State of the Art Treatment of Spinal Metastatic Disease

State of the Art Treatment of Spinal Metastatic Disease Abstract Treatment paradigms for patients with spine metastases have evolved significantly over the past decade. Incorporating stereotactic radiosurgery into these paradigms has been particularly transformative, offering precise delivery of tumoricidal radiation doses with sparing of adjacent tissues. Evidence supports the safety and efficacy of radiosurgery as it currently offers durable local tumor control with low complication rates even for tumors previously considered radioresistant to conventional radiation. The role for surgical intervention remains consistent, but a trend has been observed toward less aggressive, often minimally invasive, techniques. Using modern technologies and improved instrumentation, surgical outcomes continue to improve with reduced morbidity. Additionally, targeted agents such as biologics and checkpoint inhibitors have revolutionized cancer care, improving both local control and patient survivals. These advances have brought forth a need for new prognostication tools and a more critical review of long-term outcomes. The complex nature of current treatment schemes necessitates a multidisciplinary approach including surgeons, medical oncologists, radiation oncologists, interventionalists, and pain specialists. This review recapitulates the current state-of-the-art, evidence-based data on the treatment of spinal metastases, integrating these data into a decision framework, NOMS, which integrates the 4 sentinel decision points in metastatic spine tumors: Neurologic, Oncologic, Mechanical stability, and Systemic disease and medical co-morbidities. Spine, Tumor, Surgery, Radiosurgery, NOMS, SRS, ESCC ABBREVIATIONS ABBREVIATIONS cEBRT conventional external beam radiation CTV clinical target volume ESCC epidural spinal cord compression GTV gross tumor volume HRQOL health-related quality of life MAS minimal access surgery MESCC metastatic epidural spinal cord compression MR magnetic resonance NSCLC nonsmall cell lung carcinoma OARs organs at risk PEEK polyether ether ketone PMMA Poly-methyl-methacrylate SINS Spinal Instability Neoplastic Score SLITT spinal laser interstitial thermotherapy SOSG Spine Oncology Study Group SRS stereotactic radiosurgery SSRS spine stereotactic radiosurgery VCF vertebral compression fractures VEGF vascular endothelial growth factor Spinal metastases are a common oncologic challenge, as 20% to 40% of cancer patients are affected during the course of their illness and up to 20% of those will become symptomatic from spinal cord compression.1-5 The magnitude of this problem is expected to grow with the exponential rise in the use of targeted therapies that have demonstrated markedly improved survivals for virtually all malignant tumors, as well as the wide-spread availability of advanced diagnostic imaging, such as magnetic resonance (MR) and [18F]fluorodeoxyglucose positron emission tomography (PET). Treatment goals for patients with spine metastases are palliative and include preservation or restoration of neurological function, improved pain control and health-related quality of life (HRQOL), and maintenance of spinal stability, all in a setting of durable local tumor control. Scoring systems such as the Tomita score6 and Tokuhashi revised score7 have traditionally been used to estimate survival in this patient population and were often the basis for treatment planning. Although tremendously useful for many years, the lack of integration of major technological and systemic cancer treatments into these predictive models render them of little value in the current era of metastatic spine tumor treatment. TABLE 1. Current NOMS Decision Framework Neurologic Oncologic Mechanical Systemic Decision Low-grade ESCC + no myelopathy Radiosensitive Stable cEBRT Radiosensitive Unstable Stabilization followed by cEBRT Radioresistant Stable SSRS Radioresistant Unstable Stabilization followed by SRS High-grade ESCC +/–myelopathy Radiosensitive Stable cEBRT Radiosensitive Unstable Stabilization followed by cEBRT Radioresistant Stable Able to tolerate surgery Decompression/stabilization followed by SRS Radioresistant Stable Unable to tolerate surgery cEBRT Radioresistant Unstable Able to tolerate surgery Decompression/stabilization followed by SRS Radioresistant Unstable Unable to tolerate surgery Stabilization followed by cEBRT Neurologic Oncologic Mechanical Systemic Decision Low-grade ESCC + no myelopathy Radiosensitive Stable cEBRT Radiosensitive Unstable Stabilization followed by cEBRT Radioresistant Stable SSRS Radioresistant Unstable Stabilization followed by SRS High-grade ESCC +/–myelopathy Radiosensitive Stable cEBRT Radiosensitive Unstable Stabilization followed by cEBRT Radioresistant Stable Able to tolerate surgery Decompression/stabilization followed by SRS Radioresistant Stable Unable to tolerate surgery cEBRT Radioresistant Unstable Able to tolerate surgery Decompression/stabilization followed by SRS Radioresistant Unstable Unable to tolerate surgery Stabilization followed by cEBRT cEBRT, conventional external beam radiation; ESCC, epidural spinal cord compression; NOMS, neurologic, oncologic, mechanical and systemic; SRS, stereotactic radiosurgery; MAS, minimal access surgeries; SLITT, spinal laser interstitial thermotherapy. Low-grade ESCC is defined as grade 0 or 1 on Spine Oncology Study Group scoring system. High-grade ESCC is defined as grade 2 or 3 on the ESCC scale. Decompression options include open surgical, MAS, SLITT. Stabilization options include percutaneous cement augmentation, percutaneous pedicle screw instrumentation, and open instrumentation. For patients with significant systemic comorbidities that affect the ability to tolerate open surgery, stabilization may be limited to cement augmentation and/or percutaneous screw augmentation. Adapted from Laufer I et al8: The NOMS framework: approach to the treatment of spinal metastatic tumors. Oncologist 18:744-51, 2013. Reproduced and modified with permission. View Large TABLE 1. Current NOMS Decision Framework Neurologic Oncologic Mechanical Systemic Decision Low-grade ESCC + no myelopathy Radiosensitive Stable cEBRT Radiosensitive Unstable Stabilization followed by cEBRT Radioresistant Stable SSRS Radioresistant Unstable Stabilization followed by SRS High-grade ESCC +/–myelopathy Radiosensitive Stable cEBRT Radiosensitive Unstable Stabilization followed by cEBRT Radioresistant Stable Able to tolerate surgery Decompression/stabilization followed by SRS Radioresistant Stable Unable to tolerate surgery cEBRT Radioresistant Unstable Able to tolerate surgery Decompression/stabilization followed by SRS Radioresistant Unstable Unable to tolerate surgery Stabilization followed by cEBRT Neurologic Oncologic Mechanical Systemic Decision Low-grade ESCC + no myelopathy Radiosensitive Stable cEBRT Radiosensitive Unstable Stabilization followed by cEBRT Radioresistant Stable SSRS Radioresistant Unstable Stabilization followed by SRS High-grade ESCC +/–myelopathy Radiosensitive Stable cEBRT Radiosensitive Unstable Stabilization followed by cEBRT Radioresistant Stable Able to tolerate surgery Decompression/stabilization followed by SRS Radioresistant Stable Unable to tolerate surgery cEBRT Radioresistant Unstable Able to tolerate surgery Decompression/stabilization followed by SRS Radioresistant Unstable Unable to tolerate surgery Stabilization followed by cEBRT cEBRT, conventional external beam radiation; ESCC, epidural spinal cord compression; NOMS, neurologic, oncologic, mechanical and systemic; SRS, stereotactic radiosurgery; MAS, minimal access surgeries; SLITT, spinal laser interstitial thermotherapy. Low-grade ESCC is defined as grade 0 or 1 on Spine Oncology Study Group scoring system. High-grade ESCC is defined as grade 2 or 3 on the ESCC scale. Decompression options include open surgical, MAS, SLITT. Stabilization options include percutaneous cement augmentation, percutaneous pedicle screw instrumentation, and open instrumentation. For patients with significant systemic comorbidities that affect the ability to tolerate open surgery, stabilization may be limited to cement augmentation and/or percutaneous screw augmentation. Adapted from Laufer I et al8: The NOMS framework: approach to the treatment of spinal metastatic tumors. Oncologist 18:744-51, 2013. Reproduced and modified with permission. View Large The integration of 4 major advances has fundamentally changed the current treatment paradigms for metastatic spine tumors: (1) The development and integration of spine stereotactic radiosurgery (SSRS) has dramatically improved local control rates independent of tumor histology and size; (2) the introduction of less invasive surgical techniques including separation surgery, minimal access techniques, and percutaneous pedicle screw instrumentation and cement augmentation has shortened recovery periods and provided an earlier return to systemic treatment; (3) spinal instability has been defined by the validated Spinal Instability Neoplastic Score (SINS) criteria and is acknowledged as an independent surgical indication; and (4) targeted therapies, such as biologics and checkpoint inhibitors, have significantly improved overall and progression-free survival for most solid tumor and hematologic malignancies. The “NOMS” framework8 was developed in order to provide a comprehensive assessment of metastatic spine tumor issues allowing integration of these new advances in cancer care. This framework facilitates complex decision making and offers a common language for treating physicians across disciplines. NOMS aids in optimizing state of the art patient care as it evolves with time, adapts to and incorporates new technologies, systemic therapy, and surgical techniques.9 The four pillars of NOMS are Neurologic, Oncologic, Mechanical, and Systemic assessments. The neurologic consideration assesses both the clinical presence of myelopathy or functional radiculopathy and the radiographic degree of epidural spinal cord compression (ESCC).10 The oncologic assessment evaluates the predicted local tumor control from radiation, chemotherapy, or surgery. The mechanical assessment evaluates spinal instability secondary to pathological fractures and serves as an independent indication for procedure-based interventions, most commonly percutaneous cement augmentation. The final assessment is that of systemic disease status and medical co-morbidities, which predicts the ability of a patient to tolerate a proposed procedure, the risk-benefit ratio of treatment, and the overall survival. The objective of this review is to outline the impact of the recent cancer care advancements in the context of this clinical decision-making paradigm (Table 1). NEUROLOGIC ONCOLOGIC (NOms) In the NOMS framework, the neurologic and oncologic considerations are assessed in combination. The neurological evaluation consists of both clinical and radiographic evaluations. The radiological assessment focuses on the degree of ESCC and the clinical evaluation of the presence of myelopathy or functional radiculopathy. Myelopathy typically correlates with radiographic evidence of high-grade ESCC; therefore, although myelopathy is a critical factor, decisions are heavily dependent on the degree of ESCC. The degree of ESCC is evaluated using a 6-point scoring system validated by the Spine Oncology Study Group (SOSG; Figure 1).10 FIGURE 1. View largeDownload slide ESCC scale.10 Grades 0 to 1c represent tumor involving the bone only or varying degrees of thecal sac compression without spinal cord compression. Grades 2 and 3 are considered to be high-grade spinal cord compression and are differentiated by whether spinal fluid signal is obliterated on T2-weighted images. Adapted from Bilsky MH et al: Reliability analysis of the ESCC scale. J Neurosurg Spine 13:324-8, 2010. Reproduced with permission. FIGURE 1. View largeDownload slide ESCC scale.10 Grades 0 to 1c represent tumor involving the bone only or varying degrees of thecal sac compression without spinal cord compression. Grades 2 and 3 are considered to be high-grade spinal cord compression and are differentiated by whether spinal fluid signal is obliterated on T2-weighted images. Adapted from Bilsky MH et al: Reliability analysis of the ESCC scale. J Neurosurg Spine 13:324-8, 2010. Reproduced with permission. From an oncologic perspective, the predicted response to available therapies is taken into account. Historically, treatment responses for osseous tumors to systemic therapies were limited, and thus, conventional external beam radiation (cEBRT), often defined as 30 Gy in 10 fractions, was the mainstay of treatment for spinal tumors.11-13 Responses to cEBRT were predicated on mitotic cell death via breakage of double-stranded DNA within a tumor, which potentially resulted in spinal cord decompression.14-16 With cEBRT, 1 to 2 beams are delivered to a treatment field, but organs at risk (OARs), particularly the spinal cord, remain within the radiation field; thus, the dose of radiation is constrained by the toxicity to OARs.17 Based on the treatment response to cEBRT, tumors are classified as either radioresistant or radiosensitive. Moderately to highly radiosensitive tumors to cEBRT include most hematologic malignancies (ie, lymphoma, multiple myeloma, and plasmacytoma), as well as selected solid tumors (ie, breast, prostate, ovarian, and neuroendocrine carcinomas and seminoma).18,19 However, most solid tumors are radioresistant to cEBRT including renal cell carcinoma, colon, nonsmall cell lung carcinoma (NSCLC), thyroid, hepatocellular carcinoma, melanoma, and sarcoma.12,13,18,19 Defining responsiveness to cEBRT is critical in terms of predicting clinical outcomes. In a number of series, favorable responders (ie, radiosensitive) are more likely to maintain ambulation or remain ambulatory longer than patients with unfavorable histologies, (ie, radioresistant) after radiation treatment.19,20 Maranzano et al15 prospectively demonstrated that 67% of breast cancer patients regained ambulation compared with 20% in hepatocellular carcinoma and further showed that myeloma, breast, and prostate had response durations of 16, 12, and 10 mo, respectively.15 Others found a low success rate of