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Surgical Management of Metastatic Spine Disease
Surgical Management of Metastatic Spine Disease Rory J. Petteys, BS, Daniel M. Sciubba, MD, and Ziya L. Gokaslan, MD Metastatic disease of the spine is a common and troublesome complication in many cancer patients. Metastases may cause debilitating pain and neurologic dysfunction, significantly limiting functional ability and quality of life. With advances in chemotherapy, radiation therapy, and surgical techniques, the treatment of metastatic spine disease has facilitated improved quality of life for many patients. Surgical advances have allowed more aggressive surgical decompression, debulking, and stabilization for vertebral metastases. With an aging population and as more patients survive longer with their burden of disease, surgical management of metastatic spine disease will become more prevalent. Semin Spine Surg 21:86-92 © 2009 Elsevier Inc. All rights reserved. KEYWORDS cancer, metastases, spine surgery
M
etastatic tumors of the spine are the most common neoplastic process in the vertebral column. Cadaver studies have demonstrated that as many as 30%-90% of patients who die from cancer are found to have spinal metastases.1,2 Symptomatic metastases occur in approximately 10% of all cancer patients.3 Up to 50% will require some form of treatment, and 5%-10% may require surgical management.4,5 The highest incidence of vertebral metastasis is found in patients 40-65 years of age, which corresponds to the period of highest cancer risk.6 Spinal metastases are most likely to originate from breast, lung, or prostate tumors, which reflect the high prevalence of these tumors and their tendency to metastasize to bone.7 A 30-year review by Brihaye and coworkers found that 16.5% of symptomatic spine metastases arose from breast cancer, 15.6% from lung cancer, and 9.2% from prostate cancer.8 Men are slightly more likely to develop spinal metastases, likely because lung cancer is more prevalent in men and prostate cancer is slightly more prevalent than breast cancer.6 As survival rates for many primary cancers continue to improve, surgical management for metastases will likely be used more frequently.
Classification of Tumors Tumors of the spine are grouped into the 3 following categories: extradural, intradural-extramedullary, and intramedullary. Most spinal metastases are found in the vertebral body with or without extension into the posterior elements Department of Neurosurgery, Johns Hopkins University, Baltimore, MD. Address reprint requests to Daniel M. Sciubba, MD, Department of Neurosurgery, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Meyer 8-161, Baltimore, MD 21287. E-mail: [email protected]
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1040-7383/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.semss.2009.03.004
(Fig. 1), followed by the paravertebral regions and the epidural space, respectively. Intradural and intramedullary metastases are very rare, and, when present, often reflect spread via cerebrospinal fluid seeding of previously treated cerebral metastases.9 While all segments of the vertebral column (the axis to coccyx) are susceptible to distant metastasis, the thoracic spine is the most commonly affected site (70%), followed by the lumbar spine (20%), cervical spine, and sacrum, respectively.10 Tumors often metastasize to the spine via arterial or venous routes, frequently leading to multicentric disease. Alternatively, some tumors may invade the spine by extensive local invasion. Patients with metastatic disease of the spine may present with variable clinical histories. Rapidly growing and aggressive tumors may present with swift progression and escalation of symptoms. Tumors with extensive bony destruction can present with new pathologic fractures or frank spinal deformities. Patients with extensive systemic disease may present initially with symptoms of other organ dysfunction, anorexia, or unexplained weight loss, with spinal metastases discovered incidentally as part of an overall workup. Pain is the most common presenting symptom of patients with symptomatic spinal metastases and occurs in approximately 83%-95% of patients.5 Local pain is a deep, often nocturnal pain that may improve with activity, anti-inflammatory or corticosteroid medications, and is thought to result from periosteal stretching and inflammation. Conversely, mechanical back pain, or axial pain, is usually exacerbated with activity or movement, worsens throughout the day, and is often refractory to anti-inflammatory, corticosteroid, and narcotic medications. Relief of mechanical pain is usually best accomplished by stabilization of the spine by external bracing or operative fixation. Radicular pain occurs when
Management of metastatic spine disease
Figure 1 Preoperative axial CT scan of a patient with nonsmall cell lung carcinoma metastatic to the T9 vertebral body and pedicle.
tumors directly impinge or irritate nerve roots as they exit the spine or when tumors cause pathologic fractures leading to loss of foraminal height and nerve root impingement. Dysesthetic or neuropathic pain can occur in intradural metastases and may be described as an intense, burning sensation rather than shooting pains.9 After pain, motor dysfunction is the second most common complaint of patients with metastatic disease of the vertebral column and is due to compression of neural elements by direct tumor impingement or vertebral body collapse and retropulsion of bone fragments into the spinal canal or neural foramina. Approximately 60%-85% of patients with metastatic epidural spinal cord compression (MESCC) have objective weakness in 1 or more muscle groups at the time of diagnosis and may also have bowel, bladder, or sexual dysfunctions.7 While progression of symptoms is variable, patients with motor dysfunction often develop complete paralysis without intervention.11 The prognosis of MESCC correlates well with the patient’s neurologic status at the time of diagnosis,12 reinforcing the importance of diagnosis before the development of a neurologic deficit. In 2002, Levack et al reported that in 319 cancer patients, a median 2-month delay occurred between the report of pain to a primary care provider and the diagnosis of cord compression.13
Diagnostic Workup The workup of a patient with suspected spinal metastasis includes a thorough history and physical examination. Red flags include those specific to vertebral lesions, such as nocturnal pain, weakness, sensory changes, bowel or bladder dysfunction, and gait disturbances, and those indicative of systemic disease, such as weight loss or signs of organ dysfunction. The history of routine cancer screening should be investigated, as well as conditions that may predispose patients to malignancy. Carcinogen exposure and smoking history are also important to the inquiry. Laboratory tests should include blood chemistry, blood cell counts, prostate-specific
87 antigen in men, and serum and urine protein electrophoresis if multiple myeloma is considered. Modern multidetector computerized tomography and magnetic resonance imaging (MRI) provide highly detailed information about the anatomy of the spine and the extent of tumor involvement and are invaluable to surgical decisionmaking. MRI imaging protocols for spinal metastases should include T1- and T2-weighted images as well as contrastenhanced studies in all 3 standard axes (axial, sagittal, and coronal). Fat-suppression studies are useful for evaluating contrast-enhancing lesions within the osseus matrix. Myelography may further help to identify sites of compression but has fallen out of favor with increased use of MRI. Computed tomographic (CT) angiography may be performed to assess the vasculature of spinal metastases. Conventional digital subtraction angiography may be useful for metastases of highly vascular primary tumors, such as renal cell, thyroid, angiosarcoma, leiomyosarcoma, hepatocellular, and neuroendocrine tumors (pheochromocytoma and paraganglioma).14,15 The tumor vasculature can be identified and embolized preoperatively, thereby reducing intraoperative blood loss and facilitating complete resection of the lesion. Additionally, embolization may be an effective alternative treatment for patients who are not candidates for surgical excision. Plain radiographs serve as a screening test to identify lytic or sclerotic lesions, pathologic compression fractures, deformities, and masses. Sclerotic or blastic lesions often arise from breast or prostate cancers.16 Most metastatic lesions of the spine, however, are lytic in nature, but up to 50% of the bone must be eroded before noticeable changes are evident on radiographs.17 Therefore, plain radiographs are relatively insensitive for vertebral metastases and more advanced imaging techniques are necessary for diagnosis. Alternatively, nuclear bone scans can detect lesions at an earlier stage18 and as small as 2 mm.5 The overall sensitivity of nuclear bone scan has been reported to be 62%-89%19 but is limited by poor image resolution and must be correlated with CT or MRI to exclude benign processes and plan operative intervention.20 Unlike planar nuclear bone scans, single-photon emission computerized tomography (SPECT) provides 3-dimensional imaging and increased sensitivity and specificity over other imaging modalities.21,22 SPECT imaging can also differentiate metastatic and benign lesions.21 Therefore, SPECT is an effective tool for surveillance of the spine when metastatic disease is suspected, especially when planar bone scans are indeterminate or equivocal.23 Positron emission tomography is increasingly used for whole body surveillance of metastatic disease and is superior to planar scintigraphy.19,24 However, like other nuclear medicine studies, positron emission tomography is hindered by poor spatial resolution and requires correlation with CT or MRI.
