesion was followed with serial short interval scans for further clarification with the timing of local recurrence backdated to the date of the first suspicious CT or MRI. The proportion of patients without local recurrence at 12 months following SBRT was estimated along with the 90% confidence interval. Time to radiographic local recurrence was calculated from the date of SBRT to the date of local recurrence. The median time to local recurrence was estimated using Kaplan-Meier method (32). In addition, the symptomatic local recurrence rate at 12 months was estimated along with confidence interval using binomial distribution. Bilsky grade pre- and post-operatively as well as post-operatively and at 3 months following SBRT were compared using the Wilcoxon signed-rank test. The number of patients who experienced grade 3 or above toxicities attributed to the study treatment was recorded. Observed severe adverse event associated with SBRT including radiation myelopathy were summarized using descriptive statistics. Time to return to chemotherapy was calculated from the date of initial SBRT to the starting date of chemotherapy. The chemotherapy date was censored if patient had not received chemotherapy at time the study database was closed for final analysis. Time to return to chemotherapy was estimated using Kaplan-Meier method. Tumor histology and wound healing complications were summarized using descriptive statistics.
Sample size: Based on power calculations at the time of study initiation a total of 35 patients were enrolled in the protocol. This was based on a null hypothesis of 60% radiographic local control rate at 12 months with conventional radiation therapy (33) versus an alternative hypothesis of a local control rate of 80% at 12 months using post-operative SBRT with an 80% statistical power and type I error rate of 0.05 (onesided).
Results:
Thirty-five patients enrolled in the study between 5/20/2013 and 7/19/2017. Two patients did not receive SBRT after enrollment. One of these patients experienced rapid deterioration in clinical status post-operatively and ultimately succumbed to their illness between enrollment and the treatment
start date. The second patient elected to be treated at another institution closer to their home rather than proceeding the treatment according to the trial. Two patients underwent treatment to 2 unique target volumes. In sum, 35 targets in 33 patients were treated with post-operative spine SBRT. Baseline patient demographic, tumor, and treatment characteristics are shown in Table 2. Figure 2A shows the overall local control rate. At a median FU 10.5 months (range: 0.03-47.4 months), a total of 3 patients developed local recurrence within 12 months. The local control rate using an intention to treat analysis and per treated tumor was 91.4% (95% CI, 77%--98%). Local control rate per protocol was 90.0% (95% CI, 76%--98%). For the 3 patients that experienced local failure, the median time to recurrence 3.5 months (range 3.4-5.8 months). The recurrences were radiographic in nature and none were associated with a decline on the in neurologic function according to the ASIA impairment scale. All recurrences were symptomatic. All 3 of these patients had radiosensitive histologies and all of the failures were epidural in nature. The pre-operative Bilsky grades for these patients were 1B, 2 and 3, and were 1C, 1B and 0 respectively on the post-operative, pre-SBRT imaging. The median prescription isodose line, PTV coverage, percent of the PTV receiving 90% of the prescription dose and minimum dose of the patients that experienced local failure were 62.7% (range: 58-68%); 93.5% (range: 90.7-99.1%); 94.8% (range: 94-96.2%); and 17.8 Gy (range: 16.5-19.4 Gy), respectively. Two patients underwent re-treatment to the same spinal segment. Thirty-seven percent of patients had diffuse spine metastases at the time of SBRT. Twenty percent of patients experienced new or progressive disease within 1 vertebral level above or below the SBRT target and 37% of patients experienced new or progressive disease within 2 vertebral levels above or below the SBRT target. Excluding patients whose baseline 10 point visual analog pain score was not recorded (n=2) or whose final 10 point visual analog pain score was recorded at the time of completion of RT (n=3), the score at the time of last recorded follow-up compared to baseline was reduced in 54.2%, stable in 12.5%, increased by 1 point in 8.3% and increased by 2 or more points in 25%; 20.8% of patients reported no pain in any part of their body at the time of last follow-up. Of the patients (n=24) whose worst pain score at the time of last follow-up according to the MDACC brief pain inventory short form corresponded with the region targeted with the study treatment, 45.8% reported no pain, 29.2% reported improved pain, 4.2% reported stable pain, 8.3% reported pain that was 1 point worse, and 12.5% reported pain that was 2 points worse compared to baseline. Figure 3 summarizes pain outcomes according to the Visual Analogue score and ASIA Impairment Scale prior to SBRT and at 3-months post SBRT, 6-months post SBRT, and latest follow-up.
ASIA impairment score was grade D (motor incomplete with motor function preserved below the neurologic level with at least half of key muscles functions having a grade 3 or better) or grade E (normal neurologic function) in all patients at both baseline and the time of last follow-up. Of the 3 patients who had radiographic progression there was no associated deterioration of neurologic function. The median Bilsky grades were 2 (range: 1B-3), 1B (range 0-3), 1B (range 0-1c) pre-operatively, post-surgery, and at 3 months following SBRT, respectively. The change in Bilsky grade was statistically significant between the pre-operative and post-operative imaging (p<0.001) and from the postoperative imaging to the 3 months post-SBRT imaging (p=0.034). Figure 4 shows the pre-operative, postoperative and 3 month post-SBRT Bilsky epidural grade dichotomized as high (1c to 3) versus low (0 to 1b) grade as well as trends for individual patients. Figure 2B shows the overall survival rate. The median overall survival was 14.3 months (95% CI = [7.6, 43]). Nineteen patients died before they reached 12 months of follow-time. Eighteen out of the 19 patients died without local recurrence. Sixteen patients were alive beyond 12 months and 2 out of the 16 had local recurrence. As such, the local control rate per patient who lived beyond 12 months was 87.5% (95% CI, 62%-98%). The median time to return to systemic therapy was 0.5 months (range 0-9.4 months). No patients experienced wound dehiscence, hardware failure or myelopathy. There were no grade 3 or higher toxicities attributable to the SBRT according to NCI CTCAE v4 or the RTOG/EORTC acute and late common toxicity assessments.