only 33% in radioresistant tumors compared to 72% of patients with favorable histologies as these exhibited combined improvement in their motor strength, functional ability, and pain scores.21 Hence, patients with radiosensitive tumors can be treated effectively with cEBRT obviating the need for surgical intervention, regardless of the degree of ESCC.11,13 However, in practice, patients with radiosensitive solid tumor malignancies who are myelopathic are usually considered for upfront surgery, as the potential to achieve immediate decompression and maximize neurological recovery with cEBRT is limited. Radiosurgery is a “Game-Changer” The technical evolution and integration of SSRS has been a true paradigm changer for the treatment of spinal metastases. The safe and effective implementation of SSRS is a result of technological advancements in noninvasive patient immobilization; intensity modulated image-guided radiation delivery systems, and sophisticated planning software.22,23 Comparisons between low- (ie, cEBRT) vs high-dose per fraction radiation (ie, SSRS) have shown differences in the radiobiologic response in animal models.24 Evidence indicates that radiation of tumors delivered with a high-dose per fraction, ie >10 Gy per fraction, not only kills tumor cells via breakage of double-stranded DNA, but also causes significant damage in tumor vasculature.25 Garcia-Barros et al26 found that stereotactic radiosurgery (SRS) increases a signal transduction platform through the acid-sphingomyelinase pathway, which in turn, results in microvascular endothelial dysfunction and apoptosis, subsequent hypoperfusion of tumor tissue, and ultimately tumor cell destruction. Additionally, the release of tumor-associated antigens and proinflammatory cytokines, secondary to both the direct radiation effect and the secondary vascular damage, initiates an immune response against the tumor.27,28 Ultimately, the ability to deliver high-dose single or hypofractionated conformal radiation enables the delivery of cytotoxic tumoral doses.29 An additional major advantage of radiosurgery over cEBRT is that these treatments are typically delivered in 1 to 3 fractions rather than 10 to 20 required for cEBRT leading to better patient compliance (Figure 2). FIGURE 2. View largeDownload slide SSRS treatment. Sixty-eight-year-old female, without a previous history of cancer, presented with back pain and was found to have a T8 lesion and a lung lesion. Due to her symptomatic presentation she underwent kyphoplasty along with a biopsy from T8 yielding metastatic adenocarcinoma consistent with adenocarcinoma of lung. No epidural tumor extension was found (ESCC grade 0) but a left paraspinal extension was noted. Along with systemic treatment, the patient underwent SSRS treatment of 24 Gy in a single treatment fraction. A, Axial MR with contrast enhancement at T8 showing the vertebral body lesion with extension to the left posterior elements with a paraspinal component. No epidural cord compression seen. B, Thirteen-month follow-up MR showing good local tumor control. C, Radiosurgery treatment plan color wash. The minimum dose in the color wash (dark blue) is set to 1920 cGy or 80%. FIGURE 2. View largeDownload slide SSRS treatment. Sixty-eight-year-old female, without a previous history of cancer, presented with back pain and was found to have a T8 lesion and a lung lesion. Due to her symptomatic presentation she underwent kyphoplasty along with a biopsy from T8 yielding metastatic adenocarcinoma consistent with adenocarcinoma of lung. No epidural tumor extension was found (ESCC grade 0) but a left paraspinal extension was noted. Along with systemic treatment, the patient underwent SSRS treatment of 24 Gy in a single treatment fraction. A, Axial MR with contrast enhancement at T8 showing the vertebral body lesion with extension to the left posterior elements with a paraspinal component. No epidural cord compression seen. B, Thirteen-month follow-up MR showing good local tumor control. C, Radiosurgery treatment plan color wash. The minimum dose in the color wash (dark blue) is set to 1920 cGy or 80%. SSRS as Definitive Therapy Recent data demonstrate that SSRS yields a clinical benefit regardless of tumor histology and volume, providing durable symptomatic responses and high local-control rates.30-32 In patients without spinal cord compression (ESCC 0-1C), SSRS can be used as definitive therapy and has largely replaced en bloc resection favored by the Tokuhashi and Tomita scoring systems even for solitary metastases.33,34 This transition is based on a plethora of outcome data demonstrating excellent outcomes with SSRS for traditionally radioresistant histologies such as renal cell carcinoma,35-37 sarcoma,38 and melanoma.39 Local control rates of 88% in the noncervical spine have been shown prospectively, independent of histology.40 A multi-institutional retrospective analysis of 387 cases treated with stereotactic body radiation therapy reported local control of 84% at 2 yr. The cohort comprised various solid tumor histologies and the median treatment dose was 8 Gy in 3 fractions.41 Other series have demonstrated similar conclusions.42,43 Recently, Yamada et al30 described a case series of 811 lesions treated in 657 patients with a single-fraction SSRS in which dose was analyzed as a continuous variable ranging from 18 to 26 Gy. The median dose that covered 95% of the planning target volume (PTV D95) was 1644 cGy in the low-dose group compared to 2240 cGy in the high-dose group. Local failure rates for the low- and high-dose groups were 5% vs 0.41% at 12 mo, 15% vs 1.6% at 24 mo, and 20% vs 2.1% at 48 mo, respectively. In this study, 82% of the tumors were traditionally radioresistant and 50% had failed prior cEBRT, but tumor responses were found to be independent of both tumor histology and prior radiation for the high-dose cohorts.30 Thus, SSRS yields a clinical benefit regardless of histology, providing a durable symptomatic response and high local-control rates, but these responses appear to be dose dependent.30-32 SSRS Spine Volumes While dose is important, the contoured tumor volume is also critical. To unify treatment planning, the International Spine Radiosurgery Consortium updated contouring and planning guidelines for spinal radiosurgery planning44,45 and recent consensus guidelines have also been created for postoperative target contouring.46 It is important for treating spine surgeons to be familiar with these guidelines and actively participate in the treatment planning. One of the most important revelations is the concept that one cannot simply treat the gross tumor volume (GTV), ie the radiographically defined tumor volume, but must treat a clinical target volume (CTV), which accounts for the high probability of microscopic spread through contiguous marrow spaces. Contouring at CTV is different from intracranial SRS for brain metastases that only accounts for the GTV. Radiographic Response Assessment to SSRS With improved tumor control, another emerging consideration is the radiographic response assessment to radiation. In order to standardize practice and follow-up, the Spine response assessment in Neuro-Oncology group published criteria for imaging-based assessment of local control and pain for spinal metastases.47 They presented recommendations in treatment planning, endpoint definitions, and follow-up practice. Currently, dynamic contrast-enhanced perfusion images48 are utilized to assess the viability of tumors. These images appear to be sensitive and specific for assessing treatment responses following SSRS and changes are seen earlier than using standard MR imaging.48,49 SSRS Toxicity The balance between underdosing the tumor margins resulting in tumor progression vs overdosing and damaging OARs is extremely delicate. Constraints have been established for all major OARs.50,51 Fortunately, high-grade toxicity after SSRS occurs infrequently and most of the observed complications are mild52 including esophagitis, mucositis, dysphagia, diarrhea, paresthesias, transient laryngitis, and radiculitis.53-58 Vertebral compression fractures (VCF) following SSRS have been described in up to 40% of treatments compared with a less than 5% risk following cEBRT.59 A multi-institutional analysis found that VCF following SSRS is more likely to occur following treatment with high doses.60 Saghal et al61 suggested that caution be observed when treating with ≥20 Gy per fraction, particularly for high-risk patients. Risk factors identified are older age, a lytic session, vertebral malalignment, or the presence of a preexisting VCF and therefore some advocate pretreatment kyphoplasty in select patients.59,62,63 However, the fracture rate of 40% captured all radiographic fractures, but the symptomatic fracture rate requiring an intervention is only 7% at 5-yr follow-up.64 An ongoing controversy regarding dose-dependent fracture risk has yet to be resolved, but the demonstrated control rates at higher doses combined with the ability to stabilize most fractures with the low-risk of morbidity associated with percutaneous cement augmentation may justify more aggressive dosing. The spinal cord is the most critical OAR. A multi-institutional review reported a 0.5% (6/1075) risk of radiation-induced myelopathy with 50% of the injuries occurring at an 8 Gy equivalent dose to the spinal cord.65 Yamada et al30 analyzed 476 patients treated with SSRS and found only 2 patients (0.42%) who developed self-limited, steroid-responsive myelopathy. In patients undergoing initial SSRS, spinal cord constraints have been defined as 10 Gy to 10% of the spinal cord or a cord Dmax of 14 Gy. The tight dose constraints on the spinal cord currently prevent the treatment of high-grade ESCC. Bishop et al66 evaluated 332 treatments for predictors of local failure and found that patients with local relapse had poor tumor volume coverage, likely due to prioritizing the spinal cord constraints over tumor coverage. Lovelock et al17 found that all radiation failures occurred when less than 15 Gy was delivered to the CTV; thus, with a cord Dmax of 14 Gy and a 10% per mm fall-off, treatment of ESCC risks overdosing the spinal cord resulting in myelopathy or underdosing resulting in progressive ESCC. An early report exploring the treatment of high-grade ESCC with SSRS demonstrated this effect as a significant number of patients harboring radioresistant tumors experienced neurologic progression.67 Current spinal cord constraints prohibit the use of SSRS in the setting of high-grade ESCC. For this reason, patients with high-grade ESCC secondary to radioresistant tumors require surgical decompression. NEUROLOGIC/ONCOLOGIC SURGICAL INDICATIONS: HIGH-GRADE ESCC FROM RT-RESISTANT TUMORS Given the poor responses seen to cEBRT and the inability to deliver a cytotoxic SSRS-dose within spinal cord constraints, the SOSG in a systematic literature review made a strong recommendation for surgical stabilization and decompression in patients with radioresistant tumors in the setting of high-grade spinal cord compression.34 Patchell et al68 provided class I evidence in support of direct surgical decompression for patients with solid tumor metastases resulting in ESCC and/or neurologic deficit. In this trial, patients randomized to the surgical arm had longer overall survival, improved ambulation, and better preservation of bowel and bladder function compared to those randomized to radiation alone. This trial also highlighted the need for improved techniques for durable local tumor control, as 70% of the patients in this trial had local disease recurrence at 1-yr.68 Similarly, others have demonstrated that the completeness of resection was an independent predictor of time to recurrence, yet also emphasized the need for more durable tumor control as the 1- and 4-yr local failures rates were 70% and 96%, respectivley.69 The acknowledgment that “bad tumor biology will overcome good surgery” along with the technological advancement that led to SSRS have changed the aggressiveness; however, the indications for surgery from a neurologic and oncologic assessment remain the same, ie, high-grade spinal cord compression with or without myelopathy secondary to radioresistant tumors. Neural Protection: Timing of Surgery and Steroid Dosing A systematic review concluded that the duration and severity of neurologic deficit predict neurological recovery in patients with metastatic epidural spinal cord compression (MESCC).70 Hence, efforts to reduce the duration of ambulation loss and to prevent progression of neurologic deficits should be made to improve the probability of neurologic recovery. High-quality data on the efficacy of steroids in MESCC are lacking. Based on low-level quality evidence, it was recently shown that steroid therapy administered immediately following diagnosis of MESCC and followed by definitive treatment may increase the proportion of patients maintaining ambulation at 1-yr post-therapy with no clear effect on bowel and bladder function or survival. The authors conclude, on the basis of the evidence available, an initial 10 mg intravenous bolus of dexamethasone followed by 16 mg PO daily has been associated with fewer complications compared with 100 mg bolus and 96 mg daily. Weaning of steroids should occur rapidly after definitive treatment.71 Of note, all of the data supporting the use of dexamethasone are based on radiotherapy treatment of MESCC. To date, the role of dexamethasone in patients undergoing decompressive surgery has not been studied. Trends toward Less Invasive Surgery Hybrid Therapy: Separation Surgery and SSRS In recent years, we have seen a transition from treatment with aggressive cytoreductive surgeries, such as en bloc spondylectomy or gross total resection, to reliance on SSRS to provide the oncologic goal of tumor control.34 Hybrid therapy refers to the combination of SSRS and separation surgery. The term “separation surgery” describes a posterolateral approach that allows for stabilization and circumferential decompression of the thecal sac and nerve roots. Spinal cord decompression is ensured by resecting the posterior longitudinal ligament with reconstitution of the thecal sac. The goal of the spinal cord decompression is neurologic preservation or recovery, but