Management The ultimate goal in the treatment of spinal metastases is generally palliation of symptoms, as curative resection is usually not possible. Therefore, the therapeutic objectives are
88 focused on preservation of neurologic function, pain relief, and mechanical stabilization. Patient variables, such as age, tumor burden, life expectancy, and functional status, significantly influence the choice of therapy. With recent improvements in cancer therapies and subsequent increases in survival, many have advocated increasingly aggressive surgical management and stabilization for symptomatic metastatic spine disease. Techniques have been employed that are technically superior in decompressing the spinal cord, but potentially more morbid. The goals of surgical treatment, however, remain consistent: preserving neurologic function, reducing pain, and providing mechanical stability. Curative resection is rarely possible, except in cases of solitary metastases of renal cell carcinoma or certain primary lesions.25 Identifying appropriate candidates for surgical management requires careful patient selection and a comprehensive understanding of the anatomy and histopathology of the metastatic tumor and surrounding structures, and the biomechanical changes induced by vertebral metastases. Selecting appropriate patients for surgical management is challenging. Consequently, several authors have developed scoring systems to identify patients likely to benefit from surgery. Tokuhashi et al26 proposed a system that scores patients based on general condition, extraspinal and visceral metastases, number of vertebral metastases, primary tumor type, and presence of neurologic deficit. Good prognostic indicators (ie, few other metastases, less aggressive tumor, etc.) were scored higher (0-2 points in each category). Excisional (more extensive) surgery was recommended for patients with scores greater than 9 (of 12) and palliative therapy (limited decompression/fixation) recommended for scores less than 5. Tomita et al27 proposed a similar system that takes into account primary tumor characteristics and the presence of visceral and bone metastases. Patients with low scores (no other metastases and less aggressive primary tumor) should be considered for wide excision to reduce recurrence. Higher scores correlated with a poorer prognosis and should indicate less aggressive surgical approach. With consideration of the primary tumor histology, presence of distant metastases, and patient condition, it is possible to identify patients who could benefit from aggressive surgical management of their metastases. Biomechanical studies of the spinal column have shown that the vertebral bodies support up to 80% of the axial load on the spine.28 Because the vertebral body is the most common site of metastatic deposits, destructive lesions there can have a significant impact on the load-bearing capacity of the entire spine. This capacity is directly related to the tumor size, cross-sectional area of the remaining bony matrix, and bone mineral density. Windhagen et al demonstrated that the propensity for pathologic fractures could be predicted by calculating the product of bone mineral density and crosssectional area of intact bone.28 Taneichi et al elaborated on this concept by showing that impending collapse was predicted by 50%-60% vertebral body involvement in the thoracic spine and 35%-45% in the lower thoracic/lumbar spine.29 Metastatic involvement of the posterior elements of the spinal column, especially the facet joints, can predispose
R.J. Petteys, D.M. Sciubba, and Z.L. Gokaslan patients to dislocation and translational deformity. This, however, is uncommon due to the relatively low incidence of metastasis to the dorsal elements. Defining the degree and type of spine instability remains difficult in metastases, but the principles of Denis’s 3-column model for traumatic instability can be applied.30 In this model, 2 columns are located in the vertebral bodies and associated soft-tissue structures, and the third in the posterior elements. The criteria for identifying instability are as follows: (1) 2 or more column involvement; (2) greater than 50% loss of vertebral body height; (3) greater than 20-30 degrees of kyphotic deformity; and (4) involvement of the same column in adjacent levels. These criteria should be considered in choosing the approach and extent of reconstruction. Patients with clearly unstable spines may benefit from operative fixation and tumor debulking. Additionally, the quality of the surrounding bone and the nature of biomechanical forces in the affected region must be considered in the surgical decision-making process. High stress areas, such as the cervicothoracic and thoracolumbar junctions, may require more extensive reconstruction due to the increased translational forces in these areas. The surgical approach to resection or decompression in spinal metastases is, in large part, determined by the spinal segment involved, the location of the tumor within the vertebra, the tumor histology, and the type of reconstruction necessary. Most spine metastases causing cord compression arise from the vertebral body and extend dorsally into the spinal canal. Consequently, anterior approaches usually provide the best access to the tumor and offer the greatest ability to decompress the spinal cord. Anterior approaches are, however, associated with greater surgical morbidity than posterior or lateral extracavitary approaches. The cervical spine can be approached and reconstructed from both the anterior and the posterior techniques that are familiar to most spine surgeons. The upper thoracic spine (T1-T4) may be particularly challenging to access and may require a combined anterolateral cervical approach with sternotomy and/or thoracotomy.31 However, the high morbidity of median sternotomy usually precludes this approach in metastatic disease, making the lone posterior approach more desirable. The midthoracic spine (T5-T12) can be safely approached from a right-sided thoracotomy to minimize risk to the great vessels and aortic arch, except in cases where most tumor bulk is on the left.32-34 The lower thoracic and lumbar spine (T12-L4) may be approached via retroperitoneal or transperitoneal approaches, while disease limited to L4-L5 or the sacrum is commonly treated with posterior decompression and stabilization alone. Reconstruction after single-level vertebral body resection is commonly performed with titanium distractable or mesh cages and anterolateral plating. For patients with thoracolumbar junction lesions, 2 or more adjacent vertebrectomies, significant kyphosis, or posterior column damage from tumor or from surgical extirpation, posterior stabilization with pedicle screw instrumentation is generally indicated (Figs. 2-3). Sole posterior approaches should be limited to cases
Management of metastatic spine disease
89 Table 1 Treatment Outcomes for Metastatic Epidural Spinal Cord Compression From Witham et al Review of the Literature40
Treatment XRT alone Laminectomy ⴞ XRT Laminectomy and stabilization ⴞ XRT Anterior decompression and stabilization ⴞ XRT
Improved Surgical Neurologic Mortality Function (Mean) (Mean) 36% 42% 64%
N/A 6% 5%
75%
10%
XRT ⴝ radiation therapy; ⴞ ⴝ management included XRT in some cases, and in others it did not.
