Despite advances in the care of primary malignant

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1 J Neurosurg Spine 14: , 2011 Efficacy and cost-effectiveness analysis of external beam and stereotactic body radiation therapy in the treatment of spine metastases: a matched-pair analysis Clinical article Marsha L. Haley, M.D., 1 Peter C. Gerszten, M.D., M.P.H., 2 Dwight E. Heron, M.D., F.A.C.R.O., 1 Yue-Fang Chang, Ph.D., 2 Dave S. Atteberry, M.D., M.S., 2 and Steven A. Burton, M.D. 1 Departments of 1 Radiation Oncology and 2 Neurological Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania Object. The objective of this study was to compare the palliative efficacy and cost effectiveness of external beam radiation therapy (EBRT) to stereotactic body radiation therapy (SBRT) as primary treatment for bone metastatic disease of the spinal column. Methods. Forty-four patients were matched based on age, primary tumor site, year of treatment, and location of metastasis. Outcomes of interest were pain relief, cost-effectiveness, toxicities, and need for further intervention. Pain relief was rated as excellent, good, fair, or poor, using a radiosurgical pain scale to combine visual analog scale and verbal descriptor ordinal scale scores. Medicare fee schedules were used to compute the charges for both the technical and professional components of care. Patients in the EBRT group were treated using a linear accelerator while patients in the SBRT group were treated with the CyberKnife robotic radiosurgery system. Patients received regular follow-up evaluations by a radiation oncologist and neurosurgeon. Results. Forty-four patients (22 pairs) were analyzed. At a follow-up of 1 month, there was no statistically significant difference in pain between the 2 groups (p = 0.11). Patients who underwent SBRT had the highest total gross charge; depending on technique, EBRT treatments ranged from 29% to 71% of the SBRT charge. Patients treated using EBRT had more acute toxicities, and more of these patients underwent further intervention at the treated spinal level. There were no late complications attributed to either treatment modality. Conclusions. External beam radiation therapy remains an efficacious and cost-effective method of palliation of spine metastases. In this study, patients treated with EBRT had more acute toxicities and were more likely to require additional interventions at the treated sites. Stereotactic body radiation therapy, although more costly, resulted in comparable rates of pain relief and late treatment-related toxicity, and continues to show promise as an emerging modality for selected patients with spine metastases. (DOI: / SPINE10233) Key Words external beam radiation therapy toxicity stereotactic body radiation therapy outcome matched-pair analysis Despite advances in the care of primary malignant diseases, bone metastatic disease remains a significant source of morbidity for the patient with cancer. Approximately 50% of patients who receive a cancer diagnosis will develop metastases over the course of their disease. Of these patients, 70% will develop symptoms that are likely to affect their quality of life. 10 It has been widely reported that the spine is the most common site for bone metastatic disease, with as many as Abbreviations used in this paper: EBRT = external beam radiation therapy; LINAC = linear accelerator; SBRT = stereotactic body radiation therapy. J Neurosurg: Spine / Volume 14 / April % of patients exhibiting spinal disease at the time of autopsy. Of those with metastatic disease, 70% of symptomatic lesions are found in the thoracic spine, 20% are found in the lumbar region, and 10% are found in the cervical spine. More than 50% of patients with spine metastasis have multiple levels of involvement. 14 The majority of patients are treated with surgery, medical therapy, radiation therapy, or a combination thereof. External beam radiation therapy has been shown to offer pain relief in more than 73% of patients with spinal metastases. 10 Since Lars Leksell first coined the term radiosurgery in 1951 in the management of intracranial diseases, 537

