Case Report

Radiotherapy and Surgical Treatment of Metastatic Breast Cancer of the Spine

Hobbs JG2, Morshed RA3, Young JS2, Desai B1 and Mehta AI1*
1Department of Neurosurgery, University of Illinois at Chicago, USA
2Department of Neurosurgery, University of Chicago, USA
3Department of Neurological Surgery, University of California, USA

*Corresponding author: Ankit Mehta, Department of Neurosurgery, University of Illinois at Chicago, 912 South Wood Street M/C 799, Chicago, IL 60612, USA

Published: 24 Jun 2016
Cite this article as :Hobbs JG, Morshed RA, Young JS, Desai B, Mehta AI. Radiotherapy and Surgical Treatment of Metastatic Breast Cancer of the Spine. Clin Surg. 2016; 1: 1038.


Metastatic vertebral column tumors are found in up to 20% of cancer patients, and of these, a percentage will go on to develop compression of eloquent neurological structures. Neurosurgeons often encounter these patients in an emergent situation, and decisions regarding care must be made in an expedient manner. However, many treatment paradigms depend on the histology of the causative lesion. One of the most common malignancies that metastasize to the spine in today’s practice is breast cancer. Current standards of treatment revolve around utilization of radiation therapy through conventional external beam radiation therapy (cEBRT) for treatment of the pathological lesions with surgery reserved for select cases. Stereotactic radiosurgery (SRS)/ stereotactic body radiotherapy (SBRT) for spinal metastases is another exciting treatment avenue for patients with new data delineating its use on the horizon. In this review, we focus on the evolving treatment paradigms and future areas of investigation needed for spinal metastatic lesions with an emphasis on evidence for breast cancer lesions.
Keywords: Metastatic; Breast cancer; Spine; Stereotactic; Radiation

Metastatic Vertebral Column Tumors

Current estimates suggest spinal metastasis occurs in 20% of all cancer patients [1,2], with 5-20% of patients developing spinal cord compression [3-5]. However, as systemic therapies continue to improve and patient longevity increases, the incidence of spinal column metastasis will continually rise, with some suggesting the incidence as high as 40% of all cancer patients at some point during their disease course [2,6]. The most commonly encountered histologies in vertebral column metastases are breast, prostate, and lung cancer [7], with spinal lesions often found following diagnosis of a primary cancer. However, in 10% of patients with spinal metastases, it accounts for the first manifestation of an unknown primary tumor [8].

An estimated 1.4 million cases of breast cancer are newly diagnosed annually worldwide,representing the leading cause of cancer death among females in economically developing countries [9,10]. At the time of breast cancer diagnosis, roughly 5 percent of women have metastatic disease [11,12]. Of the metastatic lesions of breast cancer, bone metastases (with secondary spinal cord compression, pain, fractures, hypercalcemia) are the most common [10]. Jensen and colleagues found that among patients with bone metastases at the time of diagnosis, up to 43% develop skeletal events (pathological fracture, spinal cord compression, etc.), with subsequent surgical and radiation therapy [10,13].

In terms of location, approximately 95% of patients with spinal metastases will have epidural disease, with most pathology located in the vertebral body or pedicles, 5% will have intradural, and only 1% of patients will harbor intramedullary metastases [14,15]. Most symptomatic metastases occur in the thoracic spine, followed by cervical and lumbar, with the incidence being directly proportional to the higher number of vertebra and smaller canal diameter [16].

Survival in these patients is multifactorial, depending on primary tumor histology, systemic disease status, and comorbidities [17]. In general however, prognosis is poor with only 10-20% 2-year survival rate for all patients with spinal metastases. To this end, treatment of spinal metastases is purely palliative.

Current goals of treatment are usually related to improvement in a patient’s quality of life by
addressing pain control and preservation of neurological function, but goals may also include stabilization of the spine and local control of the disease [17].

As treatment modalities continue to improve and new technologies enter the clinical realm, the decision algorithm for management of these lesions will continue to evolve as new evidence arises. For example, advances in surgical techniques have allowed for more minimally destructive decompression and instrumentation techniques, while advances in radiotherapy has allowed once surgical diseases to be treated in a non-operative fashion.

In this paper, we will discuss the role of RT in the management of spinal metastases, with a focus on breast histology, which has for the most part become a non-surgical disease outside of a few circumstances, and to what extent do neurosurgeons play a role.

Role of Radiotherapy in the Management of Metastatic Spine Disease

The role for radiation therapy in metastatic spinal disease is a part of an emerging multidisciplinary approach to therapy with medical and surgical providers being paramount to effective treatment.

The Neurologic, Oncologic, Mechanical, and Systemic (NOMS) decision framework developed by a group at Memorial SloanKettering Cancer Center (MSKCC) provides a pragmatic approach to decision making regarding therapies for metastatic spinal cord compression [17]. An extensive discussion of this framework is outside the scope of this paper, but the oncologic assessment in this system provides a valuable tool for understanding and deciding on radiation treatments for these patients.

The oncological assessment is based on the particular histologic diagnosis derived from the metastatic lesion and its response to current available therapies. Apart from conservative monitoring, radiation therapy provides the least invasive form of local tumor control and is an appealing primary treatment modality for patients unsafe for or unwilling to undergo surgical therapy, while also being utilized as adjuvant therapy after surgical debulking procedures. Primary histologies are categorized as either radiosensitive or radioresistent. This delineation is based on their responsiveness to conventional external beam radiation therapy (cEBRT) [17]. This modality is delivered in an imprecise conformal manner with one or two radiation beams to a selected target area [17]. The fraction dose that can be delivered using cEBRT is significantly limited by the spinal cord and cauda equina that are often apart of the radiation field. The toxicity limits of eloquent structures will be discussed later; however, as an attempt to circumvent this pitfall, imaged guided radiation therapy (IGRT) administration has been developed to allow high doses of radiation to be delivered in close proximity to the spinal cord, maintaining safe doses to these eloquent structures while allowing tumoricidal doses the planned oncologic targets [17]. Examples of IGRT therapy include stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT). These modalities allow for the delivery of a conformal, high radiation dose to the targeted tumor volume with a steep fall-off dose gradient, which protects adjacent, often eloquent structures, delivered by a convergence of multiple beam orientations. SRS delivered in 1 fraction, and SBRT delivered in 2 to 5 fractions, provide certain benefits over cEBRT [17].