also to creating an ablative target for SSRS within spinal cord constraints. SSRS-treatment failures occur when less than 15 Gy are delivered to a portion of the CTV,17 and this dose cannot be delivered to the entire tumor margin without risking spinal cord injury unless a safe distance between the tumor and the spinal cord is created.53 To safely deliver an appropriate radiation dose, patients with high-grade ESCC caused by radioresistant tumors undergo separation surgery;8,72 however, due to the ability to deliver an ablative SSRS dose to the entire tumor volume, large paraspinal masses and vertebral body tumors do not need to be resected in order to achieve durable local tumor control. In a retrospective review of 186 patients, Laufer et al73 found postoperative adjuvant SSRS following separation surgery is safe and effective in achieving durable local tumor control.73 In this series, patients who received high-dose hypofractionated SRS (ie, 24-30 Gy in 3 fractions) demonstrated 1-yr local progression rates of less than 5% and the local progression rate after single-fraction SSRS (ie, 24 Gy) was less than 10%.73 There was no impact of radioresistant tumor histology, prior radiation, or the degree of preoperative epidural extension on recurrence rates and no patient suffered a neurological complication; however, it should be noted that these results were superior to the results of low-dose hypofractionated SSRS (ie 30 Gy in 5 fractions). Similarly, Moulding et al74 reported a 1-yr local failure risk of only 6.3% using high-dose (18-24 Gy) single fraction SRS after separation surgery and Rock et al75 reported a 92% local control rate in patients treated with radiosurgery following open surgical procedures (Figure 3). The importance of achieving adequate surgical decompression to reconstitute the thecal sac has been emphasized by Al-Omair et al76 who showed that patients who postoperatively had continued compression of the spinal cord had a significantly higher risk of local recurrence after postoperative SSRS compared to patients with sufficient separation between the tumor and the spinal cord. FIGURE 3. View largeDownload slide Separation surgery. Eighty-three-year-old female with a history of NSCLC. She underwent a routine PET-CT that demonstrated pathological fracture of T10 and a PET avid lesion with erosion of the posterior cortex of the vertebral body suggestive of spinal canal involvement. MRI demonstrated high-grade spinal cord compression (ESCC 3) at T10. Neurologically intact at presentation with mild chronic back pain. Due to the high-grade cord compression with a radioresistant tumor she underwent separation surgery followed by SSRS. A, Preoperative sagittal T1 noncontrast MRI. Note the compression at T10 (white arrow). B, Preoperative axial MRI with contrast enhancement demonstrating the ESCC3 compression. C, Postoperative x-ray demonstrating the typical construct extending from 2 levels above to 2 levels below the index level. D, Postoperative CT (computed tomography) myelogram showing reconstitution of the thecal sac at the index level. FIGURE 3. View largeDownload slide Separation surgery. Eighty-three-year-old female with a history of NSCLC. She underwent a routine PET-CT that demonstrated pathological fracture of T10 and a PET avid lesion with erosion of the posterior cortex of the vertebral body suggestive of spinal canal involvement. MRI demonstrated high-grade spinal cord compression (ESCC 3) at T10. Neurologically intact at presentation with mild chronic back pain. Due to the high-grade cord compression with a radioresistant tumor she underwent separation surgery followed by SSRS. A, Preoperative sagittal T1 noncontrast MRI. Note the compression at T10 (white arrow). B, Preoperative axial MRI with contrast enhancement demonstrating the ESCC3 compression. C, Postoperative x-ray demonstrating the typical construct extending from 2 levels above to 2 levels below the index level. D, Postoperative CT (computed tomography) myelogram showing reconstitution of the thecal sac at the index level. Minimal Access Surgery Prompt postoperative recovery and return to oncologic treatment is a key goal in patients with spinal tumors. The utilization of minimal access surgery (MAS) techniques for this population are gaining popularity as they entail limited perioperative morbidity, allow for quick recovery, and have shown to lead to less blood loss, low transfusion rates, and short hospitalizations.77-80 Conventional radiation can sometimes be started within 1 wk of MAS surgery and SSRS can be delivered immediately, unlike open surgeries where the risk of wound complications frequently delays radiation therapy.81,82 Current MAS techniques for the treatment of spinal metastases include percutaneous instrumentation, mini-open approaches for decompression,83 and tumor removal with or without tubular/expandable retractors and thoracoscopy/endoscopy. Tatsui et al 84,85 pioneered the use of spinal laser interstitial thermotherapy (SLITT) for ESCC as they describe decreased pain and improved quality of life at 3 mo without disruption of systemic therapy. Other surgical adjuncts such as intraoperative navigation are likewise currently being utilized86 and the technological advancement is likely to continue to advance this field. The surgical treatment of spinal metastases across institutions is variable and controversial because much of the literature principally reflects single institution case series. A recent systematic review highlights the lack of uniformity in treatment and reporting for decompressive surgery for the treatment of MESCC.87 Another recent systematic literature review found that although some studies have shown superiority of outcomes using MAS techniques, especially using “mini-open” decompression, the available data are still of low quality and strong recommendations cannot be made.88 It is important to acknowledge that some centers and literature still support more aggressive surgeries including en bloc resections,89 particularly in the setting of solitary renal cell and thyroid spine metastases. More aggressive open surgical strategies including corpectomies and combined anterior–posterior approaches90,91 are sometimes necessary with severe instability and/or deformity; however, these are becoming less frequent due to enhanced collaboration between oncologists and surgeons allowing for earlier treatment especially in the setting of SSRS. In centers and regions without SSRS, treatment should follow well-established paradigms of more aggressive surgeries especially in metastases with known resistance to cEBRT. Optimizing Spine Implants for Oncologic Indications Surgical implants are improving spine stabilization and postoperative imaging quality to evaluate for recurrence. Polyether ether ketone (PEEK) and carbon-fiber-reinforced PEEK are currently available materials used for pedicle screw-rod systems and vertebral body replacement cages. Their radiolucent property permits improved, artifact-free radiographic imaging. The modulus of elasticity is similar to bone, lessening the risk of subsidence, but it provides strength similar to titanium constructs.92 Poly-methyl-methacrylate (PMMA) bone cement is commonly used, allowing custom shaping of supports and constructs at the time of surgery for anterior column support.93 Preliminary reports demonstrate safety and efficacy of radiation using both PEEK94 and PMMA95 materials. The use of robotic technologies96 is growing and 3-dimensional printing of plastic polymer or titanium constructs emerges, allowing for custom implants to be created for individual patients, and is expected to be available for use in the future. Timing of Postoperative Radiation Radiation therapy is known to impair wound tissue repair through multiple mechanisms and surgical wound complications following radiation treatment remains a major concern.97,98 Keam et al99 evaluated wound complication rates occurring in patients receiving cEBRT compared to SSRS before undergoing spine surgery and found no significant differences.99 Importantly, they conclude that preoperative SSRS is associated with clinically acceptable rates of wound morbidity.99 Surgeons tend to wait several weeks before operating after cEBRT. A systematic review emphasized the lack on uniform data reporting, but suggested a 1 wk interval between surgery and SSRS based on animal models and limited human studies.100 Intraoperative Radiation: Brachytherapy Despite technologic advancement in SSRS, spinal cord toxicity remains a problem, particularly in the setting of circumferential tumor around the spinal dura and previously irradiated targets.17,53,101,102 An appealing solution to delivering therapeutic dose to dural margin using a short-range source is the use of single-dose intraoperative brachytherapy.103 This short-range delivery strategy allows treating the surface with a high dose, single fraction of 25 Gy while sparing the spinal cord (considering a prescription of 10 Gy to 1 mm). Initial reports used rigid plaques incorporating 192Ir- and 90Y-based sources with a polycarbonate backing,104 yet these were not found clinically useful due to the fabrication process, short half-life, and inflexibility of the device. The P32 plaque delivers a very high dose with a steep dose fall-off making it an ideal dural radiation plaque. This plaque has a relatively long half-life and does not require special intraoperative shielding. In small series, P32 has been shown to a useful adjunct to surgical intervention following epidural decompression.105-107 MECHANICAL STABILITY (noMs) In the NOMS framework, mechanical instability serves as an indication for surgery regardless of the degree of ESCC or the radiosensitivity of the tumor, as radiotherapy and systemic therapy do not restore mechanical stability of the spine. The SOSG defined spinal instability as a “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.”108 To facilitate the assessment of mechanical stability and to unify reporting and decision making across institutions, the SOSG developed a scoring system; the SINS (Table 2).108 SINS evaluates 6 parameters: location, pain, alignment, lesion character (ie, osteolysis), vertebral body collapse, and posterior element involvement. High SINS scores (13-18) reliably predict the need for surgical stabilization while low SINS scores (0-6) are considered stable and the intermediate SINS (7-12) tumors needs further refinement, but essentially the need for treatment is based on the discretion and experience of the spine surgeon.109 TABLE 2. SINS Component Scoring SINS component Score Location Junctional (occiput-C2, C7-T2, T11-L1, L5-S1) 3 Mobile spine (C3-C6, L2-L4) 2 Semi-rigid (T3-T10) 1 Rigid (S2-S5) 0 Pain Yes 3 Occasional pain but not mechanical 1 Pain-free lesion 0 Bone lesion Lytic 2 Mixed (lytic/blastic) 1 Blastic 0 Radiographic spinal alignment Subluxation/translation present 4 De novo deformity (kyphosis/scoliosis) 2 Normal alignment 0 Vertebral body collapse >50% collapse 3 <50% collapse 2 No collapse with >50% body involved 1 None of the above 0 Posterolateral involvement of spinal elements Bilateral 3 Unilateral 1 None of the above 0 Total Stable 0-6 Indeterminate 7-12 Unstable 13-18 SINS component Score Location Junctional (occiput-C2, C7-T2, T11-L1, L5-S1) 3 Mobile spine (C3-C6, L2-L4) 2 Semi-rigid (T3-T10) 1 Rigid (S2-S5) 0 Pain Yes 3 Occasional pain but not mechanical 1 Pain-free lesion 0 Bone lesion Lytic 2 Mixed (lytic/blastic) 1 Blastic 0 Radiographic spinal alignment Subluxation/translation present 4 De novo deformity (kyphosis/scoliosis) 2 Normal alignment 0 Vertebral body collapse >50% collapse 3 <50% collapse 2 No collapse with >50% body involved 1 None of the above 0 Posterolateral involvement of spinal elements Bilateral 3 Unilateral 1 None of the above 0 Total Stable 0-6 Indeterminate 7-12 Unstable 13-18 Reproduced with permission from Fisher CG, DiPaola CP, Ryken TC, et al. A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group. Spine. Oct 15 2010;35(22):E1221-1229.108 View Large TABLE 2. SINS Component Scoring SINS component Score Location Junctional (occiput-C2, C7-T2, T11-L1, L5-S1) 3 Mobile spine (C3-C6, L2-L4) 2 Semi-rigid (T3-T10) 1 Rigid (S2-S5) 0 Pain Yes 3 Occasional pain but not mechanical 1 Pain-free lesion 0 Bone lesion Lytic 2 Mixed (lytic/blastic) 1 Blastic 0 Radiographic spinal alignment Subluxation/translation present 4 De novo deformity (kyphosis/scoliosis) 2 Normal alignment 0 Vertebral body collapse >50% collapse 3 <50% collapse 2 No collapse with >50% body involved 1 None of the above 0 Posterolateral involvement of spinal elements Bilateral 3 Unilateral 1 None of the above 0 Total Stable 0-6 Indeterminate 7-12 Unstable 13-18 SINS component Score Location Junctional (occiput-C2, C7-T2, T11-L1, L5-S1) 3 Mobile spine (C3-C6, L2-L4) 2 Semi-rigid (T3-T10) 1 Rigid (S2-S5) 0 Pain Yes 3 Occasional pain but not mechanical 1 Pain-free lesion 0 Bone lesion Lytic 2 Mixed (lytic/blastic) 1 Blastic 0 Radiographic spinal alignment Subluxation/translation present 4 De novo deformity (kyphosis/scoliosis) 2 Normal alignment 0 Vertebral body collapse >50% collapse 3 <50% collapse 2 No collapse with >50% body involved 1 None of the above 0 Posterolateral involvement of spinal elements Bilateral 3 Unilateral 1 None of the above 0 Total Stable 0-6 Indeterminate 7-12 Unstable 13-18 Reproduced with permission from Fisher CG, DiPaola CP, Ryken TC, et al. A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group. Spine. Oct 15 2010;35(22):E1221-1229.108 View Large Stabilization Traditionally, stabilization was achieved via open surgery with data showing low complication rates. In an analysis of 318 patients who underwent separation surgery for solid malignancies, 2.8% experienced hardware failure.110 With the growing interest in MAS techniques, percutaneous stabilization is revolutionizing stabilization in cancer as it enables preservation of muscle attachments and posterior elements (Figure 4).111 This strategy has been shown to be a safe and effective option for palliation of mechanically unstable, cancer-related, VCFs with posterior element involvement.111,112 Bone quality in cancer patients is typically poor due to the osteolytic metastases, chemotherapy, radiation, and other