Symptom Management and Supportive Care

The Metastatic Spine Disease Multidisciplinary Working Group Algorithms ADAM N. WALLACE,a CLIFFORD G. ROBINSON,b JEFFREY MEYER,e NAM D. TRAN,f,g,h AFSHIN GANGI,i MATTHEW R. CALLSTROM,j SAMUEL T. CHAO,l BRIAN A. VAN TINE,c JONATHAN M. MORRIS,j BRIAN M. BRUEL,k JEREMIAH LONG,a ROBERT D. TIMMERMAN,e JACOB M. BUCHOWSKI,d JACK W. JENNINGSa a

Mallinckrodt Institute of Radiology, bDepartment of Radiation Oncology, cDepartment of Internal Medicine, and dDepartment of Orthopaedic Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA; eDepartment of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas,Texas, USA; fNeurooncology Program, H. Lee Moffitt Cancer Center and Research Institute, gDepartment of Neurosurgery, and hDepartment of Orthopedics, University of South Florida College of Medicine,Tampa, Florida, USA; iDepartment of Interventional Radiology, University of Strasbourg School of Medicine, Strasbourg, France; jDepartment of Radiology, Mayo Clinic, Rochester, Minnesota, USA; kDepartment of Anesthesiology and Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA; lDepartment of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio, USA Disclosures of potential conflicts of interest may be found at the end of this article.

Key Words. Spine x Metastatic x Radiotherapy x Ablation techniques x Vertebroplasty x Kyphoplasty

ABSTRACT The Metastatic Spine Disease Multidisciplinary Working Group consists of medical and radiation oncologists, surgeons, and interventional radiologists from multiple comprehensive cancer centers who have developed evidence- and expert opinionbased algorithms for managing metastatic spine disease. The purpose of these algorithms is to facilitate interdisciplinary referrals by providing physicians with straightforward

recommendations regarding the use of available treatment options, including emerging modalities such as stereotactic body radiation therapy and percutaneous tumor ablation. This consensus document details the evidence supporting the Working Group algorithms and includes illustrative cases to demonstrate how the algorithms may be applied. The Oncologist 2015;20:1205–1215

Implications for Practice: The Metastatic Spine Disease Multidisciplinary Working Group algorithms can facilitate interdisciplinary referrals by providing physicians with straightforward recommendations regarding available treatment options, including emerging modalities such as stereotactic body radiation therapy and percutaneous tumor ablation.

INTRODUCTION spinal cord compression (MESCC) [7–9]. Pain and neurologic deficits resulting from these complications lead to impaired mobility, loss of functional independence, and overall decreased quality of life [10]. Management of metastatic spine disease requires multidisciplinary input. Treatment options not only include continually evolving medical therapy regimens, surgical techniques, and radiation technologies, but also emerging minimally invasive interventions. Two of the most recent therapeutic advances include stereotactic body radiation therapy (SBRT) and percutaneous tumor ablation. Stereotactic body radiation therapy uses advances in radiation dose delivery systems to treat spinal tumors with higher doses of radiation while minimizing dose to the spinal cord. As a result, SBRT has the potential to produce more durable pain relief and local control of spinal metastases, including radiation-resistant tumor

Correspondence: Adam N. Wallace, M.D., Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, Saint Louis, Missouri 63110, USA.Telephone: 608-347-0294; E-Mail: [email protected] Received March 5, 2015; accepted for publication July 17, 2015; published Online First on September 9, 2015. ©AlphaMed Press 1083-7159/2015/$20.00/ 0 http://dx.doi.org/10.1634/theoncologist.2015-0085

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More than 1.4 million patients are diagnosed with cancer annually in the United States, 70% of whom will develop bone metastases [1]. The spine is the most common site of osseous metastatic disease because of several pathophysiologic factors, including the presence of vascular red marrow in adult vertebrae and communication of deep thoracic and pelvic veins with valveless vertebral venous plexuses [2, 3]. Tumor cells within the spine produce cytokines that induce osteoclast-mediated osteolysis and the release of growth factors that promote tumor growth [4]. Thus, a cycle is established resulting in osseous destruction [5]. Some primary tumors, such as prostate cancer, also stimulate osteoblasts, which results in sclerotic metastases [6]. Patients most commonly presentwithuncomplicatedspinalpain;however, disease progression renders patients at risk for pathologic fracture, with or without mechanical instability, and metastatic epidural

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histologies [11]. Percutaneous tumor ablation is performed by accessing the vertebral body under imaging guidance and generating cytotoxic temperatures that cause tumor necrosis. These procedures can be performed in an outpatient setting under conscious sedation, require minimal recovery, and do not hinder or delay adjuvant radiation or chemotherapy [12–15]. Physicians involved in the care of patients with metastatic spine diseaseshouldbefamiliar withthesetreatments andreferpatients appropriately based on best available evidence. The Metastatic Spine Disease Multidisciplinary Working Group consists of medical and radiation oncologists, surgeons, and interventional radiologists from multiple comprehensive cancer centers who have developed evidence- and expert opinion-based algorithms for managing metastatic spine disease (Fig. 1). The purpose of these algorithms is to facilitate interdisciplinary referrals by providing physicians with straightforward recommendations regarding the use of available treatment options, including SBRT and percutaneous tumor ablation.This consensus document details the evidence supporting the Working Group algorithms, grades each therapeutic recommendation according to the Oxford Center for Evidence-Based Medicine system [16], and includes illustrative cases to demonstrate how the algorithms may be applied. Lastly, areas of management uncertainty that should be addressed with future prospective clinical trials are briefly discussed.