Discussion: As long term cancer survivorship continues to increase, obtaining durable local control of spinal metastases is essential in order to maximize quality of life. A large body of literature suggests excellent outcomes following spine SBRT to intact vertebrae (4,11-12,20-25) with rates of durable local control and pain control ranging from 70-100%. Similarly, a growing body of literature suggests comparably excellent local control following SBRT to solid tumor spine metastases following surgery (5-10,13-19). However, data regarding post-operative spine SBRT published to date is limited to retrospective series and a critical review. We present the first prospective trial to evaluate SBRT in the post-operative setting. Our data suggest excellent outcomes with greater than 90% local control at 1 year following SBRT, with minimal toxicity. Similar to prior studies, all three local recurrences in this trial were epidural in nature. We had low rates of high grade epidural disease post-operatively, yet still saw epidural failures. In fact, all three
of the recurrence were in patients with low grade residual epidural disease post-operatively and target volume coverage in these patients was similar to the rest of the cohort. This supports the notion that the epidural space represents the region at greatest risk of recurrence following spine SBRT. Future investigations will be important to investigate approaches to improve epidural control rates. SBRT did result in further downgrading of epidural disease in a significant number of patients with residual high grade epidural disease post-operatively. This is consistent with prior retrospective data demonstrating a significant epidural response rate of 74% (25) in patients undergoing SBRT for MESCC. Thus, while surgical decompression and downgrading of epidural disease appears to be essential in maximizing local control, radio-surgical decompression appears to occur as well. Future investigations will be important to further understand the frequency and time course of this effect and to investigate how it may be utilized to manage spine metastases in the least invasive manner while augmenting the likelihood of durable local control. A historical concern of radiation dose escalation in the post-operative setting is a potentially increased risk of hardware failure following SBRT. However, no patients in our study experienced this toxicity suggesting that the risk may not be increased compared to the historically low rates following surgery alone or surgery followed by conventional RT. This study suggests that post-operative SBRT following surgery for spine metastases represents a highly efficacious as well as safe treatment modality. However, future investigation into the most appropriate patient population to apply this technology will be important. Specifically, more than half of our patients succumbed to their disease within one year of treatment and 37% of patients experienced failure in adjacent vertebral levels. Future recursive partitioning analyses and development of other stratification systems will be essential to properly identify patients that are most likely to benefit from the more durable local control associated with SBRT in the post-operative setting rather than the simpler, faster, less expensive and less labor intensive alternative of conventional RT.It is important to note that the prescription dose utilized in this study is conservative relative to current practices at many large institutions. This study was developed when the practice of spine SBRT was in its infancy. The dose was selected in order to be uniform in allowing acceptable target coverage while meeting spinal cord constraints in all patients, including in those with large volumes involving 3 vertebral levels. Future studies comparing different fractionation regimens and dose escalation will be important. Although this manuscript represents an important contribution to the literature, there are several limitations. First, it was a single arm study and a larger scale randomized controlled study will be
important to confirm the results. Second, although our primary endpoint was 1 year local control, nineteen patients died prior to this time point. Nonetheless, 18 of the 19 patients died without LR and of the patients alive after 1 year, local control remained excellent at 87.5%. Larger studies will be important to confirm our results. Third, to facilitate enrollment this study enrolled a broad spectrum of post-operative patients. Future studies designed to more specifically study those most likely to benefit from the more durable local control of SBRT, such as patients with radioresistant primary tumors or oligometastases, are needed. Fourth, although this study suggests improvement in pain control following post-operative spine SBRT in the majority of patients, it is important to note that pain control is a subjective measure that is impacted by many factors such as pain in other sites beyond the lesion targeted in the study, as well as the relative intensity of pain at other sites. Thus, caution must be used in interpreting pain as a surrogate for tumor control. Pain measures are particularly difficult to understand in post-operative patients as they are potentially confounded by many other factors such as wound healing and hardware failure. Finally, the patients enrolled in this trial were all radiation naïve. Future investigations will be important to evaluate the role of post-operative SBRT in the re-irradiation setting.
Conclusions: To conclude, we present the first prospective study to evaluate SBRT for solid tumor spine metastases in the post-operative setting and demonstrate excellent local control with low toxicity. These data suggest that post-operative spine SBRT may be associated with superior rates of local control compared to conventional RT, however a formal comparative study is warranted for confirmation.
References: 1. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: A randomised trial. Lancet. 2005;366(9486):643648. 2. Klekamp J, Samii H. Surgical results for spinal metastases. Acta Neurochir (Wien). 1998;140(9):957967.
3. Klimo P,Jr, Thompson CJ, Kestle JR, Schmidt MH. A meta-analysis of surgery versus conventional radiotherapy for the treatment of metastatic spinal epidural disease. Neuro Oncol. 2005;7(1):64-76. 4. Sahgal A, Larson DA, Chang EL. Stereotactic body radiosurgery for spinal metastases: A critical review. Int J Radiat Oncol Biol Phys. 2008;71(3):652-665. 5. Al-Omair A, Masucci L, Masson-Cote L, et al. Surgical resection of epidural disease improves local control following postoperative spine stereotactic body radiotherapy. Neuro Oncol. 2013;15(10):14131419. 6. Gerszten PC, Germanwala A, Burton SA, Welch WC, Ozhasoglu C, Vogel WJ. Combination kyphoplasty and spinal radiosurgery: A new treatment paradigm for pathological fractures. J Neurosurg Spine. 2005;3(4):296-301. 7. Rock JP, Ryu S, Shukairy MS, et al. Postoperative radiosurgery for malignant spinal tumors. Neurosurgery. 2006;58(5):891-8; discussion 891-8. 8. Gerszten PC, Monaco EA, 3rd. Complete percutaneous treatment of vertebral body tumors causing spinal canal compromise using a transpedicular cavitation, cement augmentation, and radiosurgical technique. Neurosurg Focus. 2009;27(6):E9. 9. Massicotte E, Foote M, Reddy R, Sahgal A. Minimal access spine surgery (MASS) for decompression and stabilization performed as an out-patient procedure for metastatic spinal tumours followed by spine stereotactic body radiotherapy (SBRT): First report of technique and preliminary outcomes. Technol Cancer Res Treat. 2012;11(1):15-25. 10. Laufer I, Iorgulescu JB, Chapman T, et al. 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. 2013;18(3):207-214. 11. Tseng CL, Soliman H, Myrehaug S, et al. Imaging-based outcomes for 24 gy in 2 daily fractions for patients with de novo spinal metastases treated with spine stereotactic body radiation therapy (SBRT). Int J Radiat Oncol Biol Phys. 2018;102(3):499-507.
12. Sprave T, Verma V, Forster R, et al. Randomized phase II trial evaluating pain response in patients with spinal metastases following stereotactic body radiotherapy versus three-dimensional conformal radiotherapy. Radiother Oncol. 2018;128(2):274-282. 13. Bate BG, Khan NR, Kimball BY, Gabrick K, Weaver J. Stereotactic radiosurgery for spinal metastases with or without separation surgery. J Neurosurg Spine. 2015;22(4):409-415. 14. Moulding HD, Elder JB, Lis E, et al. Local disease control after decompressive surgery and adjuvant high-dose single-fraction radiosurgery for spine metastases. J Neurosurg Spine. 2010;13(1):87-93. 15. Sellin JN, Suki D, Harsh V, et al. Factors affecting survival in 43 consecutive patients after surgery for spinal metastases from thyroid carcinoma. J Neurosurg Spine. 2015;23(4):419-428. 16. Sellin JN, Gressot LV, Suki D, et al. Prognostic factors influencing the outcome of 64 consecutive patients undergoing surgery for metastatic melanoma of the spine. Neurosurgery. 2015;77(3):386-93; discussion 393. 17. Harel R, Emch T, Chao S, et al. Quantitative evaluation of local control and wound healing following surgery and stereotactic spine radiosurgery for spine tumors. World Neurosurg. 2016;87:48-54. 18. Redmond KJ, Lo SS, Fisher C, Sahgal A. Postoperative stereotactic body radiation therapy (SBRT) for spine metastases: A critical review to guide practice. Int J Radiat Oncol Biol Phys. 2016;95(5):1414-1428. 19. Chan MW, Thibault I, Atenafu EG, et al. Patterns of epidural progression following postoperative spine stereotactic body radiotherapy: Implications for clinical target volume delineation. J Neurosurg Spine. 2016;24(4):652-659. 20. Ahmed KA, Stauder MC, Miller RC, et al. Stereotactic body radiation therapy in spinal metastases. Int J Radiat Oncol Biol Phys. 2012;82(5):e803-9. 21. Chang EL, Shiu AS, Mendel E, et al. Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure. J Neurosurg Spine. 2007;7(2):151-160. 22. 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). 2007;32(2):193-199.