co-morbidities, such as osteoporosis. To overcome screw failure, several strategies have been developed in both an open and MAS setting. Fenestrated pedicle screws allow the injection of PMMA bone cement through the screw into the vertebral body, decreasing the risk of screw pull-out.113,114 Alternatively, expandable screws contain an internal mechanism that shortens the screw and allows a slotted tip to expand, thus increasing the screw purchase with the bony surface.115 These technologies seem promising, but have yet to be validated in large scale clinical studies. FIGURE 4. View largeDownload slide Percutaneous stabilization. Seventy-six-year-old female with metastatic urothelial carcinoma and large disease burden with metastases to bone, liver, lung and lymph nodes. Presented with severe debilitating mechanical back pain and evidence of pathological T10 vertebral body fracture found on CT. MRI demonstrated low-grade cord compression (ESCC 1C) at T10. SINS score 14. Due to the debilitating pain, unstable spine, radioresistant tumor but low-grade cord compression she underwent a stabilizing procedure (without decompression) followed by SSRS. Procedure of choice was T9-11 percutaneous stabilization with cement augmented screws and T10 kyphoplasty. A, Preoperative sagittal CT demonstrating the compression fracture at T10. B, Preoperative axial T2 MRI showing ESCC 1C. C, Sagittal and D, Anterior–posterior (AP) x-rays demonstrating the stabilizing construct. FIGURE 4. View largeDownload slide Percutaneous stabilization. Seventy-six-year-old female with metastatic urothelial carcinoma and large disease burden with metastases to bone, liver, lung and lymph nodes. Presented with severe debilitating mechanical back pain and evidence of pathological T10 vertebral body fracture found on CT. MRI demonstrated low-grade cord compression (ESCC 1C) at T10. SINS score 14. Due to the debilitating pain, unstable spine, radioresistant tumor but low-grade cord compression she underwent a stabilizing procedure (without decompression) followed by SSRS. Procedure of choice was T9-11 percutaneous stabilization with cement augmented screws and T10 kyphoplasty. A, Preoperative sagittal CT demonstrating the compression fracture at T10. B, Preoperative axial T2 MRI showing ESCC 1C. C, Sagittal and D, Anterior–posterior (AP) x-rays demonstrating the stabilizing construct. Kyphoplasty/Vertebroplasty and Radiofrequency Ablation Current evidence strongly supports kyphoplasty and vertebroplasty for symptomatic compression fractures due to metastatic disease.116-119 Kyphoplasty, by temporarily inflating a balloon within the affected vertebral body, creates a cavity that can be filled with bone cement and may also permit reduction of a wedge fracture.120 Berenson et al118 provided prospective randomized data, in the CAFÉ study, showing significant pain reduction and improvement in disability indexes that persist for up to 6 mo when kyphoplasty was performed compared to a noninterventional control arm. Other data further support kyphoplasty for symptomatic osteolytic tumors to control pain, provided that no overt instability or myelopathy is present.116,117 Similarly, pain reduction has been shown after vertebroplasty in patients with spinal metastases.121 Technically, the insertion technique for a radiofrequency electrode is similar to percutaneous cement augmentation. Hence, radiofrequency ablation can be performed at the same time as percutaneous cement augmentation, or as an independent procedure to destroy tumor tissue within the vertebral body.122 Long-term outcomes are unclear, but this technology may be a useful addition to the minimally invasive methods available for palliative treatment.123 SYSTEMIC DISEASE (nomS) The Systemic evaluation of NOMS relates to the patients co-morbidities, overall disease burden, and ability to withstand the proposed treatment. As treatment for metastatic spine disease is of palliative nature, estimation of the expected survival and overall risk-benefit ratio are of great importance. Treatment goals are focused on whether the patients are likely to adequately recover from the indicated procedure and continue systemic therapy. Prognostication Several scoring systems such as the Tokuhashi revised score,7 the Tomita score,6 and the Bauer modified score124,125 have been developed to estimate expected survival in patients with spinal metastases. Over time and with the integration of modern cancer care, their utility has been questioned and reliability is currently uncertain.126,127 New prediction models attempt to overcome the shortcomings of these models with increased survival times and next generation therapies by identifying more prognostic factors associated with outcomes. The Skeletal Oncology Research Group created a nomogram to estimate survival for patients with spine metastatic disease.128 This method has been externally validated and shown to accurately estimate 3- and 12-mo survival for operable spine metastatic disease.129 Patients should be considered for surgery as long as reasonable systemic therapy is available for the postoperative period, in general, without adhering strictly to rigid prediction models. Targeted Agents: The Impact of Biologics and Checkpoint Inhibitors Modern tools allow for the assessment of genomic and proteomic alterations and epigenetic and posttranslational modifications at the molecular level.130 Genetic analysis leading to revolutionary molecular therapeutics including receptor tyrosine kinases, immune checkpoint inhibitors, and vaccine-based cancer treatments have been described in metastatic melanoma, lung cancer, renal cell cancer, breast cancer, and prostate cancer.131,132 These tools have been studied largely in nonspinal tumors, yet interest on the effect they may have on spine cancer care is growing.133,134 The treatment of metastatic melanoma has been groundbreaking as it is currently known that those with positive BRAF mutation may also respond well to immunotherapy with improved survival even in advanced metastatic disease.135 Median survivals of over 2 yr have been described for NSCLC positive for epidermal growth factor receptor mutation136 and renal cell carcinoma which was traditionally considered resistant to traditional chemotherapy, may respond well to new immunotherapies.137 Promising therapeutic results have been demonstrated combining ionizing radiation and immune checkpoint inhibitors including CTLA-4 and PD-1inhibitors, such as Ipilimumab, Nivolumab, and Pembrolizumab. The abscopal effect was first described by Postow et al,138 in a case report describing the induction of metastatic tumor regression at sites distant from the original radiation therapy location. Following this observation, studies showed that radiotherapy enhances the immune system and then checkpoint inhibitor therapy expands the patient's activated T-cell population inducing tumor cell-specific killing.138 This effect is suspected to be better associated with hypofractionated rather than single-fraction radiation therapy139 and was also shown in murine models.140 Vascular endothelial growth factor (VEGF) inhibitors may also act in synergy with radiation. Axitinib, an oral TKI-VEGF inhibitor has been used in murine models in combination with SRS to inhibit the acid sphingomyelinase pathway that leads to endothelial dysfunction, potentially acting as a radiosensitizer.141 Albeit the fact that systemic therapy is considered to be more effective for visceral than for osseous disease, it may still have an important role in the treatment of spine metastases, particularly when combined with SSRS. Critical Review of Outcomes HRQOL assessments are gaining interest, particularly with patient-reported outcome measures that provide a deep insight to treatment benefits and limitations. Wang et al142 prospectively report significant and lasting reduction in pain at 6 mo after stereotactic body radiation therapy with other series supporting these findings.143,144 In a prospective multicenter study, Fehlings et al145 showed that surgery, as an adjunct to radiation and chemotherapy, provides improvement in HRQOL measures with acceptable risks. Another prospective cohort study,146 from the Global Spine Tumor Study Group database, analyzed 922 consecutive patients with spinal metastases who underwent surgery, showing that physical functioning score improved rapidly after surgery and these improvements were sustained in those patients who survived up to 2 yr after surgery. CONCLUSION Despite major radiation and medical advancements in cancer care, surgery still plays a major role in the treatment paradigm for patients with spinal metastases. Surgery is particularly important for those with high-grade ESCC necessitating separation of the epidural tumor from the spinal cord, but also for spinal stabilization as facilitated by SINS. MAS techniques and improved implants and technologies offer less surgical-related morbidity and rapid continuation of systemic therapies. The integration of SSRS has revolutionized treatment and overcoming radioresistance is a major step in achieving durable tumor control. Targeted therapies are redefining cancer care yet their precise role for spinal tumors is yet to be fully determined. The NOMS framework offers an algorithm for state of the art, reliable, and reproducible patient treatment, ideally managed by a dedicated, multidisciplinary team. Disclosures Dr Fisher is a consultant for Medtronic and NuVasive. Dr Bilsky is a consultant for Globus and Brainlab and receives royalties from Depuy/Synthes. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Cobb CA , Leavens ME , Eckles N . Indications for nonoperative treatment of spinal cord compression due to breast cancer . J Neurosurg . 1977 ; 47 ( 5 ): 653 - 658 . Google Scholar CrossRef Search ADS PubMed 2. Wong DA , Fornasier VL , Macnab I . Spinal metastases . Spine . 1990 ; 15 ( 1 ): 1 - 4 . Google Scholar CrossRef Search ADS PubMed 3. Klimo P Jr , Schmidt MH . 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Partial volume tolerance of the spinal cord and complications of single-dose radiosurgery . Cancer . 2007 ; 109 ( 3 ): 628 - 636 . Google Scholar CrossRef Search ADS PubMed 102. Emami B , Lyman J , Brown A et al. Tolerance of normal tissue to therapeutic irradiation . Int J Radiat Oncol Biol Phys . 1991 ; 21 ( 1 ): 109 - 122 . Google Scholar CrossRef Search ADS PubMed 103. Willett CG , Czito BG , Tyler DS . Intraoperative radiation therapy . J Clin Oncol . 2007 ; 25 ( 8 ): 971 - 977 . Google Scholar CrossRef Search ADS PubMed 104. Delaney TF , Chen GT , Mauceri TC et al. Intraoperative dural irradiation by customized 192iridium and 90yttrium brachytherapy plaques . Int J Radiat Oncol Biol Phys . 2003 ; 57 ( 1 ): 239 - 245 . Google Scholar CrossRef Search ADS PubMed 105. Folkert MR , Bilsky MH , Cohen GN et al. Intraoperative 32P high-dose rate brachytherapy of the dura for recurrent primary and metastatic intracranial and spinal tumors . 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The Tokuhashi score: effectiveness and pitfalls . Eur Spine J . 2016 ; 25 ( 3 ): 673 - 678 . Google Scholar CrossRef Search ADS PubMed 127. Dardic M , Wibmer C , Berghold A , Stadlmueller L , Froehlich EV , Leithner A . Evaluation of prognostic scoring systems for spinal metastases in 196 patients treated during 2005–2010 . Eur Spine J . 2015 ; 24 ( 10 ): 2133 - 2141 . Google Scholar CrossRef Search ADS PubMed 128. Paulino Pereira NR , Janssen SJ , Van Dijk E et al. Development of a prognostic survival algorithm for patients with metastatic spine disease . J Bone Joint Surg . 2016 ; 98 ( 21 ): 1767 - 1776 . Google Scholar CrossRef Search ADS PubMed 129. Paulino Pereira NR , Mclaughlin L , Janssen SJ et al. The SORG nomogram accurately predicts 3- and 12-months survival for operable spine metastatic disease: external validation . J Surg Oncol . 2017 ; 115 ( 8 ): 1019 - 1027 . Google Scholar CrossRef Search ADS PubMed 130. Goodwin CR , Abu-Bonsrah N , Bilsky MH et al. Clinical decision making . Spine . 2016 ; 41 ( suppl 20 ): S171 - S177 . Google Scholar CrossRef Search ADS PubMed 131. Goodwin CR , Abu-Bonsrah N , Rhines LD et al. Molecular markers and targeted therapeutics in metastatic tumors of the spine . Spine . 2016 ; 41 ( suppl 20 ): S218 - S223 . Google Scholar CrossRef Search ADS PubMed 132. Tobin NP , Foukakis T , De Petris L , Bergh J . The importance of molecular markers for diagnosis and selection of targeted treatments in patients with cancer . J Intern Med . 2015 ; 278 ( 6 ): 545 - 570 . Google Scholar CrossRef Search ADS PubMed 133. Caruso JP , Cohen-Inbar O , Bilsky MH , Gerszten PC , Sheehan JP . Stereotactic radiosurgery and immunotherapy for metastatic spinal melanoma . Neurosurg Focus . 2015 ; 38 ( 3 ): E6 . Google Scholar CrossRef Search ADS PubMed 134. Shankar GM , Choi BD , Grannan BL , Oh K , Shin JH . Effect of immunotherapy status on outcomes in patients with metastatic melanoma to the spine. Spine . 2017 ; 42 ( 12 ): E721 - E725 . Google Scholar CrossRef Search ADS PubMed 135. Margolin K . The promise of molecularly targeted and immunotherapy for advanced melanoma . Curr Treat Options Oncol . 2016 ; 17 ( 9 ): 48 . Google Scholar CrossRef Search ADS PubMed 136. Olaussen KA , Postel-Vinay S . Predictors of chemotherapy efficacy in non-small-cell lung cancer: a challenging landscape . Ann Oncol . 2016 ; 27 ( 11 ): 2004 - 2016 . Google Scholar CrossRef Search ADS PubMed 137. Ghatalia P , Zibelman M , Geynisman DM , Plimack ER . Checkpoint inhibitors for the treatment of renal cell carcinoma . Curr Treat Options Oncol . 2017 ; 18 ( 1 ): 7 . Google Scholar CrossRef Search ADS PubMed 138. Postow MA , Callahan MK , Barker CA et al. Immunologic correlates of the abscopal effect in a patient with melanoma . N Engl J Med . 2012 ; 366 ( 10 ): 925 - 931 . Google Scholar CrossRef Search ADS PubMed 139. Dewan MZ , Galloway AE , Kawashima N et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody . Clin Cancer Res . 2009 ; 15 ( 17 ): 5379 - 5388 . Google Scholar CrossRef Search ADS PubMed 140. Demaria S , Bhardwaj N , Mcbride WH , Formenti SC . Combining radiotherapy and immunotherapy: a revived partnership . Int J Radiat Oncol Biol Phys . 