2 M. L. Haley et al. technological advances have made stereotaxy a technique of localization using a cardinal coordinate system applicable for the treatment of extracranial targets. Historically, the majority of patients with spinal metastatic disease who received extracranial radiosurgery had been previously treated with EBRT. Extracranial radiosurgery, however, remains an emerging option as a primary modality for the treatment of spinal metastatic disease. The University of Pittsburgh Cancer Institute has published results from one of the largest series of patients to undergo extracranial radiosurgery for the treatment of spinal metastatic disease. In a recent publication of 500 cases, 13% underwent radiosurgery as the primary treatment for spinal metastases without prior EBRT. In this cohort, radiographic tumor control was demonstrated in 90% of cases with nonmelanoma histology, determined by direct comparison by at least 2 authors of the study using pre- and posttreatment cross-sectional studies and confirmed by a written radiology report. 6 Despite the increasing use of SBRT as a primary treatment modality for spinal metastases, there has been no direct comparison with the standard of EBRT. To explore this question, we performed a matched-pair analysis comparing SBRT to EBRT in the primary radiotherapeutic treatment of spinal metastatic disease. Methods Study Population We reviewed the University of Pittsburgh database on extracranial radiosurgery and identified 143 patients who underwent SBRT to the spine without having undergone prior EBRT. A cohort of patients treated with EBRT only was identified for comparison. The match parameters, chosen by a multidisciplinary panel consisting of radiation oncologists and neurosurgeons, included age (by decade), primary tumor site, year of treatment, and location of metastasis (cervical, thoracic, or lumbar spine). All patients had undergone treatment because of pain from spinal metastatic disease. Histological confirmation of the primary tumor site was required, with subsequent radiographically documented spinal metastases. Biopsy of the bone site of involvement was not required for study entry. Exclusion criteria were age < 45 or > 80 years old, sacral location, prior radiation therapy, lack of follow-up (except in case of death), treatment prior to 2001, and prior spine surgery in the affected area. Cases involving EBRT that were treated during the inclusion period were then reviewed and 22 cases were selected that met all match criteria. Outcome Assessment The primary outcomes of interest were pain relief and monetary cost of treatment. Secondary outcomes were toxicities of treatment and need for further intervention. The time point chosen for toxicity and efficacy assessment was 1 month after the completion of treatment. Although many patients had longer follow-up, pain relief was achieved in 4 weeks for the majority of patients in an earlier published clinical trial. 13 Therefore, 1 month was chosen as a consistent evaluation point for both groups. In most cases, the pain response for patients treated with EBRT was recorded using a verbal descriptor ordinal scale, long considered valid and reliable for rating pain in cancer patients. 4 The SBRT patients were evaluated using the visual analog scale. In each case, pain levels were recorded before treatment and at the 1-month follow-up visit. Although studies have shown a positive linear correlation between the scales, 4 there is no standardized method of comparison between the two. To compare the data, we used a radiosurgical pain scale that categorizes pain relief into 4 results: excellent, good, fair, and poor. Excellent outcome was defined as complete relief without requiring any analgesics. Good outcome was defined as complete pain relief while still requiring analgesics. Fair was defined as partial (> 50%) pain relief, and poor was defined as < 50% relief. 12 Analgesics were defined as narcotics, over the counter pain medications, or steroids used for pain relief. Morphine conversions were not used; we simply recorded whether analgesics were increased, decreased, or remained the same, and this was applied to the radiosurgical pain scale. In our data set, if the patient experienced complete pain relief and did not require any analgesics, the patient was placed into the excellent category. If complete relief of pain occurred but the patient continued to require the same or a reduced dose of analgesics, we placed the patient into the good category. If pain decreased but analgesics increased, we placed the patient into the fair category. If, at the follow-up visit, a patient experienced increased pain compared with the pretreatment assessment, regardless of analgesic usage, this was considered a poor result. Patients were analyzed in 2 groups a combination of excellent and good result versus fair and poor result. National Cancer Institute Common Toxicity Criteria (version 