23. Jin JY, Chen Q, Jin R, et al. Technical and clinical experience with spine radiosurgery: A new technology for management of localized spine metastases. Technol Cancer Res Treat. 2007;6(2):127-133. 24. Puvanesarajah V, Lo SL, Aygun N, et al. Prognostic factors associated with pain palliation after spine stereotactic body radiation therapy. J Neurosurg Spine. 2015:1-10. 25. Lee I, Omodon M, Rock J, Shultz L, Ryu S. Stereotactic radiosurgery for high-grade metastatic epidural cord compression. J Radiosurg SBRT. 2014;3(1):51-58. 26. Redmond KJ, Robertson S, Lo SS, et al. Consensus contouring guidelines for postoperative stereotactic body radiation therapy for metastatic solid tumor malignancies to the spine. Int J Radiat Oncol Biol Phys. 2017;97(1):64-74. 27. Cox BW, Spratt DE, Lovelock M, et al. International spine radiosurgery consortium consensus guidelines for target volume definition in spinal stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2012;83(5):e597-605. 28. Bilsky MH, Laufer I, Fourney DR, et al. Reliability analysis of the epidural spinal cord compression scale. J Neurosurg Spine. 2010;13(3):324-328. 29. Kirshblum SC, Waring W, Biering-Sorensen F, Burns SP, Johansen M, Schmidt-Read M, Donovan W, Graves D, Jha A, Jones L, Mulcahey MJ, Krassioukov A. Reference for the 2011 revision of the International Standards for Neurological Classification of Spinal Cord Injury. J Spinal Cord Med. 2011 Nov;34(6):547-54
30. Wallerstein SL. Scaling clinical pain and pain relief. In: Bromm B, ed. Pain Measurement in Man: Neurophysiological Correlates of Pain. New York, NY: Elsevier; 1984. 31. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med 1994;23(2):129-138. 32. Kaplan, E.L.; Meier, P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-481.
33. Rades D, Lange M, Veninga T, et al. Preliminary results of spinal cord compression recurrence evaluation (score-1) study comparing short-course versus long-course radiotherapy for local control of malignant epidural spinal cord compression. Int J Radiat Oncol Biol Phys. 2009;73(1):228-234.
Figure legends:
Figure 1: Figure 1 shows the (A) pre-operative sagittal T1 post gadolinium and (B) axial FSE T2 weighted MRIs, (C) post-operative CT myelogram with PTV (red) and thecal sac (blue) contours, and (D) treatment plan for an example patient with colorectal carcinoma metastatic to the L4 vertebral body. The prescription dose for all patients on this clinical trial was 30 Gy in 5 fractions prescribed to a median prescription isodose line of 61% (range: 53 – 71%). Median PTV coverage and V90% of the PTV for all patients was 90.2% (range: 82.6 - 96.2%) and 94.4 (range: 90.2-97.7%), respectively.
Figure 2: (A) Local recurrence: Median local recurrence was not reached. 95% confidence intervals are indicated with dotted lines. (B) Overall survival. 95% confidence intervals are indicated with dotted lines.
Figure 3: Mean change in two patient-reported pain scores compared to before SBRT: (A) visual analog pain score (VAS) and (B) worst pain score according to MD Anderson Brief Pain Inventory (BPI). The error bars show the standard deviation.
Figure 4: Bilsky grade at pre-operative, post-operative (pre-SBRT) and approximately 3 months postSBRT time points: (A) dichotomized as high (1c to 3) versus low (0 to 1b) and (B) showing Bilsky grade at each time point for individual patients.
Table legends:
Table 1: Five fraction dose constraints for organs at risk. *Note that for constraints specified as 0.1 cc, for the majority of patients this was applied as a maximum point dose. The 0.1 cc volume was specified in the protocol to allow the treating physicians flexibility in clinical decision making if allowing slightly
higher doses to a pixel or very small volume resulted in what was deemed to be clinically meaningful improvements in CTV and PTV coverage.
Table 2: Patient, tumor, and treatment characteristics. Abbreviations: KPS = Karnofsky performance status; ASIA = American Spinal Injury Association Impairment Scale; NSCLC = non-small cell lung cancer; RT = radiation therapy; CTV = clinical target volume; PTV = planning treatment volume.