2005 ; 63 ( 3 ): 655 - 666 . Google Scholar CrossRef Search ADS PubMed 141. Miller JA , Balagamwala EH , Angelov L et al. Spine stereotactic radiosurgery with concurrent tyrosine kinase inhibitors for metastatic renal cell carcinoma . J Neurosurg Spine . 2016 ; 25 ( 6 ): 766 - 774 . Google Scholar CrossRef Search ADS PubMed 142. Wang XS , Rhines LD , Shiu AS et al. Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: a phase 1–2 trial . Lancet Oncol . 2012 ; 13 ( 4 ): 395 - 402 . Google Scholar CrossRef Search ADS PubMed 143. Zeng L , Chow E , Zhang L et al. Comparison of pain response and functional interference outcomes between spinal and non-spinal bone metastases treated with palliative radiotherapy . Support Care Cancer . 2012 ; 20 ( 3 ): 633 - 639 . Google Scholar CrossRef Search ADS PubMed 144. Wu JSY , Monk G , Clark T , Robinson J , Eigl BJC , Hagen N . Palliative radiotherapy improves pain and reduces functional interference in patients with painful bone metastases: a quality assurance study . Clin Oncol . 2006 ; 18 ( 7 ): 539 - 544 . Google Scholar CrossRef Search ADS 145. Fehlings MG , Nater A , Tetreault L et al. Survival and clinical outcomes in surgically treated patients with metastatic epidural spinal cord compression: results of the prospective multicenter AOSpine study . J Clin Oncol . 2016 ; 34 ( 3 ): 268 - 276 . Google Scholar CrossRef Search ADS PubMed 146. Choi D , Fox Z , Albert T et al. Rapid improvements in pain and quality of life are sustained after surgery for spinal metastases in a large prospective cohort . Br J Neurosurg . 2016 ; 30 ( 3 ): 337 - 344 . Google Scholar CrossRef Search ADS PubMed COMMENT In this invited review on the treatment of metastatic tumors to the spinal column, the authors provide a thorough and thoughtful discussion of the evolving treatment options available for patients with spinal metastases. The authors provide historical context for the evolution of stereotactic radiosurgery as it applies to the spine and the significance of local tumor control, particularly in the postoperative setting. The radiobiology, benefits, and limitations of stereotactic radiosurgery are discussed with focus on how such technology can be integrated into multi-modality decision making. The authors also highlight several major advances that have significantly changed the treatment paradigm for spinal metastases including separation surgery, the characterization of spinal column instability in the oncologic setting, and a greater understanding and appreciation for evolving systemic therapies such as checkpoint inhibitors and the molecular profiling of solid tumor malignancies. Learning how to clinically integrate these factors, especially the latter, to better the lives of these patients is an ongoing challenge and requires further investigation. Extensively referenced, this review is an excellent resource for anyone who seeks to update any knowledge gaps in the rapidly evolving area of spinal oncology. The authors are commended for their excellent work with this review. John H. Shin Boston, Massachusetts Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

State of the Art Treatment of Spinal Metastatic Disease

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Publisher
Congress of Neurological Surgeons
Copyright
Copyright © 2018 by the Congress of Neurological Surgeons
ISSN
0148-396X
eISSN
1524-4040
D.O.I.
10.1093/neuros/nyx567
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Abstract

Abstract Treatment paradigms for patients with spine metastases have evolved significantly over the past decade. Incorporating stereotactic radiosurgery into these paradigms has been particularly transformative, offering precise delivery of tumoricidal radiation doses with sparing of adjacent tissues. Evidence supports the safety and efficacy of radiosurgery as it currently offers durable local tumor control with low complication rates even for tumors previously considered radioresistant to conventional radiation. The role for surgical intervention remains consistent, but a trend has been observed toward less aggressive, often minimally invasive, techniques. Using modern technologies and improved instrumentation, surgical outcomes continue to improve with reduced morbidity. Additionally, targeted agents such as biologics and checkpoint inhibitors have revolutionized cancer care, improving both local control and patient survivals. These advances have brought forth a need for new prognostication tools and a more critical review of long-term outcomes. The complex nature of current treatment schemes necessitates a multidisciplinary approach including surgeons, medical oncologists, radiation oncologists, interventionalists, and pain specialists. This review recapitulates the current state-of-the-art, evidence-based data on the treatment of spinal metastases, integrating these data into a decision framework, NOMS, which integrates the 4 sentinel decision points in metastatic spine tumors: Neurologic, Oncologic, Mechanical stability, and Systemic disease and medical co-morbidities. Spine, Tumor, Surgery, Radiosurgery, NOMS, SRS, ESCC ABBREVIATIONS ABBREVIATIONS cEBRT conventional external beam radiation CTV clinical target volume ESCC epidural spinal cord compression GTV gross tumor volume HRQOL health-related quality of life MAS minimal access surgery MESCC metastatic epidural spinal cord compression MR magnetic resonance NSCLC nonsmall cell lung carcinoma OARs organs at risk PEEK polyether ether ketone PMMA Poly-methyl-methacrylate SINS Spinal Instability Neoplastic Score SLITT spinal laser interstitial thermotherapy SOSG Spine Oncology Study Group SRS stereotactic radiosurgery SSRS spine stereotactic radiosurgery VCF vertebral compression fractures VEGF vascular endothelial growth factor Spinal metastases are a common oncologic challenge, as 20% to 40% of cancer patients are affected during the course of their illness and up to 20% of those will become symptomatic from spinal cord compression.1-5 The magnitude of this problem is expected to grow with the exponential rise in the use of targeted therapies that have demonstrated markedly improved survivals for virtually all malignant tumors, as well as the wide-spread availability of advanced diagnostic imaging, such as magnetic resonance (MR) and [18F]fluorodeoxyglucose positron emission tomography (PET). Treatment goals for patients with spine metastases are palliative and include preservation or restoration of neurological function, improved pain control and health-related quality of life (HRQOL), and maintenance of spinal stability, all in a setting of durable local tumor control. Scoring systems such as the Tomita score6 and Tokuhashi revised score7 have traditionally been used to estimate survival in this patient population and were often the basis for treatment planning. Although tremendously useful for many years, the lack of integration of major technological and systemic cancer treatments into these predictive models render them of little value in the current era of metastatic spine tumor treatment. TABLE 1. Current NOMS Decision Framework Neurologic Oncologic Mechanical Systemic Decision Low-grade ESCC + no myelopathy Radiosensitive Stable cEBRT Radiosensitive Unstable Stabilization followed by cEBRT Radioresistant Stable SSRS Radioresistant Unstable Stabilization followed by SRS High-grade ESCC +/–myelopathy Radiosensitive Stable cEBRT Radiosensitive Unstable Stabilization followed by cEBRT Radioresistant Stable Able to tolerate surgery Decompression/stabilization followed by SRS Radioresistant Stable Unable to tolerate surgery cEBRT Radioresistant Unstable Able to tolerate surgery Decompression/stabilization followed by SRS Radioresistant Unstable Unable to tolerate surgery Stabilization followed by cEBRT Neurologic Oncologic Mechanical Systemic Decision Low-grade ESCC + no myelopathy Radiosensitive Stable cEBRT Radiosensitive Unstable Stabilization followed by cEBRT Radioresistant Stable SSRS Radioresistant Unstable Stabilization followed by SRS High-grade ESCC +/–myelopathy Radiosensitive Stable cEBRT Radiosensitive Unstable Stabilization followed by cEBRT Radioresistant Stable Able to tolerate surgery Decompression/stabilization followed by SRS Radioresistant Stable Unable to tolerate surgery cEBRT Radioresistant Unstable Able to tolerate surgery Decompression/stabilization followed by SRS Radioresistant Unstable Unable to tolerate surgery Stabilization followed by cEBRT cEBRT, conventional external beam radiation; ESCC, epidural spinal cord compression; NOMS, neurologic, oncologic, mechanical and systemic; SRS, stereotactic radiosurgery; MAS, minimal access surgeries; SLITT, spinal laser interstitial thermotherapy. Low-grade ESCC is defined as grade 0 or 1 on Spine Oncology Study Group scoring system. High-grade ESCC is defined as grade 2 or 3 on the ESCC scale. Decompression options include open surgical, MAS, SLITT. Stabilization options include percutaneous cement augmentation, percutaneous pedicle screw instrumentation, and open instrumentation. For patients with significant systemic comorbidities that affect the ability to tolerate open surgery, stabilization may be limited to cement augmentation and/or percutaneous screw augmentation. Adapted from Laufer I et al8: The NOMS framework: approach to the treatment of spinal metastatic tumors. Oncologist 18:744-51, 2013. Reproduced and modified with permission. View Large TABLE 1. Current NOMS Decision Framework Neurologic Oncologic Mechanical Systemic Decision Low-grade ESCC + no myelopathy Radiosensitive Stable cEBRT Radiosensitive Unstable Stabilization followed by cEBRT Radioresistant Stable SSRS Radioresistant Unstable Stabilization followed by SRS High-grade ESCC +/–myelopathy Radiosensitive Stable cEBRT Radiosensitive Unstable Stabilization followed by cEBRT Radioresistant Stable Able to tolerate surgery Decompression/stabilization followed by SRS Radioresistant Stable Unable to tolerate surgery cEBRT Radioresistant Unstable Able to tolerate surgery Decompression/stabilization followed by SRS Radioresistant Unstable Unable to tolerate surgery Stabilization followed by cEBRT Neurologic Oncologic Mechanical Systemic Decision Low-grade ESCC + no myelopathy Radiosensitive Stable cEBRT Radiosensitive Unstable Stabilization followed by cEBRT Radioresistant Stable SSRS Radioresistant Unstable Stabilization followed by SRS High-grade ESCC +/–myelopathy Radiosensitive Stable cEBRT Radiosensitive Unstable Stabilization followed by cEBRT Radioresistant Stable Able to tolerate surgery Decompression/stabilization followed by SRS Radioresistant Stable Unable to tolerate surgery cEBRT Radioresistant Unstable Able to tolerate surgery Decompression/stabilization followed by SRS Radioresistant Unstable Unable to tolerate surgery Stabilization followed by cEBRT cEBRT, conventional external beam radiation; ESCC, epidural spinal cord compression; NOMS, neurologic, oncologic, mechanical and systemic; SRS, stereotactic radiosurgery; MAS, minimal access surgeries; SLITT, spinal laser interstitial thermotherapy. Low-grade ESCC is defined as grade 0 or 1 on Spine Oncology Study Group scoring system. High-grade ESCC is defined as grade 2 or 3 on the ESCC scale. Decompression options include open surgical, MAS, SLITT. Stabilization options include percutaneous cement augmentation, percutaneous pedicle screw instrumentation, and open instrumentation. For patients with significant systemic comorbidities that affect the ability to tolerate open surgery, stabilization may be limited to cement augmentation and/or percutaneous screw augmentation. Adapted from Laufer I et al8: The NOMS framework: approach to the treatment of spinal metastatic tumors. Oncologist 18:744-51, 2013. Reproduced and modified with permission. View Large The integration of 4 major advances has fundamentally changed the current treatment paradigms for metastatic spine tumors: (1) The development and integration of spine stereotactic radiosurgery (SSRS) has dramatically improved local control rates independent of tumor histology and size; (2) the introduction of less invasive surgical techniques including separation surgery, minimal access techniques, and percutaneous pedicle screw instrumentation and cement augmentation has shortened recovery periods and provided an earlier return to systemic treatment; (3) spinal instability has been defined by the validated Spinal Instability Neoplastic Score (SINS) criteria and is acknowledged as an independent surgical indication; and (4) targeted therapies, such as biologics and checkpoint inhibitors, have significantly improved overall and progression-free survival for most solid tumor and hematologic malignancies. The “NOMS” framework8 was developed in order to provide a comprehensive assessment of metastatic spine tumor issues allowing integration of these new advances in cancer care. This framework facilitates complex decision making and offers a common language for treating physicians across disciplines. NOMS aids in optimizing state of the art patient care as it evolves with time, adapts to and incorporates new technologies, systemic therapy, and surgical techniques.9 The four pillars of NOMS are Neurologic, Oncologic, Mechanical, and Systemic assessments. The neurologic consideration assesses both the clinical presence of myelopathy or functional radiculopathy and the radiographic degree of epidural spinal cord compression (ESCC).10 The oncologic assessment evaluates the predicted local tumor control from radiation, chemotherapy, or surgery. The mechanical assessment evaluates spinal instability secondary to pathological fractures and serves as an independent indication for procedure-based interventions, most commonly percutaneous cement augmentation. The final assessment is that of systemic disease status and medical co-morbidities, which predicts the ability of a patient to tolerate a proposed procedure, the risk-benefit ratio of treatment, and the overall survival. The objective of this review is to outline the impact of the recent cancer care advancements in the context of this clinical decision-making paradigm (Table 1). NEUROLOGIC ONCOLOGIC (NOms) In the NOMS framework, the neurologic and oncologic considerations are assessed in combination. The neurological evaluation consists of both clinical and radiographic evaluations. The