Figure 2 Postoperative X-ray of a patient who underwent posterior transpedicular vertebrectomy and reconstruction with distractible titanium cage and pedicle screw and rod stabilization for T9 metastasis of nonsmall cell lung carcinoma causing cord compression.
where an anterior approach is contraindicated due to the high surgical morbidity and potential destabilization, for example, transthoracic approach in patients with severe lung disease. Decompression from a lone posterior approach is challenging, but possible, and has been increasingly used in the treatment of metastatic spine disease. Some authors have advocated a bilateral transpedicular approach via costotransversectomy to decompress the ventral spinal cord.33 Reconstruction of the anterior 2 columns of the spine can then be performed with polymethylmethacrylate or autologous graft secured with a titanium mesh cage,35 expandible titanium
Figure 3 Intraoperative photograph of posterior vertebrectomy and reconstruction with distractible titanium cage and pedicle screw and rod fixation for metastatic spine disease. (Color version of figure is available online.)
cage (Fig. 3),34 chest tube,33 or Steinman pins.36 The authors prefer autologous graft secured with a distractable cage in cases where long-term survival is expected. When expected survival is short, the technique described by Errico and Cooper37 of polymethylmethacrylate secured with chest tubes is preferred. Some authors have observed higher complication rates with this transpedicular approach33,34; others have not.38 Because the posterior elements are resected to remove the diseased anterior elements, a 3-column injury is created, which may lead to postoperative mechanical instability and failure of osseous fusion. Therefore, it is necessary to provide stability with instrumented fixation (ie, pedicle screws and rods). Metastatic epidural spinal cord compression is generally considered a surgical emergency and is defined by radiographic evidence of tumor elements in the spine causing displacement of the spinal cord from its normal position within the spinal canal. It occurs in 5%-10% of cancer patients and up to 40% of patients with concomitant nonspinal bone metastases,39 with approximately 25,000 symptomatic cases reported annually in the USA.32 Traditional treatments for MESCC include corticosteroids, radiotherapy, and surgery. Until recently, surgical treatment was limited to decompressive laminectomy, but this limited approach failed to address compression from the vertebral body and destabilized the posterior elements, leading to spinal instability, worsened neurologic function, and pain.40 With this potential for decompensation and improvements in surgical technique, aggressive circumferential surgical decompression with instrumented stabilization has become a mainstay of treatment. Witham et al presented a review of the literature from 1964 to 2005 for radiation and surgical management of MESCC and demonstrated improved outcomes with the evolution of more extensive surgical decompression and stabilization (Table 1).40 Studies of radiation therapy alone demonstrated a mean 36% improvement and 17% decline in neurologic function. Studies of laminectomy with or without radiation therapy showed similar results: a mean 42% improvement and 13% decline. A small, but not insignificant, surgical mortality was reported in the laminectomy studies (mean, 6%). In the articles that addressed patients treated with decom-
90 pression and posterior stabilization, motor improvement was observed in 64% (mean) and pain relief was achieved in 88% (mean) of patients, with mortality comparable to laminectomy alone (mean, 5%). Studies of patients who received anterior decompression with stabilization demonstrated the greatest improvement in functional neurologic status (75% mean), albeit with a slight increase in surgical mortality (10% mean). In the first multicenter prospective randomized controlled trial of direct decompressive surgical resection with radiation therapy vs. radiation therapy alone, Patchell et al demonstrated greater improvements in neurologic function for patients treated with surgery.41 In this study, both groups of patients received 30 Gy of external beam radiation delivered in 10 fractions. The goals of surgery were spinal cord decompression, resection of as much tumor bulk as possible, and stabilization. A statistically significant (P ⫽ 0.001) improvement was observed in the overall posttreatment ambulatory rate of the group treated with surgery (84% vs. 57% radiation alone). Patients treated with surgery also retained the ability to walk longer than those treated with radiation alone (median of 122 vs. 13 days, P ⫽ 0.003). Patients who were ambulatory before treatment were more likely to remain ambulatory after surgical decompression with radiation therapy (94%) than after radiation alone (74%, P ⫽ 0.024). Furthermore, more nonambulatory patients regained the ability to walk following surgery (62% vs. 19%, P ⫽ 0.012). Perhaps most importantly, Patchell et al demonstrated that functional ability (Frankel scores), muscle strength (Asia scores), continence, and survival time were all significantly improved in patients treated with surgery and radiation therapy rather than radiation therapy alone. Median survival time in the surgery group was 126 days compared with 100 days in the radiation therapy alone group (P ⫽ 0.033). As such, Patchell et al concluded that select patients with MESCC treated with surgery and radiation therapy experience improved survival time, maintain ambulation longer, and regain ambulation more frequently than those treated with radiation therapy alone. With these findings, it is possible to make recommendations for radiation therapy alone vs. surgery with radiation therapy in the treatment of MESCC. Radiation alone is still indicated in MESCC caused by highly radiosensitive tumors, such as lymphoma, myeloma, and small-cell lung carcinoma without spinal instability. Patients with significant tumor intrusion of the spinal canal, rapidly progressive neurologic decline, or expected survival less than 3 months may also benefit from radiation alone, although the latter is not universally agreed upon. Surgical decompression and stabilization is indicated in patients with MESCC caused by radioresistant tumors, tumors that recur after radiation therapy, patients with spinal instability, cord compression due to bone, patients that experience rapid neurologic decline during radiation therapy, and cases where tissue diagnosis is necessary (Fig. 1). Additionally, in patients with solitary metastases with relatively indolent courses, such as renal cell carcinoma in the absence of other systemic metastases, total
R.J. Petteys, D.M. Sciubba, and Z.L. Gokaslan en bloc resection and spondylectomy may be indicated with curative resection possible. Despite vast improvements in imaging modalities over the last 2 decades, tissue from spinal metastases is often needed for definitive diagnosis. In fact, as many as 10%-20% of metastatic lesions of the spine will have no known primary tumor when the spine lesion is discovered, and biopsy may be necessary.42 If a primary tumor of the spine is considered possible, the surgeon should be involved in planning the biopsy approach so the tract may be excised in a later operation, as recurrence along the biopsy tract can occur with some tumors, especially chordomas.43