Table 1: Five-fraction dose constraints for organs at risk Organ at risk Spinal cord
Dose constraint (Gy)* 25 to 0.1 cc
Cauda equina
25 to 0.1 cc
Trachea
32.5 to 0.1 cc
Esophagus
32.5 to 0.1 cc
Heart and pericardium Skin
40 to 0.1 cc
Great vessels
55 to 0.1 cc
Renal cortex
17.5 Gy to 200 cc
35 to 0.1 cc
*Note that for constraints specified as 0.1 cc, for the majority of patients this was applied as a maximum point dose. The 0.1 cc volume was specified in the protocol to allow the treating physicians flexibility in clinical decision making if allowing slightly higher doses to a pixel or very small volume resulted in what was deemed to be clinically meaningful improvements in CTV and PTV coverage. Table 2: Patient, tumor, and treatment characteristics Median (range) or Number (%) 63 (21 - 75)
Age Sex
Race
Male Female White Black Asian
KPS score (baseline) ASIA score (baseline)
Histology
Radiosensitive
E D Lung cancer Renal cell carcinoma Breast cancer Melanoma NSCLC Pancreatic cancer Prostate cancer Other (fewer than 2 patients) Yes
22 (62.9%) 13 (37.1%) 24 (68.6%) 8 (22.9%) 3 (8.6%) 70 (50 - 100) 25 (71.4%) 10 (28.6%) 7 (20%) 6 (17.1%) 5 (14.3%) 2 (5.7%) 2 (5.7%) 2 (5.7%) 2 (5.7%) 9 (25.7%) 23 (65.7%)
No Yes Diffuse spinous No metastases prior to RT Unknown Number of vertebral levels treated Cervical Location of treated Thoracic tumor Lumbar 3 Volume of CTV (cm ) Volume of PTV (cm3) Maximum dose to PTV (Gy) Minimum dose to PTV (Gy) Prescription Isodose (%) Coverage (%) Percent of PTV receiving 90% of prescription dose Maximum point dose to spinal cord (Gy) Maximum point dose to spinal cord + 2mm (Gy) Subtotal Resection extent Gross Total Biopsy
12 (34.3%) 13 (37.1%) 19 (54.3%) 3 (8.6%) 2 (1 - 3) 7 (18.9%) 22 (59.5%) 8 (21.6%) 74.1 (21.4 - 238.5) 95.4 (27 - 257) 49.9 (43.5 - 57.1) 16.7 (5.7 - 19.7) 61 (53 - 71) 90.2 (82.6 - 96.2) 94.4 (90.2-97.7) 21.4 (18.4 - 23.5) 24.7 (22.6 - 27.6) 25 (71.4%) 6 (17.1%) 4 (11.4%)
A
B
C
D
SBRT
A
SBRT
B
A
B
A
B
S0360-3016(19)33892-1
DOI:
https://doi.org/10.1016/j.ijrobp.2019.10.011
Reference:
ROB 25985
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 14 May 2019 Revised Date:
20 September 2019
Accepted Date: 1 October 2019
Please cite this article as: Redmond KJ, Sciubba D, Khan M, Gui C, Lo S-fL, Gokaslan ZL, Leaf B, Kleinberg L, Grimm J, Ye X, Lim M, A Phase II Study of Post-Operative Stereotactic Body Radiation Therapy (SBRT) for Solid Tumor Spine Metastases, International Journal of Radiation Oncology • Biology • Physics (2019), doi: https://doi.org/10.1016/j.ijrobp.2019.10.011. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
A Phase II Study of Post-Operative Stereotactic Body Radiation Therapy (SBRT) for Solid Tumor Spine Metastases
Kristin J. Redmond, M.D., M.P.H.1, Daniel Sciubba, M.D. 2, Majid Khan, M.D.3, Chengcheng Gui, B.S.1 , Sheng-fu Larry Lo, M.D. 2, Ziya L. Gokaslan, M.D. 4, Brianne Leaf, B.A.1, Lawrence Kleinberg, M.D. 1, Jimm Grimm, Ph.D. 1, Xiaobu Ye, M.D.,M.S.2**, Michael Lim, M.D.3**
Corresponding author: Kristin J. Redmond, M.D., M.P.H 401 North Broadway, Suite 1440 Baltimore, MD 21231 Phone: 410-614-1642 Fax: 410-502-1419 Email: [email protected]
Statistical analysis : Xiaobu Ye, M.D., M.S. 600 North Wolfe Street, Meyer 8-181D Baltimore, MD 21287 Phone : 410-614-6261 Email: [email protected]
1. Department of Radiation Oncology and Molecular Radiation Sciences, The John Hopkins University, Baltimore, MD, USA 2. Department Neurological Surgery, The John Hopkins University, Baltimore, MD, USA 3. Department of Radiology, The John Hopkins University, Baltimore, MD, USA
4. Department of Neurological Surgery, The Warren Alpert Medical School of Brown University, Providence, RI, USA
Running Title: Phase II study of post-operative spine SBRT **Drs. Lim and Ye are co-senior authors of this manuscript.
Key words: Post-operative spine stereotactic body radiation therapy (SBRT), solid tumor spine metastases, stereotactic radiosurgery,
Funding: no funding was received to support this clinical trial
Conflict of Interest Statement: Dr. Redmond has research funding from Elekta AB and has received honorarium and travel expenses for a meeting from Accuray. Dr. Kleinberg has research funding from Accuray and Novocure. Dr. Grimm has research funding from Accuray, Novocure and holds a patent for his DVH evaluator software. Dr. Sciubba works as a consultant for Medtronic, Depuy-Synthes, Stryker, Nuvasive, K2M, Globus, Baxter. Dr. Khan works as a consultant for Stryker Medical Corporation, Medwaves, Avecure Corporation. Dr. Lim has research support from Arbor, Aegenus, Altor, BMS, Accuray, DNAtrix, Kyrin-Kyowa; works as a consultant for Tocagen, SQZ Technologies, Stryker, and Baxter. Dr Gokaslan has grants from AO spine.
A Phase II Study of Post-Operative Stereotactic Body Radiation Therapy (SBRT) for Solid Tumor Spine Metastases Abstract: Objectives: In patients with spinal instability, cord compression, or neurologic deficits, the standard of care is surgery followed by radiation therapy (RT). Recurrence rates following conventional RT remain high. The purpose of this study is to prospectively examine the efficacy of post-operative SBRT in patients who have undergone surgical intervention for spine metastases. We hypothesize that post-operative SBRT to the spine would be associated with higher local control than historical rates following conventional RT. Methods: 35 adult patients with a KPS ≥40 and spine metastases from solid tumors with no prior overlapping RT and target volumes ≤3 consecutive vertebral levels were enrolled. 33 patients were treated. 2 patients underwent treatment to 2 target volumes for a total of 35 target volumes. All patients received SBRT 30 Gy in 5 fractions. Patients were followed with neurologic exam and CT and/or MRI every 3 months. Neurologic function was assessed at the same time points using the ASIA impairment score. Pain was rated according to the 10 point visual analog scale and MDACC brief pain index. Toxicity was recorded according to NCI CTCAE v4. The primary objective was the rate of radiographic local recurrence at 12 months following completion of SBRT. Results: Patient characteristics: 34.3% had radio-resistant primaries; 71.4% were ASIA E and the remainder ASIA D; the median baseline KPS was 70 (range 50-100). Radiographic and symptomatic local control at 1 year were 90% (95% confidence interval: 76%-98%). The median time to recurrence in these 3 patients was 3.5 months (range 3.4-5.8 months), all had radiosensitive tumors, and all recurrences were epidural. No patients experienced wound dehiscence, hardware failure or spinal cord myelopathy. The median time to return to systemic therapy was 0.5 months (range 0-9.4 months). Conclusions: This prospective study of post-operative spine SBRT demonstrates excellent local control with low toxicity. These data suggest superior rates of local control compared to conventional RT, however a formal comparative study is warranted.
