Stereotactic Body Radiotherapy with Helical Tomotherapy for Pain Palliation in Spine Metastasis

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1 Technology in Cancer Research and Treatment ISSN February 22. Epub ahead of print. Adenine Press (2013) Stereotactic Body Radiotherapy with Helical Tomotherapy for Pain Palliation in Spine Metastasis DOI: /tcrt To evaluate the pain response, local tumor control and toxicity of stereotactic body radiotherapy (SBRT) with helical tomotherapy (HT) in the patients with spine metastasis. From May 2009 to June 2010, 22 patients with 31 lesions were treated by SBRT. Dose scheme were 24 Gy in 3 fractions (87.1%), 30 Gy in 5 fractions (9.7%), and 16 Gy in a single fraction (3.2%). Pain was assessed using a numerical rating scale. Analgesic consumption was recalculated into the daily oral morphine-equivalent dose (OMED). The response criteria of International Bone Metastases Consensus Group (IBMCG) was used. The median follow-up duration was 10 months (range 3-23 months). After SBRT the mean pain score decreased significantly (4.32 before SBRT, 0.71 at 3 months). However, median OMED didn t decrease until 3 months after SBRT (Median OMED; 34.5 mg before SBRT, 45 mg at 3 months). Pain response rate and pain progression-free survival rate at 3 month was 96.8 and 93.5%, respectively. Local progression-free survival rate at 3 month was 93.5%. There was no severe acute toxicity. SBRT with HT is a safe and effective treatment modality for local tumor control and pain palliation associated with spine metastasis. M. S. Kim, M.D. 1 K. C. Keum, M.D. 1 J. H. Cha, M.D. 1 J. H. Kim, R.T.T. 1 J. S. Seong, M.D., Ph.D. 1 C. G. Lee, M.D. 1 K. C. Nam, Ph.D. 2 W. S. Koom, M.D. 1 * 1 Department of Radiation Oncology, College of Medicine, Yonsei University, Seoul, Republic of Korea 2 Department of Medical Engineering, College of Medicine, Yonsei University, Seoul, Republic of Korea Key words: Stereotactic body radiotherapy; Helical tomotherapy; Spine metastasis; Pain palliation. Introduction Spine metastases occur in 30 to 40% of cancer patients and have been found in up to 90% at autopsy depending on their primary lesions (1). Patients with spine metastasis commonly present with pain caused by the invasion of tumor cells and sensitization of nervous system. This in turn causes a reduced quality of life (2). A metastatic lesion in the spine may affect neurological structures, such as nerve roots or the spinal cord, and cause neurologic deficiencies. Therefore, the aims of palliative treatments for spinal metastasis should be to relieve pain, maintain function and get local tumor control. Radiotherapy is a wellaccepted and effective treatment modality, and the mainstays of treatment for spine metastasis (3). The fundamental flaw of conventional radiotherapy to spine is the low radiation tolerance of the spinal cord. The concept of SBRT involves the delivery Abbreviations: 3D-CRT: 3D Conformal Radiation Therapy; CT: Computed Tomography; CTV: Clinical Target Volume; ECOG: Eastern Cooperative Oncology Group; GTV: Gross Tumor Volume; HT: Helical Tomotherapy: IBMCG: International Bone Metastases Consensus Group; IG-IMRT: Image-guided Intensity-modulated Radiation Therapy; MRI: Magnetic Resonance Imaging; MVCT: Megavoltage CT; OMED: Oral Morphine-equivalent Dose; PTV: Planning Target Volume; RTOG: Radiation Therapy and Oncology Group; SBRT: Stereotactic Body Radiotherapy. *Corresponding author: W. S. Koom, M.D. Phone: Fax: mdgold@yuhs.ac 1

2 2 Kim et al. of high dose of radiation to pathologic entity while sparing normal tissue (4). Radiosurgery was initially developed by Lars Leksell for the treatment of cranial pathology. For the extracranial pathology, the spine is suitable site for radiosurgery or SBRT in terms of minimal organ movement. The targeting accuracy and precision of radiosurgery or SBRT for spine has been reported (5). Hamilton et al. (6) first described the possibility of linear-accelerator based SBRT to the spine. By using this technique, it is possible to increase the dose intensity to tumor targets near the spinal cord without increasing the risk of normal tissue complications-most importantly, radiation induced myelopathy. The Consensus expert opinion of the Spine Oncology Study Group provided evidence-based recommendation of radiosurgery for spine metastases (3). Recent high-precision techniques in the delivery of radiation have allowed clinicians to expand SBRT applications to treat spine metastases close to the spinal cord during the last few years (7-10). Radiosurgery has been suggested as a safe and effective procedure with durable pain response and local control. In a report by Spine Oncology Study Group Recommendations, stereotactic radiosurgery showed