|Year : 2015 | Volume
| Issue : 3 | Page : 94-100
Strategies for Management of Spinal Metastases: A Comprehensive Review
Zhantao Deng, Bin Xu, Jiewen Jin, Jianning Zhao, Haidong Xu
Department of Orthopedics, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu, China
|Date of Submission||02-Mar-2015|
|Date of Acceptance||23-May-2015|
|Date of Web Publication||30-Jun-2015|
Dr. Haidong Xu
Department of Orthopedics, School of Medicine, Jinling Hospital, Nanjing University, No. 305, Zhongshan East Road, Nanjing 210002, Jiangsu
Source of Support: None, Conflict of Interest: None
Spinal metastasis is the most common tumor in the spine and can easily expand to the epidural space. A series of approaches have been developed to deal with this problem including radiation, surgery, and medicine. The further goal of the treatment is to relieve pain, stabilize spinal structure, maintain neurologic function and improve the quality of life. Different frameworks have been proposed to optimize the best therapy for different patients. This review briefly summarizes different treatments for spinal metastases and some popular decision-making frameworks.
Keywords: Assessment, radiotherapy, spinal metastases, surgery
|How to cite this article:|
Deng Z, Xu B, Jin J, Zhao J, Xu H. Strategies for Management of Spinal Metastases: A Comprehensive Review. Cancer Transl Med 2015;1:94-100
|How to cite this URL:|
Deng Z, Xu B, Jin J, Zhao J, Xu H. Strategies for Management of Spinal Metastases: A Comprehensive Review. Cancer Transl Med [serial online] 2015 [cited 2019 Jan 17];1:94-100. Available from: http://www.cancertm.com/text.asp?2015/1/3/94/159536
| Introduction|| |
Spinal metastasis is the most commonly encountered tumor of the spine, which is second only to pulmonary and hepatic metastasis. , Due to the extensive arterial blood supply in vertebral column, the metastases can overwhelmingly accumulate in the osseous elements in the spine as well as expand to epidural space by different degrees. Along the vertebral column, the thoracic spine and lumbar spine are preferable for the metastatic tumors compared with the cervical and sacral segments.  The neoplastic substitution of the bone tissue progressively destructs the structural elements in spine, resulting in loss of stability and compression of the intra-canal nerve structures.  From the review of literature, about 10% of tumor patients develop symptomatic spinal metastases  and spinal cord compression.  Although there is widespread agreement in literature regarding the need to treat symptomatic metastases, the best treatment protocol to adopt is still a matter needs discussion. Modern oncology provides numerous treatment options that include radiotherapy, surgery, chemotherapy, immunotherapy, and hormone therapy. , The goals of treating spinal metastases are relieving pain, stabilizing spinal structure, recovering or maintaining neurologic function, controlling the metastases in local area, and improving quality of life. It is commonly accepted that spinal metastases are expressions of systemic diseases; therefore, in order to reach the goals above, multi-disciplinary treatment should be applied. Several decades ago, a single choice, either radiotherapy or surgery was made for the treatment of patients with metastases. Currently, treatment involving complex multimodality assessments, combination of traditional surgery and radiotherapy, and the integration of new technologies such as stereotactic radiosurgery (SRS) and percutaneous cement augmentation are widely accepted, which prolong the survival time and quality of life to some extent. In this review, we systematically summarized the general treatments and assessment criteria for patients with spinal metastases.
| Radiation for Management of Spinal Metastases|| |
Radiation is commonly accepted as the most effective and least invasive modality for local tumor control. Prior to radiotherapy, the sensitivity of tumors to radiation should be assessed. In this assessment, one or two radiation beams are delivered without precise conformal techniques, and tumor response indicates whether it is radiosensitive or radioresistant. Tumor histology is a vital factor that influences the response. Lymphoma, seminoma, choriocarcinoma, and myeloma are commonly accepted as radiosensitive histologies, ,, while solid tumors such as renal, thyroid, hepatocellular, colon, nonsmall cell lung carcinomas, sarcoma and melanoma are usually radioresistant histologies. , However, there are some radiosensitive solid tumors, including breast, prostate, ovarian, small cell lung carcinoma and neuroendocrine carcinomas. 