Current radiation therapy (RT) dosing, based on randomized, controlled trials, along with meta-analyses, have shown excellent
pain control and minimal side effects with a number of fractionation schemes (30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, or 8 Gy in one fraction [18-21]. In fact, the recently published American Society for Therapeutic Radiation Oncology Task Force Guidelines found no evidence that a single fraction of 8 Gy was inferior to more prolonged RT course for pain relief, though single fraction dosing is associated with a 20% repeat treatment incidence compared to 8% with fractionated RT [22]. As stated above, cEBRT is limited by the tolerance of surrounding structures, which leads can lead to sub therapeutic dose delivery in terms of tumor control probability [23]. In patients with poorly anticipated length of survival from their systemic disease, this may not be problematic. But for disease states with a prolonged survival, cEBRT becomes less appealing due to the decreased probability of long-term tumor control for more resistant histologies. Other benefits of SBRT/ SRS include minimizing the volume of bone marrow irradiated to include only the affected areas, allowing the continuation of systemic therapies and decreasing risk of affecting blood counts compared to cEBRT, convenience of patients due to smaller number and shorter duration of outpatient visits for dosing, minimal radiation to the adjacent normal tissue while maximizing target dose, and decreased fusion/instrumentation failure compared to cEBRT in post-operative RT [24].

Prior to initiating therapy, the patient is immobilized for highresolution CT and non-contrasted magnetic resonance imaging (MRI) for treatment planning. The CT allows visualization of the sclerotic and lytic components of the pathology, while the MRI provides delineation of soft tissue structures and the extent of disease beyond the bony vertebral segment. These images are then fused for treatment planning with the following parameters defined. Gross tumor volume (GTV) is the radiographically visible tumor based on the fused imaging, encompassing the sclerotic and lytic pathology of the CT scan with the additional soft tissue extension and any signal change visualized on the MRI. The clinical target volume (CTV) includes the areas that have the potential for harboring microscopic disease not seen on imaging. The exact definition and application of CTV may vary from institution to institution. Practices may include no additional volume added for CTV such that CTV=GTV, others may add an anatomically based CTV (i.e. encompass part or the entirety of an involved vertebral body or posterior elements based on local disease) to the GTV, increasing the treatment field [25]. Planning target volume (PTV) is a 2 to 3 mm geometric expansion beyond the CTV, which accounts for potential errors in patient setup, organ motion, and mechanical limitations of the image guidance and treatment delivery systems. It also allows for safer dosing limits to the spinal cord and cauda equina, minimizing the risk of long term radiation myelopathy while providing doses adequate to alleviate pain and control the disease locally [23]. In the post-operative setting, treatment planning can range from the entirety of the tumor bed and any area concerning for residual disease while others include the entire vertebral body and any adjacent areas of tumor extension or the postoperative levels of vertebrectomy and any residual tumor in the target volumes [26].

The critical structures which are contoured above and below the target volume (TV; the planned area to be treated with radiation) prior to therapy include the spinal cord, cauda equina and the cal sac by using CT [27], CT-MRI fusion [28], or CT-myelogram [28,29], with some authors advocating an organ at risk volume that includes a 1 to 2 mm expansion applied to the spinal cord/cauda equina [26,30].
Additionally, dose constraints are applied to these structures at risk to account for set-up errors, patient motion, and mechanical motion limitations of the system [31,32]. The dose to other surrounding organs (bowel, liver, kidneys) re also kept to safe levels [33].

Radiosensitivity varies among solid tumors, of which breast cancer has routinely been shown to have favorable responses to radiation response with the use of conventional external beam radiation treatment (cEBRT) and other radiotherapy options [1-20,34-40]. Regardless of the level of epidural spinal cord compression (ESCC), radiation therapy to radiosensitive tumors such as breast has led to improved local tumor control, ambulatory status, and pain relief for patients [17]. Favorable tumor histology such as breast (along with myeloma, lymphoma, prostate) are associated with a better survival prognosis, as well as better ambulatory function following treatment [38,41-43]. Maranzano and Latini [42] determined that metastatic breast cancer patients have a response duration of 12 months, with 67% patients regaining ambulation from a non-ambulatory state. Rades et al. [44] recently published a new scoring system to estimate survival in patients that underwent radiation therapy for metastatic spinal cord compression from breast cancer, finding scores correlated significantly with the presence of visceral metastases, time developing motor deficits, ambulatory status, involved vertebrae and Eastern Cooperative Oncology Group (ECOG) score [44].

Gerszten and colleagues conducted a systematic literature review suggesting that SRS is safe and effective, provides an incremental benefit over conventional radiotherapy in terms of durable symptomatic response and local control independent of histology, especially for radiosensitive histology [24]. The NOMS framework achieves durable tumor control by emphasizing use of cEBRT for radiosensitive tumors in both low-grade ESCC (with no myelopathy) as well as high-grade ESCC (+/- myelopathy) [17]. This defines radiation as the primary treatment for spinal metastases, while delineating surgical intervention for separation of the tumor from the critical neurological structures to create a margin to allow radiation therapy rather than gross total resection [17].

Toxicity and Shortcomings of Radiotherapy

One major complication from radiotherapy is the development or progression of vertebral compression fractures. These fractures can occur after SBRT and after single fraction SRS to spinal metastasis [45]. Investigators from MSKCC reported that following singlefraction SRS to vertebral metastases, there is a nearly 40% incidence of new or progressive vertebral compression fractures [46]. Risk factors for these compression fractures included lytic tumors, location below T10, and >41% of the vertebrae involved by the tumor. One study showed that a pre-existing vertebral compression fractures were more likely to progress, become symptomatic (i.e. pain), and require surgery than de novo fractures [47]. This highlights the need for careful patient planning and selection for radiation therapy, because in the face of impending mechanical instability secondary to a compression fracture, a surgical approach followed by radiation treatment would likely represent a better option than radiation alone.

Furthermore, evidence supports a limit in the amount of SBRT that the spinal cord can tolerate, which invariably limits the total amount of radiation applied [23,48]. For example, for fractionated radiation given at 2 Gy per fraction, a homogenous dose of 45 Gy results in a <0.5% risk of radiation-induced myelopathy [49]. The spinal cord is estimated to be able to tolerate 8-10 Gy of homogenous
exposure if given a single fraction [50,51]. Based on the treatment of 177 patients with radiosurgery for spine metastases with single fraction of 8–18 Gy, Ryu and colleagues recommended limiting the volume of the spinal cord that received a dose of >10 Gy to 10% of the spinal cord volume contour [52]. Nevertheless, there may be an anatomical difference (i.e., cervical, thoracic, lumbar) in the tolerance of the spinal cord to radiation. For instance, the cauda equina may be more resistant than the rest of the spinal cord, although this finding has not been consistently shown across studies [52]. Sahgal et al. [53] based on dosimetric data from their cohort of patients who developed radiation-induced myelopathy after SBRT, suggested that 10 Gy in a single fraction is safe and proposed that a normalized 2 Gy equivalent biologically effective dose of 35 Gy [54] given in up to 5 fractions is low-risk, although additional considerations may be necessary if the spinal cord has been previously irradiated [48-54]. Another review published by the Quantitative Analysis of North Tissue Effects in the Clinic concluded that for partial cord irradiation, a maximum cord dose of 13 Gy in a single fraction or 20 Gy in 3 fractions was associated with a <1% risk of injury [55]. With regard to the radiation dose experienced other organs such as a the lungs, small bowel, esophagus, and kidneys, high-grade toxicities have not been reported after SBRT [25]. This is not to say that patients do not experience complications from the radiation delivered to those structures. Toxicities reported after spine radiosurgery include dysphagia, esophagitis, nausea, vomiting, lethargy, paresthesia, pain flare, vasculitis, skin hyper pigmentation, transient laryngitis and radiculitis, and wound complications [23,26-28,56-58]. There is some evidence that prophylactic dexamethasone use can reduce pain flares [59,60]. More work is needed to identify other supportive and prophylactic adjuncts that can reduce these side effects of radiation therapy that greatly impair the quality of life of the patients suffering from them.