2.0) grading was used to score side effects. Medicare 2010 Hospital Setting fee schedules were used to compute the charge data for both the technical and professional components of care; the charges for radiosurgical fiducial placement were added as an addendum for those cases in the thoracic and lumbar regions in which it is commonly used in our SBRT treatment protocol. Patients undergoing EBRT were treated on a LINAC using a minimum beam energy of 6 MV. External beam and SBRT dose and fractionation were decided by the treating radiation oncologist. The majority of patients in the EBRT group (91%) were treated with either 20 Gy in 5 fractions or 30 Gy in 10 fractions; the remaining patients were treated with other fractionation techniques (with total doses ranging from 23.5 Gy to 35 Gy.) Fifty percent of the SBRT patients received 16 Gy (prescribed to the 80% isodose line for a maximum tumor dose of 20 Gy), 25% received 18 Gy, and the remaining 25% received doses ranging from 14 Gy to 20 Gy. All SBRT patients were treated in a single fraction. The SBRT patients were treated using the CyberKnife robotic radiosurgical system (Accuray, Inc.) according to our treatment protocol, which has been previously described in the literature. 5 Patients were evaluated on follow-up by a neurosurgeon, radiation oncologist, and/or medical oncologist. 538 J Neurosurg: Spine / Volume 14 / April 2011

3 Efficacy of EBRT and SBRT for spine metastases Statistical Analysis Statistical analysis was performed using SAS version A probability value < 0.05 was used to determine statistical significance. Survival was calculated using Kaplan-Meyer estimates. The McNemar test for matched pairs was used for statistical analysis of pain and toxicities. Results Patient Characteristics Forty-four patients were analyzed to determine the efficacy and cost-effectiveness of the 2 treatment regimens (Table 1). There were 11 pairs of patients with breast carcinoma, 8 pairs with non small cell lung carcinoma, 2 pairs with renal cell carcinoma, and 1 pair with carcinoma of unknown primary site. The median age for the SBRT group was 56 years (range years), and for the EBRT group the median age was 57 years (range years). The majority of patients were female (75%), and the thoracic spine (55%) was the most common site treated. Most of the EBRT patients had only 1 vertebral level involved with disease (64%). Four patients had 2 levels involved, and 3 patients had 3 or more vertebral levels involved with metastatic disease. In the SBRT group, 3 patients had 2 vertebral bodies involved with disease and therefore both vertebral bodies were treated using SBRT; the remainder had 1 level involved. All of the SBRT patients and 41% of the EBRT patients had blastic disease. The remainder of the EBRT patients had a mixture of epidural and sclerotic disease, with 1 patient presenting with cord compression. Pain Relief and Survival At the 1-month follow-up, there was no statistically significant difference in pain relief between the 2 groups (p = 0.11). As expected, there was no significant difference in overall survival between the groups (p = 0.99). Median survival was 10 months for patients in the EBRT group and 10.5 months for patients in the SBRT group. Thirty-eight patients (86%) completed longer-term follow-up (> 90 days.) Toxicity More patients in the EBRT group developed acute toxicities (p = 0.01). In this group, 3 patients developed National Cancer Institute Common Toxicity Criteria acute Grade 1 or 2 esophagitis. One patient developed fatigue, 1 had Grade 1 nausea, and 1 developed Grade 1 thrombocytopenia. In the SBRT group, 1 patient experienced Grade 2 nausea and vomiting. The patients who developed gastrointestinal toxicity were treated with antiemetics, and those who developed esophagitis were treated with topical mucosal agents such as magic mouthwash. The patients with thrombocytopenia and fatigue were simply observed, because these were Grade 1 toxicities. No morbidity was associated with fiducial placement. For those patients that were followed > 90 days, there were no J Neurosurg: Spine / Volume 14 / April 2011 TABLE 1: Patient and tumor characteristics Variable EBRT SBRT median age (yrs) no. of males (%) 3 (14) 8 (36) no. of females (%) 19 (86) 14 (64) primary tumor site (%) lung 8 (36) 8 (36) breast 11 (50) 11 (50) renal 2 (9) 2 (9) unknown 1 (5) 1 (5) late complications attributed to either modality of treatment. Further Intervention Three of the patients in the EBRT group later underwent surgical procedures at