Introduction:
The standard of care in patients with an isolated, symptomatic region of malignant epidural spinal cord compression (MESCC) is decompressive surgery and adjuvant conventional radiation therapy (RT), based on level I data demonstrating improved ambulation following surgery compared to RT alone (1). The goal of surgery is circumferential decompression of the involved level of the spinal cord with stabilization of the vertebral column. RT is typically prescribed following surgery, historically using simple AP/PA field to deliver a total dose of approximately 30 Gy in 10 fractions. Unfortunately, local control and pain control with this approach is poor with rates as low as 30% (2). Given the increasing long term cancer survivorship and the resultant need for more durable local control, SBRT is being utilized as an alternative to low dose conventionally fractionated RT, allowing delivery of a higher biologically equivalent dose in a fewer number of fractions. Numerous retrospective series suggest excellent outcomes following SBRT to both intact and post-operative lesions with local control ranging from 70-100% across tumor histologies (3-25). In addition, a single prospective study comparing 24 Gy in a single fraction using SBRT to 3-dimensional conformal radiation to a total dose of 30 Gy in 10 fractions found significantly lower pain scores following SBRT at 6 months following completion of therapy (12). This improvement in local control compared to conventional RT is vital, given the high risk of deterioration in neurologic function, re-operation, and worsening pain as well as quality of life in patients with progressive spine disease. As a result, the practice of SBRT for spine metastases has been increasing in throughout academic and community practices, and consensus contouring guidelines have been published for both intact and post-operative targets (26-27). Nonetheless, to date, no prospective studies of SBRT to the spine in the post-operative setting have been published. The purpose of this phase II clinical trial is to prospectively evaluate outcomes after SBRT to the spine following surgical intervention for solid tumor metastases.
Methods:
Patient selection: Patients age 12 years or older were eligible for enrollment in this single institution study which was registered on clinicaltrials.gov (***) and had approval of the institutional review board. All patients had histologically proven solid tumor malignancy with metastasis to the spine. Patients were required to have radiographic evidence of spinal metastasis and must have undergone surgical resection (gross
total, subtotal, or biopsy) of the spinal lesion(s) no more than 16 weeks prior to SBRT treatment. The extent of epidural involvement was defined according to the Bilsky grading scale (28). High-grade was defined as Bilsky grade 2 or 3, low grade as Bilsky grade 1a, 1b, or 1c and no epidural disease as Bilsky grade 0. SBRT targets involved at maximum 3 consecutive vertebral levels, although multiple targets per patient were permitted. Patients were required to have a minimum KPS of at least 40. There was no limitation to the number of sites of metastases, but for categorization for data analyses, oligometastatic disease was defined as no more than 5 total sites of involvement and diffuse spine disease was defined as greater that 3 vertebral levels of involvement prior to SBRT. Renal cell carcinoma, sarcoma, melanoma, thyroid carcinoma and hepatocellular carcinoma were considered radio-resistant histologies. Patients were excluded if they had prior RT or SBRT to involved level of the spine, if their spine disease was from leukemia, lymphoma or myeloma, or if they had uncontrolled intercurrent illness. Delineation of target volumes and objects at risk: All patients underwent CT simulation utilizing immobilization for a reproducible radiosurgery setup. Intravenous contrast was administered for the CT in cases of extensive paraspinal extension. Patients underwent high resolution MRI simulation including at minimum T1 with gadolinium, T2 and STIR axial and sagittal sequences. In cases of significant metal artifact on MRI due to spinal instrumentation, patients underwent CT myelogram. For the sake of RT planning, the following datasets were fused using the treatment planning software: 1) CT simulation; 2) CT myelogram (if performed); 3) pre-operative diagnostic scan; 4) MRI simulation. Target delineation was according to the consensus contouring guidelines for post-operative patients (26). Although the guidelines were not published until several years after initiation of this study, …***these guidelines reflect the institutional practice for years prior to the submission and publication of the manuscript. The spinal cord planning risk volume (PRV) was defined as the true spinal cord according to CT myelogram or T2 weighted MRI plus a 2 mm radial expansion or the thecal sac without expansion for patients with targets below the conus. Figure 1 shows the pre-operative sagittal (1A) and axial (1B) MRIs and post-operative CT myelogram with contours (1C) for both the PTV and thecal sac for an example patient. The normal tissue dose constraints are outlined in Table 1. Note that for the constraints specified as to a 0.1 cc volume, this was applied as a maximum point dose in the majority of patients. The 0.1 cc volume was specified in the protocol to allow the treating physicians flexibility in clinical decision making if allowing slightly higher doses to a pixel or very small volume resulted in what was deemed to be clinically meaningful improvements in CTV and PTV coverage.
Radiation prescription, dosimetry, and treatment: Patients were treated to a total dose of 30 Gy in 6 Gy per fraction. Patients were required to receive at least 2 fractions the first week. Goal PTV coverage was >90% receiving >90% of prescription dose but coverage was compromised to meet normal tissue constraints. Figure 1D shows an example treatment plan. Patients were treated using a linear accelerator with nominal beam energy of 6 MV. Cone beam CT guidance and/or orthogonal imaging was utilized for precise patient setup. All patients who initiated protocol treatment were followed per the study calendar.
Evaluation of local control and toxicity: Patients were followed with CT and/or MRI of the treated region every 3 months for at least 2 years following completion of SBRT. Bilsky grading (12) was performed by a board certified neuroradiologist based on the 1) immediately pre-operative MRI; 2) post-operative CT myelogram or MRI; and 3) first MRI post-SBRT, which was performed at approximately 3 months following treatment. Follow-up evaluations were performed every 3 months and included neurologic evaluation by the American Spinal Injury Association (ASIA) Impairment Scale (29), and pain evaluation by the 10 point visual analog scale (30) and MD Anderson Cancer Center (MDACC) Brief Pain Inventory Short Form (31). Toxicity was recorded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) Version 4 as well as the RTOG/EORTC acute and late common toxicity assessments for CNS and spinal cord.
Patients were considered to have symptomatic progression if: 1) there was radiographic evidence of progression on CT and/or MRI based on direct comparisons by at least 2 members of the team of the most recently obtained radiographic images compared to the immediate pretreatment images AND 2) the patient had progressive symptoms defined as worsening neurologic function attributable to tumor growth at the level treated according to the ASIA Impairment Scale OR worsening pain attributable to tumor growth at the treated level according to the MDACC brief pain inventory (short form) defined as a new score ≥5 at the treated level of spine.
Statistical methods:
The primary objective of this phase II trial was radiographic local recurrence at 12 months following completion of SBRT. Radiographic local recurrence was defined as progressive disease on CT and/or MRI in the treatment volume or at the margin of the treatment field when compared to imaging studies prior to the post-operative SBRT. If equivocal, the lesion was followed with serial short interval scans for further clarification with the timing of local recurrence backdated to the date of the first suspicious CT or MRI. The proportion of patients without local recurrence at 12 months following SBRT was estimated along with the 90% confidence interval. Time to radiographic local recurrence was calculated from the date of SBRT to the date of local recurrence. The median time to local recurrence was estimated using Kaplan-Meier method (32). In addition, the symptomatic local recurrence rate at 12 months was estimated along with confidence interval using binomial distribution. Bilsky grade pre- and post-operatively as well as post-operatively and at 3 months following SBRT were compared using the Wilcoxon signed-rank test. The number of patients who experienced grade 3 or above toxicities attributed to the study treatment was recorded. Observed severe adverse event associated with SBRT including radiation myelopathy were summarized using descriptive statistics. Time to return to chemotherapy was calculated from the date of initial SBRT to the starting date of chemotherapy. The chemotherapy date was censored if patient had not received chemotherapy at time the study database was closed for final analysis. Time to return to chemotherapy was estimated using Kaplan-Meier method. Tumor histology and wound healing complications were summarized using descriptive statistics.