Given the principle of SBRT is treating the tumor volume while minimizing the dose at the vertebral-segment-spinal cord interface, treating the involved vertebral bodies is generally regarded as safe and effective with low rates of treatment failure reported [34,61,62]. However, epidural failure or failure at the thecal sac-vertebral body interface is more common given the relative under dosing of microscopic epidural tumor with sub therapeutic radiation doses, with some authors suggesting that the proximity of the target volume (TV) to the thecal sac is a significant risk for this type of failure (e.g. TV within 1mm of epidural space) [26,34,30,63]. The consequence of treatment failure at the interface can be significant, particularly if tumor growth results in malignant epidural cord compression. Intentionally excluded areas within the TV and in intentional avoided areas beyond the tumor margin have also been reported [26-63]. Currently, it remains unclear if the practice of treating only the visible tumor is superior to treating the anatomical margin beyond the tumor itself by encompassing the entire vertebral body and adjacent pedicles, lamina, and spinous process. Although to date reports from major academic institutions that typically target the tumor alone have been similar to those sites that target the anatomical margins [34-64]. Finally, the practice of applying no margin into the adjacent soft tissues for paravertebral disease may increase the risk of margin failure, as paraspinal muscles do not provide a barrier to tumor spread/growth. As such, Sahgal et al. [65] state that a small margin of 0.5cm along the paraspinal muscles may be responsible if the disease extends beyond the vertebral body on MRI [65].

One final consideration regarding the limitations and
shortcomings for SBRT is its significant cost. Given a single fraction of SBRT can cost >$70,000, while a single fraction course of palliative radiotherapy is approximately $18,000 and a 10 fraction course of palliative radiotherapy is approximately $57,000, prospective trials exploring the differences in disease control, pain relief, quality of life, and survival are needed to determine if the cost differential is clinically justified [66].

Role for Surgeons

Historically, surgery in the form of posterior decompression (i.e. laminectomy) was used as a sole treatment for spinal metastases [67]. With the development of radiotherapy however, such surgeries were eventually abandoned in part due to a randomized trial in which laminectomy plus radiotherapy did not provide any additional benefit to radiotherapy alone [68,69]. However, performing a laminectomy often did not address the anterior location of a metastatic lesion and could cause destabilization in patients already with a component of anterior instability. It is therefore important to reconsider surgeries role in the treatment of breast cancer spinal metastases.

Typical goals of surgery in a patient with a spinal metastasis are to relieve medically refractory pain, restore or preserve neurological function, maintain structural stability of the spine, or correct a significant spinal deformity due to the lesion. As spinal metastases may be the first manifestation of cancer in up to 20% of individuals [70], another goal may include obtaining tissue for a histological diagnosis in patients with an unknown primary tumor. It is also essential to consider what the patient’s goals of care are. For some, a focus may be maintaining the ability to walk and their prior independence while for others pain relief may be the main focus [53].

Although no definitive guidelines exist, proposed indications for surgical resection of a lesion include relapse after or progression while undergoing radiotherapy and chemotherapy, spinal instability or a pathological fracture, and in patients who meet the entry criteria defined by Patchell et al. [68-71] (i.e. patient with a radio-insensitive primary tumor, true displacement of spinal cord seen on MRI, single area of cord compression, and no total paraplegia for longer than 48h). The choice of whether or not to undergo surgical management should be tailored to each individual patient and formulated by a multidisciplinary team in conjunction with the patient’s own desires. Factors that may influence the choice of therapy include the timing of neurological symptom onset, life expectancy of the patient, mechanism of cord compression, prior treatment modalities, and the number of compressing spinal metastases. For example, it is important to address signs of acute cord compression immediately while symptoms may still be reversible, which usually requires emergent decompression in order to avoid neurological sequelae.

Although posterior decompression alone has fallen out of favor in the management of spinal metastases, surgeons are now treating spinal metastases with a more anterior approach with the goal of resecting as much of the lesion as possible along with circumferential decompression of the spinal cord. A major study demonstrating the benefit of this approach came from Patchell and colleagues who conducted a prospective randomized study in which patients with spinal cord compression caused by a single metastatic lesion were assigned to receive either surgery followed by radiotherapy (30 Gy in ten fractions) or radiotherapy alone. Patients needed to have an expected survival of at least 3 months, MRI evidence of metastatic epidural spinal cord compression restricted to a single contiguous
area, a cancer origin other than CNS or spinal column, no prior history of cord compression or preexisting neurological disease, and at least 1 neurological symptom. Exclusion criteria included patients with very radiosensitive tumors (lymphomas, leukemia, multiple myeloma, and germ-cell tumors), multiple areas of spinal cord compression, or total paraplegia for longer than 48 hours. Fifty patients were randomized to initial surgery, and of these, all but 3 patients received post-operative radiotherapy. The goal of surgery was to remove as much tumor as possible, provide immediate decompression, and provide intraoperative spinal stabilization when needed. Fiftyone patients were randomized to initial radiotherapy, and of these, one required surgery because of deterioration of strength during radiotherapy. Primary endpoints were ability to walk and ambulatory time after treatment. The study was discontinued on interim analysis due to the superior response of the group randomized to surgery plus radiotherapy. The percentage of patients retaining ability to walk after treatment was 84% in the surgery arm compared to 57% in radiation alone arm. Patients treated with surgery were also able to walk for a significantly longer period of time than those treated with radiation alone (median 122 d vs. 13 d). In the surgery arm, 10 out of 16 paraplegic patients regained ability to walk compared to 3 out of 16 patients in radiation alone arm. Surgery did not increase hospital stay length and actually decreased the use of morphine and steroids. 30- day morbidity was worse in RT only group. Median survival was also improved in the surgery arm (126 days) compared to the radiation alone arm (100 days) which the authors attributed to the higher ambulatory rates in the surgery group [71]. These results have also been supported by a meta-analysis by Klimo et al. [72] comparing surgery (with or without preoperative or post-operative adjunctive radiotherapy) with radiation alone in patients with symptomatic spinal cord compression, which found that patients were 1.3 times more likely to be ambulatory after treatment and twice as likely to regain ambulatory function.