Adjuvant Therapies Despite advancements in chemotherapeutic agents, these therapies are commonly limited in the treatment of metastatic spine disease. There are, however, certain metastases that have shown improved outcomes with neoadjuvant therapies followed by resection, including germ cell tumors, high-risk neuroblastomas,44 Ewing’s sarcoma,45 and osteogenic sarcomas. Additionally, superior sulcus nonsmall cell lung carcinomas (Pancoast’s tumor) were previously considered unresectable due to the high morbidity and limited gains of surgery. With neoadjuvant etoposide, cisplatin, and radiation therapy, however, 66% of patients with these tumors will have minimal residual tumor at operation, thus increasing the likelihood of achieving a negative margin resection.46 Other modalities of pharmacologic therapies have proven effective in the treatment of spine metastases. Corticosteroids are essential in cases of cord compression. However, there is currently no consensus for the optimal dosing regimen in cord compression and no conclusive data support high-dose (96 mg/d) vs. low-dose (16 mg/d) steroids. Vecht et al compared initial intravenous bolus doses of 10 and 100 mg but showed no differences in outcomes, including pain, ambulation, and bladder function.47 Conventional external beam radiation therapy (XRT) has long been used in the treatment of spinal metastases. Numerous studies in the 1960s and 1970s demonstrated no difference in outcome between patients treated with XRT alone and those treated with surgical decompression with or without XRT.48 However, surgical treatment in these studies consisted of only laminectomy, which is now thought to be inadequate, as most spinal metastases arise from the ventral elements of the vertebral column and laminectomy alone further destabilizes the spine. XRT is a useful treatment option in radiosensitive tumors, such as lymphoma, multiple myeloma, small-cell lung carcinoma, testicular seminoma, neuroblastoma, and Ewing’s sarcoma. It can also be helpful in patients expected to survive less than 3 months, who cannot tolerate surgery, or with diffuse spinal involvement. XRT is typically administered in fractionated doses over 10-14 days with a total dose of 25-40 Gy.49 Standard protocol involves the diseased level and a 5-cm margin, effectively including 2 vertebral levels above and below the target.50 Local disease control is dependent on the radiation dose delivered to the targeted lesion, which is limited by the low
Management of metastatic spine disease tolerance of the spinal cord to radiation damage. Unfortunately, conventional XRT lacks the precision necessary to deliver large single-fraction doses to the vertebral column near radiosensitive neural structures. Thus, the actual dose delivered to the target is often far below the optimal therapeutic dose.51 Alternatively, stereotactic radiosurgery has proven effective with fewer complications. While radiotherapies have proven effective at tumor control, preservation of neurologic function, and pain relief, these modalities cannot address spinal instability or deformity and subsequent pain or dysfunction. Additionally, cord compression and neurologic dysfunction caused by retropulsion of bone fragments secondary to pathologic fracture is not relieved by radiation therapy. When it is used as adjuvant or neoadjuvant therapy with surgical resection, the timing of radiation therapy must be carefully considered. Studies have demonstrated deleterious effects of radiation therapy on wound and bone healing and graft incorporation after surgical resection and reconstruction.51 Following surgical resection, a 3- to 4-week delay before beginning radiotherapy may be advisable.
Conclusions With the introduction of new technologies and techniques, the management paradigm for patients with metastatic disease of the spine has become increasingly complex. Improved imaging technologies have provided enhanced visualization and characterization of metastases. Surgical techniques and fixation devices have evolved to allow more aggressive decompression and more effective stabilization of the vertebral column, leading to improved functional outcomes. With further improvements, the treatment of spinal metastases will likely become increasingly multimodal in nature, with multiple specialties represented.
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R.J. Petteys, D.M. Sciubba, and Z.L. Gokaslan 44. Sandberg DI, Bilsky MH, Kushner BH, et al: Treatment of spinal involvement in neuroblastoma patients. Pediatr Neurosurg 39:291-298, 2003 45. Ilaslan H, Sundaram M, Unni KK, et al: Primary Ewing’s sarcoma of the vertebral column. Skeletal Radiol 33:506-513, 2004 46. Rusch VW, Giroux DJ, Kraut MJ, et al: Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: Initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Thorac Cardiovasc Surg 121:472-483, 2001 47. Vecht CJ, Haaxma-Reiche H, van Putten WL, et al: Initial bolus of conventional versus high-dose dexamethasone in metastatic spinal cord compression. Neurology 39:1255-1257, 1989 48. Young RF, Post EM, King GA: Treatment of spinal epidural metastases. Randomized prospective comparison of laminectomy and radiotherapy. J Neurosurg 53:741-748, 1980 49. Linstadt D: Spinal cord, in Leidbel S, Phillips T (eds): Textbook of Radiation Oncology. Philadelphia, PA, WB Saunders, 1998, pp 408411 50. Loblaw DA, Laperriere NJ: Emergency treatment of malignant extradural spinal cord compression: An evidence-based guideline. J Clin Oncol 16:1613-1624, 1998 51. Emery SE, Brazinski MS, Koka A, et al: The biological and biomechanical effects of irradiation on anterior spinal bone grafts in a canine model. J Bone Joint Surg Am 76:540-548, 1994
M
etastatic tumors of the spine are the most common neoplastic process in the vertebral column. Cadaver studies have demonstrated that as many as 30%-90% of patients who die from cancer are found to have spinal metastases.1,2 Symptomatic metastases occur in approximately 10% of all cancer patients.3 Up to 50% will require some form of treatment, and 5%-10% may require surgical management.4,5 The highest incidence of vertebral metastasis is found in patients 40-65 years of age, which corresponds to the period of highest cancer risk.6 Spinal metastases are most likely to originate from breast, lung, or prostate tumors, which reflect the high prevalence of these tumors and their tendency to metastasize to bone.7 A 30-year review by Brihaye and coworkers found that 16.5% of symptomatic spine metastases arose from breast cancer, 15.6% from lung cancer, and 9.2% from prostate cancer.8 Men are slightly more likely to develop spinal metastases, likely because lung cancer is more prevalent in men and prostate cancer is slightly more prevalent than breast cancer.6 As survival rates for many primary cancers continue to improve, surgical management for metastases will likely be used more frequently.