consistent pain response with % and approximately 90% local control rates (11). However, most of these studies reported a response rate using pain scores without considering the effects of analgesics. Analgesics are major confounding factor when measuring pain response of radiotherapy for bone metastasis. In order to promote consistency in clinical trials, the International Bone Metastases Consensus Group (IBMCG) reached a consensus for pain response in combination with the use of analgesics when reporting the end points of palliative radiotherapy (12). The purpose of this study was to evaluate the pain response using the criteria of IBMCG, local tumor control and toxicity of SBRT in the patients with spine metastasis. Materials and Methods Patient Selection From May 2009 to June 2010, 22 patients with 31 spinal metastatic lesions were treated with SBRT using helical tomotherapy (HT). SBRT was not applied to the patients who had developed cord compression with neurologic deficit, which needed surgical intervention. All data have been collected on a consistent treatment and follow-up protocol. The information was obtained from the medical records including age, gender, primary cancer diagnosis, number and location of spinal metastases, and primary disease status. Previous spine surgery or radiotherapy and dosages of analgesics before SBRT were registered. Stereotactic Body Radiotherapy The patients were immobilized in thermoplastic head-shoulder masks for the cervical spine. For thoracic and lumbar spine, a customized total body vacuum bag was used. Planning computed tomography (CT) data sets and structures were transferred to the HT planning workstation using DICOM RT, for treatment planning with a tomotherapy Hi-Art System, version 2.0 (TomoTherapy, Madison, WI). The gross tumor volume (GTV) was defined as a gross tumor mass or osteolytic lesion identified on the CT scan, hypermetabolic lesion on the PET-CT, high signal intensity lesion on T2 weighted magnetic resonance image (MRI) or enhanced lesion on the gadolinium T1 weighted MRI. MRI was performed for all patients. We divided vertebra into 5 parts as follows; vertebral body, pedicle, transverse process, lamina, and spinous process. The adjacent part to the GTV was defined as a clinical target volume (CTV). For example, if the GTV involved the pedicle and lateral part of vertebral body, then the CTV encompassed the vertebral body, pedicle, transverse process, and lamina. Spinous process, contralateral pedicle, and lamina were excluded from CTV. In postoperative treatment, the surgical Figure 1: Gross target volume, clinical target volume and typical iso-dose line for T9 lesion. Left; Red line: GTV, Blue line: CTV, Yellow line: spinal cord/ Right; Orange area: 110% of prescribed dose, Red area: 100% of prescribed dose, Light green area: 90% of prescribed dose, Green area: 80% of prescribed dose, Blue area: 70% of prescribed dose.

3 SBRT in Spine Metastasis 3 Table I Pain response criteria. Pain response Pain score OMED Complete response Reduction to zero and Stable or reduced Partial response Reduction by 2 scores or more and Stable or reduced Stable pain and Reduction by 25% or more Pain progression Increase by 2 scores or more and Stable or increased Increase by 1 score or stable and Increased by 25% or more Stable pain Not meet the above criteria Abbreviations: OMED: Oral morphine-equivalent dose. bed was included within the CTV. Planning target volume (PTV) was not delineated. The spinal cord was delineated as the critical structure based on the MRI from 6 mm above to 6 mm below the CTV. We did not include the whole spinal canal. We contoured the cord and added 2 mm safety margin. We prescribed radiation dose using simultaneous integrated boost technique. GTV was the boost volume. The dose for CTV was 80% of the prescribed dose for GTV. We set a goal of dose coverage for GTV and CTV that V100 of GTV and CTV received minimum D80% and for spinal cord that V0.1cc of spinal cord didn t exceed D120% (Figure 1). Fractionation was determined depending on the distance between the tumor and the spinal cord and intended to reduce the spinal cord toxicity. If there was 5 mm distance between the tumor and the spinal cord, we prescribed 16 Gy in a single fraction. If the tumor was close to the spinal cord, we prescribed 24 Gy in 3 fractions. In case of re-irradiation or cord compression, we prescribed 30 Gy in 5 fractions. The maximal dose to the spinal cord was limited to 10 Gy for 16 Gy in single fraction, 18 Gy for 24 Gy in 3 fractions or 30 Gy in 5 fractions. Megavoltage CT (MVCT) was undertaken for all patients before and after every fraction of the treatment. Using MVCT, interfraction movement was checked and corrected. We discussed the targeting