Conventional external beam radiation therapy (cEBRT) is the traditional radiotherapy, which delivers radiation beam without precise conformal techniques. Because of the narrow space in spine and severe consequences of injuring the spinal cord, the fractional dose that can be delivered using cEBRT is significantly limited. To deal with this limitation, new technologies have been developed. Image guided radiation therapy (IGRT) is the combination of imaging and radiation. With the help of image guiding, high doses of radiation can be delivered in close proximity to the spinal cord while maintaining radiation exposure of the spinal cord, and other adjacent vital structures, within the limits of safety.  SRS, stereotactic radiotherapy, three-dimensional conformal radiation therapy, and intensity modulated radiation therapy are therapies that rely on IGRT and have higher spatial precision.
For patients with radiosensitive tumors, cEBRT is recommended and has been proven to provide symptomatic relief and satisfactory local control rates. ,, Rades et al. studied 1,852 patients and found that improved local control as well as improved survival were significantly associated with favorable histology (breast cancer, prostate cancer, lymphoma/myeloma). Even when there is evidence of high-grade epidural spinal cord compression (ESCC) from radiosensitive tumors, cEBRT is still suggested because of the ability of cEBRT to cause mitotic cell death within the tumor and subsequent spinal cord decompression without causing damage to surrounding neurologic tissues.  Those studies confirmed that patients with favorable histologies are more likely to have good postradiation ambulation and remain ambulatory longer than patients with unfavorable primary histologies. , Due to the delicate structure of the spine, the radiation dose and fractionation should be accurately calculated and vary according to the goal of treatment. Compared with short-course radiation providing short-term palliation, higher dose radiotherapy regimens provide better long-term palliation. ,,
Patients with radioresistant tumors are referred for excisional surgery in the hope of improving local control due to the historically poor responses to cEBRT. However, Greco et al. showed that single-dose IGRT may be effectively used to locally control metastatic deposits regardless of histology and the target organ, provided that sufficiently high doses (> 22 Gy) of radiation are delivered. In addition, growing evidence suggests that despite some cEBRT radioresistant histologies, durable local tumor control can be achieved in these tumors using SRS. , SRS relies on IGRT platforms and can deliver high doses of tightly focused radiation in the mode of a single fraction or in 3-5 fractions using a hypofractionated schedule. A series of researches showed that high-dose SRS has more than 85% of radiographic and clinical responses regardless of tumor histology. ,, These findings suggest that, compared with extensive surgical interventions, SRS may be a better first-line treatment.  In general, the complications of SRS are less serious, including dysphagia, esophagitis, mucositis, paresthesia, transient laryngitis, and transient radiculitis. , One multicenter research found only 0.5% patients developed radiation-induced myelopathy after spinal radiosurgery.  Another complication of SRS that is becoming apparent is delayed vertebral body fracture.  The assumed maximal safe radiation dose to a single voxel on the spinal cord (cord Dmax) is 14 Gy.  However, radioresistant tumors with high-grade ESCC still generally require surgical decompression because of the limitations of spinal cord dose constraints. Epidural compression can be treated with SRS; however, it increases the risk of incidence of radiation-induced myelopathy and the risk of side effects of an effective dose delivery at the dural margin. With increasing doses, radiation-induced vertebral fracture is the most serious and prevalent side effect of SRS.  Apart from patients who have radioresistant tumors with high-grade ESCC, radiation therapy provides adequate local tumor control, pain control and maintenance, or recovery of neurologic function for all other patients.
| Surgical Strategies for Management of Spinal Metastases|| |
The improvement in adjuvant therapy has led to a decrease in surgery for metastatic disease in favor of radiation therapy.  The evolution and popularization of surgical techniques and instrumentation brought surgery back to the forefront of treatment options. At the same time, the goals of surgery have shifted from oncologic control to mainly palliative control of pain, preservation or restoration of neurologic function and mechanical stability.  The role of surgery is adjuvant to radiotherapy and/or chemotherapy as indicated by the primary cancer pathology.  Although radiation can control local tumor effectively, it has no impact on spinal stability. Spinal instability is the loss of spinal integrity as a result of a neoplastic process that is associated with movement-related pain, symptomatic or progressive deformity, and/or neural compromise of under-physiologic loads.  Mechanical instability serves as an indication for surgery regardless of the neurologic or oncologic assessment. Patients with fracture subluxations 5 mm or 3.5 mm subluxation and 11° angulation between C1 and C2 with movement-related pain in neck require instrumented spine fixation.  All patients with clear manifestations of cervical, thoracic or lumbar mechanical instability require surgical stabilization because steroids and radiation can improve neither the mechanical pain nor spinal stability.