Classification of Tumors Tumors of the spine are grouped into the 3 following categories: extradural, intradural-extramedullary, and intramedullary. Most spinal metastases are found in the vertebral body with or without extension into the posterior elements Department of Neurosurgery, Johns Hopkins University, Baltimore, MD. Address reprint requests to Daniel M. Sciubba, MD, Department of Neurosurgery, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Meyer 8-161, Baltimore, MD 21287. E-mail: [email protected]
86
1040-7383/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.semss.2009.03.004
(Fig. 1), followed by the paravertebral regions and the epidural space, respectively. Intradural and intramedullary metastases are very rare, and, when present, often reflect spread via cerebrospinal fluid seeding of previously treated cerebral metastases.9 While all segments of the vertebral column (the axis to coccyx) are susceptible to distant metastasis, the thoracic spine is the most commonly affected site (70%), followed by the lumbar spine (20%), cervical spine, and sacrum, respectively.10 Tumors often metastasize to the spine via arterial or venous routes, frequently leading to multicentric disease. Alternatively, some tumors may invade the spine by extensive local invasion. Patients with metastatic disease of the spine may present with variable clinical histories. Rapidly growing and aggressive tumors may present with swift progression and escalation of symptoms. Tumors with extensive bony destruction can present with new pathologic fractures or frank spinal deformities. Patients with extensive systemic disease may present initially with symptoms of other organ dysfunction, anorexia, or unexplained weight loss, with spinal metastases discovered incidentally as part of an overall workup. Pain is the most common presenting symptom of patients with symptomatic spinal metastases and occurs in approximately 83%-95% of patients.5 Local pain is a deep, often nocturnal pain that may improve with activity, anti-inflammatory or corticosteroid medications, and is thought to result from periosteal stretching and inflammation. Conversely, mechanical back pain, or axial pain, is usually exacerbated with activity or movement, worsens throughout the day, and is often refractory to anti-inflammatory, corticosteroid, and narcotic medications. Relief of mechanical pain is usually best accomplished by stabilization of the spine by external bracing or operative fixation. Radicular pain occurs when
Management of metastatic spine disease
Figure 1 Preoperative axial CT scan of a patient with nonsmall cell lung carcinoma metastatic to the T9 vertebral body and pedicle.
tumors directly impinge or irritate nerve roots as they exit the spine or when tumors cause pathologic fractures leading to loss of foraminal height and nerve root impingement. Dysesthetic or neuropathic pain can occur in intradural metastases and may be described as an intense, burning sensation rather than shooting pains.9 After pain, motor dysfunction is the second most common complaint of patients with metastatic disease of the vertebral column and is due to compression of neural elements by direct tumor impingement or vertebral body collapse and retropulsion of bone fragments into the spinal canal or neural foramina. Approximately 60%-85% of patients with metastatic epidural spinal cord compression (MESCC) have objective weakness in 1 or more muscle groups at the time of diagnosis and may also have bowel, bladder, or sexual dysfunctions.7 While progression of symptoms is variable, patients with motor dysfunction often develop complete paralysis without intervention.11 The prognosis of MESCC correlates well with the patient’s neurologic status at the time of diagnosis,12 reinforcing the importance of diagnosis before the development of a neurologic deficit. In 2002, Levack et al reported that in 319 cancer patients, a median 2-month delay occurred between the report of pain to a primary care provider and the diagnosis of cord compression.13
Diagnostic Workup The workup of a patient with suspected spinal metastasis includes a thorough history and physical examination. Red flags include those specific to vertebral lesions, such as nocturnal pain, weakness, sensory changes, bowel or bladder dysfunction, and gait disturbances, and those indicative of systemic disease, such as weight loss or signs of organ dysfunction. The history of routine cancer screening should be investigated, as well as conditions that may predispose patients to malignancy. Carcinogen exposure and smoking history are also important to the inquiry. Laboratory tests should include blood chemistry, blood cell counts, prostate-specific
87 antigen in men, and serum and urine protein electrophoresis if multiple myeloma is considered. Modern multidetector computerized tomography and magnetic resonance imaging (MRI) provide highly detailed information about the anatomy of the spine and the extent of tumor involvement and are invaluable to surgical decisionmaking. MRI imaging protocols for spinal metastases should include T1- and T2-weighted images as well as contrastenhanced studies in all 3 standard axes (axial, sagittal, and coronal). Fat-suppression studies are useful for evaluating contrast-enhancing lesions within the osseus matrix. Myelography may further help to identify sites of compression but has fallen out of favor with increased use of MRI. Computed tomographic (CT) angiography may be performed to assess the vasculature of spinal metastases. Conventional digital subtraction angiography may be useful for metastases of highly vascular primary tumors, such as renal cell, thyroid, angiosarcoma, leiomyosarcoma, hepatocellular, and neuroendocrine tumors (pheochromocytoma and paraganglioma).14,15 The tumor vasculature can be identified and embolized preoperatively, thereby reducing intraoperative blood loss and facilitating complete resection of the lesion. Additionally, embolization may be an effective alternative treatment for patients who are not candidates for surgical excision. Plain radiographs serve as a screening test to identify lytic or sclerotic lesions, pathologic compression fractures, deformities, and masses. Sclerotic or blastic lesions often arise from breast or prostate cancers.16 Most metastatic lesions of the spine, however, are lytic in nature, but up to 50% of the bone must be eroded before noticeable changes are evident on radiographs.17 Therefore, plain radiographs are relatively insensitive for vertebral metastases and more advanced imaging techniques are necessary for diagnosis. Alternatively, nuclear bone scans can detect lesions at an earlier stage18 and as small as 2 mm.5 The overall sensitivity of nuclear bone scan has been reported to be 62%-89%19 but is limited by poor image resolution and must be correlated with CT or MRI to exclude benign processes and plan operative intervention.20 Unlike planar nuclear bone scans, single-photon emission computerized tomography (SPECT) provides 3-dimensional imaging and increased sensitivity and specificity over other imaging modalities.21,22 SPECT imaging can also differentiate metastatic and benign lesions.21 Therefore, SPECT is an effective tool for surveillance of the spine when metastatic disease is suspected, especially when planar bone scans are indeterminate or equivocal.23 Positron emission tomography is increasingly used for whole body surveillance of metastatic disease and is superior to planar scintigraphy.19,24 However, like other nuclear medicine studies, positron emission tomography is hindered by poor spatial resolution and requires correlation with CT or MRI.