the treated site, ranging from 1 to 6 months after treatment. The procedures consisted of a corpectomy and stabilization at 1 month, a laminectomy at 5 months, and 2 kyphoplastic procedures, one at 1 month and the other at 6 months after completion of treatment. One EBRT patient received an injection of samarium 6 months after completion of treatment. Each of the EBRT patients who underwent further intervention had a breast or lung primary carcinoma. There were 2 SBRT patients who received repeat stereotactic radiosurgery to the same area. Both patients experienced an initial improvement in their pain after SBRT. The lesions were confined to a single vertebral body without evidence of fracture, and it was believed that SBRT could provide a much more conformal dose of radiation to that site of disease than fractionated radiotherapy, leading to a better symptomatic response with less acute toxicity. Five of the patients in the EBRT group later underwent SBRT to the initial area, ranging from 1 to 32 months after treatment (mean 9 months). These patients underwent SBRT rather than further EBRT to avoid exceeding the recommended total radiation dose to the adjacent spinal cord and/or spinal nerve roots. Cost Effectiveness We used the Medicare charges associated with SBRT as the basis of comparison for the 4 EBRT treatment schedules because SBRT had the highest total gross charge (Table 2). Although some centers do not use fiducials, our center continues to use fiducial placement for lesions of the thoracic spine and for lesions adjacent to spinal instrumentation or other implants. Therefore, it was essential to include this cost in the analysis of the data. The costs of treating side effects with short-term antiemetics and topical mucosal agents such as magic mouthwash were considered negligible and were not included in the cost analysis. We applied a cost modeling analysis using the financial and observed outcome data for the patients in both cohorts. Because most modern radiation therapy depart- 539

4 M. L. Haley et al. TABLE 2: Cost comparison of SBRT versus EBRT* EBRT Technique Actual Cost ($) Percentage of SBRT Cost 30 Gy/10 fxs (3D plan) Gy/5 fxs (3D plan) Gy/10 fxs (2D plan) Gy/5 fxs (2D plan) * Based on 2010 Medicare Hospital Setting fee schedule reimbursement rates for both professional and technical components. An SBRT cost of $ was used for comparison with the EBRT techniques. This table does not include the cost of retreatment. Abbreviation: fxs = fractions. ments use 3D rather than 2D planning, we chose to use these charges for the model. Twenty-three percent of the EBRT patients in this study later underwent further SBRT therapy to the same vertebral area, while only 9% of the SBRT patients underwent a second course of SBRT. If we apply this to 100 patients, the total cost of radiosurgery, with 9% of patients requiring repeat SBRT, is $842,420. The total cost of 30 Gy in 10 fractions, assuming 23% require later radiosurgical treatment, is $676,309. For 20 Gy in 5 fractions, the total cost is $499,911. This amounts to 80% for the 30 Gy EBRT course and 59% for the 20 Gy EBRT course when SBRT is used as the benchmark total cost (Fig. 1). Fig. 1. Bar graph representation of the cost-modeling analysis. Stereotactic body radiation therapy has the highest total gross charge and therefore is used as the benchmark (100%). Thirty Gray in 10 fractions is 80% of the SBRT cost. Twenty Gray in 5 fractions is 59% of the SBRT cost. All costs include retreatment with SBRT in 9% of SBRT patients and 23% of EBRT patients. Discussion One of the main goals of local radiation therapy in the treatment of spinal tumors is palliation of pain. 11 The concept of hypofractionated radiotherapy for symptomatic bone metastases originated nearly 30 years ago and has been studied in multiple randomized and nonrandomized clinical trials. Single fraction radiotherapy was found to be as efficacious as multiple-fraction radiotherapy. However, patients treated with single fractions have been reported to have a higher rate of retreatment. 2 The majority of the published trials used 8 Gy in a single fraction, although none of these trials were specifically focused on spinal metastases as a separate oncological entity. The administration of a large single fraction has a theoretical advantage for relatively radioresistant tumors but may be radiobiologically undesirable because of the risk of late tissue damage to the spinal cord 3 (defined as neurological changes occurring later than 6 months after treatment). 