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Theprimarygoal oftreatingasymptomaticspinal metastases isthe prevention of skeletal-related events (SREs), which include bone pain,pathologicvertebralcompressionfracture(VCF),andMESCC. For this indication, osteoclast inhibition with bisphosphonates is the mainstay of medical therapy (grade A). A meta-analysis of 34 studies showed that in patients with metastatic breast cancer, intravenous bisphosphonates reduced the overall risk of a SRE by 17% (relative risk, 0.83; 95% confidence interval [CI], 0.72–0.95; p 5 .008) [17]. Similarly, meta-analysis of 1,955 patients with prostate cancer from 10 controlled studies found that bisphosphonates lowered rates of SREs by 5.2% (odds ratio, 0.79; 95% CI 0.62–1.00;p5.05)[18].Inpatientswithlungcancer,ameta-analysis of 6 studies with 1,170 patients showed a 19% reduction in the risk of developing a new SRE within the first 2 years of bisphosphonate treatment (relative risk, 0.81; 95% CI, 0.67–0.97) [19]. Denosumab is a more recently developed osteoclast inhibitor. This fully human monoclonal antibody binds to and inhibits activation of nuclear factor kB ligand, which regulates osteoclast formation, function, and survival. In a study of 2,046 patients with advanced breast cancer randomized to receive monthly doses of 120 mg of subcutaneous denosumab or 4 mg of the intravenous bisphosphonate zoledronic acid, denosumab significantly delayed the time to first on-study SRE by 18% (hazard ratio [HR], 0.82; 95% CI, 0.71–0.95; p 5 .01 for superiority) [20]. In a similar study of 1,904 patients with metastatic castrationresistant prostate cancer (CRPC), the median time to first SRE was 20.7 months with denosumab therapy compared with 17.1 months with zoledronic acid (HR, 0.82; 95% CI, 0.71–0.95; p 5 .08 for superiority) [21]. Finally, in a randomized study of 1,776 patients with solid tumors, including non-small cell lung cancer, the median time to first SRE was 20.6 months with denosumab therapy compared with 16.3 months with zoledronic acid (HR, 0.84; 95% CI, 0.71–0.98; p = .0007 for noninferiority; p = .06 for superiority ) [22].

Metastatic Spine Disease Algorithms For patients with multiple spinal metastases from CRPC, systemic radionuclide therapy with radium-223 (223Ra) is also recommended for prevention of SREs (grade A). 223Ra is a calcium analog that is incorporated directly into calcium hydroxyapatite and emits radioactive a-particles [23]. Alpharadin in Symptomatic Prostate Cancer was an international double-blind, placebocontrolled randomized trial that compared 223Ra with placebo in 809 patients with CRPC bone metastases. Patients treated with 223Ra had longer times to a SRE (13.6 vs. 8.4 months; HR, 0.610; 95% CI, 0.461–0.807; p 5 .00046) and improved overall survival (14.0 vs. 11.2 months; HR, 0.695; 95% CI, 0.552–0.875; p = .00185) [24]. Recommendations regarding the use of adjuvant therapies to achieve local tumor control in asymptomatic patients depend on patient-specific factors, including life expectancy, performance status, and tumor burden.The relative accuracy with which different prognostic scoring systems estimate life expectancy is controversial, but the Tokuhashi and Tomita systems are commonly used [25]. Performance status is measured with the validated and widely used Karnofsky Performance Scale [26]. Observation is recommended for patients with asymptomatic spinal metastases and life expectancy less than 6 months, poor performance status, or widespread visceral metastatic disease, because therapy is unlikely to improve survival. The exception is patients with radiographic progression of tumor into the epidural space and sufficiently long life expectancy to be at risk for spinal cord compression. In such cases, conventional external beam radiation therapy (cEBRT) may be considered (grade B) [10]. For patients with life expectancy greater than 6 months, good performance status, and few visceral metastases, observation and medical management is a reasonable option; however, more aggressive therapies aimed at preventing a SRE and achieving local tumor control may also be considered for two reasons. First,the relative impact of a SRE on these patients’ quality of life is much higher. Second, achieving tumor control with local therapies may enable a chemotherapy-free interval or extend the utility of an existing chemotherapy. Conventional external beam radiation therapy is the standard adjuvant therapy for local control of spinal metastases [10] (grade A); however, retrospective and prospective case series have reported impressive rates of local tumor control using SBRT [27]. In a phase I/II study that included 63 patients with 74 spinal metastases treated with SBRT (30 Gy in 5 fractions or 27 Gy in 3 fractions), the actuarial 1-year rate of freedom from imagingdocumented tumor progression was 84%, and no radiationinduced neuropathy or myelopathy was observed during a median follow-up of 24.3 months [28]. In another prospective series, single-fraction SBRT (mean, 20 Gy; range, 12.5–25 Gy) used as a primary treatment (i.e., no prior cEBRT) achieved a 90% (59 of 65) overall rate of local tumor control, including rates of 75% and 100% in patients with melanoma and renal cell carcinoma metastases, respectively. When used as a salvage therapy to treat radiographic tumor progression after cEBRT, the local tumor control rate was 88% (45 of 51). No radiationrelated complications were reported during a median followup of 21 months (range, 3–53 months) [11]. Most patients treated with SBRT in these and other seminal studies had only one or two spinal metastases [29]; therefore, the Working Group generally recommends SBRT for patients with a maximum of three