Management The ultimate goal in the treatment of spinal metastases is generally palliation of symptoms, as curative resection is usually not possible. Therefore, the therapeutic objectives are
88 focused on preservation of neurologic function, pain relief, and mechanical stabilization. Patient variables, such as age, tumor burden, life expectancy, and functional status, significantly influence the choice of therapy. With recent improvements in cancer therapies and subsequent increases in survival, many have advocated increasingly aggressive surgical management and stabilization for symptomatic metastatic spine disease. Techniques have been employed that are technically superior in decompressing the spinal cord, but potentially more morbid. The goals of surgical treatment, however, remain consistent: preserving neurologic function, reducing pain, and providing mechanical stability. Curative resection is rarely possible, except in cases of solitary metastases of renal cell carcinoma or certain primary lesions.25 Identifying appropriate candidates for surgical management requires careful patient selection and a comprehensive understanding of the anatomy and histopathology of the metastatic tumor and surrounding structures, and the biomechanical changes induced by vertebral metastases. Selecting appropriate patients for surgical management is challenging. Consequently, several authors have developed scoring systems to identify patients likely to benefit from surgery. Tokuhashi et al26 proposed a system that scores patients based on general condition, extraspinal and visceral metastases, number of vertebral metastases, primary tumor type, and presence of neurologic deficit. Good prognostic indicators (ie, few other metastases, less aggressive tumor, etc.) were scored higher (0-2 points in each category). Excisional (more extensive) surgery was recommended for patients with scores greater than 9 (of 12) and palliative therapy (limited decompression/fixation) recommended for scores less than 5. Tomita et al27 proposed a similar system that takes into account primary tumor characteristics and the presence of visceral and bone metastases. Patients with low scores (no other metastases and less aggressive primary tumor) should be considered for wide excision to reduce recurrence. Higher scores correlated with a poorer prognosis and should indicate less aggressive surgical approach. With consideration of the primary tumor histology, presence of distant metastases, and patient condition, it is possible to identify patients who could benefit from aggressive surgical management of their metastases. Biomechanical studies of the spinal column have shown that the vertebral bodies support up to 80% of the axial load on the spine.28 Because the vertebral body is the most common site of metastatic deposits, destructive lesions there can have a significant impact on the load-bearing capacity of the entire spine. This capacity is directly related to the tumor size, cross-sectional area of the remaining bony matrix, and bone mineral density. Windhagen et al demonstrated that the propensity for pathologic fractures could be predicted by calculating the product of bone mineral density and crosssectional area of intact bone.28 Taneichi et al elaborated on this concept by showing that impending collapse was predicted by 50%-60% vertebral body involvement in the thoracic spine and 35%-45% in the lower thoracic/lumbar spine.29 Metastatic involvement of the posterior elements of the spinal column, especially the facet joints, can predispose
R.J. Petteys, D.M. Sciubba, and Z.L. Gokaslan patients to dislocation and translational deformity. This, however, is uncommon due to the relatively low incidence of metastasis to the dorsal elements. Defining the degree and type of spine instability remains difficult in metastases, but the principles of Denis’s 3-column model for traumatic instability can be applied.30 In this model, 2 columns are located in the vertebral bodies and associated soft-tissue structures, and the third in the posterior elements. The criteria for identifying instability are as follows: (1) 2 or more column involvement; (2) greater than 50% loss of vertebral body height; (3) greater than 20-30 degrees of kyphotic deformity; and (4) involvement of the same column in adjacent levels. These criteria should be considered in choosing the approach and extent of reconstruction. Patients with clearly unstable spines may benefit from operative fixation and tumor debulking. Additionally, the quality of the surrounding bone and the nature of biomechanical forces in the affected region must be considered in the surgical decision-making process. High stress areas, such as the cervicothoracic and thoracolumbar junctions, may require more extensive reconstruction due to the increased translational forces in these areas. The surgical approach to resection or decompression in spinal metastases is, in large part, determined by the spinal segment involved, the location of the tumor within the vertebra, the tumor histology, and the type of reconstruction necessary. Most spine metastases causing cord compression arise from the vertebral body and extend dorsally into the spinal canal. Consequently, anterior approaches usually provide the best access to the tumor and offer the greatest ability to decompress the spinal cord. Anterior approaches are, however, associated with greater surgical morbidity than posterior or lateral extracavitary approaches. The cervical spine can be approached and reconstructed from both the anterior and the posterior techniques that are familiar to most spine surgeons. The upper thoracic spine (T1-T4) may be particularly challenging to access and may require a combined anterolateral cervical approach with sternotomy and/or thoracotomy.31 However, the high morbidity of median sternotomy usually precludes this approach in metastatic disease, making the lone posterior approach more desirable. The midthoracic spine (T5-T12) can be safely approached from a right-sided thoracotomy to minimize risk to the great vessels and aortic arch, except in cases where most tumor bulk is on the left.32-34 The lower thoracic and lumbar spine (T12-L4) may be approached via retroperitoneal or transperitoneal approaches, while disease limited to L4-L5 or the sacrum is commonly treated with posterior decompression and stabilization alone. Reconstruction after single-level vertebral body resection is commonly performed with titanium distractable or mesh cages and anterolateral plating. For patients with thoracolumbar junction lesions, 2 or more adjacent vertebrectomies, significant kyphosis, or posterior column damage from tumor or from surgical extirpation, posterior stabilization with pedicle screw instrumentation is generally indicated (Figs. 2-3). Sole posterior approaches should be limited to cases
Management of metastatic spine disease
89 Table 1 Treatment Outcomes for Metastatic Epidural Spinal Cord Compression From Witham et al Review of the Literature40
Treatment XRT alone Laminectomy ⴞ XRT Laminectomy and stabilization ⴞ XRT Anterior decompression and stabilization ⴞ XRT
Improved Surgical Neurologic Mortality Function (Mean) (Mean) 36% 42% 64%
N/A 6% 5%
75%
10%
XRT ⴝ radiation therapy; ⴞ ⴝ management included XRT in some cases, and in others it did not.