Data specifically examining more extensive surgical decompression in breast cancer spinal metastases is limited. In the randomized study by Patchell et al, [71]. breast cancer accounted for 11% of patients in both arms of the study but results were not stratified by tumor type. Shehadi et al. [73] reported a retrospective review of 87 patients with metastatic breast cancer spinal disease treated with resection and aggressive decompression. Of the 76 patients who were ambulatory pre-operatively, 98% were still ambulatory post-operatively. Of the 11 patients who were non-ambulatory preoperatively, four patients were alive at 3 months postoperatively, three of which regained ambulation. Pain was also significantly reduced in these patients. Tancioni et al. [74] reported a retrospective study of 23 breast cancer patients treated with decompressive surgery followed by radiotherapy. Complete remission of pain that lasted until death or progression of disease in another skeletal site was obtained in 96.1%. Remarkably, all patients had complete recovery of neurologic deficit. While such results are promising, they do not examine differences that may exist between different subtypes of breast cancer, indicating a future area of study.

The above reports demonstrate the revitalization of surgical care for patients with spinal metastases. The exact surgical approach however depends on the tumor location, degree of infiltration, and whether reconstruction is required or not. Although a complete detailing of surgical approaches to the spine is outside the scope of this review, surgeons have used anterior (e.g. transthoracic, retroperitoneal, transoral, transmandibular, transnasal, and transcervical) and
posterolateral approaches (e.g. costotransversectomy, lateral extracavitary) including newer minimally invasive approaches for removing spinal metastases and achieving decompression [75,76]. Kaloostian et al. [76] performed various meta-analyses for different surgical approaches for metastatic spinal cord disease. 832 patients who had undergone vertebral body resection and stabilization for anteriorly located metastatic processes were reviewed. Percent motor improvement ranged from 32–100%, percent pain improvement ranged from 60–100%, and mortality ranged from 0–30%. Molina et al. [77] completed a retrospective study of 11 outcome reports examining endoscopic video-assisted thoracoscopic surgery (VATS) and mini-open minimal access spine surgery (MASS) approaches in cases of metastatic spine disease. Both procedures showed efficacy in treating neurological dysfunction and pain with complication rates, operative blood loss, and median length of stay being lower in the minimally invasive cohort of patients.

As an additional procedural approach to improving quality of life in these patients, vertebroplasty and kyphoplasty have been used to reinforce involved vertebral bodies. For vertebroplasty, a needle is fluoroscopically guided into the diseased bone, and PMMA cement is injected into the malignant bone cavity. Kyphoplasty differs in that a balloon is inflated within the vertebral body to create a low-pressure space to inject the cement. Lee and colleagues provided vertebroplasty for patients with solitary metastases. Of 19 patients, the 8 that had breast cancer all experienced immediate pain improvement and reduction in analgesic requirement [78]. Kaloostian et al. [76] performed a meta-analysis of vertebroplasty and kyphoplasty for metastatic spine disease. 864 patients who underwent vertebroplasty were included in the analysis, and percent mobility improvement ranged from 52- 70%, percent pain improvement ranged from 73-100%, and percent pain increase ranged from 0-13%. 277 patients who underwent kyphoplasty were included in the analysis, and percent mobility improvement ranged from 65-91%, percent pain improvement ranged from 80-100%, and percent pain increase was 0%. In 2011, Berenson and colleagues reported the Cancer Patient Fracture Evaluation (CAFE) study, a randomized controlled trial comparing balloon kyphoplasty with non-surgical management for patients with painful vertebral body compression fractures. The primary endpoint was back-specific functional status measured by the Roland-Morris disability questionnaire (RDQ) score at 1 month. Patients needed to be at least 21 years old, one to three compression fractures from T5- L5 secondary to cancer, and RDQ score of at least 10. Patients were excluded if they had osteoblastic tumors or primary bone tumors, substantial clinical morbidities, VCF morphology deemed unsuitable for kyphoplasty by the treating physician, requirement of additional surgical treatment for the fracture, or needed treatment with highdose steroids or intravenous pain medication. 65 of the 70 patients assigned to the kyphoplasty arm and 52 of the 64 patients to the nonsurgical management arm were analyzed. While there was no change in the RDQ score in the non-surgical group, the mean RDQ score in the kyphoplasty group decreased from 17.6 to 9.1 at 1 month [79].

As suggested in the original study by Patchell et al. [71], a critical component of choosing particular patients for surgical management is to consider the life expectancy of a patient. In their study, only patients with a life-expectancy greater than 3 months were included. To address this, several scoring systems have been developed to help predict prognosis of patients with metastatic spinal disease. Tokuhashi et al. [80] first proposed a 12-point scoring system aimed to estimate patient prognosis based on 6 parameters
including: the general condition of the patient, the number of extra spinal bone metastases, the number of metastases in the vertebral body, metastases to the major internal organs, the primary site of cancer, and the severity of spinal cord palsy. In a later report, the group developed a revised 15-point scoring system based on the same parameters in order to improve the consistency between predicted and actual survival. This revised scoring system had a consistency rate between predicted prognosis based on the criteria and the actual survival period of 86.4% in patients prospectively analyzed and 82.5% in patients evaluated retrospectively. Total scores of 0 to 8, 9 to 11, and 12 to 15 predicted a life expectancy of less than 6 months, 6 months or more, and 1 year or more, respectively. These prognostic criteria were useful for predicting the prognosis irrespective of treatment modality. Patients with a life expectancy predicted to be less than 6 months were recommended to undergo conservative treatment while those with more favorable score could undergo some form of surgery [81]. Tomita and colleagues developed another 10-point scoring system based on grade of malignancy, presence of visceral metastases, and number of bone metastases. Based on these scores, wide or marginal excision for long-term local control was recommended for a score of 2–3 points, marginal or intralesional excision for middle-term local control for a score of 4 –5 points, palliative surgery for shortterm palliation for a score of 6-7, and non-operative management for a score of 8-10 [82]. The revised Tokuhashi scoring system has been shown to provide prognosis for patients with breast cancer [83]. However, Wang and colleagues reported that in patients with breast cancer spinal metastases with ER/HR negative status, surgery was associated with a higher mortality risk and shorter median survival. The authors suggested that the Tokuhashi and Tomita scoring systems should be modified in these subtypes [84]. Another scoring system called the spinal instability neoplastic score (SINS) reported by Fourney and colleagues in the Spine Oncology Study Group has been used to quantify preoperative tumor-related spinal instability as an indication for surgery. Scoring was based on location, pain, bone lesion, radiographic spinal alignment, vertebral body collapse, and posterolateral involvement of spinal elements. The sensitivity and specificity of SINS for potentially unstable or unstable lesions were 95.7% and 79.5%, respectively, and the κ statistic for predictive validity was 0.712 (95% CI, 0.676 to 0.766) [85]. As we continue to improve our ability to predict which subgroups of patients will benefit most from surgical management, its role and the best surgical approaches in patients with spinal metastases are likely to be better defined.