radiological assessment focuses on the degree of ESCC and the clinical evaluation of the presence of myelopathy or functional radiculopathy. Myelopathy typically correlates with radiographic evidence of high-grade ESCC; therefore, although myelopathy is a critical factor, decisions are heavily dependent on the degree of ESCC. The degree of ESCC is evaluated using a 6-point scoring system validated by the Spine Oncology Study Group (SOSG; Figure 1).10 FIGURE 1. View largeDownload slide ESCC scale.10 Grades 0 to 1c represent tumor involving the bone only or varying degrees of thecal sac compression without spinal cord compression. Grades 2 and 3 are considered to be high-grade spinal cord compression and are differentiated by whether spinal fluid signal is obliterated on T2-weighted images. Adapted from Bilsky MH et al: Reliability analysis of the ESCC scale. J Neurosurg Spine 13:324-8, 2010. Reproduced with permission. FIGURE 1. View largeDownload slide ESCC scale.10 Grades 0 to 1c represent tumor involving the bone only or varying degrees of thecal sac compression without spinal cord compression. Grades 2 and 3 are considered to be high-grade spinal cord compression and are differentiated by whether spinal fluid signal is obliterated on T2-weighted images. Adapted from Bilsky MH et al: Reliability analysis of the ESCC scale. J Neurosurg Spine 13:324-8, 2010. Reproduced with permission. From an oncologic perspective, the predicted response to available therapies is taken into account. Historically, treatment responses for osseous tumors to systemic therapies were limited, and thus, conventional external beam radiation (cEBRT), often defined as 30 Gy in 10 fractions, was the mainstay of treatment for spinal tumors.11-13 Responses to cEBRT were predicated on mitotic cell death via breakage of double-stranded DNA within a tumor, which potentially resulted in spinal cord decompression.14-16 With cEBRT, 1 to 2 beams are delivered to a treatment field, but organs at risk (OARs), particularly the spinal cord, remain within the radiation field; thus, the dose of radiation is constrained by the toxicity to OARs.17 Based on the treatment response to cEBRT, tumors are classified as either radioresistant or radiosensitive. Moderately to highly radiosensitive tumors to cEBRT include most hematologic malignancies (ie, lymphoma, multiple myeloma, and plasmacytoma), as well as selected solid tumors (ie, breast, prostate, ovarian, and neuroendocrine carcinomas and seminoma).18,19 However, most solid tumors are radioresistant to cEBRT including renal cell carcinoma, colon, nonsmall cell lung carcinoma (NSCLC), thyroid, hepatocellular carcinoma, melanoma, and sarcoma.12,13,18,19 Defining responsiveness to cEBRT is critical in terms of predicting clinical outcomes. In a number of series, favorable responders (ie, radiosensitive) are more likely to maintain ambulation or remain ambulatory longer than patients with unfavorable histologies, (ie, radioresistant) after radiation treatment.19,20 Maranzano et al15 prospectively demonstrated that 67% of breast cancer patients regained ambulation compared with 20% in hepatocellular carcinoma and further showed that myeloma, breast, and prostate had response durations of 16, 12, and 10 mo, respectively.15 Others found a low success rate of only 33% in radioresistant tumors compared to 72% of patients with favorable histologies as these exhibited combined improvement in their motor strength, functional ability, and pain scores.21 Hence, patients with radiosensitive tumors can be treated effectively with cEBRT obviating the need for surgical intervention, regardless of the degree of ESCC.11,13 However, in practice, patients with radiosensitive solid tumor malignancies who are myelopathic are usually considered for upfront surgery, as the potential to achieve immediate decompression and maximize neurological recovery with cEBRT is limited. Radiosurgery is a “Game-Changer” The technical evolution and integration of SSRS has been a true paradigm changer for the treatment of spinal metastases. The safe and effective implementation of SSRS is a result of technological advancements in noninvasive patient immobilization; intensity modulated image-guided radiation delivery systems, and sophisticated planning software.22,23 Comparisons between low- (ie, cEBRT) vs high-dose per fraction radiation (ie, SSRS) have shown differences in the radiobiologic response in animal models.24 Evidence indicates that radiation of tumors delivered with a high-dose per fraction, ie >10 Gy per fraction, not only kills tumor cells via breakage of double-stranded DNA, but also causes significant damage in tumor vasculature.25 Garcia-Barros et al26 found that stereotactic radiosurgery (SRS) increases a signal transduction platform through the acid-sphingomyelinase pathway, which in turn, results in microvascular endothelial dysfunction and apoptosis, subsequent hypoperfusion of tumor tissue, and ultimately tumor cell destruction. Additionally, the release of tumor-associated antigens and proinflammatory cytokines, secondary to both the direct radiation effect and the secondary vascular damage, initiates an immune response against the tumor.27,28 Ultimately, the ability to deliver high-dose single or hypofractionated conformal radiation enables the delivery of cytotoxic tumoral doses.29 An additional major advantage of radiosurgery over cEBRT is that these treatments are typically delivered in 1 to 3 fractions rather than 10 to 20 required for cEBRT leading to better patient compliance (Figure 2). FIGURE 2. View largeDownload slide SSRS treatment. Sixty-eight-year-old female, without a previous history of cancer, presented with back pain and was found to have a T8 lesion and a lung lesion. Due to her symptomatic presentation she underwent kyphoplasty along with a biopsy from T8 yielding metastatic adenocarcinoma consistent with adenocarcinoma of lung. No epidural tumor extension was found (ESCC grade 0) but a left paraspinal extension was noted. Along with systemic treatment, the patient underwent SSRS treatment of 24 Gy in a single treatment fraction. A, Axial MR with contrast enhancement at T8 showing the vertebral body lesion with extension to the left posterior elements with a paraspinal component. No epidural cord compression seen. B, Thirteen-month follow-up MR showing good local tumor control. C, Radiosurgery treatment plan color wash. The minimum dose in the color wash (dark blue) is set to 1920 cGy or 80%. FIGURE 2. View largeDownload slide SSRS treatment. Sixty-eight-year-old female, without a previous history of cancer, presented with back pain and was found to have a T8 lesion and a lung lesion. Due to her symptomatic presentation she underwent kyphoplasty along with a biopsy from T8 yielding metastatic adenocarcinoma consistent with adenocarcinoma of lung. No epidural tumor extension was found (ESCC grade 0) but a left paraspinal extension was noted. Along with systemic treatment, the patient underwent SSRS treatment of 24 Gy in a single treatment fraction. A, Axial MR with contrast enhancement at T8 showing the vertebral body lesion with extension to the left posterior elements with a paraspinal component. No epidural cord compression seen. B, Thirteen-month follow-up MR showing good local tumor control. C, Radiosurgery treatment plan color wash. The minimum dose in the color wash (dark blue) is set to 1920 cGy or 80%. SSRS as Definitive Therapy Recent data demonstrate that SSRS yields a clinical benefit regardless of tumor histology and volume, providing durable symptomatic responses and high local-control rates.30-32 In patients without spinal cord compression (ESCC 0-1C), SSRS can be used as definitive therapy and has largely replaced en bloc resection favored by the Tokuhashi and Tomita scoring systems even for solitary metastases.33,34 This transition is based on a plethora of outcome data demonstrating excellent outcomes with SSRS for traditionally radioresistant histologies such as renal cell carcinoma,35-37 sarcoma,38 and melanoma.39 Local control rates of 88% in the noncervical spine have been shown prospectively, independent of histology.40 A multi-institutional retrospective analysis of 387 cases treated with stereotactic body radiation therapy reported local control of 84% at 2 yr. The cohort comprised various solid tumor histologies and the median treatment dose was 8 Gy in 3 fractions.41 Other series have demonstrated similar conclusions.42,43 Recently, Yamada et al30 described a case series of 811 lesions treated in 657 patients with a single-fraction SSRS in which dose was analyzed as a continuous variable ranging from 18 to 26 Gy. The median dose that covered 95% of the planning target volume (PTV D95) was 1644 cGy in the low-dose group compared to 2240 cGy in the high-dose group. Local failure rates for the low- and high-dose groups were 5% vs 0.41% at 12 mo, 15% vs 1.6% at 24 mo, and 20% vs 2.1% at 48 mo, respectively. In this study, 82% of the tumors were traditionally radioresistant and 50% had failed prior cEBRT, but tumor responses were found to be independent of both tumor histology and prior radiation for the high-dose cohorts.30 Thus, SSRS yields a clinical benefit regardless of histology, providing a durable symptomatic response and high local-control rates, but these responses appear to be dose dependent.30-32 SSRS Spine Volumes While dose is important, the contoured tumor volume is also critical. To unify treatment planning, the International Spine Radiosurgery Consortium updated contouring and planning guidelines for spinal radiosurgery planning44,45 and recent consensus guidelines have also been created for postoperative target contouring.46 It is important for treating spine surgeons to be familiar with these guidelines and actively participate in the treatment planning. One of the most important revelations is the concept that one cannot simply treat the gross tumor volume (GTV), ie the radiographically defined tumor volume, but must treat a clinical target volume (CTV), which accounts for the high probability of microscopic spread through contiguous marrow spaces. Contouring at CTV is different from intracranial SRS for brain metastases that only accounts for the GTV. Radiographic Response Assessment to SSRS With improved tumor control, another emerging consideration is the radiographic response assessment to radiation. In order to standardize practice and follow-up, the Spine response assessment in Neuro-Oncology group published criteria for imaging-based assessment of local control and pain for spinal metastases.47 They presented recommendations in treatment planning, endpoint definitions, and follow-up practice. Currently, dynamic contrast-enhanced perfusion images48 are utilized to assess the viability of tumors. These images appear to be sensitive and specific for assessing treatment responses following SSRS and changes are seen earlier than using standard MR imaging.48,49 SSRS Toxicity The balance between underdosing the tumor margins resulting in tumor progression vs overdosing and damaging OARs is extremely delicate. Constraints have been established for all major OARs.50,51 Fortunately, high-grade toxicity after SSRS occurs infrequently and most of the observed complications are mild52 including esophagitis, mucositis, dysphagia, diarrhea, paresthesias, transient laryngitis, and radiculitis.53-58 Vertebral compression fractures (VCF) following SSRS have been described in up to 40% of treatments compared with a less than 5% risk following cEBRT.59 A multi-institutional analysis found that VCF following SSRS is more likely to occur following treatment with high doses.60 Saghal et al61 suggested that caution be observed when treating with ≥20 Gy per fraction, particularly for high-risk patients. Risk factors identified are older age, a lytic session, vertebral malalignment, or the presence of a preexisting VCF and therefore some advocate pretreatment kyphoplasty in select patients.59,62,63 However, the fracture rate of 40% captured all radiographic fractures, but the symptomatic fracture rate requiring an intervention is only 7% at 5-yr follow-up.64 An ongoing controversy regarding dose-dependent fracture risk has yet to be resolved, but the demonstrated control rates at higher doses combined with the ability to stabilize most fractures with the low-risk of morbidity associated with percutaneous cement augmentation may justify more aggressive dosing. The spinal cord is the most critical OAR. A multi-institutional review reported a 0.5% (6/1075) risk of radiation-induced myelopathy with 50% of the injuries occurring at an 8 Gy equivalent dose to the spinal cord.65 Yamada et al30 analyzed 476 patients treated with SSRS and found only 2 patients (0.42%) who developed self-limited, steroid-responsive myelopathy. In patients undergoing initial SSRS, spinal cord constraints have been defined as 10 Gy to 10% of the spinal cord or a cord Dmax of 14 Gy. The tight dose constraints on the spinal cord currently prevent the treatment of high-grade ESCC. Bishop et al66 evaluated 332 treatments for predictors of local failure and found that patients with local relapse had poor tumor volume coverage, likely due to prioritizing the spinal cord constraints over tumor coverage. Lovelock et al17 found that all radiation failures occurred when less than 15 Gy was delivered to the CTV; thus, with a cord Dmax of 14 Gy and a 10% per mm fall-off, treatment of ESCC risks overdosing the spinal cord resulting in myelopathy or underdosing resulting in progressive ESCC. An early report exploring the treatment of high-grade ESCC with SSRS demonstrated this effect as a significant number of patients harboring radioresistant tumors experienced neurologic progression.67 Current spinal cord constraints prohibit the use of SSRS in the setting of high-grade ESCC. For this reason, patients with high-grade ESCC secondary to radioresistant tumors require surgical decompression. NEUROLOGIC/ONCOLOGIC SURGICAL INDICATIONS: HIGH-GRADE ESCC FROM RT-RESISTANT TUMORS Given the poor responses seen to cEBRT and the inability to deliver a cytotoxic SSRS-dose within spinal cord constraints, the SOSG in a systematic literature review made a strong recommendation for surgical stabilization and decompression in patients