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Figure 1. Metastatic Spine Disease Multidisciplinary Working Group Algorithms for managing asymptomatic spinal metastases (A), uncomplicated painful spinal metastases (B), spinal metastases complicated by stable (C) and unstable (D) fractures, and metastatic epidural spinal cord compression (MESCC) (E). Treatment strategies are listed in descending order of recommendation. The letter in parentheses after each therapy denotes the grade of that therapeutic recommendation according to the Oxford Center for Evidencebased Medicine Levels of Evidence grading system [16]. Life expectancy may be assessed by a number of scoring systems; the Tokuhashi and Tomita systems are commonly used [25].The Karnofsky Performance Scale is a validated method for measuring performance status [26]. Conventional external beam radiation therapy is only recommended for asymptomatic patients with life expectancy of less than 6 months, poor performance status, or widespread visceral metastases when radiographic tumor progression portends MESCC. Likewise, cEBRT is recommended for patients with a pathologic fracture and life expectancy of less than 6 months, poor performance status, or widespread visceral metastases only when they are at risk for MESCC or have persistent pain after vertebral augmentation. Adjuvant radiation therapy, ablation, and vertebral augmentation may be considered for asymptomatic patients with life expectancy greater than 6 months, good performance status, and few visceral metastases who opt for an aggressive treatment plan. When SBRT is listed as preferable to cEBRT (i.e.,“SBRT . cEBRT”), cEBRT is recommended when SBRT is unavailable or contraindicated for reasons not included in the algorithms.When cEBRT is listed as preferable to SBRT (i.e.,“cEBRT . SBRT”), SBRTmay be considered for the treatment of three or fewer spinal metastases that do not adequately respond to cEBRT.Vertebral augmentation may be considered for prevention of radiation-induced vertebral compression fracture (e.g., “SBRT . EBRT 6 VA”). Algorithms assume optimization of systemic chemotherapy. First-line therapies for pain palliation include oral analgesics and nonpharmacologic interventions for chronic pain [41]. Osteoclast inhibitors and systemic radionuclide therapy are recommended for prevention of skeletal-related events and pain palliation, as indicated [17–22]. Abbreviations: cEBRT, conventional external beam radiation therapy; LE, life expectancy; mo, months; PS, performance status; SBRT, stereotactic body radiation therapy; VA, vertebral augmentation.

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spinal metastases (grade C) and recommends cEBRT for patients with more than three spinal metastases (grade A). However, SBRTmay be considered in patients with more than three spinal metastases who have failed cEBRT and have three or fewer progressive tumors at imminent risk of causing MESCC (grade C). While retreatment of such tumors with cEBRT is often limited because of the cumulative tolerance of the spinal cord, the precision of SBRT enables the safe delivery of biologically effective doses [30–33]. Percutaneous tumor ablation may be considered when spinal metastases do not respond to radiation therapy, the cumulative tolerance of the spinal cord to radiation has been reached, or inclusion criteria in clinical trials preclude radiation therapy (grade C) [12, 15, 34–36]. In a multicenter retrospective study of spinal metastases treated with radiofrequency ablation (RFA), the local control rate was 77% (10 of 13) after median imaging follow-up of 92 days [15]. In another retrospective case series of osseous metastases treated with cryoablation, a local control rate of 97% (30 of 31) was reported after median follow-up of 10 months (range, 1–24 months) [12].These results are concordant with the experience of these authors (Figs. 2, 3). Additionally, in a large multicenter retrospective case series of 128 radiofrequencyablated spinal metastases, no permanent thermal nerve injuries or other serious complications were reported [15]. Similarly, no major complication was reported in a single-center case series of 31 spinal metastases treated with cryoablation [12]. Therefore, given the low riskandpotential forlocal tumorcontrol, ablation is a reasonable therapeutic option when radiation therapy cannot be offered or is ineffective. An important exception is patients with epidural tumor extension. Ablation is not contraindicated when the posterior vertebral body cortex is eroded by tumor; however, ablation cannot be performed safely when epidural tumor abuts or surrounds the spinal cord [13]. These patients should instead be referred for surgical intervention because MESCC may be imminent.