Future Directions

The management of breast cancer spinal metastases is likely to evolve over the coming decade given the development of new chemotherapy, further characterization of tumor pathophysiology, and better delineation of the roles of radiotherapy and surgery. For example, several clinical trials are aimed at comparing external beam radiation with stereotactic radiosurgery for relief of pain symptoms and local tumor control. RTOG 0631 is a randomized phase II/III trial designed to compare stereotactic body radiation therapy (1 x 16 Gy) with external-beam radiation therapy (1 x 8 Gy) in treating patients with 1-3 spine metastases, with the goal of assessing successful delivery of radiation and pain improvement (NCT00922974). Ryu et al. [86] reported the phase II results demonstrating the feasibility of providing this form of radiation for spinal metastases, and phase III results are pending. Investigators at Radboud University and others in the Netherlands are conducting a phase III trial also comparing conventional radiotherapy (1 x 8Gy) with stereotactic radiotherapy
(1 x 20 Gy), assessing impact on pain control (NCT02407795).

Table 1

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Table 1
Recruiting and ongoing therapeutic clinical trials related to treatment of spinal metastases.

SRS: Stereotatic radiosurgery; SBRT: stereotactic body radiotherapy; IGRT: Image guided radiotherapy; VMAT: volumetric modulated arc therapy; IORT: intraoperative radiotherapy; RT: radiotherapy; EBRT: external beam radiotherapy; CRT: conventional radiotherapy; MSCC: metastatic spinal cord compression.

The optimal dose regimen of stereotactic radiosurgery to maximize local control while prevent adverse events also still needs to be determined. Investigators at MSKCC in conjunction with other centers are examining single fraction (24 Gy) or hypofractionated (3 x 9 Gy) stereotactic radiosurgery’s role in the post-operative setting (NCT02320825). Although hypofractionated doses may decrease the incidence of complications such as vertebral compression fractures, recent results in previously non-irradiated renal cell carcinoma spinal metastases show better 1- and 2-year local control rates with single rather than multifractionated stereotactic radiosurgery [87]. The applicability of this finding to breast cancer has yet to be determined. Alternatively, other investigators at the Albert Einstein College of Medicine in collaboration with the National Cancer Institute are examining the efficacy of adaptive staged stereotactic body radiotherapy where single-fraction treatment can be provided with an additional dose 14-21 days later depending on diagnostic interval imaging and spinal cord dose constraints, with the aim of assessing radiographic response (NCT02527304).

Lastly, it is important to consider instances in which new surgical techniques may be used. Investigators at UMC Utrecht are assessing stereotactic body radiotherapy followed by surgical stabilization in patients with unstable spine metastases in a phase I/II study (NCT02622841). Others are comparing survival outcomes between minimally invasive surgery with current standard treatments of spinal metastases including surgical resection, chemotherapy, and radiotherapy (NCT02367378). It is important to note that while many of these trials will likely accrue a substantial number of patients with breast cancer spinal metastases, there is still a lack of data delineating outcome with different breast cancer subtypes.

It is also important to consider new forms of medical management for spinal metastases. Denosumab and bisphosphonates (e.g. zoledronic acid) have been used for the treatment of skeletal-related events and pain in women with boney metastases from breast cancer [88-91]. However, new TGF-β and Src tyrosine kinase inhibitors are other classes of agents that show promise in targeting bone metastases [88-92]. In addition to preventing bone-related pain and fractures,
there is an interest in whether these agents can actually prevent formation of bone lesions. For example, there is some evidence that zoledronic acid, when added to chemotherapy, increases the elimination of disseminated tumors cells from the bone marrow [93]. Such findings warrant further investigation to determine if this or similar agents may prevent formation of spinal metastases. A current clinical trial by Amgen is assessing denosumab’s ability to prevent bone metastases with the primary end-point of bone metastasis-free survival (NCT01077154).

Although some trials have looked at breast cancer patients as a group, most do not distinguish between the various subtypes based on hormone receptor and HER2 status. The subtype of breast cancer can significantly impact overall survival and outcomes in patients with breast cancer spinal metastases. Triple negative and ER/HR negative status breast cancer spinal metastases are correlated with worse overall survival after treatment and may thus warrant different considerations in the treatment of these patients [84,94]. These markers may also relate to characteristics of a lesions such as whether these lesions are blastic versus lytic [95]. As more biomarkers of breast cancer are revealed, it is likely that treatment strategies will need to be tailored to the specific subtype of breast cancer (Table 1).


As new information from randomized trials comes to light, the role of neurosurgeons in the treatment of metastatic spinal disease from breast cancer will continue to evolve. Currently, the disease burden of the spine itself is managed through the utilization of SBRT/ SRS, with indications for surgery following a more supportive rather than curative role. With further improvements of radiation dosing regimens and adjuvant hormonal therapies, it will be interesting to see what the future holds for these patients. Ideally, we would move from a palliative philosophy to a curative philosophy. However, at the present, we have yet to arrive at this destination.