The indications for surgical intervention of spinal metastases are generally summarized as follows: intractable pain unresponsive to nonoperative measures, such as radiation therapy, chemotherapy, or hormonal therapy; existence of a growing tumor that is resistant to radiation therapy, chemotherapy, or hormonal therapy; patients who have reached spinal cord tolerance after prior radiation therapy; spinal instability manifested as pathologic fracture, progressive deformity, or neurologic deficit; clinically significant neural compression, especially by bone or bone debris. ,
Patients with spinal metastases may undergo a wide range of surgical interventions, ranging from wide tumor excision to limited decompression. Different scales are proposed and among them, the Tokuhashi scale is the most popular one [Table 1].  It sets six parameters for consideration including the patient's performance status, tumor histology, the number of extraspinal bone metastases, the number of vertebral metastases, the extent of visceral metastases, and the extent of neurologic deficit. The severity of palsy was classified into three grades based on the findings of Frankel's classification.  The major judgment criterion in this scoring system is the expected survival of the patients. For patients with expected survival longer than 1 year, who generally have a favorable tumor histology, good functional and neurologic scores, and limited metastatic disease, excisional surgery is recommended. Patients expected to survive < 6 months are recommended to undergo conservative treatment, and those in between are recommended limited palliative surgery. Tomita et al.  took tumor histology and the extent of visceral and bone metastases into consideration and applied largely short-term palliation or terminal care to patients with rapidly growing tumor while suggesting wide or marginal excision for patients with slow-growing tumors [Table 2] and [Table 3]. Gasbarrini et al.  posed a concise and practical flow-chart of the surgical strategy for spinal metastases [Figure 1]. This strategy is focused on the safety of anesthetization, which plays an important role in ensuring the safety of patients during and after surgery. Also, different kinds of auxiliary therapies are used in various situations. Harrington  devised a five-category classification scheme for metastatic spine tumors based on bone destruction and neurologic compromise: (1) no significant neurologic involvement, (2) involvement of bone without collapse or instability, (3) major neurologic impairment (sensory or motor) without significant involvement of bone, (4) vertebral collapse with pain resulting from mechanical causes or instability, but with no significant neurologic compromise, and (5) vertebral collapse or instability combined with major neurologic impairment. He mainly recommended that patients in categories 1, 2 and 3 be treated nonsurgically with chemotherapy, hormonal manipulation, and/or local irradiation.
|Table 1: Tokuhashi scoring system for preoperative evaluation of spinal metastases prognosis |
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|Table 2: Tomita scoring system for preoperative evaluation of spinal metastases |
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|Table 3: Treatment goals and surgical strategies with Tomita scoring system |
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|Figure 1. The flow-chart of the surgical strategy for the spinal metastases|
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As suggested by those scoring systems, the excision strategy may range from limited intralesional curettage to en bloc wide marginal excision of the tumor. Depending on the location of the tumor and the goal of the operation, different methods may be used, including an anterior, posterior, or lateral approach, or a combination of them. The vertebral body is the most common element being invaded, and as a result, the anterior approach is the most direct route to the lesion. On the other hand, extensive bone resection is generally required with anterior approaches while the posterior approaches to the spine allow direct access to the spinal cord. The overwhelming majority of modern surgical procedures for spinal metastases involve instrumented spinal stabilization. Various reconstruction instrumentation systems are available. Modern posterior stabilization systems generally involve multilevel pedicle instrumentation using titanium polyaxial screw-rod systems.  Ventral support is achieved by using a variety of cages, which may be composed of titanium or polyetherketone or polymethyl-methacrylate (PMMA) cement.  In addition to the traditional open surgical methods, current techniques involve a combination of percutaneous instrumentation, image guidance, and minimally invasive decompression techniques.