with radioresistant tumors in the setting of high-grade spinal cord compression.34 Patchell et al68 provided class I evidence in support of direct surgical decompression for patients with solid tumor metastases resulting in ESCC and/or neurologic deficit. In this trial, patients randomized to the surgical arm had longer overall survival, improved ambulation, and better preservation of bowel and bladder function compared to those randomized to radiation alone. This trial also highlighted the need for improved techniques for durable local tumor control, as 70% of the patients in this trial had local disease recurrence at 1-yr.68 Similarly, others have demonstrated that the completeness of resection was an independent predictor of time to recurrence, yet also emphasized the need for more durable tumor control as the 1- and 4-yr local failures rates were 70% and 96%, respectivley.69 The acknowledgment that “bad tumor biology will overcome good surgery” along with the technological advancement that led to SSRS have changed the aggressiveness; however, the indications for surgery from a neurologic and oncologic assessment remain the same, ie, high-grade spinal cord compression with or without myelopathy secondary to radioresistant tumors. Neural Protection: Timing of Surgery and Steroid Dosing A systematic review concluded that the duration and severity of neurologic deficit predict neurological recovery in patients with metastatic epidural spinal cord compression (MESCC).70 Hence, efforts to reduce the duration of ambulation loss and to prevent progression of neurologic deficits should be made to improve the probability of neurologic recovery. High-quality data on the efficacy of steroids in MESCC are lacking. Based on low-level quality evidence, it was recently shown that steroid therapy administered immediately following diagnosis of MESCC and followed by definitive treatment may increase the proportion of patients maintaining ambulation at 1-yr post-therapy with no clear effect on bowel and bladder function or survival. The authors conclude, on the basis of the evidence available, an initial 10 mg intravenous bolus of dexamethasone followed by 16 mg PO daily has been associated with fewer complications compared with 100 mg bolus and 96 mg daily. Weaning of steroids should occur rapidly after definitive treatment.71 Of note, all of the data supporting the use of dexamethasone are based on radiotherapy treatment of MESCC. To date, the role of dexamethasone in patients undergoing decompressive surgery has not been studied. Trends toward Less Invasive Surgery Hybrid Therapy: Separation Surgery and SSRS In recent years, we have seen a transition from treatment with aggressive cytoreductive surgeries, such as en bloc spondylectomy or gross total resection, to reliance on SSRS to provide the oncologic goal of tumor control.34 Hybrid therapy refers to the combination of SSRS and separation surgery. The term “separation surgery” describes a posterolateral approach that allows for stabilization and circumferential decompression of the thecal sac and nerve roots. Spinal cord decompression is ensured by resecting the posterior longitudinal ligament with reconstitution of the thecal sac. The goal of the spinal cord decompression is neurologic preservation or recovery, but also to creating an ablative target for SSRS within spinal cord constraints. SSRS-treatment failures occur when less than 15 Gy are delivered to a portion of the CTV,17 and this dose cannot be delivered to the entire tumor margin without risking spinal cord injury unless a safe distance between the tumor and the spinal cord is created.53 To safely deliver an appropriate radiation dose, patients with high-grade ESCC caused by radioresistant tumors undergo separation surgery;8,72 however, due to the ability to deliver an ablative SSRS dose to the entire tumor volume, large paraspinal masses and vertebral body tumors do not need to be resected in order to achieve durable local tumor control. In a retrospective review of 186 patients, Laufer et al73 found postoperative adjuvant SSRS following separation surgery is safe and effective in achieving durable local tumor control.73 In this series, patients who received high-dose hypofractionated SRS (ie, 24-30 Gy in 3 fractions) demonstrated 1-yr local progression rates of less than 5% and the local progression rate after single-fraction SSRS (ie, 24 Gy) was less than 10%.73 There was no impact of radioresistant tumor histology, prior radiation, or the degree of preoperative epidural extension on recurrence rates and no patient suffered a neurological complication; however, it should be noted that these results were superior to the results of low-dose hypofractionated SSRS (ie 30 Gy in 5 fractions). Similarly, Moulding et al74 reported a 1-yr local failure risk of only 6.3% using high-dose (18-24 Gy) single fraction SRS after separation surgery and Rock et al75 reported a 92% local control rate in patients treated with radiosurgery following open surgical procedures (Figure 3). The importance of achieving adequate surgical decompression to reconstitute the thecal sac has been emphasized by Al-Omair et al76 who showed that patients who postoperatively had continued compression of the spinal cord had a significantly higher risk of local recurrence after postoperative SSRS compared to patients with sufficient separation between the tumor and the spinal cord. FIGURE 3. View largeDownload slide Separation surgery. Eighty-three-year-old female with a history of NSCLC. She underwent a routine PET-CT that demonstrated pathological fracture of T10 and a PET avid lesion with erosion of the posterior cortex of the vertebral body suggestive of spinal canal involvement. MRI demonstrated high-grade spinal cord compression (ESCC 3) at T10. Neurologically intact at presentation with mild chronic back pain. Due to the high-grade cord compression with a radioresistant tumor she underwent separation surgery followed by SSRS. A, Preoperative sagittal T1 noncontrast MRI. Note the compression at T10 (white arrow). B, Preoperative axial MRI with contrast enhancement demonstrating the ESCC3 compression. C, Postoperative x-ray demonstrating the typical construct extending from 2 levels above to 2 levels below the index level. D, Postoperative CT (computed tomography) myelogram showing reconstitution of the thecal sac at the index level. FIGURE 3. View largeDownload slide Separation surgery. Eighty-three-year-old female with a history of NSCLC. She underwent a routine PET-CT that demonstrated pathological fracture of T10 and a PET avid lesion with erosion of the posterior cortex of the vertebral body suggestive of spinal canal involvement. MRI demonstrated high-grade spinal cord compression (ESCC 3) at T10. Neurologically intact at presentation with mild chronic back pain. Due to the high-grade cord compression with a radioresistant tumor she underwent separation surgery followed by SSRS. A, Preoperative sagittal T1 noncontrast MRI. Note the compression at T10 (white arrow). B, Preoperative axial MRI with contrast enhancement demonstrating the ESCC3 compression. C, Postoperative x-ray demonstrating the typical construct extending from 2 levels above to 2 levels below the index level. D, Postoperative CT (computed tomography) myelogram showing reconstitution of the thecal sac at the index level. Minimal Access Surgery Prompt postoperative recovery and return to oncologic treatment is a key goal in patients with spinal tumors. The utilization of minimal access surgery (MAS) techniques for this population are gaining popularity as they entail limited perioperative morbidity, allow for quick recovery, and have shown to lead to less blood loss, low transfusion rates, and short hospitalizations.77-80 Conventional radiation can sometimes be started within 1 wk of MAS surgery and SSRS can be delivered immediately, unlike open surgeries where the risk of wound complications frequently delays radiation therapy.81,82 Current MAS techniques for the treatment of spinal metastases include percutaneous instrumentation, mini-open approaches for decompression,83 and tumor removal with or without tubular/expandable retractors and thoracoscopy/endoscopy. Tatsui et al 84,85 pioneered the use of spinal laser interstitial thermotherapy (SLITT) for ESCC as they describe decreased pain and improved quality of life at 3 mo without disruption of systemic therapy. Other surgical adjuncts such as intraoperative navigation are likewise currently being utilized86 and the technological advancement is likely to continue to advance this field. The surgical treatment of spinal metastases across institutions is variable and controversial because much of the literature principally reflects single institution case series. A recent systematic review highlights the lack of uniformity in treatment and reporting for decompressive surgery for the treatment of MESCC.87 Another recent systematic literature review found that although some studies have shown superiority of outcomes using MAS techniques, especially using “mini-open” decompression, the available data are still of low quality and strong recommendations cannot be made.88 It is important to acknowledge that some centers and literature still support more aggressive surgeries including en bloc resections,89 particularly in the setting of solitary renal cell and thyroid spine metastases. More aggressive open surgical strategies including corpectomies and combined anterior–posterior approaches90,91 are sometimes necessary with severe instability and/or deformity; however, these are becoming less frequent due to enhanced collaboration between oncologists and surgeons allowing for earlier treatment especially in the setting of SSRS. In centers and regions without SSRS, treatment should follow well-established paradigms of more aggressive surgeries especially in metastases with known resistance to cEBRT. Optimizing Spine Implants for Oncologic Indications Surgical implants are improving spine stabilization and postoperative imaging quality to evaluate for recurrence. Polyether ether ketone (PEEK) and carbon-fiber-reinforced PEEK are currently available materials used for pedicle screw-rod systems and vertebral body replacement cages. Their radiolucent property permits improved, artifact-free radiographic imaging. The modulus of elasticity is similar to bone, lessening the risk of subsidence, but it provides strength similar to titanium constructs.92 Poly-methyl-methacrylate (PMMA) bone cement is commonly used, allowing custom shaping of supports and constructs at the time of surgery for anterior column support.93 Preliminary reports demonstrate safety and efficacy of radiation using both PEEK94 and PMMA95 materials. The use of robotic technologies96 is growing and 3-dimensional printing of plastic polymer or titanium constructs emerges, allowing for custom implants to be created for individual patients, and is expected to be available for use in the future. Timing of Postoperative Radiation Radiation therapy is known to impair wound tissue repair through multiple mechanisms and surgical wound complications following radiation treatment remains a major concern.97,98 Keam et al99 evaluated wound complication rates occurring in patients receiving cEBRT compared to SSRS before undergoing spine surgery and found no significant differences.99 Importantly, they conclude that preoperative SSRS is associated with clinically acceptable rates of wound morbidity.99 Surgeons tend to wait several weeks before operating after cEBRT. A systematic review emphasized the lack on uniform data reporting, but suggested a 1 wk interval between surgery and SSRS based on animal models and limited human studies.100 Intraoperative Radiation: Brachytherapy Despite technologic advancement in SSRS, spinal cord toxicity remains a problem, particularly in the setting of circumferential tumor around the spinal dura and previously irradiated targets.17,53,101,102 An appealing solution to delivering therapeutic dose to dural margin using a short-range source is the use of single-dose intraoperative brachytherapy.103 This short-range delivery strategy allows treating the surface with a high dose, single fraction of 25 Gy while sparing the spinal cord (considering a prescription of 10 Gy to 1 mm). Initial reports used rigid plaques incorporating 192Ir- and 90Y-based sources with a polycarbonate backing,104 yet these were not found clinically useful due to the fabrication process, short half-life, and inflexibility of the device. The P32 plaque delivers a very high dose with a steep dose fall-off making it an ideal dural radiation plaque. This plaque has a relatively long half-life and does not require special intraoperative shielding. In small series, P32 has been shown to a useful adjunct to surgical intervention following epidural decompression.105-107 MECHANICAL STABILITY (noMs) In the NOMS framework, mechanical instability serves as an indication for surgery regardless of the degree of ESCC or the radiosensitivity of the tumor, as radiotherapy and systemic therapy do not restore mechanical stability of the spine. The SOSG defined spinal instability as a “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.”108 To facilitate the assessment of mechanical stability and to unify reporting and decision making across institutions, the SOSG developed a scoring system; the SINS (Table 2).108 SINS evaluates 6 parameters: location, pain, alignment, lesion character (ie, osteolysis), vertebral body collapse, and posterior element involvement. High SINS scores (13-18) reliably predict the need for surgical stabilization while low SINS scores (0-6) are considered stable and the intermediate SINS (7-12) tumors needs further refinement, but essentially the need for treatment is based on the discretion and experience of the spine surgeon.109 TABLE 2. SINS Component Scoring SINS component Score Location Junctional (occiput-C2, C7-T2, T11-L1, L5-S1) 3 Mobile spine (C3-C6, L2-L4) 2 Semi-rigid (T3-T10) 1 Rigid (S2-S5) 0 Pain Yes 3 Occasional pain but not mechanical 1 Pain-free lesion 0 Bone lesion Lytic 2 Mixed (lytic/blastic) 1 Blastic 0 Radiographic spinal alignment Subluxation/translation present 4 De novo deformity (kyphosis/scoliosis) 2 Normal alignment 0 Vertebral body