  1. Cobb CA, Leavens ME, Eckles N. Indications for nonoperative treatment of spinal cord compression due to breast cancer. J Neurosurg. 1977; 47: 653-658.
  2. Walsh GL, Gokaslan ZL, McCutcheon IE, Mineo MT, Yasko AW, Swisher SG, et al. Anterior approaches to the thoracic spine in patients with cancer: indications and results. Ann Thorac Surg. 1997; 64: 1611-1618.
  3. Bach F, Larsen BH, Rohde K, Børgesen SE, Gjerris F, Bøge-Rasmussen T, et al. Metastatic spinal cord compression. Occurrence, symptoms, clinical presentations and prognosis in 398 patients with spinal cord compression. Acta Neurochir (Wien). 1990; 107: 37-43.
  4. Barron KD, Hirano A, Araki S, Terry RD. Experiences with metastatic neoplasms involving the spinal cord. Neurology. 1959; 9: 91-106.
  5. Joaquim AF, Powers A, Laufer I, Bilsky MH. An update in the management of spinal metastases. Arq Neuropsiquiatr. 2015; 73: 795-802.
  6. Ortiz Gómez JA. The incidence of vertebral body metastases. Int Orthop. 1995; 19: 309-311.
  7. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics. CA Cancer J Clin. 2000; 50: 7-33.
  8. Delank KS, Wendtner C, Eich HT, Eysel P. The treatment of spinal metastases. Dtsch Arztebl Int. 2011; 108: 71-79.
  9. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011; 61: 69-90.
  10. Svendsen ML, Gammelager H, Sværke C, Yong M, Chia VM, Christiansen CF, et al. Hospital visits among women with skeletal-related events secondary to breast cancer and bone metastases: a nationwide populationbased cohort study in Denmark. Clin Epidemiol. 2013; 5: 97-103.
  11. Louwman WJ, Voogd AC, van Dijck JA, Nieuwenhuijzen GA, Ribot J, Pruijt JF, et al. On the rising trends of incidence and prognosis for breast cancer patients diagnosed 1975-2004: a long-term population-based study in southeastern Netherlands. Cancer Causes Control. 2008; 19: 97-110.
  12. Søgaard KK, Cronin-Fenton DP, Pedersen L, Sørensen HT, Lash TL. Survival in Danish patients with breast cancer and inflammatory bowel disease: a nationwide cohort study. Inflamm Bowel Dis. 2008; 14: 519-525.
  13. Jensen AØ, Jacobsen JB, Nørgaard M, Yong M, Fryzek JP, Sørensen HT. Incidence of bone metastases and skeletal-related events in breast cancer patients: a population-based cohort study in Denmark. BMC Cancer. 2011; 11: 29.
  14. Perrin RG, Livingston KE, Aarabi B. Intradural extramedullary spinal metastasis. A report of 10 cases. J Neurosurg. 1982; 56: 835-837.
  15. Schick U, Marquardt G, Lorenz R. Intradural and extradural spinal metastases. Neurosurg Rev. 2001; 24: 1-5.
  16. Bucholtz JD. Metastatic epidural spinal cord compression. Semin Oncol Nurs. 1999; 15: 150-159.
  17. Laufer I, Rubin DG, Lis E, Cox BW, Stubblefield MD, Yamada Y, et al. The NOMS framework: approach to the treatment of spinal metastatic tumors. Oncologist. 2013; 18: 744-751.
  18. [No authors listed]. 8 Gy single fraction radiotherapy for the treatment of metastatic skeletal pain: randomised comparison with a multifraction schedule over 12 months of patient follow-up. Bone Pain Trial Working Party. Radiother Oncol. 1999; 52: 111-121.
  19. Chow E, Harris K, Fan G, Tsao M, Sze WM. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol. 2007; 25: 1423-1436.
  20. Maranzano E, Bellavita R, Rossi R, De Angelis V, Frattegiani A, Bagnoli R, et al. Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized, multicenter trial. J Clin Oncol. 2005; 23: 3358-3365.
  21. Rades D, Stalpers LJ, Hulshof MC, Zschenker O, Alberti W, Koning CC. Effectiveness and toxicity of single-fraction radiotherapy with 1 x 8 Gy for metastatic spinal cord compression. Radiother Oncol. 2005; 75: 70-73.
  22. Lutz S, Berk L, Chang E, Chow E, Hahn C, Hoskin P, et al. Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys. 2011; 79: 965-976.
  23. Chawla S, Schell MC, Milano MT. Stereotactic body radiation for the spine: a review. Am J Clin Oncol. 2013; 36: 630-636.
  24. Gerszten PC, Mendel E, Yamada Y. Radiotherapy and radiosurgery for metastatic spine disease: what are the options, indications, and outcomes? Spine (Phila Pa 1976). 2009; 34: S78-92.
  25. Sahgal A, Larson DA, Chang EL. Stereotactic body radiosurgery for spinal metastases: a critical review. Int J Radiat Oncol Biol Phys. 2008; 71: 652- 665.
  26. Chang EL, Shiu AS, Mendel E, Mathews LA, Mahajan A, Allen PK, et al. Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure. J Neurosurg Spine. 2007; 7: 151-160.
  27. Sahgal A, Chou D, Ames C, Ma L, Lamborn K, Huang K, et al. Imageguided robotic stereotactic body radiotherapy for benign spinal tumors: theUniversity of California San Francisco preliminary experience. Technol Cancer Res Treat. 2007; 6: 595-604.
  28. Yamada Y, Lovelock DM, Yenice KM, Bilsky MH, Hunt MA, Zatcky J, et al. Multifractionated image-guided and stereotactic intensity-modulated radiotherapy of paraspinal tumors: a preliminary report. Int J Radiat Oncol Biol Phys. 2005; 62: 53-61.
  29. Wright JL, Lovelock DM, Bilsky MH, Toner S, Zatcky J, Yamada Y. Clinical outcomes after reirradiation of paraspinal tumors. Am J Clin Oncol. 2006; 29: 495-502.
  30. Milker-Zabel S, Zabel A, Thilmann C, Schlegel W, Wannenmacher M, Debus J. Clinical results of retreatment of vertebral bone metastases by stereotactic conformal radiotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2003; 55: 162-167.
  31. Foote M, Letourneau D, Hyde D, Massicotte E, Rampersaud R, Fehlings M, et al. Technique for stereotactic body radiotherapy for spinal metastases. J Clin Neurosci. 2011; 18: 276-279.
  32. Ma L, Sahgal A, Hossain S, Chuang C, Descovich M, Huang K, Gottschalk A. Nonrandom intrafraction target motions and general strategy for correction of spine stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys. 2009; 75: 1261-1265.
  33. Timmerman RD. An overview of hypofractionation and introduction to this issue of seminars in radiation oncology. Semin Radiat Oncol. 2008; 18: 215-222.
  34. Gerszten PC, Burton SA, Ozhasoglu C, Welch WC. Radiosurgery for spinal metastases: clinical experience in 500 cases from a single institution. Spine (Phila Pa 1976). 2007; 32: 193-199.