| Minimally Invasive Surgery for Management of Spinal Metastases|| |
Conventional surgery has a serious of drawbacks including huge cost, burden on the health care system, and delays in receiving postoperative radiotherapy/chemotherapy.  With the goal to reduce the morbidity of invasive open surgical procedures, minimally invasive approaches are being developed.  Minimally invasive surgery both achieves the surgical goals of critical neural structure decompression (spinal cord and cauda equina) and maintenance of spine stability, and reduces the morbidity of major open spine surgery. It can provide patients with less operation time, blood loss, hospital stay, and complication rates, all of which may lead to lower morbidity rates in patient. ,, There are several applications of minimally invasive surgery, including percutaneous vertebroplasty (PVP), percutaneous kyphoplasty (PKP), radiofrequency ablation (RFA), cryoablation, and transarterial embolization. 
For painful pathologic compression fractures without gross spinal instability or significant posterior element involvement, PVP or PKP are most commonly used. , In PVP, bone cement is injected through a minimal incision into the fractured site. In PKP, a balloon is inserted into the fractured site, followed by inflation-deflation to create a cavity into which the filler material is injected, and the balloon is taken out prior to cement injection.  PMMA, the most commonly used among numerous cement formulations, provides additional reinforcement to the vertebral body. Mende et al.  performed a systematic review of literature which resulted in a strong recommendation for the use of PVP or PKP in the setting of symptomatic osteolytic tumors. The most common complication of PVP and PKP is cement leakage,  which, fortunately, are clinically asymptomatic in most cases and need no intervention. 
Radiofrequency ablation is also used in the treatment of spinal metastases. RFA uses an electromagnetic current with 300-500 KHz frequency to trigger molecular friction movements, which is guided by imaging and results in temperature increase and diffusion in the tumor. The temperature should rise higher than 70°C in order to achieve irreversible cell death by coagulation necrosis of the cell proteins.  Palussiere et al.  showed that 70-90% of patients with metastases experience considerable relief after RFA. And if the treatment fails, it can be offered again. However, as in the spine, if no protection (CO 2 dissection) was provided, heating can easily damage neighboring nerve structures.  The heating induced by RFA does not produce consolidation, so the combination with an injection of cement can achieve the pain relief and spinal reinforcement. 
| Contemporary Strategies for Management of Spinal Metastases: A Step Toward Personalized Treatment|| |
Surgery can restore or preserve the mechanical stability, decompress the circumferential stress of the spinal cord to preserve neurologic function as well as provide an access to delivery of tumoricidal radiation doses to the entire tumor volume while avoiding toxicity to the spinal cord. At the same time, radiation can control the tumor locally by the least invasive way. Thus, the combination of surgery and radiation makes a great step in the treatment of spinal metastases. Separation surgery is a new process in which only minimal tumor is resected to make a separation between the tumor and the spinal cord, leaving the bulk of the tumor mass to be treated with radiation.  The traditional surgeries often fail in local tumor control, due to the inability to achieve negative margins based on anatomical constraints and aggressive tumor biology.  By making a small margin of 2-3 mm between the spinal cord and the tumor, it is safer to administer the tumoricidal radiation doses afforded by SRS to the entire tumor mass. The separation surgery is often accomplished by a posteriolateral laminectomy including a unilateral or bilateral facetectomy using a high-speed 3-mm matchstick bur.  Laufer et al.  compared the local control of subgroups of 186 patients with ESCC from spinal metastases treated with single-fraction (24 Gy) SRS, or high-dose hypofractionated (median total dose 27 Gy in 3 fractions, total dose range 24-30 Gy) SRS or low-dose hypofractionated (median total dose 30 Gy in 5 or 6 fractions, total dose range 18-36 Gy) SRS. They found a significant improvement in local control with high-dose hypofractionated SRS (4.1% cumulative incidence of local progression at 1-year, hazard ratio [HR] 0.12, P = 0.04) compared with low-dose hypofractionated SRS (22.6% local progression at 1-year, HR 1). They also found that there was no association between histology-specific sensitivity to radiation, previous radiation, and the degree of pre- or post-operative ESCC. Thus, in patients with radioresistant tumors causing high-grade ESCC, separation surgery is a good choice, which avoids the risks associated with extensive or gross-total tumor resection by a small separation between the tumor and the spinal cord.