Given the low risk and potential for local tumor control, ablation is a reasonable therapeutic option when radiation therapy cannot be offered or is ineffective.

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Vertebral augmentation may be considered for fracture prophylaxis after radiation therapy or percutaneous ablation for local tumor control, especially in patients with relatively good prognoses. The rate of pathologic VCF at sites treated with cEBRT is approximately 3% [37]but rangesfrom11% to39% after SBRT with median times to fracture of 2–25 months [38]. However, the benefits of prophylactic vertebral augmentation before or after radiation therapy have not been validated. Therefore, the Working Group does not recommend routine use of vertebral augmentation for fracture prophylaxis, but it is a reasonable consideration for patients with longer life expectancies or who are otherwise at higher risk of VCF owing to extensive osteolytic tumor or osteoporosis (grade D) [38]. Data evaluating the benefit of ablation with and without vertebral augmentation are similarly lacking. However, vertebral augmentation can be performed at the same time as ablation through the same percutaneous access cannula with

Metastatic Spine Disease Algorithms minimal increased risk and no increase in recovery duration [13, 15, 39]. In the case series by Anchala et al. [15], vertebral augmentation was performed after 96% (92 of 96) of spinal RFAs without symptomatic extravasation, and two of the four vertebrae that were not augmented subsequently fractured 3 and 12 months after ablation. Therefore, given the low risk and potential benefit, it is recommended that ablation be followed with vertebral augmentation in nearly all cases (grade D).

UNCOMPLICATED PAINFUL SPINAL METASTASES Uncomplicated spinal metastases are defined as those not associated with pathologic VCF or MESCC. The pathophysiology of uncomplicated metastatic bone pain is thought to be due to biochemical stimulation of endosteal nociceptors by periosteal stretching, inflammation, and tumor-derived cytokines [40]. First-line therapies for pain palliation include oral analgesics administered according to one of several available evidence-based clinical guidelines and nonpharmacologic interventions for chronic pain, such as rehabilitation care and psychological coping strategies (grade A) [41]. Bisphosphonates are also recommended for pain palliation, as well as for decreasing the risk of SREs (grade A). In patients with lung cancer, meta-analysis of 6 studies with 1,170 patients showed that adding bisphosphonates to standard treatments resulted in better pain control [19]. Similar results were observed in meta-analyses of patients with breast and prostate cancer [18, 42]. Conventional external beam radiation therapy is the standard of care for painful spinal metastases that are incompletely palliated with the aforementioned treatments (grade A). A meta-analysis of 25 trials found overall and complete pain response rates of 60% (1,696 of 2,818) and 23% (620 of 2,641), respectively, 12 weeks after treatment with a single fraction of 8 Gy. The main primary sites represented in these studies were prostate, breast, and lung [37]. The American Society for Radiation Oncology recommends 8 Gy single-fraction therapy for palliation of metastatic bone pain, because multiple meta-analyses comparing single and multifraction therapy have shown no palliative difference, and single-fraction therapy is less expensive and more convenient for patients [37, 43]. Stereotactic body radiation therapy is recommended for patients with life expectancy greater than 6 months, good performance status, and few visceral metastases to maximize the likelihood of achieving local tumor control in addition to pain relief (grade C). In the previously cited prospective study of single-fraction SBRT (mean, 20 Gy; range, 12.5–25 Gy), long-term improvement of pain was reported by 86% (290 of 336) of patients overall, and 96% and 94% of patients with melanoma and renal cell carcinoma metastases, respectively [11]. As for patients with asymptomatic disease, SBRT is generally only recommended for patients with a maximum of three spinal metastases to remain concordant with the existing literature [29]. However, SBRT may be considered in patients with more than three spinal metastases who have three or fewer painful spinal metastases that do not respond, incompletely respond, or become recurrently painful after cEBRT and cannot be retreated with cEBRT because of spinal cord dose constraints (grade C).