collapse >50% collapse 3 <50% collapse 2 No collapse with >50% body involved 1 None of the above 0 Posterolateral involvement of spinal elements Bilateral 3 Unilateral 1 None of the above 0 Total Stable 0-6 Indeterminate 7-12 Unstable 13-18 SINS component Score Location Junctional (occiput-C2, C7-T2, T11-L1, L5-S1) 3 Mobile spine (C3-C6, L2-L4) 2 Semi-rigid (T3-T10) 1 Rigid (S2-S5) 0 Pain Yes 3 Occasional pain but not mechanical 1 Pain-free lesion 0 Bone lesion Lytic 2 Mixed (lytic/blastic) 1 Blastic 0 Radiographic spinal alignment Subluxation/translation present 4 De novo deformity (kyphosis/scoliosis) 2 Normal alignment 0 Vertebral body collapse >50% collapse 3 <50% collapse 2 No collapse with >50% body involved 1 None of the above 0 Posterolateral involvement of spinal elements Bilateral 3 Unilateral 1 None of the above 0 Total Stable 0-6 Indeterminate 7-12 Unstable 13-18 Reproduced with permission from Fisher CG, DiPaola CP, Ryken TC, et al. A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group. Spine. Oct 15 2010;35(22):E1221-1229.108 View Large TABLE 2. SINS Component Scoring SINS component Score Location Junctional (occiput-C2, C7-T2, T11-L1, L5-S1) 3 Mobile spine (C3-C6, L2-L4) 2 Semi-rigid (T3-T10) 1 Rigid (S2-S5) 0 Pain Yes 3 Occasional pain but not mechanical 1 Pain-free lesion 0 Bone lesion Lytic 2 Mixed (lytic/blastic) 1 Blastic 0 Radiographic spinal alignment Subluxation/translation present 4 De novo deformity (kyphosis/scoliosis) 2 Normal alignment 0 Vertebral body collapse >50% collapse 3 <50% collapse 2 No collapse with >50% body involved 1 None of the above 0 Posterolateral involvement of spinal elements Bilateral 3 Unilateral 1 None of the above 0 Total Stable 0-6 Indeterminate 7-12 Unstable 13-18 SINS component Score Location Junctional (occiput-C2, C7-T2, T11-L1, L5-S1) 3 Mobile spine (C3-C6, L2-L4) 2 Semi-rigid (T3-T10) 1 Rigid (S2-S5) 0 Pain Yes 3 Occasional pain but not mechanical 1 Pain-free lesion 0 Bone lesion Lytic 2 Mixed (lytic/blastic) 1 Blastic 0 Radiographic spinal alignment Subluxation/translation present 4 De novo deformity (kyphosis/scoliosis) 2 Normal alignment 0 Vertebral body collapse >50% collapse 3 <50% collapse 2 No collapse with >50% body involved 1 None of the above 0 Posterolateral involvement of spinal elements Bilateral 3 Unilateral 1 None of the above 0 Total Stable 0-6 Indeterminate 7-12 Unstable 13-18 Reproduced with permission from Fisher CG, DiPaola CP, Ryken TC, et al. A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group. Spine. Oct 15 2010;35(22):E1221-1229.108 View Large Stabilization Traditionally, stabilization was achieved via open surgery with data showing low complication rates. In an analysis of 318 patients who underwent separation surgery for solid malignancies, 2.8% experienced hardware failure.110 With the growing interest in MAS techniques, percutaneous stabilization is revolutionizing stabilization in cancer as it enables preservation of muscle attachments and posterior elements (Figure 4).111 This strategy has been shown to be a safe and effective option for palliation of mechanically unstable, cancer-related, VCFs with posterior element involvement.111,112 Bone quality in cancer patients is typically poor due to the osteolytic metastases, chemotherapy, radiation, and other co-morbidities, such as osteoporosis. To overcome screw failure, several strategies have been developed in both an open and MAS setting. Fenestrated pedicle screws allow the injection of PMMA bone cement through the screw into the vertebral body, decreasing the risk of screw pull-out.113,114 Alternatively, expandable screws contain an internal mechanism that shortens the screw and allows a slotted tip to expand, thus increasing the screw purchase with the bony surface.115 These technologies seem promising, but have yet to be validated in large scale clinical studies. FIGURE 4. View largeDownload slide Percutaneous stabilization. Seventy-six-year-old female with metastatic urothelial carcinoma and large disease burden with metastases to bone, liver, lung and lymph nodes. Presented with severe debilitating mechanical back pain and evidence of pathological T10 vertebral body fracture found on CT. MRI demonstrated low-grade cord compression (ESCC 1C) at T10. SINS score 14. Due to the debilitating pain, unstable spine, radioresistant tumor but low-grade cord compression she underwent a stabilizing procedure (without decompression) followed by SSRS. Procedure of choice was T9-11 percutaneous stabilization with cement augmented screws and T10 kyphoplasty. A, Preoperative sagittal CT demonstrating the compression fracture at T10. B, Preoperative axial T2 MRI showing ESCC 1C. C, Sagittal and D, Anterior–posterior (AP) x-rays demonstrating the stabilizing construct. FIGURE 4. View largeDownload slide Percutaneous stabilization. Seventy-six-year-old female with metastatic urothelial carcinoma and large disease burden with metastases to bone, liver, lung and lymph nodes. Presented with severe debilitating mechanical back pain and evidence of pathological T10 vertebral body fracture found on CT. MRI demonstrated low-grade cord compression (ESCC 1C) at T10. SINS score 14. Due to the debilitating pain, unstable spine, radioresistant tumor but low-grade cord compression she underwent a stabilizing procedure (without decompression) followed by SSRS. Procedure of choice was T9-11 percutaneous stabilization with cement augmented screws and T10 kyphoplasty. A, Preoperative sagittal CT demonstrating the compression fracture at T10. B, Preoperative axial T2 MRI showing ESCC 1C. C, Sagittal and D, Anterior–posterior (AP) x-rays demonstrating the stabilizing construct. Kyphoplasty/Vertebroplasty and Radiofrequency Ablation Current evidence strongly supports kyphoplasty and vertebroplasty for symptomatic compression fractures due to metastatic disease.116-119 Kyphoplasty, by temporarily inflating a balloon within the affected vertebral body, creates a cavity that can be filled with bone cement and may also permit reduction of a wedge fracture.120 Berenson et al118 provided prospective randomized data, in the CAFÉ study, showing significant pain reduction and improvement in disability indexes that persist for up to 6 mo when kyphoplasty was performed compared to a noninterventional control arm. Other data further support kyphoplasty for symptomatic osteolytic tumors to control pain, provided that no overt instability or myelopathy is present.116,117 Similarly, pain reduction has been shown after vertebroplasty in patients with spinal metastases.121 Technically, the insertion technique for a radiofrequency electrode is similar to percutaneous cement augmentation. Hence, radiofrequency ablation can be performed at the same time as percutaneous cement augmentation, or as an independent procedure to destroy tumor tissue within the vertebral body.122 Long-term outcomes are unclear, but this technology may be a useful addition to the minimally invasive methods available for palliative treatment.123 SYSTEMIC DISEASE (nomS) The Systemic evaluation of NOMS relates to the patients co-morbidities, overall disease burden, and ability to withstand the proposed treatment. As treatment for metastatic spine disease is of palliative nature, estimation of the expected survival and overall risk-benefit ratio are of great importance. Treatment goals are focused on whether the patients are likely to adequately recover from the indicated procedure and continue systemic therapy. Prognostication Several scoring systems such as the Tokuhashi revised score,7 the Tomita score,6 and the Bauer modified score124,125 have been developed to estimate expected survival in patients with spinal metastases. Over time and with the integration of modern cancer care, their utility has been questioned and reliability is currently uncertain.126,127 New prediction models attempt to overcome the shortcomings of these models with increased survival times and next generation therapies by identifying more prognostic factors associated with outcomes. The Skeletal Oncology Research Group created a nomogram to estimate survival for patients with spine metastatic disease.128 This method has been externally validated and shown to accurately estimate 3- and 12-mo survival for operable spine metastatic disease.129 Patients should be considered for surgery as long as reasonable systemic therapy is available for the postoperative period, in general, without adhering strictly to rigid prediction models. Targeted Agents: The Impact of Biologics and Checkpoint Inhibitors Modern tools allow for the assessment of genomic and proteomic alterations and epigenetic and posttranslational modifications at the molecular level.130 Genetic analysis leading to revolutionary molecular therapeutics including receptor tyrosine kinases, immune checkpoint inhibitors, and vaccine-based cancer treatments have been described in metastatic melanoma, lung cancer, renal cell cancer, breast cancer, and prostate cancer.131,132 These tools have been studied largely in nonspinal tumors, yet interest on the effect they may have on spine cancer care is growing.133,134 The treatment of metastatic melanoma has been groundbreaking as it is currently known that those with positive BRAF mutation may also respond well to immunotherapy with improved survival even in advanced metastatic disease.135 Median survivals of over 2 yr have been described for NSCLC positive for epidermal growth factor receptor mutation136 and renal cell carcinoma which was traditionally considered resistant to traditional chemotherapy, may respond well to new immunotherapies.137 Promising therapeutic results have been demonstrated combining ionizing radiation and immune checkpoint inhibitors including CTLA-4 and PD-1inhibitors, such as Ipilimumab, Nivolumab, and Pembrolizumab. The abscopal effect was first described by Postow et al,138 in a case report describing the induction of metastatic tumor regression at sites distant from the original radiation therapy location. Following this observation, studies showed that radiotherapy enhances the immune system and then checkpoint inhibitor therapy expands the patient's activated T-cell population inducing tumor cell-specific killing.138 This effect is suspected to be better associated with hypofractionated rather than single-fraction radiation therapy139 and was also shown in murine models.140 Vascular endothelial growth factor (VEGF) inhibitors may also act in synergy with radiation. Axitinib, an oral TKI-VEGF inhibitor has been used in murine models in combination with SRS to inhibit the acid sphingomyelinase pathway that leads to endothelial dysfunction, potentially acting as a radiosensitizer.141 Albeit the fact that systemic therapy is considered to be more effective for visceral than for osseous disease, it may still have an important role in the treatment of spine metastases, particularly when combined with SSRS. Critical Review of Outcomes HRQOL assessments are gaining interest, particularly with patient-reported outcome measures that provide a deep insight to treatment benefits and limitations. Wang et al142 prospectively report significant and lasting reduction in pain at 6 mo after stereotactic body radiation therapy with other series supporting these findings.143,144 In a prospective multicenter study, Fehlings et al145 showed that surgery, as an adjunct to radiation and chemotherapy, provides improvement in HRQOL measures with acceptable risks. Another prospective cohort study,146 from the Global Spine Tumor Study Group database, analyzed 922 consecutive patients with spinal metastases who underwent surgery, showing that physical functioning score improved rapidly after surgery and these improvements were sustained in those patients who survived up to 2 yr after surgery. CONCLUSION Despite major radiation and medical advancements in cancer care, surgery still plays a major role in the treatment paradigm for patients with spinal metastases. Surgery is particularly important for those with high-grade ESCC necessitating separation of the epidural tumor from the spinal cord, but also for spinal stabilization as facilitated by SINS. MAS techniques and improved implants and technologies offer less surgical-related morbidity and rapid continuation of systemic therapies. The integration of SSRS has revolutionized treatment and overcoming radioresistance is a major step in achieving durable tumor control. 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Rapid improvements in pain and quality of life are sustained after surgery for spinal metastases in a large prospective cohort . Br J Neurosurg . 2016 ; 30 ( 3 ): 337 - 344 . Google Scholar CrossRef Search ADS PubMed COMMENT In this invited review on the treatment of metastatic tumors to the spinal column, the authors provide a thorough and thoughtful discussion of the evolving treatment options available for patients with spinal metastases. The authors provide historical context for the evolution of stereotactic radiosurgery as it applies to the spine and the significance of local tumor control, particularly in the postoperative setting. The radiobiology, benefits, and limitations of stereotactic radiosurgery are discussed with focus on how such technology can be integrated into multi-modality decision making. The authors also highlight several major advances that have significantly changed the treatment paradigm for spinal metastases including separation surgery, the characterization of spinal column instability in the oncologic setting, and a greater understanding and appreciation for evolving systemic therapies such as checkpoint inhibitors and the molecular profiling of solid tumor malignancies. Learning how to clinically integrate these factors, especially the latter, to better the lives of these patients is an ongoing challenge and requires further investigation. Extensively referenced, this review is an excellent resource for anyone who seeks to update any knowledge gaps in the rapidly evolving area of spinal oncology. The authors are commended for their excellent work with this review. John H. Shin Boston, Massachusetts Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

NeurosurgeryOxford University Press

Published: Feb 22, 2018

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