Open surgery with postoperative radiation is an overwhelming current trend. This has changed the goals of surgery, which is now mainly to safely and effectively provide the space for tumoricidal radiation to gross residual tumor volumes. Patchell et al.  showed that surgical decompression followed by cEBRT yielded significantly superior results, when compared to cEBRT alone. Rock et al.  reported a 92% local control rate in patients treated with radiosurgery following open surgical procedures. Rades et al.  found patients could gain more improvement of motor function from the therapy of surgery plus radiotherapy compared with radiotherapy alone. Xu et al.  reported that a patient with lung cancer metastasis to the spine, after receiving surgery and postoperative radiation, showed improvement of the local situation of the spine in 24 months.
There are different kinds of decision-making frameworks in dealing with spinal metastases. No matter what kind of framework is used, the aim is to integrate multimodality therapy to optimize local tumor control, pain relief, and restoration or preservation of neurologic function and minimize morbidity in this often systemically ill patient population. The neurologic, oncologic, mechanical, and systemic decision framework consists of the neurologic (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 Spine Oncology Study Group scoring system), oncologic, mechanical, and systemic considerations, and incorporates the use of cEBRT, spinal SRS, and minimally invasive and open surgical interventions (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) [Table 4].  Briefly, the neurology guided consideration is an assessment of the degree of ESCC, myelopathy, and/or functional radiculopathy. The oncology guided consideration is predicated on the expected tumoral response and durability of response to available treatments such as surgery, cEBRT therapy, SRS, immunotherapy, and chemotherapy. Pathologic fractures are characterized by mechanical instability, and the treatment includes brace application, percutaneous cement and/or pedicle screw augmentation, or open surgery. The fourth considering point is the extent of systemic disease and medical comorbidities to evaluate the ability of the patient to tolerate a proposed treatment and the overall expected patient survival based on extent of disease and tumor histology.  Paton et al.  proposed a novel decision model called LMNOP that describes the key factors in formulating the management plan, while recognizing the individualization of each patient. The LMNOP system evaluates the number of spinal levels involved and the location of disease in the spine (L), mechanical instability (M), tumor-related instability may be graded using a combination of clinical and radiologic criteria called the spine instability neoplastic score.  Neurology (N), oncology (O), patient fitness, and prognosis response to prior therapy (P) are shown in [Table 5]. In general, for patients with ESCC (N) or mechanical instability (M), surgery is recommended depending on their fitness/prognosis (P) and the location/extent of disease (L). Percutaneous vertebral augmentation can treat mild-moderate instability (M) in the absence of spinal cord compression (N), which is an attractive therapy for patients who are unfit for more extensive surgery (P) and have an estimated survival of < 3-6 months (P) or have multiple levels of disease (L). Highly radiosensitive tumors (O), regardless of the degree of spinal cord compression (N), are treated with cEBRT. Patients with radioresistant tumors (O) without significant cord compression (N) are offered SRS to control local tumor growth. Radiosurgery is also an option for tumor progression when external beam radiotherapy has failed (P). 
Overall, all treatment decisions are predicated on the patient's ability to tolerate the proposed intervention based on the extent of systemic comorbidities and tumor burden. Numerous prognostic scoring systems exist to help the estimation of the expected survival of patients and the quality of life with spinal metastases.
In conclusion, spinal metastatic tumor is a systematic disease. The goal of the treatment is to relieve pain, stabilize spinal structure, maintain neurologic function, and improve quality of life. Modern technology has equipped with different approaches to deal with this problem, including surgery, radiation, and pharmacologic therapy. Among them, surgery and radiation are the most popular and effective ones. Timely diagnosis and appropriate treatment selection are vital in optimizing the outcomes of treatment of metastatic spinal disease. Although different decision-making frameworks are proposed, their validity and utility still need to be tested with more cases and clinical trials.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]