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Figure 2. Images from a 39-year-old man with neurofibromatosis and stage IV (T1b, N1, M1) malignant peripheral nerve sheath tumor. (A, B): Axial computed tomography (CT) images show a right lower lobe pulmonary metastasis (white arrows) and lytic T8 vertebral body metastasis (black arrows). The patient was enrolled in a systemic chemotherapy clinical trial. (C, D): Axial CT images obtained 3 months later show an interval decrease in the size of the pulmonary metastasis but enlargement of the T8 metastasis. (E, F): Sagittal short tau inversion recovery (STIR) (E) and postcontrast, fat-suppressed, T1-weighted (F) magnetic resonance imaging (MRI) again demonstrate the T2-hyperintense, enhancing T8 metastasis (white arrowheads). Inclusion criteria of the systemic chemotherapy clinical trial, to which the visceral metastases were responding, precluded radiation therapy of the T8 metastasis. Therefore, the T8 metastasis was radiofrequency ablated. (G, H): Anteroposterior (G) and lateral (H) fluoroscopic images show bipedicular working cannulae. The navigational ablation probe has been placed through the left cannula and is curving into the posterior central vertebral body (dotted white arrows). (I, J): Sagittal STIR (I) and postcontrast, fat-suppressed, T1-weighted (J) MRI obtained 6 months later show signal void corresponding to cement in the ablation cavity (white dots) and T2-hyperintense, enhancing granulation tissue surrounding the ablation cavity (white block arrows).There is a new T2-hyperintense, enhancing metastasis involving the posterior elements of T7 with extension into the epidural space (black dots). (K, L): Axial (K) and sagittal (L) 18F-fluorodeoxyglucose (FDG) positron emission tomography-CT also obtained 6 months after radiofrequency ablation shows the new hypermetabolic T7 metastasis (black dot) but no increased FDG uptake in the T8 vertebral body.

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Therefore, although the efficacy of percutaneous ablation is only supported by level 4 evidence, it is safe and reasonable to use ablation as a salvage therapy when there is no other option (Fig. 3).

PATHOLOGIC VERTEBRAL COMPRESSION FRACTURE WITH OR WITHOUT SPINAL INSTABILITY Spinal metastases increase bone resorption, which predisposes to pathologic VCF. In the placebo arms of several phase III trials, pathologic VCF occurred in 39% of patients with breast cancer, 22% of patients with prostate cancer, and 22% of patients with lung cancer or other solid tumors during 12, 15, and 21 months of follow-up, respectively [54]. Surgery is the standard of care for pathologic VCF complicated by spinal instability (grade C). The Working Group subscribes to the Spine Oncology Study Group definition of spinal instability as the “loss of spinal integrity as a result of a neoplastic process that is associated with movement-related pain, symptomatic or progressive deformity and/or neural compromise under physiological loads” [8].The Spine Instability Neoplastic Score (SINS) is an 18-point scoring system based on this definition that categorizes fractures as stable (0–6 points), potentially unstable (7–12 points), or unstable (13–18 points). Factors that increase the ©AlphaMed Press 2015

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Systemic radionuclide therapy is also an option for palliation of multifocal osteoblastic metastases, particularly hormoneresistant prostate and breast cancer (grade A). These agents are incorporated into bone matrix at sites of increased osteoblastic activity and emit radioactive a- or b-particles that reduce tumor volume and decrease production of painsensitizing cytokines [44]. The palliative efficacy of various systemic radionuclides have been demonstrated in multiple systematic reviews [24, 45–47]. For example, in a systematic review of 16 prospective studies evaluating Strontium-89, the mean overall and complete response rates were 76% and 32%, respectively, with a response duration of up to 15 months [45]. Percutaneous tumor ablation is recommended for pain palliation when radiation therapy cannot be offered or is incompletely effective (grade C) [12, 13, 15, 34, 48–53]. In a retrospective study of 128 radiofrequency-ablated spinal metastases, patients reported a mean preprocedure pain score of 7.51/10 6 2.46 and decreased mean pain scores 1 week (1.73/10 6 2.28; p , .0001), 1 month (2.25/10 6 2.44; p , .0001), and 6 months (1.75/10 6 2.62; p 5 .009) after treatment [15]. In a recent study of 31 cryoablated spinal metastases, patients with a preprocedure median pain score of 8 6 1 reported a postprocedure median pain score of 3 6 1 at 1-week, 1-month, and 3-month follow-up (p , .001) [12].

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Figure 3. Images from a 51-year-old woman with renal cell carcinoma (clear cell type), stage IV (T2a, NX, M1) with midback pain. (A): Sagittal computed tomography image shows osteolytic metastases involving the T11, L2, L3, and L5 vertebral bodies (white block arrows). Her life expectancy was greater than 6 months, her performance status was excellent, and she had no other evidence of metastatic disease; however, she had more than three spinal metastases. She was treated with conventional external beam radiation therapy to the thoracolumbar spine, but 3 months later her back pain continued to worsen. (B, C): T1- (B) and T2-weighted (C) magnetic resonance imaging (MRI) of the lower thoracic spine shows interval enlargement of the T11 metastasis and a new T12 metastasis (white arrowheads) with epidural extension, but no clinical or radiographic evidence of spinal cord compression. Her life expectancy was still greater than 6 months, her performance status remained excellent, and she still had no visceral metastases. Because the cumulative tolerance of the lower thoracic spinal cord had been reached, she could not receive additional radiation therapy; therefore, radiofrequency ablation and vertebral augmentation of T11 and T12 were performed, after which her back pain resolved. (D, E): Sagittal T1- (D) and T2-weighted (E) MRI obtained 3 months later shows signal void in the T11 and T12 vertebral bodies corresponding to cement (white asterisks) with retraction of previously seen epidural tumor. Fatty replacement of the T10 and L1 vertebral body marrow is related to prior radiation therapy.