8 The modern LINAC is equipped for a wide variety of treatment modalities, including intensity-modulated radiation therapy, stereotactic treatment, and image-guided radiation therapy. These advances allow more precise target definition and conformality, making hypofractionation more feasible and with the potential to reduce toxicities often observed with large fraction sizes. In 2004, Chang et al. 1 published Phase I results of near-simultaneous CT image-guided stereotactic radiotherapy for treating spinal metastases. The technique was found to be feasible and highly accurate in the 15 patients studied. In 2005, Yamada et al. 15 at Memorial Sloan-Kettering Cancer Center published results of 35 patients treated with intensity-modulated stereotactic radiotherapy, with similar results. Since that time, multiple centers have employed fractionated SBRT for the treatment of spinal metastases. The development of the Gamma Knife (Leksell) and LINAC-based radiosurgery allowed the delivery of highly conformal doses of radiation delivered in a single fraction. The first CyberKnife (Accuray) prototypes were used in the 1990s, and in 2001 the FDA granted clearance for treatment of extracranial lesions. 9 Researchers at Georgetown University Hospital recently published an analysis of pain and quality of life assessment of 200 patients treated with the CyberKnife for spinal tumors. In this series, the CyberKnife produced durable pain relief with very few side effects, allowing patients to maintain quality of life. 5 A recent literature review suggests that SBRT may provide an incremental benefit over EBRT for metastatic spinal disease, with more durable pain control and local control of disease. 7 The University of Pittsburgh Cancer Institute, the site of the second CyberKnife installation, began using the robotic radiosurgical system in 2001 for spinal applications, and since that time we have managed more than 1000 cases. In our institution as well as others, SBRT is emerging as a primary treatment modality for select patients with previously untreated spinal metastatic disease. Despite the rapid adoption of this treatment paradigm, there remains a dearth of clinical data to support superiority of this approach compared the current standard of care. In our matched-pair analysis of 44 patients with previously untreated spine metastases, we found no statistically significant difference in pain relief at 1 month posttreatment between the EBRT and SBRT patients. Although there were significantly more acute toxicities in the EBRT group, these were low-grade aand self-limited, and all resolved in less than 8 weeks after treatment. In the patients followed for more than 90 days, neither group showed late treatment-related toxicities. External beam radiation therapy remains a cost-effective method of palliation for spine metastases in the 540 J Neurosurg: Spine / Volume 14 / April 2011

5 Efficacy of EBRT and SBRT for spine metastases vast majority of patients. The main disadvantages are reflected in the risk of acute toxicities as a result of the comparatively limited inability to exclude a significant volume of normal tissue from the treatment, and the need for multiple fractions. These limitations, however, may decrease in the era of intensity modulation and imageguided radiotherapy as the gap is narrowed between EBRT and stereotactic radiotherapy. In our study, SBRT provided equivalent pain relief to EBRT. The clear disadvantages of SBRT include the higher treatment costs and the need for fiducial placement, an invasive procedure (albeit minimally invasive). Although no morbidity was associated with fiducial placement in this series, the potential complications associated with fiducial implantation are not insignificant. In addition, some patients with painful bone metastatic disease require medication before radiotherapy treatment to be able to tolerate the duration of the CyberKnife procedure, which is usually significantly longer than a fraction of EBRT. There are clearly limitations to the current study. It serves as a relative, not an absolute, comparison of pain between the 2 treatment modalities. Although we corrected for the use of narcotic medication with the radiosurgical pain scale, unless exact morphine equivalents are provided, the use of narcotic analgesics may affect the overall assessment of efficacy of either treatment option. In addition, the patients were not matched by initial pain levels, which could translate into a ceiling effect, thereby affecting ultimate pain