Sample size: Based on power calculations at the time of study initiation a total of 35 patients were enrolled in the protocol. This was based on a null hypothesis of 60% radiographic local control rate at 12 months with conventional radiation therapy (33) versus an alternative hypothesis of a local control rate of 80% at 12 months using post-operative SBRT with an 80% statistical power and type I error rate of 0.05 (onesided).
Results:
Thirty-five patients enrolled in the study between 5/20/2013 and 7/19/2017. Two patients did not receive SBRT after enrollment. One of these patients experienced rapid deterioration in clinical status post-operatively and ultimately succumbed to their illness between enrollment and the treatment
start date. The second patient elected to be treated at another institution closer to their home rather than proceeding the treatment according to the trial. Two patients underwent treatment to 2 unique target volumes. In sum, 35 targets in 33 patients were treated with post-operative spine SBRT. Baseline patient demographic, tumor, and treatment characteristics are shown in Table 2. Figure 2A shows the overall local control rate. At a median FU 10.5 months (range: 0.03-47.4 months), a total of 3 patients developed local recurrence within 12 months. The local control rate using an intention to treat analysis and per treated tumor was 91.4% (95% CI, 77%--98%). Local control rate per protocol was 90.0% (95% CI, 76%--98%). For the 3 patients that experienced local failure, the median time to recurrence 3.5 months (range 3.4-5.8 months). The recurrences were radiographic in nature and none were associated with a decline on the in neurologic function according to the ASIA impairment scale. All recurrences were symptomatic. All 3 of these patients had radiosensitive histologies and all of the failures were epidural in nature. The pre-operative Bilsky grades for these patients were 1B, 2 and 3, and were 1C, 1B and 0 respectively on the post-operative, pre-SBRT imaging. The median prescription isodose line, PTV coverage, percent of the PTV receiving 90% of the prescription dose and minimum dose of the patients that experienced local failure were 62.7% (range: 58-68%); 93.5% (range: 90.7-99.1%); 94.8% (range: 94-96.2%); and 17.8 Gy (range: 16.5-19.4 Gy), respectively. Two patients underwent re-treatment to the same spinal segment. Thirty-seven percent of patients had diffuse spine metastases at the time of SBRT. Twenty percent of patients experienced new or progressive disease within 1 vertebral level above or below the SBRT target and 37% of patients experienced new or progressive disease within 2 vertebral levels above or below the SBRT target. Excluding patients whose baseline 10 point visual analog pain score was not recorded (n=2) or whose final 10 point visual analog pain score was recorded at the time of completion of RT (n=3), the score at the time of last recorded follow-up compared to baseline was reduced in 54.2%, stable in 12.5%, increased by 1 point in 8.3% and increased by 2 or more points in 25%; 20.8% of patients reported no pain in any part of their body at the time of last follow-up. Of the patients (n=24) whose worst pain score at the time of last follow-up according to the MDACC brief pain inventory short form corresponded with the region targeted with the study treatment, 45.8% reported no pain, 29.2% reported improved pain, 4.2% reported stable pain, 8.3% reported pain that was 1 point worse, and 12.5% reported pain that was 2 points worse compared to baseline. Figure 3 summarizes pain outcomes according to the Visual Analogue score and ASIA Impairment Scale prior to SBRT and at 3-months post SBRT, 6-months post SBRT, and latest follow-up.
ASIA impairment score was grade D (motor incomplete with motor function preserved below the neurologic level with at least half of key muscles functions having a grade 3 or better) or grade E (normal neurologic function) in all patients at both baseline and the time of last follow-up. Of the 3 patients who had radiographic progression there was no associated deterioration of neurologic function. The median Bilsky grades were 2 (range: 1B-3), 1B (range 0-3), 1B (range 0-1c) pre-operatively, post-surgery, and at 3 months following SBRT, respectively. The change in Bilsky grade was statistically significant between the pre-operative and post-operative imaging (p<0.001) and from the postoperative imaging to the 3 months post-SBRT imaging (p=0.034). Figure 4 shows the pre-operative, postoperative and 3 month post-SBRT Bilsky epidural grade dichotomized as high (1c to 3) versus low (0 to 1b) grade as well as trends for individual patients. Figure 2B shows the overall survival rate. The median overall survival was 14.3 months (95% CI = [7.6, 43]). Nineteen patients died before they reached 12 months of follow-time. Eighteen out of the 19 patients died without local recurrence. Sixteen patients were alive beyond 12 months and 2 out of the 16 had local recurrence. As such, the local control rate per patient who lived beyond 12 months was 87.5% (95% CI, 62%-98%). The median time to return to systemic therapy was 0.5 months (range 0-9.4 months). No patients experienced wound dehiscence, hardware failure or myelopathy. There were no grade 3 or higher toxicities attributable to the SBRT according to NCI CTCAE v4 or the RTOG/EORTC acute and late common toxicity assessments.