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SINS are mechanical pain, osteolytic lesions, involvement of junctional levels (e.g., T11–L1), subluxation or translation of the affected level, more than 50% vertebral body collapse, and involvement of posterolateral spinal elements (Fig. 4). Surgical referral is recommended for SINS $ 7 points [8, 9]. The surgeon will then weigh the relative risks of instability versus surgical stabilization. Vertebral augmentation is recommended for first-line palliation of pain related to stable pathologic VCF (grade B) [55]. The Cancer Patient Fracture Evaluation study was a multicenter randomized controlled trial that included 117 patients with neoplastic VCFs treated with vertebral augmentation versus non-surgical management.The primary endpoint was back-specific functional status measured by the RolandMorris disability questionnaire (RDQ; 24-point scale). At 1-month follow-up, the mean RDQ score in the vertebral augmentation group improved by 8.3 points (95% CI, 6.4–10.2; p , .0001) compared with 0.1 points (95% CI, 0.8–1.0; p 5 .83) in the control group [55]. Vertebral augmentation is also recommended for patients with spinal instability who are not

surgical candidates because of short life expectancy, poor performance status, widespread visceral metastatic disease, or other surgical contraindications (grade D). Although vertebral augmentation will not entirely restore spinal stability, it may provide some pain relief [55]. Recommendations regarding adjuvant radiation therapy and percutaneous tumor ablation depend on the patient’s clinical status. For patients with life expectancy of less than 6 months, poor performance status, or visceral metastatic disease, cEBRT is only recommended when painful stable fractures are incompletely palliated with vertebral augmentation or to attenuate tumor progression in the setting of impending MESCC (grade B) [10]. For patients with life expectancy greater than 6 months, good performance status, and few visceral metastases, adjuvant combination radiation therapy and ablation are recommended to maximize the likelihood of local tumor control (SBRT, grade C; cEBRT, grade A; ablation, grade C) (Fig. 5) [14]. As with uncomplicated disease, recommendations regarding cEBRT versus SBRT are based on the number of spinal metastases [29]. Whether

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Figure 4. Images from a 64-year-old man with stage IV (T3a, NX, M1b) castration-resistant prostate cancer and low back pain previously treated with conventional external beam radiation therapy and systemic radionuclide therapy. (A, B): Sagittal computed tomography (A) and T2-weighted magnetic resonance imaging (B) of the thoracolumbar spine show diffuse osteoblastic metastases and a pathologic fracture of L1 (white arrows).The Spine Instability Neoplastic Score is 11 because there is more than 50% vertebral body collapse (3 points) of a junctional level (3 points) that is causing focal kyphosis (2 points) and mechanical back pain (3 points) [8, 9]. There is also moderate spinal canal stenosis caused by fracture fragment retropulsion. Despite the patient’s widespread osseous metastatic disease, his life expectancy was still greater than 6 months, his performance status was good, and he had no visceral metastases. (C): Lateral radiograph shows postsurgical changes of L1 corpectomy and posterior spinal fusion from T11 to L3 with improved sagittal spinal alignment.

METASTATIC EPIDURAL SPINAL CORD COMPRESSION Metastatic epidural spinal cord compression occurs in 10%– 20% of patients with spinal metastases [7]. Neural compromise is most often due to posterior extension of vertebral body tumor and affects the thoracic cord in 60%–80% of cases [1]. Of patients with MESCC, 90% present with pain, which usually precedes the onset of neurological deficits by several weeks [58]. Multiple studies have shown an association between loss of ambulation and shortened life expectancy [10]. Combination surgery and cEBRT is the standard of care for treatment of MESCC (surgery, grade A; cEBRT, grade A) (Fig. 6). Kim et al. [10] performed a meta-analysis of 33 studies with 2,495 patients with MESCC and found that among nonambulatory patients, 64% were able to ambulate

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Patients with slowly progressive, incomplete neurological deficits and spinal cord compression caused by bone alone (rather than tumor) are most likely to benefit from surgery. In contrast, rapidly progressive neurological symptoms or complete deficits lasting more than 12 hours portend a low likelihood of significant recovery.