  35. Gilbert RW, Kim JH, Posner JB. Epidural spinal cord compression from metastatic tumor: diagnosis and treatment. Ann Neurol. 1978; 3: 40-51.
  36. Katagiri H, Takahashi M, Inagaki J, Kobayashi H, Sugiura H, Yamamura S, et al. Clinical results of nonsurgical treatment for spinal metastases. Int J Radiat Oncol Biol Phys. 1998; 42: 1127-1132.
  37. Maranzano E, Latini P, Perrucci E, Beneventi S, Lupattelli M, Corgna E. Short-course radiotherapy (8 Gy x 2) in metastatic spinal cord compression: an effective and feasible treatment. Int J Radiat Oncol Biol Phys. 1997; 38: 1037-1044.
  38. Rades D, Fehlauer F, Schulte R, Veninga T, Stalpers LJ, Basic H, et al. Prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression. J Clin Oncol. 2006; 24: 3388-3393.
  39. Rades D, Fehlauer F, Stalpers LJ, Wildfang I, Zschenker O, Schild SE, et al. A prospective evaluation of two radiotherapy schedules with 10 versus 20 fractions for the treatment of metastatic spinal cord compression: final results of a multicenter study. Cancer. 2004; 101:2687-2692.
  40. Rades D, Karstens JH, Alberti W. Role of radiotherapy in the treatment of motor dysfunction due to metastatic spinal cord compression: comparison of three different fractionation schedules. Int J Radiat Oncol Biol Phys. 2002; 54: 1160-1164.
  41. Helweg-Larsen S, Sørensen PS, Kreiner S. Prognostic factors in metastatic spinal cord compression: a prospective study using multivariate analysis of variables influencing survival and gait function in 153 patients. Int J Radiat Oncol Biol Phys. 2000; 46: 1163-1169.
  42. Maranzano E, Latini P. Effectiveness of radiation therapy without surgery in metastatic spinal cord compression: final results from a prospective trial. Int J Radiat Oncol Biol Phys. 1995; 32: 959-967.
  43. Prasad D, Schiff D. Malignant spinal-cord compression. Lancet Oncol. 2005; 6: 15-24.
  44. Rades D, Conde AJ, Garcia R, Cacicedo J, Segedin B, Perpar A, et al. A new instrument for estimation of survival in elderly patients irradiated for metastatic spinal cord compression from breast cancer. Radiat Oncol. 2015; 10: 173.
  45. Greco C, Pares O, Pimentel N, Moser E, Louro V, Morales X, et al. Spinal metastases: From conventional fractionated radiotherapy to single-dose SBRT. Rep Pract Oncol Radiother. 2015; 20: 454-463.
  46. Rose PS, Laufer I, Boland PJ, Hanover A, Bilsky MH, Yamada J, et al. Risk of fracture after single fraction image-guided intensity-modulated radiation therapy to spinal metastases. J Clin Oncol. 2009; 27: 5075-5079.
  47. Germano IM, Carai A, Pawha P, Blacksburg S, Lo YC, Green S. Clinical outcome of vertebral compression fracture after single fraction spine radiosurgery for spinal metastases. Clin Exp Metastasis. 2016; 33: 143-149.
  48. Sahgal A, Ma L, Gibbs I, Gerszten PC, Ryu S, Soltys S, et al. Spinal cord tolerance for stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys. 2010; 77: 548-553./a>
  49. Schultheiss TE, Kun LE, Ang KK, Stephens LC. Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys. 1995; 31: 1093-1112.
  50. Macbeth FR, Wheldon TE, Girling DJ, Stephens RJ, Machin D, Bleehen NM, et al. Radiation myelopathy: estimates of risk in 1048 patients in three randomized trials of palliative radiotherapy for non-small cell lung cancer. The Medical Research Council Lung Cancer Working Party. Clin Oncol (R Coll Radiol). 1996; 8: 176-181.
  51. Rades D, Stalpers LJ, Veninga T, Schulte R, Hoskin PJ, Obralic N, et al. Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression. J Clin Oncol. 2005; 23: 3366-3375.
  52. Ryu S, Jin JY, Jin R, Rock J, Ajlouni M, Movsas B, et al. Partial volume tolerance of the spinal cord and complications of single-dose radiosurgery. Cancer. 2007; 109: 628-636.
  53. Sahgal A, Ma L, Weinberg V, Gibbs IC, Chao S, Chang UK, et al. Reirradiation human spinal cord tolerance for stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys. 2012; 82: 107-116.
  54. Abrahm JL, Banffy MB, Harris MB. Spinal cord compression in patients with advanced metastatic cancer: "all I care about is walking and living my life". JAMA. 2008; 299: 937-946.
  55. Kirkpatrick JP, van der Kogel AJ, Schultheiss TE. Radiation dose-volume effects in the spinal cord. Int J Radiat Oncol Biol Phys. 2010; 76: S42-49.
  56. Benzil DL, Saboori M, Mogilner AY, Rocchio R, Moorthy CR. Safety and efficacy of stereotactic radiosurgery for tumors of the spine. J Neurosurg. 2004; 101: 413-418.
  57. Degen JW, Gagnon GJ, Voyadzis JM, McRae DA, Lunsden M, Dieterich S, et al. CyberKnife stereotactic radiosurgical treatment of spinal tumors for pain control and quality of life. J Neurosurg Spine. 2005; 2: 540-549.
  58. Hamilton AJ, Lulu BA, Fosmire H, Gossett L. LINAC-based spinal stereotactic radiosurgery. Stereotact Funct Neurosurg. 1996; 66: 1-9.
  59. Chow E, Meyer RM, Ding K, Nabid A, Chabot P, Wong P, et al. Dexamethasone in the prophylaxis of radiation-induced pain flare after palliative radiotherapy for bone metastases: a double-blind, randomised placebo-controlled, phase 3 trial. Lancet Oncol. 2015; 16: 1463-1472.
  60. Khan L, Chiang A, Zhang L, Thibault I, Bedard G, Wong E, et al. Prophylactic dexamethasone effectively reduces the incidence of pain flare following spine stereotactic body radiotherapy (SBRT): a prospective observational study. Support Care Cancer. 2015; 23: 2937-2943.
  61. Nelson JW, Yoo DS, Sampson JH, Isaacs RE, Larrier NA, Marks LB, et al. Stereotactic body radiotherapy for lesions of the spine and paraspinal regions. Int J Radiat Oncol Biol Phys. 2009; 73: 1369-1375.
  62. Ryu S, Rock J, Rosenblum M, Kim JH. Patterns of failure after single-dose radiosurgery for spinal metastasis. J Neurosurg. 2004; 101: 402-405.
  63. Nguyen QN, Shiu AS, Rhines LD, Wang H, Allen PK, Wang XS, et al. Management of spinal metastases from renal cell carcinoma using stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys. 2010; 76: 1185-1192.
  64. Sahgal A, Ames C, Chou D, Ma L, Huang K, Xu W, et al. Stereotactic body radiotherapy is effective salvage therapy for patients with prior radiation of spinal metastases. Int J Radiat Oncol Biol Phys. 2009; 74: 723-731.