Figure 2 Postoperative X-ray of a patient who underwent posterior transpedicular vertebrectomy and reconstruction with distractible titanium cage and pedicle screw and rod stabilization for T9 metastasis of nonsmall cell lung carcinoma causing cord compression.
where an anterior approach is contraindicated due to the high surgical morbidity and potential destabilization, for example, transthoracic approach in patients with severe lung disease. Decompression from a lone posterior approach is challenging, but possible, and has been increasingly used in the treatment of metastatic spine disease. Some authors have advocated a bilateral transpedicular approach via costotransversectomy to decompress the ventral spinal cord.33 Reconstruction of the anterior 2 columns of the spine can then be performed with polymethylmethacrylate or autologous graft secured with a titanium mesh cage,35 expandible titanium
Figure 3 Intraoperative photograph of posterior vertebrectomy and reconstruction with distractible titanium cage and pedicle screw and rod fixation for metastatic spine disease. (Color version of figure is available online.)
cage (Fig. 3),34 chest tube,33 or Steinman pins.36 The authors prefer autologous graft secured with a distractable cage in cases where long-term survival is expected. When expected survival is short, the technique described by Errico and Cooper37 of polymethylmethacrylate secured with chest tubes is preferred. Some authors have observed higher complication rates with this transpedicular approach33,34; others have not.38 Because the posterior elements are resected to remove the diseased anterior elements, a 3-column injury is created, which may lead to postoperative mechanical instability and failure of osseous fusion. Therefore, it is necessary to provide stability with instrumented fixation (ie, pedicle screws and rods). Metastatic epidural spinal cord compression is generally considered a surgical emergency and is defined by radiographic evidence of tumor elements in the spine causing displacement of the spinal cord from its normal position within the spinal canal. It occurs in 5%-10% of cancer patients and up to 40% of patients with concomitant nonspinal bone metastases,39 with approximately 25,000 symptomatic cases reported annually in the USA.32 Traditional treatments for MESCC include corticosteroids, radiotherapy, and surgery. Until recently, surgical treatment was limited to decompressive laminectomy, but this limited approach failed to address compression from the vertebral body and destabilized the posterior elements, leading to spinal instability, worsened neurologic function, and pain.40 With this potential for decompensation and improvements in surgical technique, aggressive circumferential surgical decompression with instrumented stabilization has become a mainstay of treatment. Witham et al presented a review of the literature from 1964 to 2005 for radiation and surgical management of MESCC and demonstrated improved outcomes with the evolution of more extensive surgical decompression and stabilization (Table 1).40 Studies of radiation therapy alone demonstrated a mean 36% improvement and 17% decline in neurologic function. Studies of laminectomy with or without radiation therapy showed similar results: a mean 42% improvement and 13% decline. A small, but not insignificant, surgical mortality was reported in the laminectomy studies (mean, 6%). In the articles that addressed patients treated with decom-
90 pression and posterior stabilization, motor improvement was observed in 64% (mean) and pain relief was achieved in 88% (mean) of patients, with mortality comparable to laminectomy alone (mean, 5%). Studies of patients who received anterior decompression with stabilization demonstrated the greatest improvement in functional neurologic status (75% mean), albeit with a slight increase in surgical mortality (10% mean). In the first multicenter prospective randomized controlled trial of direct decompressive surgical resection with radiation therapy vs. radiation therapy alone, Patchell et al demonstrated greater improvements in neurologic function for patients treated with surgery.41 In this study, both groups of patients received 30 Gy of external beam radiation delivered in 10 fractions. The goals of surgery were spinal cord decompression, resection of as much tumor bulk as possible, and stabilization. A statistically significant (P ⫽ 0.001) improvement was observed in the overall posttreatment ambulatory rate of the group treated with surgery (84% vs. 57% radiation alone). Patients treated with surgery also retained the ability to walk longer than those treated with radiation alone (median of 122 vs. 13 days, P ⫽ 0.003). Patients who were ambulatory before treatment were more likely to remain ambulatory after surgical decompression with radiation therapy (94%) than after radiation alone (74%, P ⫽ 0.024). Furthermore, more nonambulatory patients regained the ability to walk following surgery (62% vs. 19%, P ⫽ 0.012). Perhaps most importantly, Patchell et al demonstrated that functional ability (Frankel scores), muscle strength (Asia scores), continence, and survival time were all significantly improved in patients treated with surgery and radiation therapy rather than radiation therapy alone. Median survival time in the surgery group was 126 days compared with 100 days in the radiation therapy alone group (P ⫽ 0.033). As such, Patchell et al concluded that select patients with MESCC treated with surgery and radiation therapy experience improved survival time, maintain ambulation longer, and regain ambulation more frequently than those treated with radiation therapy alone. With these findings, it is possible to make recommendations for radiation therapy alone vs. surgery with radiation therapy in the treatment of MESCC. Radiation alone is still indicated in MESCC caused by highly radiosensitive tumors, such as lymphoma, myeloma, and small-cell lung carcinoma without spinal instability. Patients with significant tumor intrusion of the spinal canal, rapidly progressive neurologic decline, or expected survival less than 3 months may also benefit from radiation alone, although the latter is not universally agreed upon. Surgical decompression and stabilization is indicated in patients with MESCC caused by radioresistant tumors, tumors that recur after radiation therapy, patients with spinal instability, cord compression due to bone, patients that experience rapid neurologic decline during radiation therapy, and cases where tissue diagnosis is necessary (Fig. 1). Additionally, in patients with solitary metastases with relatively indolent courses, such as renal cell carcinoma in the absence of other systemic metastases, total
R.J. Petteys, D.M. Sciubba, and Z.L. Gokaslan en bloc resection and spondylectomy may be indicated with curative resection possible. Despite vast improvements in imaging modalities over the last 2 decades, tissue from spinal metastases is often needed for definitive diagnosis. In fact, as many as 10%-20% of metastatic lesions of the spine will have no known primary tumor when the spine lesion is discovered, and biopsy may be necessary.42 If a primary tumor of the spine is considered possible, the surgeon should be involved in planning the biopsy approach so the tract may be excised in a later operation, as recurrence along the biopsy tract can occur with some tumors, especially chordomas.43