after surgical intervention compared with 29% of patients treated with radiation therapy alone (p # .001). Similar results were seen with paraplegic patients, 42% of whom regained ambulation after surgery compared with 10% of patients treated with radiation therapy alone (p # .001). These results are likely due to newer surgical techniques that enable more complete spinal cord decompression through direct removal of bone and tumor and advances in spinal instrumentation that permit immediate restoration of spinal stability [59]. When patients present with neurological deficits, corticosteroid therapy should be initiated and surgery performed as soon as possible to prevent further neurological deterioration [1]. Patients with slowly progressive, incomplete neurological deficits and spinal cord compression caused by bone alone (rather than tumor) are most likely to benefit from surgery. In contrast, rapidly progressive neurological symptoms or complete deficits lasting more than 12 hours portend a low likelihood of significant recovery [58]. Unfortunately, the majority of patients with MESCC are not candidates for surgery. In these cases, radiation therapy alone is still beneficial, as seen in the meta-analysis by Kim ©AlphaMed Press 2015

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combination ablation and radiation therapy achieves better local tumor control than radiation therapy alone has yet to be tested; however, ablation can be performed at the same time as vertebral augmentation through the same percutaneous access cannula with minimal increased risk and no increase in recovery duration [13, 15, 39]. In a retrospective series by Greenwood et al. [14], combination vertebral augmentation, RFA and radiation therapy achieved radiographic local tumor control rates of 92% (12 of 13) and 100% (10 of 10) at 3- and 6-month follow-up, respectively, despite systemic disease progression. Ablation may also be considered for cavity creation prior to vertebral augmentation when tumor has eroded through the posterior vertebral body cortex, because cement instillation can displace tumor into the epidural space [56, 57].Wallace etal. [13] performed combination RFA and vertebral augmentation of 32 vertebrae with tumor erosion of the posterior vertebral body cortex and reported no instances of symptomatic tumor displacement or other major complication.

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Figure 5. Images from a 63-year-old man with stage IV (T4a, N3, M1c) chest wall desmoplastic melanoma and lower back pain. (A–C): Axial computed tomography (CT) (A) and positron emission tomography (PET)-CT (B) images show a lytic L5 metastasis containing 18 F-fluorodeoxyglucose (FDG)-avid soft tissue (white arrows), and a corresponding sagittal CT image (C) shows an associated pathologic compression fracture (white arrowhead). The patient’s life expectancy was greater than 6 months, his performance status was good, he had no visceral metastatic disease, and he had only one other asymptomatic T4 spinal metastasis. Also, melanoma is a typically radiationresistant histology. Therefore, he underwent unfractionated stereotactic body radiation therapy (21 Gy) followed by radiofrequency ablation and vertebral augmentation. (D–F): Axial (D) and sagittal (E) CT images show the target volume of radiation therapy, and a lateral fluoroscopic image (F) shows the radiofrequency ablation probe within the tumor. His pain subsequently improved to the point that it did not limit his daily living. (G): PET-CTobtained 3 months later shows no FDG uptake in the treated L5 lesion to suggest recurrent or residual tumor.

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et al. [10] and other systematic reviews (grade A). A wide range of cEBRT schedules have been used for treatment of MESCC, none of which has been shown to be superior in systematic reviews [60]. Stereotactic body radiation therapy should only be performed in the setting of a clinical trial on highly selected patients with life expectancy greater than 6 months, good performance status, few visceral

metastases, and pretreatment 4/5 motor strength [61]. Additionally, centers performing SBRT in the setting of MESCC must be capable of expedited treatment planning to avoid further neurological deterioration. Lastly, tumors that completely efface the epidural space surrounding the spinal cord cannot be adequately treated with SBRT without causing radiation-induced myelopathy [62].

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Figure 6. Images from a 57-year-old woman with history of right nephrectomy for a renal cell carcinoma (clear cell type), stage I (T1, N0, M0), now with sudden onset back pain. (A, B): Axial T1-weighted, fat-suppressed, postcontrast (A) and T2-weighted (B) magnetic resonance imaging shows an enhancing mass destroying the right pedicle and transverse process of the T7 vertebra (white block arrows). Posterior extension of the mass causes 50% spinal canal stenosis and mass effect on the spinal cord (white arrowhead). The patient’s life expectancy was otherwise greater than 6 months, her performance status was excellent, and she had no other evidence of metastatic disease. (C, D): Anteroposterior (C) and lateral (D) radiographs show postsurgical changes of laminectomies at T6,T7, and T8 for posterior decompression and epidural tumor resection, T7 corpectomy, and posterior instrumented fusion from T5 through T9. She tolerated surgery well and her pain was relieved. Postoperatively, she underwent stereotactic body radiation therapy (27 Gy in 3 fractions) to maximize the likelihood of long-term local tumor control, especially given the radiation-resistant tumor histology. (E–H): Axial (E, F), sagittal (G), and coronal (H) computed tomography images show the target volume of stereotactic body radiation therapy, which included areas of gross disease on preoperative magnetic resonance imaging, as well as areas of likely microscopic disease extension, as defined by the radiation oncologist and surgeon. Repeat imaging 1 year after treatment showed no local recurrence.