accuracy and intrafraction patient motion in a previous study (13). Pain Assessment Patients were interviewed by a physician before the start of radiotherapy, at 2 weeks after SBRT, then every month for 3 months, and then every 3 months for 1 year. In some cases, especially as patients were in the terminal stages of their disease, we obtained follow-up information by telephone conversation with the patient or a caregiver. Pain was assessed using a numerical rating scale where 0 was no pain and 10 was pain as bad as you can imagine. The consumption of analgesics was recalculated into the daily oral morphine-equivalent dose (OMED) (14). The pain response was determined by IBMCG recommendation (12). This criteria take into account the potential confounding effect of pain medication based on the numerical rating scale of pain and OMED. Patients who did not meet IBMCG criteria for complete response, partial response, or pain progression were defined as stable pain. In the stable pain group, patients showed increased OMED (by 25% or more) and reduced pain (by one scores or more) (Table I). Spine metastatic lesions were classified as response group (complete response, partial response or stable pain) and pain progression. The Image follow-ups were performed by MRI or CT before the start of radiotherapy, at every month for 3 months after SBRT, and then every 3 months for 1 year. The performance status was assessed using the eastern cooperative oncology group (ECOG) performance status (15). All patients were evaluated for the problems related to the spine metastasis including neurologic deficit, spine instability and cord compression grade (16). Statistical Analysis Pain progression was defined as a change of response category directed to poor pain response. Local failure was defined as a progression of spine lesion based on image study. Estimates of pain progression-free survival, overall survival, and local recurrence free survival were calculated using the Kaplan- Meier method. Results Patient Characteristics The patient characteristics are presented in Table II. The median age was 56 years (range years). Performance status in most patients was less than ECOG 3 (67.7%). The most frequent primary tumor sites were lung (25.8%) or colorectum (25.8%). Fifty-two percent of the patients had progression of primary diseases or extra-spinal metastases. Spine and treatment characterics are shown in Table III. The spinal levels treated were cervical in 6 (19.4%), thoracic in 15 (48.4%), lumbar in 5 (16.1%), sacral in 1 (3.2%), cervical and thoracic in 3 (9.7%), and thoracic and lumbar in 1 (3.2%) lesion. Nineteen percent of the lesions showed spine instability and grade 4 cord compression was found in 6.5% of the lesions. Two lesions (6.5%) were previously irradiated and 5 lesions (16.1%) got surgery before SBRT. At baseline, sixty-one percent of the patients used opioids. None of them

4 4 Kim et al. Table II Patients characteristics. Table III Spine and treatment characteristics. Characteristics No.(%) No.(%) Age (years) Median (range) 56 (36-80) Gender Male 9 (40.9) Female 13 (59.1) Performance ECOG 0 5 (16.1) ECOG 1 12 (38.7) ECOG 2 4 (12.9) ECOG 3 10 (32.3) Primary tumor site Thyroid 4 (12.9) Lung 8 (25.8) Breast 3 (9.7) Stomach 2 (6.5) Hepatobiliary 4 (2.9) Colorectum 8 (25.8) Prostate 1 (3.2) Soft tissue 1 (3.2) Disease status out of RT target Non-PD 10 (32.3) PD 16 (51.6) Not assessed 5 (16.1) Abbreviations: ECOG: Eastern cooperative oncology group; RT: Radiotherapy; PD: Progression of disease. used bisphosphonates. Eighty-seven percent of the lesions received 24 Gy in 3 fractions, 9.7% received 30 Gy in 5 fractions, 3.2% received 16 Gy in a single fraction. Pain Response Until 3 months after SBRT, follow-up was available for all patients. At 2 weeks after SBRT, rapid decrease of mean pain score was observed and this score was maintained. However, median OMED didn t decrease significantly until 3 months after SBRT (Figure 2). The mean pain score 6 standard deviation was before SBRT, at 2 weeks, at 1 months, at 2 months, and at 3 months. The median OMED (range) was 34.5 mg ( ) before SBRT, 30.0 mg ( ) at 2 weeks, 30.0 mg ( ) at 1 month, 30.0 mg ( ) at 2 month, and 45.0 mg ( ) at 3 months. The response rates according to the IBMCG response criteria were presented in Figure 3. Maximum pain response was observed in 2 weeks after SBRT. The overall response rate for respond group (complete, partial response and the stable pain) was 100% at 2 weeks, 96.8% at 1 month and 3 months after SBRT. Survival Rate and Toxicity The median follow-up duration was 10 months (range 3-23 months). Overall pain progression was observed in 2 lesions Treated spine level C spine 6 (19.4) T spine 15 (48.4) L spine 5 (16.1) Sacrum 1 (3.2) C-T spine 3 (9.7) T-L spine 1 (3.2) Treated spine number 1 19 (61.3) 2 7 (22.6) 3 4 (12.9) 6 1 (3.2) Spine instability No 21 (67.7) Borderline 4 (12.9) Yes 6 (19.4) Cord compression grade* 0 16 (51.6) 1 7 (22.6) 2 5 (16.1) 3 1 (3.2) 4 2 (6.5) Dose scheme 16 Gy/1 fx 1 (3.2) 24 Gy/3 fx 27 (87.1) 30 Gy/5 fx 3 (9.7) Reirradiation No 29 (93.5) Yes 2 (6.5) Spine surgery before RT No 26 (83.9) Yes 5 (16.1) *Cord compression grade. 