Adjuvant Therapies Despite advancements in chemotherapeutic agents, these therapies are commonly limited in the treatment of metastatic spine disease. There are, however, certain metastases that have shown improved outcomes with neoadjuvant therapies followed by resection, including germ cell tumors, high-risk neuroblastomas,44 Ewing’s sarcoma,45 and osteogenic sarcomas. Additionally, superior sulcus nonsmall cell lung carcinomas (Pancoast’s tumor) were previously considered unresectable due to the high morbidity and limited gains of surgery. With neoadjuvant etoposide, cisplatin, and radiation therapy, however, 66% of patients with these tumors will have minimal residual tumor at operation, thus increasing the likelihood of achieving a negative margin resection.46 Other modalities of pharmacologic therapies have proven effective in the treatment of spine metastases. Corticosteroids are essential in cases of cord compression. However, there is currently no consensus for the optimal dosing regimen in cord compression and no conclusive data support high-dose (96 mg/d) vs. low-dose (16 mg/d) steroids. Vecht et al compared initial intravenous bolus doses of 10 and 100 mg but showed no differences in outcomes, including pain, ambulation, and bladder function.47 Conventional external beam radiation therapy (XRT) has long been used in the treatment of spinal metastases. Numerous studies in the 1960s and 1970s demonstrated no difference in outcome between patients treated with XRT alone and those treated with surgical decompression with or without XRT.48 However, surgical treatment in these studies consisted of only laminectomy, which is now thought to be inadequate, as most spinal metastases arise from the ventral elements of the vertebral column and laminectomy alone further destabilizes the spine. XRT is a useful treatment option in radiosensitive tumors, such as lymphoma, multiple myeloma, small-cell lung carcinoma, testicular seminoma, neuroblastoma, and Ewing’s sarcoma. It can also be helpful in patients expected to survive less than 3 months, who cannot tolerate surgery, or with diffuse spinal involvement. XRT is typically administered in fractionated doses over 10-14 days with a total dose of 25-40 Gy.49 Standard protocol involves the diseased level and a 5-cm margin, effectively including 2 vertebral levels above and below the target.50 Local disease control is dependent on the radiation dose delivered to the targeted lesion, which is limited by the low
Management of metastatic spine disease tolerance of the spinal cord to radiation damage. Unfortunately, conventional XRT lacks the precision necessary to deliver large single-fraction doses to the vertebral column near radiosensitive neural structures. Thus, the actual dose delivered to the target is often far below the optimal therapeutic dose.51 Alternatively, stereotactic radiosurgery has proven effective with fewer complications. While radiotherapies have proven effective at tumor control, preservation of neurologic function, and pain relief, these modalities cannot address spinal instability or deformity and subsequent pain or dysfunction. Additionally, cord compression and neurologic dysfunction caused by retropulsion of bone fragments secondary to pathologic fracture is not relieved by radiation therapy. When it is used as adjuvant or neoadjuvant therapy with surgical resection, the timing of radiation therapy must be carefully considered. Studies have demonstrated deleterious effects of radiation therapy on wound and bone healing and graft incorporation after surgical resection and reconstruction.51 Following surgical resection, a 3- to 4-week delay before beginning radiotherapy may be advisable.
Conclusions With the introduction of new technologies and techniques, the management paradigm for patients with metastatic disease of the spine has become increasingly complex. Improved imaging technologies have provided enhanced visualization and characterization of metastases. Surgical techniques and fixation devices have evolved to allow more aggressive decompression and more effective stabilization of the vertebral column, leading to improved functional outcomes. With further improvements, the treatment of spinal metastases will likely become increasingly multimodal in nature, with multiple specialties represented.
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92 35. Dvorak MF, Kwon BK, Fisher CG, et al: Effectiveness of titanium mesh cylindrical cages in anterior column reconstruction after thoracic and lumbar vertebral body resection. Spine 28:902-908, 2003 36. Fourney DR, Abi-Said D, Rhines LD, et al: Simultaneous anterior-posterior approach to the thoracic and lumbar spine for the radical resection of tumors followed by reconstruction and stabilization. J Neurosurg 94:232-244, 2001 37. Errico TJ, Cooper PR: A new method of thoracic and lumbar body replacement for spinal tumors: Technical note. Neurosurgery 32:678680, 1993, discussion 680-671 38. Gerszten PC, Welch WC: Current surgical management of metastatic spinal disease. Oncol Williston Park 14:1013-1024, discussion 1024, 1029-1030, 2000 39. Schiff D: Spinal cord compression. Neurol Clin 21:67-86, viii, 2003 40. Witham TF, Khavkin YA, Gallia GL, et al: Surgery insight: Current management of epidural spinal cord compression from metastatic spine disease. Nat Clin Pract Neurol 2:87-94, 2006 41. Patchell RA, Tibbs PA, Regine WF, et al: Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: A randomised trial. Lancet 366:643-648, 2005 42. Lis E, Bilsky MH, Pisinski L, et al: Percutaneous CT-guided biopsy of osseous lesion of the spine in patients with known or suspected malignancy. AJNR Am J Neuroradiol 25:1583-1588, 2004 43. York JE, Kaczaraj A, Abi-Said D, et al: Sacral chordoma: 40-year experience at a major cancer center. Neurosurgery 44:74-79, 1999, discussion 79-80
R.J. Petteys, D.M. Sciubba, and Z.L. Gokaslan 44. Sandberg DI, Bilsky MH, Kushner BH, et al: Treatment of spinal involvement in neuroblastoma patients. Pediatr Neurosurg 39:291-298, 2003 45. Ilaslan H, Sundaram M, Unni KK, et al: Primary Ewing’s sarcoma of the vertebral column. Skeletal Radiol 33:506-513, 2004 46. Rusch VW, Giroux DJ, Kraut MJ, et al: Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: Initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Thorac Cardiovasc Surg 121:472-483, 2001 47. Vecht CJ, Haaxma-Reiche H, van Putten WL, et al: Initial bolus of conventional versus high-dose dexamethasone in metastatic spinal cord compression. Neurology 39:1255-1257, 1989 48. Young RF, Post EM, King GA: Treatment of spinal epidural metastases. Randomized prospective comparison of laminectomy and radiotherapy. J Neurosurg 53:741-748, 1980 49. Linstadt D: Spinal cord, in Leidbel S, Phillips T (eds): Textbook of Radiation Oncology. Philadelphia, PA, WB Saunders, 1998, pp 408411 50. Loblaw DA, Laperriere NJ: Emergency treatment of malignant extradural spinal cord compression: An evidence-based guideline. J Clin Oncol 16:1613-1624, 1998 51. Emery SE, Brazinski MS, Koka A, et al: The biological and biomechanical effects of irradiation on anterior spinal bone grafts in a canine model. J Bone Joint Surg Am 76:540-548, 1994