Discussion: As long term cancer survivorship continues to increase, obtaining durable local control of spinal metastases is essential in order to maximize quality of life. A large body of literature suggests excellent outcomes following spine SBRT to intact vertebrae (4,11-12,20-25) with rates of durable local control and pain control ranging from 70-100%. Similarly, a growing body of literature suggests comparably excellent local control following SBRT to solid tumor spine metastases following surgery (5-10,13-19). However, data regarding post-operative spine SBRT published to date is limited to retrospective series and a critical review. We present the first prospective trial to evaluate SBRT in the post-operative setting. Our data suggest excellent outcomes with greater than 90% local control at 1 year following SBRT, with minimal toxicity. Similar to prior studies, all three local recurrences in this trial were epidural in nature. We had low rates of high grade epidural disease post-operatively, yet still saw epidural failures. In fact, all three
of the recurrence were in patients with low grade residual epidural disease post-operatively and target volume coverage in these patients was similar to the rest of the cohort. This supports the notion that the epidural space represents the region at greatest risk of recurrence following spine SBRT. Future investigations will be important to investigate approaches to improve epidural control rates. SBRT did result in further downgrading of epidural disease in a significant number of patients with residual high grade epidural disease post-operatively. This is consistent with prior retrospective data demonstrating a significant epidural response rate of 74% (25) in patients undergoing SBRT for MESCC. Thus, while surgical decompression and downgrading of epidural disease appears to be essential in maximizing local control, radio-surgical decompression appears to occur as well. Future investigations will be important to further understand the frequency and time course of this effect and to investigate how it may be utilized to manage spine metastases in the least invasive manner while augmenting the likelihood of durable local control. A historical concern of radiation dose escalation in the post-operative setting is a potentially increased risk of hardware failure following SBRT. However, no patients in our study experienced this toxicity suggesting that the risk may not be increased compared to the historically low rates following surgery alone or surgery followed by conventional RT. This study suggests that post-operative SBRT following surgery for spine metastases represents a highly efficacious as well as safe treatment modality. However, future investigation into the most appropriate patient population to apply this technology will be important. Specifically, more than half of our patients succumbed to their disease within one year of treatment and 37% of patients experienced failure in adjacent vertebral levels. Future recursive partitioning analyses and development of other stratification systems will be essential to properly identify patients that are most likely to benefit from the more durable local control associated with SBRT in the post-operative setting rather than the simpler, faster, less expensive and less labor intensive alternative of conventional RT.It is important to note that the prescription dose utilized in this study is conservative relative to current practices at many large institutions. This study was developed when the practice of spine SBRT was in its infancy. The dose was selected in order to be uniform in allowing acceptable target coverage while meeting spinal cord constraints in all patients, including in those with large volumes involving 3 vertebral levels. Future studies comparing different fractionation regimens and dose escalation will be important. Although this manuscript represents an important contribution to the literature, there are several limitations. First, it was a single arm study and a larger scale randomized controlled study will be
important to confirm the results. Second, although our primary endpoint was 1 year local control, nineteen patients died prior to this time point. Nonetheless, 18 of the 19 patients died without LR and of the patients alive after 1 year, local control remained excellent at 87.5%. Larger studies will be important to confirm our results. Third, to facilitate enrollment this study enrolled a broad spectrum of post-operative patients. Future studies designed to more specifically study those most likely to benefit from the more durable local control of SBRT, such as patients with radioresistant primary tumors or oligometastases, are needed. Fourth, although this study suggests improvement in pain control following post-operative spine SBRT in the majority of patients, it is important to note that pain control is a subjective measure that is impacted by many factors such as pain in other sites beyond the lesion targeted in the study, as well as the relative intensity of pain at other sites. Thus, caution must be used in interpreting pain as a surrogate for tumor control. Pain measures are particularly difficult to understand in post-operative patients as they are potentially confounded by many other factors such as wound healing and hardware failure. Finally, the patients enrolled in this trial were all radiation naïve. Future investigations will be important to evaluate the role of post-operative SBRT in the re-irradiation setting.
Conclusions: To conclude, we present the first prospective study to evaluate SBRT for solid tumor spine metastases in the post-operative setting and demonstrate excellent local control with low toxicity. These data suggest that post-operative spine SBRT may be associated with superior rates of local control compared to conventional RT, however a formal comparative study is warranted for confirmation.
References: 1. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: A randomised trial. Lancet. 2005;366(9486):643648. 2. Klekamp J, Samii H. Surgical results for spinal metastases. Acta Neurochir (Wien). 1998;140(9):957967.
3. Klimo P,Jr, Thompson CJ, Kestle JR, Schmidt MH. A meta-analysis of surgery versus conventional radiotherapy for the treatment of metastatic spinal epidural disease. Neuro Oncol. 2005;7(1):64-76. 4. Sahgal A, Larson DA, Chang EL. Stereotactic body radiosurgery for spinal metastases: A critical review. Int J Radiat Oncol Biol Phys. 2008;71(3):652-665. 5. Al-Omair A, Masucci L, Masson-Cote L, et al. Surgical resection of epidural disease improves local control following postoperative spine stereotactic body radiotherapy. Neuro Oncol. 2013;15(10):14131419. 6. Gerszten PC, Germanwala A, Burton SA, Welch WC, Ozhasoglu C, Vogel WJ. Combination kyphoplasty and spinal radiosurgery: A new treatment paradigm for pathological fractures. J Neurosurg Spine. 2005;3(4):296-301. 7. Rock JP, Ryu S, Shukairy MS, et al. Postoperative radiosurgery for malignant spinal tumors. Neurosurgery. 2006;58(5):891-8; discussion 891-8. 8. Gerszten PC, Monaco EA, 3rd. Complete percutaneous treatment of vertebral body tumors causing spinal canal compromise using a transpedicular cavitation, cement augmentation, and radiosurgical technique. Neurosurg Focus. 2009;27(6):E9. 9. Massicotte E, Foote M, Reddy R, Sahgal A. Minimal access spine surgery (MASS) for decompression and stabilization performed as an out-patient procedure for metastatic spinal tumours followed by spine stereotactic body radiotherapy (SBRT): First report of technique and preliminary outcomes. Technol Cancer Res Treat. 2012;11(1):15-25. 10. Laufer I, Iorgulescu JB, Chapman T, et al. 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. 2013;18(3):207-214. 11. Tseng CL, Soliman H, Myrehaug S, et al. Imaging-based outcomes for 24 gy in 2 daily fractions for patients with de novo spinal metastases treated with spine stereotactic body radiation therapy (SBRT). Int J Radiat Oncol Biol Phys. 2018;102(3):499-507.
12. Sprave T, Verma V, Forster R, et al. Randomized phase II trial evaluating pain response in patients with spinal metastases following stereotactic body radiotherapy versus three-dimensional conformal radiotherapy. Radiother Oncol. 2018;128(2):274-282. 13. Bate BG, Khan NR, Kimball BY, Gabrick K, Weaver J. Stereotactic radiosurgery for spinal metastases with or without separation surgery. J Neurosurg Spine. 2015;22(4):409-415. 14. Moulding HD, Elder JB, Lis E, et al. Local disease control after decompressive surgery and adjuvant high-dose single-fraction radiosurgery for spine metastases. J Neurosurg Spine. 2010;13(1):87-93. 15. Sellin JN, Suki D, Harsh V, et al. Factors affecting survival in 43 consecutive patients after surgery for spinal metastases from thyroid carcinoma. J Neurosurg Spine. 2015;23(4):419-428. 16. Sellin JN, Gressot LV, Suki D, et al. Prognostic factors influencing the outcome of 64 consecutive patients undergoing surgery for metastatic melanoma of the spine. Neurosurgery. 2015;77(3):386-93; discussion 393. 17. Harel R, Emch T, Chao S, et al. Quantitative evaluation of local control and wound healing following surgery and stereotactic spine radiosurgery for spine tumors. World Neurosurg. 2016;87:48-54. 18. Redmond KJ, Lo SS, Fisher C, Sahgal A. Postoperative stereotactic body radiation therapy (SBRT) for spine metastases: A critical review to guide practice. Int J Radiat Oncol Biol Phys. 2016;95(5):1414-1428. 19. Chan MW, Thibault I, Atenafu EG, et al. Patterns of epidural progression following postoperative spine stereotactic body radiotherapy: Implications for clinical target volume delineation. J Neurosurg Spine. 2016;24(4):652-659. 20. Ahmed KA, Stauder MC, Miller RC, et al. Stereotactic body radiation therapy in spinal metastases. Int J Radiat Oncol Biol Phys. 2012;82(5):e803-9. 21. Chang EL, Shiu AS, Mendel E, et al. Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure. J Neurosurg Spine. 2007;7(2):151-160. 22. 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). 2007;32(2):193-199.