0: No visible tumor within the spinal canal. 1: Tumor in the spinal canal without dural involvement. 2: Tumor involving the dura. 3: Tumor compressing the spinal cord. 4: Tumor compressing the spinal cord with abnormal neurologic examination. (6.5%). Pain progression-free survival rate at 3 month and 6 months was 93.5%. Local progression-free survival rate at 3 month and 6 months was 93.5 and 81.3%, respectively. Overall progression of treated spine on image study was observed in 5 lesions (16.1%). The overall survival rate at 3 and 6 months was 93.5 and 64.5%, respectively. There was no severe acute toxicity. The grade 2 (Common Toxicity Criteria Adverse Events, version 3.0) esophagitis was observed in 2 patients with thoracic spine lesions close to the esophagus. There were no clinically detectable radiationinduced myelopathy. Compression fracture at the treated spine occurred in 6 lesions (19.4%). Among them, 1 lesion showed radiographic evidence of tumor progression, whereas 5 lesions showed vertebral body fractures without evidence of tumor progression.

5 SBRT in Spine Metastasis 5 Figure 2: Pain score and oral morphine-equivalent dose (OMED) before and after stereotactic body radiotherapy. Figure 3: Pain response rate using the criteria of International Bone Metastases Consensus Group. UE 5 unevaluable; PP 5 pain progression; SP 5 stable pain; PR 5 partial response; CR 5 complete response.

6 6 Kim et al. Discussion The present study demonstrates the effectiveness of SBRT for pain response using IBMCG criteria, which include both changes in the numerical rating scale of pain and in OMED. Two studies for palliative radiotherapy to bone metastasis applying the criteria of the IBMCG showed 49 and 72% response rate, respectively (17, 18). For the patients with spine metastasis using IBMCG criteria, radiotherapy-related response was found in 37% of the patients at 2 months after radiotherapy (19). In this study, the SBRT for painful spine metastasis attained excellent pain response with around 90% at 3 months. All patients were evaluated in a regular schedule. The mean pain score decreased rapidly at 2 weeks after SBRT. Pain progression-free survival rate at 3 and 6 months was 93.5%. Although there is no comparative group and pain has complex mechanism, excellent pain and local tumor control was achieved using SBRT for spine metastasis. Comparison data between SBRT and 3D-conformal radiation therapy (3D-CRT) that is still the standard of care is insufficient. There are no randomized trials proving the superiority of SBRT over 3D-CRT. Gerszten et al. (20) reported a systemic review of conventional radiotherapy and radiosurgery for metastatic spine disease. They reported the mean local control rate of conventional radiotherapy and radiosurgery was 77% (range 61-89%) and 90% (range %), respectively. They concluded that a more durable response and local control could be made with radiosurgery, regardless of radioresistant histology. Chang et al. (21) studied patterns of failure after SBRT for spinal metastasis. They found two major recurrences: 1) the adjacent site to the treated spine, and 2) the epidural space. They suggested consideration of routine treatment of the pedicle and posterior part of the spine. However, in this study, there were a total of 5 lesions with progression that occurred in the radiation field, not at the adjacent site. Our target volume was similar to a consensus guideline reported by the International Spine Radiosurgery Consortium Consensus (22) and there was no marginal failure. In the IBMCG response criteria, meaningful pain score was addressed by 2 points change after radiotherapy (12). If the pain score was decreased by 1 score with no increased OMED or the pain was reduced by 2 score or more with increased OMED (by 25% or more), this lesion could not be classified into any response group. Zaikova et al. (19) pointed the limitation of the IBMCG criteria. Among 229 patients with painful spine metastases, 19% of the patients could not be classified by formal criteria. We categorized these lesions into stable pain, which ranged 3-40% according to evaluation time. Although the effect of radiotherapy on stable pain could not be identified clearly, this group was defined as pain responding group after SBRT. The most feared complication after