  65. Sahgal A, Bilsky M, Chang EL, Ma L, Yamada Y, Rhines LD, et al. Stereotactic body radiotherapy for spinal metastases: current status, with a focus on its application in the postoperative patient. J Neurosurg Spine. 2011; 14: 151-166.
  66. Lewis SL, Porceddu S, Nakamura N, Palma DA, Lo SS, Hoskin P, et al. Definitive Stereotactic Body Radiotherapy (SBRT) for Extracranial Oligometastases: An International Survey of >1000 Radiation Oncologists. Am J Clin Oncol. 2015.
  67. Harrington KD. Anterior decompression and stabilization of the spine as a treatment for vertebral collapse and spinal cord compression from metastatic malignancy. Clin Orthop Relat Res. 1988; 177-197.
  68. Cole JS, Patchell RA. Metastatic epidural spinal cord compression. Lancet Neurol. 2008; 7: 459-466.
  69. Young RF, Post EM, King GA. Treatment of spinal epidural metastases. Randomized prospective comparison of laminectomy and radiotherapy. J Neurosurg. 1980; 53: 741-748.
  70. Schiff D, O'Neill BP, Suman VJ. Spinal epidural metastasis as the initial manifestation of malignancy: clinical features and diagnostic approach. Neurology. 1997; 49: 452-456.
  71. Patchell RA, Tibbs PA, Regine WF, Payne R, Saris S, Kryscio RJ, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet. 2005; 366: 643-648.
  72. Klimo P Jr, Thompson CJ, Kestle JR, Schmidt MH. A meta-analysis of surgery versus conventional radiotherapy for the treatment of metastatic spinal epidural disease. Neuro Oncol. 2005; 7: 64-76.
  73. Shehadi JA, Sciubba DM, Suk I, Suki D, Maldaun MV, McCutcheon IE, et al. Surgical treatment strategies and outcome in patients with breast cancer metastatic to the spine: a review of 87 patients. Eur Spine J. 2007; 16: 1179- 1192.
  74. Tancioni F, Navarria P, Mancosu P, Pedrazzoli P, Morenghi E, Santoro A, et al. Surgery followed by radiotherapy for the treatment of metastatic epidural spinal cord compression from breast cancer. Spine (Phila Pa 1976). 2011; 36: E1352-1359.
  75. Ju DG, Yurter A, Gokaslan ZL, Sciubba DM. Diagnosis and surgical management of breast cancer metastatic to the spine. World J Clin Oncol. 2014; 5: 263-271.
  76. Kaloostian PE, Yurter A, Zadnik PL, Sciubba DM, Gokaslan ZL. Current paradigms for metastatic spinal disease: an evidence-based review. Ann Surg Oncol. 2014; 21: 248-262.
  77. Molina CA, Gokaslan ZL, Sciubba DM. A systematic review of the current role of minimally invasive spine surgery in the management of metastatic spine disease. Int J Surg Oncol. 2011; 2011: 598148.
  78. Lee B, Franklin I, Lewis JS, Coombes RC, Leonard R, Gishen P, et al. The efficacy of percutaneous vertebroplasty for vertebral metastases associated with solid malignancies. Eur J Cancer. 2009; 45: 1597-1602.
  79. Berenson J, Pflugmacher R, Jarzem P, Zonder J, Schechtman K, Tillman JB, et al. Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicentre, randomised controlled trial. Lancet Oncol. 2011; 12: 225-235.
  80. Tokuhashi Y, Matsuzaki H, Toriyama S, Kawano H, Ohsaka S. Scoring system for the preoperative evaluation of metastatic spine tumor prognosis. Spine (Phila Pa 1976). 1990; 15: 1110-1113.
  81. Tokuhashi Y, Matsuzaki H, Oda H, Oshima M, Ryu J. A revised scoring system for preoperative evaluation of metastatic spine tumor prognosis. Spine (Phila Pa 1976) 2005; 30: 2186-2219.
  82. Tomita K, Kawahara N, Kobayashi T, Yoshida A, Murakami H, Akamaru T. Surgical strategy for spinal metastases. Spine (Phila Pa 1976). 2001; 26: 298-306.
  83. Ulmar B, Richter M, Cakir B, Muche R, Puhl W, Huch K. The Tokuhashi score: significant predictive value for the life expectancy of patients with breast cancer with spinal metastases. Spine (Phila Pa 1976) 2005: 30: 2222- 2226.
  84. Wang M, Jensen AB, Morgen SS, Wu CS, Sun M, Li H, et al. Survival analysis of breast cancer subtypes in patients with spinal metastases. Spine (Phila Pa 1976). 2014; 39: 1620-1627.
  85. Fourney DR, Frangou EM, Ryken TC, Dipaola CP, Shaffrey CI, Berven SH, et al. Spinal instability neoplastic score: an analysis of reliability and validity from the spine oncology study group. J Clin Oncol. 2011; 29: 3072- 3077.
  86. Ryu S, Pugh SL, Gerszten PC, Yin FF, Timmerman RD, Hitchcock YJ, et al. RTOG 0631 Phase II/III Study of Image-Guided Stereotactic Radiosurgery for Localized (1-3) Spine Metastases: Phase II Results. Int J Radiat Oncol Biol Phys. 2011; 81: S131-131S132.
  87. Ghia AJ, Chang EL, Bishop AJ, Pan HY, Boehling NS, Amini B, et al. Single-fraction versus multifraction spinal stereotactic radiosurgery for spinal metastases from renal cell carcinoma: secondary analysis of Phase I/II trials. J Neurosurg Spine. 2016; 24: 829-836.
  88. Li BT, Wong MH, Pavlakis N. Treatment and Prevention of Bone Metastases from Breast Cancer: A Comprehensive Review of Evidence for Clinical Practice. J Clin Med. 2014; 3: 1-24.
  89. Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, doubleblind study. J Clin Oncol. 2010; 28: 5132-5139.
  90. Van Poznak CH, Temin S, Yee GC, Janjan NA, Barlow WE, Biermann JS, et al. American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol 2011; 29: 1221-1222.
  91. Wong R, Wiffen PJ. Bisphosphonates for the relief of pain secondary to bone metastases. Cochrane Database Syst Rev. 2002; CD002068.
  92. Tan AR, Alexe G, Reiss M. Transforming growth factor-beta signaling: emerging stem cell target in metastatic breast cancer? Breast Cancer Res Treat. 2009; 115: 453-495.
  93. Aft R, Naughton M, Trinkaus K, Watson M, Ylagan L, Chavez-MacGregor M, et al. Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol. 2010; 11: 421-428.
  94. Bollen L, Wibmer C, Wang M, van der Linden YM, Leithner A, Jensen AB, et al. Molecular phenotype is associated with survival in breast cancer patients with spinal bone metastases. Clin Exp Metastasis. 2015; 32: 1-5.
  95. Lin J, Goldstein L, Nesbit A, Chen MY. Influence of Hormone Receptor Status on Spinal Metastatic Lesions in Patients with Breast Cancer. World Neurosurg. 2016; 85: 42-48.