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FUTURE RESEARCH The Working Group algorithms highlight several areas in which additional research is needed to define the most appropriate treatment strategy. First, case series suggest that SBRT offers the potential for higher rates of pain relief and more durable local tumor control [27, 29, 63]; however, a phase III trial, RTOG 0631, is currently underway comparing the safety and efficacy of SBRT with cEBRT [64]. Second, the results of percutaneous tumor ablation seen in retrospective case series must be validated in randomized controlled trials. A multicenter, prospective clinical trial (NCT02225223) is recently underway that will assess the palliative efficacy of RFA and vertebral augmentation before or after failed radiation therapy. Third, the benefit of combination radiation and ablation therapy should be compared with that of either therapy alone. Radiation therapy is dependent on oxygen for cytotoxicity and is thought to be deficient in killing centrally located tumor cells that are often hypoxic. Conversely, the cytotoxic temperatures generated at the center of an ablation volume dissipate with distance, resulting in less reliable necrosis of the tumor periphery. In a preliminary cohort study, Di Staso et al. [65] compared the pain responses of 15 patients with solitary skeletal metastases treated with RFA followed by cEBRT (20 Gy in 5 fractions) with 30 patients treated with cEBRT alone. At 12-week follow-up, patients in the combined treatment group more frequently reported both complete (53% [8 of 15] vs. 17% [5 of 30]; p 5 .027) and at least partial (93% [14 of 15] vs. 60% [18 of 30]; p 5 .048) pain relief. Finally, as risk factors for radiation- and ablation-induced VCF emerge, the long-term clinical benefit of prophylactic vertebral augmentation will need to be evaluated [66].

CONCLUSION The Metastatic Spine Disease Multidisciplinary Working Group algorithms provide an evidence- and expert opinion-based framework for managing patients with spinal metastases

and facilitating appropriate interdisciplinary referrals. These algorithms add to existing treatment guidelines by incorporating indications for emerging therapies, including SBRT and percutaneous tumor ablation. These algorithms will be refined as data from future prospective clinical trials become available.

ACKNOWLEDGMENTS DFINE, Inc. paid for transportation and lodging for attendees of the initial Metastatic Spine Disease Multidisciplinary Working Group meeting in January 2014. The authors acknowledge Dr. Anderanik Tomasian for his critical review of the manuscript.

AUTHOR CONTRIBUTIONS Conception/Design: Adam N.Wallace, Clifford G. Robinson, Jeffrey Meyer, Nam D.Tran, Afshin Gangi, Matthew R. Callstrom, Samuel T. Chao, Brian A.Van Tine, Jonathan M. Morris, Brian M. Bruel, Jeremiah Long, Robert D. Timmerman, Jacob M. Buchowski, Jack W. Jennings Manuscript writing: Adam N. Wallace, Clifford G. Robinson, Jeffrey Meyer, Nam D.Tran, Afshin Gangi, Matthew R. Callstrom, Samuel T. Chao, Brian A.Van Tine, Jonathan M. Morris, Brian M. Bruel, Jeremiah Long, Robert D. Timmerman, Jacob M. Buchowski, Jack W. Jennings Final approval of manuscript: Adam N. Wallace, Clifford G. Robinson, Jeffrey Meyer, Nam D. Tran, Afshin Gangi, Matthew R. Callstrom, Samuel T. Chao, Brian A.Van Tine, Jonathan M. Morris, Brian M. Bruel, Jeremiah Long, Robert D. Timmerman, Jacob M. Buchowski, Jack W. Jennings

DISCLOSURES Clifford G. Robinson: Varian (RF); Jeffrey Meyer: Peregrine Pharmaceuticals, Inc. (RF), UpToDate, Inc. (other); Nam D.Tran: DFine, Inc. (H); Afshin Gangi: Galil Medical (other); Matthew R. Callstrom: Medtronic, Covidien (C/A), Galil Medical (RF); Brian A.Van Tine: DFINE (C/A, H); Brian M. Bruel: Medtronic, Boston Scientific (C/A, H), Jazz Pharmaceuticals (RF); Robert Timmerman: Varian Medical Systems (RF); Jacob M. Buchowski: Advance Medical, CoreLink, Inc., Globus Medical, Inc., Medtronic, Stryker, Inc. (C/A), Globus Medical, Inc., Broadwater/Vertical Health, Orthofix, Stryker, Inc. (H), multiple entities (ET), AO Foundation, Wolters Kluwer Health, Inc. (other); Jack W. Jennings: DFINE, Inc. (C/A, H). The other authors indicated no financial relationships. (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/ inventor/patent holder; (SAB) Scientific advisory board

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The Metastatic Spine Disease Multidisciplinary Working Group Algorithms.

The Metastatic Spine Disease Multidisciplinary Working Group consists of medical and radiation oncologists, surgeons, and interventional radiologists ...
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