radiotherapy to spine is radiation induced myelopathy. Despite possibility of underreported myelopathy due to progressive diseases or mortalities, there was no myelopathy in our protocol. The maximal dose limitation to spinal cord (10 Gy in single fraction or 18 Gy in 3 or more fractions) and isocenter verification using MVCT were safe. Compression fracture after high dose radiotherapy to spine has began to emerge as a potential treatment related toxicities (23). However, data is not plentiful regarding the risk of vertebral fracture after radiotherapy to the spine. Rose et al. (24) studied 62 patients undergoing single fraction image-guided intensitymodulated radiation therapy (IG-IMRT) to spinal metastases and reported the risk factors of fracture after IG-IMRT. They found that lytic disease involving more than 40% of the vertebral body and location at or below T10 confer a high risk of fracture. Lesions located between T10 and the sacrum were 4.6 times more likely to fracture than were lesions above T10. Lytic lesions were 6.8 times more likely to fracture than were sclerotic and mixed lesions. The fracture progression was caused by the combined effects of local high-dose radiation delivery and the cumulative loading effect on structurally compromised bone. In this study, compression fracture at the treated spine occurred in 6 lesions (19.4%). Among them, 4 compression fracture lesions were below T10. Lytic diseases involving more than 40% of the vertebral body were 5 of 6 lesions. More concern for compression fracture of spine is needed in high dose radiotherapy to metastatic spine lesions. There exists an inherent uncertainty to evaluate pain response for radiotherapy. Chow et al. (12) and the IBMCG recommended a run-in period for analgesic adjustment to avoid confounding increases in analgesics. It allows a more reliable baseline pain scoring before radiotherapy. During follow-up period, variable pain can be caused by multiple metastatic sites, and frequently analgesics are used. In this study, the median OMED didn t decreased significantly until 3 months after SBRT. This may reflect sub-optimal doses of analgesics due to omission of run-in period or subsequent analgesics for newly developed pain after SBRT. However, run-in period for analgesics adjustment is not feasible to all patients suffering from pain. Despite this limitation, our results show promising pain response rate considering pain score and analgesics. Several literatures have provided possibility for SBRT as a primary treatment option for spine metastasis (5, 25-28). However, issues such as proper radiation dosage, target delineation, accurate treatment planning and delivery, lack of long-term follow-up data remain as the main questions to be

7 SBRT in Spine Metastasis 7 investigated. Radiation therapy and oncology group (RTOG) is conducting a phase II/III study (RTOG 0631) utilizing single fraction SBRT for 1-3 spinal metastases ( clinicaltrials/protocoltable/studydetails.aspx?study50631) (29). The phase II component will determine the feasibility of successfully delivering image-guided radiosurgery/sbrt for spine metastases in a cooperative group setting. The phase III component will determine whether image-guided radiosurgery/sbrt (single dose of 16 Gy) improves pain control as compared to conventional external beam radiotherapy (single dose of 8 Gy) in a randomized controlled fashion. Besides, the variables such as life expectancy, performance status, risk of spinal cord compression and compression fracture after radiotherapy should be considered in further SBRT study. In summary, excellent pain response rates was obtained by the SBRT for spine metastasis. In addition, there was no severe acute toxicity or myelopathy. SBRT seems to be a safe and effective treatment modality that can be used to achieve favorable local tumor control and palliation of pain associated with spine metastasis. Acknowledgments This study was supported by a grant from the Korea Healthcare Technology R&D Project, the Ministry for Health, Welfare & Family Affairs, and the Republic of Korea (A084120). Conflict of Interest None. References 1. Wong, D. A., Fornasier, V. L., MacNab, I. Spinal metastases: the obvious, the occult, and the impostors. Spine (Phila Pa 1976) 15, 1-4 (1990). 2. Neeta Pandit-Taskar, M., Maria Batraki, B., Chaitanya, R. Divgi, M. Radiopharmaceutical therapy for palliation of bone pain from osseous metastases. The Journal of Nuclear Medicine 45, (2004). 3. Petersen, C. M., Rundquist, P. J. Validation of spinal motion with the spine reposition sense device. J Neuroeng Rehabil 6, 12 (2009). 4. Sheehan, J. P., Shaffrey, C. I., Schlesinger, D., Williams, B. J., Arlet, V., Larner, J. 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