23. Jin JY, Chen Q, Jin R, et al. Technical and clinical experience with spine radiosurgery: A new technology for management of localized spine metastases. Technol Cancer Res Treat. 2007;6(2):127-133. 24. Puvanesarajah V, Lo SL, Aygun N, et al. Prognostic factors associated with pain palliation after spine stereotactic body radiation therapy. J Neurosurg Spine. 2015:1-10. 25. Lee I, Omodon M, Rock J, Shultz L, Ryu S. Stereotactic radiosurgery for high-grade metastatic epidural cord compression. J Radiosurg SBRT. 2014;3(1):51-58. 26. Redmond KJ, Robertson S, Lo SS, et al. Consensus contouring guidelines for postoperative stereotactic body radiation therapy for metastatic solid tumor malignancies to the spine. Int J Radiat Oncol Biol Phys. 2017;97(1):64-74. 27. Cox BW, Spratt DE, Lovelock M, et al. International spine radiosurgery consortium consensus guidelines for target volume definition in spinal stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2012;83(5):e597-605. 28. Bilsky MH, Laufer I, Fourney DR, et al. Reliability analysis of the epidural spinal cord compression scale. J Neurosurg Spine. 2010;13(3):324-328. 29. Kirshblum SC, Waring W, Biering-Sorensen F, Burns SP, Johansen M, Schmidt-Read M, Donovan W, Graves D, Jha A, Jones L, Mulcahey MJ, Krassioukov A. Reference for the 2011 revision of the International Standards for Neurological Classification of Spinal Cord Injury. J Spinal Cord Med. 2011 Nov;34(6):547-54
30. Wallerstein SL. Scaling clinical pain and pain relief. In: Bromm B, ed. Pain Measurement in Man: Neurophysiological Correlates of Pain. New York, NY: Elsevier; 1984. 31. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med 1994;23(2):129-138. 32. Kaplan, E.L.; Meier, P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-481.
33. Rades D, Lange M, Veninga T, et al. Preliminary results of spinal cord compression recurrence evaluation (score-1) study comparing short-course versus long-course radiotherapy for local control of malignant epidural spinal cord compression. Int J Radiat Oncol Biol Phys. 2009;73(1):228-234.
Figure legends:
Figure 1: Figure 1 shows the (A) pre-operative sagittal T1 post gadolinium and (B) axial FSE T2 weighted MRIs, (C) post-operative CT myelogram with PTV (red) and thecal sac (blue) contours, and (D) treatment plan for an example patient with colorectal carcinoma metastatic to the L4 vertebral body. The prescription dose for all patients on this clinical trial was 30 Gy in 5 fractions prescribed to a median prescription isodose line of 61% (range: 53 – 71%). Median PTV coverage and V90% of the PTV for all patients was 90.2% (range: 82.6 - 96.2%) and 94.4 (range: 90.2-97.7%), respectively.
Figure 2: (A) Local recurrence: Median local recurrence was not reached. 95% confidence intervals are indicated with dotted lines. (B) Overall survival. 95% confidence intervals are indicated with dotted lines.
Figure 3: Mean change in two patient-reported pain scores compared to before SBRT: (A) visual analog pain score (VAS) and (B) worst pain score according to MD Anderson Brief Pain Inventory (BPI). The error bars show the standard deviation.
Figure 4: Bilsky grade at pre-operative, post-operative (pre-SBRT) and approximately 3 months postSBRT time points: (A) dichotomized as high (1c to 3) versus low (0 to 1b) and (B) showing Bilsky grade at each time point for individual patients.
Table legends:
Table 1: Five fraction dose constraints for organs at risk. *Note that for constraints specified as 0.1 cc, for the majority of patients this was applied as a maximum point dose. The 0.1 cc volume was specified in the protocol to allow the treating physicians flexibility in clinical decision making if allowing slightly
higher doses to a pixel or very small volume resulted in what was deemed to be clinically meaningful improvements in CTV and PTV coverage.
Table 2: Patient, tumor, and treatment characteristics. Abbreviations: KPS = Karnofsky performance status; ASIA = American Spinal Injury Association Impairment Scale; NSCLC = non-small cell lung cancer; RT = radiation therapy; CTV = clinical target volume; PTV = planning treatment volume.
Table 1: Five-fraction dose constraints for organs at risk Organ at risk Spinal cord
Dose constraint (Gy)* 25 to 0.1 cc
Cauda equina
25 to 0.1 cc
Trachea
32.5 to 0.1 cc
Esophagus
32.5 to 0.1 cc
Heart and pericardium Skin
40 to 0.1 cc
Great vessels
55 to 0.1 cc
Renal cortex
17.5 Gy to 200 cc
35 to 0.1 cc
*Note that for constraints specified as 0.1 cc, for the majority of patients this was applied as a maximum point dose. The 0.1 cc volume was specified in the protocol to allow the treating physicians flexibility in clinical decision making if allowing slightly higher doses to a pixel or very small volume resulted in what was deemed to be clinically meaningful improvements in CTV and PTV coverage. Table 2: Patient, tumor, and treatment characteristics Median (range) or Number (%) 63 (21 - 75)
Age Sex
Race
Male Female White Black Asian
KPS score (baseline) ASIA score (baseline)
Histology
Radiosensitive
E D Lung cancer Renal cell carcinoma Breast cancer Melanoma NSCLC Pancreatic cancer Prostate cancer Other (fewer than 2 patients) Yes
22 (62.9%) 13 (37.1%) 24 (68.6%) 8 (22.9%) 3 (8.6%) 70 (50 - 100) 25 (71.4%) 10 (28.6%) 7 (20%) 6 (17.1%) 5 (14.3%) 2 (5.7%) 2 (5.7%) 2 (5.7%) 2 (5.7%) 9 (25.7%) 23 (65.7%)
No Yes Diffuse spinous No metastases prior to RT Unknown Number of vertebral levels treated Cervical Location of treated Thoracic tumor Lumbar 3 Volume of CTV (cm ) Volume of PTV (cm3) Maximum dose to PTV (Gy) Minimum dose to PTV (Gy) Prescription Isodose (%) Coverage (%) Percent of PTV receiving 90% of prescription dose Maximum point dose to spinal cord (Gy) Maximum point dose to spinal cord + 2mm (Gy) Subtotal Resection extent Gross Total Biopsy
12 (34.3%) 13 (37.1%) 19 (54.3%) 3 (8.6%) 2 (1 - 3) 7 (18.9%) 22 (59.5%) 8 (21.6%) 74.1 (21.4 - 238.5) 95.4 (27 - 257) 49.9 (43.5 - 57.1) 16.7 (5.7 - 19.7) 61 (53 - 71) 90.2 (82.6 - 96.2) 94.4 (90.2-97.7) 21.4 (18.4 - 23.5) 24.7 (22.6 - 27.6) 25 (71.4%) 6 (17.1%) 4 (11.4%)
A
B
C
D
SBRT
A
SBRT
B
A
B
A
B