assessment. The type of lesions differed between the 2 groups, with more epidural and sclerotic disease in the EBRT group. One patient with EBRT presented with cord compression and was not a candidate for surgery. These differences in the type of disease present could account for the higher need for salvage treatment in the EBRT group. The retreatment rates for EBRT in our study were substantially higher than in some of the aforementioned randomized trials and the meta-analysis; the studies therein were not limited to spinal metastases, however, and SBRT was not available as an option for retreatment when some of the older studies were published. Finally, we did not account for extent of extraneural disease and performance status, which may also have affected the results. Conclusions Our study represents one of the first attempts to compare SBRT and EBRT for spinal metastatic disease in a matched-pair analysis. Our findings suggest that for the majority of previously untreated patients, EBRT remains efficacious and is the least costly radiotherapeutic approach to management, at the expense of higher acute toxicity. The general trend in the management of patients with spinal metastases, whether it be minimally invasive surgical therapies or more focused radiotherapy treatments, has been to emphasize a decrease in morbidity while at the same time improving clinical outcome. Stereotactic body radiation therapy perfectly fits this treatment paradigm of providing a rapid and durable J Neurosurg: Spine / Volume 14 / April 2011 symptomatic improvement in an outpatient setting while minimizing the acute morbidity associated with standard fractionated radiotherapy. Stereotactic body radiation therapy should be considered for select patients with oligometastatic disease or for tumors that are relatively resistant to standard fractionated radiotherapy. We believe that our results are revealing and should prove informative in future randomized trials designed to provide more conclusive results. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: Heron, Gerszten, Bur ton. Acquisition of data: Haley, Chang. Analysis and interpretation of data: Heron, Haley, Gerszten, Chang, Atteberry. Drafting the article: Haley, Burton. Critically revising the article: Heron, Gers zten, Atteberry. Reviewed final version of the manuscript and ap proved it for submission: all authors. Acknowledgments The authors would like to acknowledge Carol Rawlins, Karlotta Ashby, Carol J. Kennedy, R.N., and Kim Hodges for their efforts in the preparation of this manuscript. References 1. 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. 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6 M. L. Haley et al. 11. Lu C, Stomper PC, Drislane FW, Wen PY, Block CC, Humphrey CC, et al: Suspected spinal cord compression in breast cancer patients: a multidisciplinary risk assessment. Breast Cancer Res Treat 51: , Lunsford LD, Niranjan A, Young R, Brisman R, Cunningham D, Lindquist C, et al: Radiosurgery Practice Guideline Initiative: Stereotactic Radiosurgery for Patients With Intractable Typical Trigeminal Neuralgia Who Have Failed Medical Management. Radiosurgery Practice Guideline Report #1-03, Issued January Harrisburg, PA: International RadioSurgery Association, 2009 ( org/tn%20guideline-updatedjan2009.pdf) [Accessed December 13, 2010] 13. Tong D, Gillick L, Hendrickson FR: The palliation of symptomatic osseous metastases: final results of the Study by the Radiation Therapy Oncology Group. Cancer 50: , Tse V: Spinal metastasis and metastatic disease to the spine and related structures. ( com/article/ overview) [Accessed December 13, 2010] 15. Yamada Y, Lovelock DM, Yenice KM, Bilsky MH, Hunt MA, Zatcky J, et al: Multifractionated image-guided and stereotactic intensity-modulated radiotherapy of paraspinal tumors: a preliminary report. Int J Radiat Oncol Biol Phys 62:53 61, 2005 Manuscript submitted March 19, Accepted December 7, Current address for Dr. Haley: Department of Radiation On cology, Altoona Regional Health System, Altoona, Pennsylvania. Portions of this work were presented as a brief abstract at the CNS Annual Meeting, September 20, 2007, San Diego, California. Please include this information when citing this paper: published online February 11, 2011; DOI: / SPINE Address correspondence to: Dwight E. Heron, M.D., F.A.C.R.O., University of Pittsburgh Cancer Institute, Department of Radiation Oncology, 5150 Centre Avenue, Pittsburgh, Pennsylvania herond2@upmc.edu. 542 J Neurosurg: Spine / Volume 14 / April 2011