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Oncology (Williston Park). Author manuscript; available in PMC 2016 December 19. Published in final edited form as: Oncology (Williston Park). 1990 April ; 4(4): 47–58.
Diagnosis and treatment of epidural metastases M. Loreto Yáñez, M.D.1, Julie J. Miller, M.D., Ph.D.2, and Tracy T. Batchelor, M.D.2,3,4 1Department
of Radiation Oncology, Fundación Arturo López Pérez, Santiago, Chile
2Department
of Neurology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
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3Department
Radiation Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
4Division
of Hematology/Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
Abstract
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Epidural metastases occur in 5–10% of cancer patients and represent a neurological emergency. Patients most commonly present with acute onset of motor weakness, and restoration of neurologic function is critically dependent on prompt diagnosis and treatment. In this review, we discuss the clinical, epidemiological and radiologic features associated with epidural metastases and resulting spinal cord compression. We further review current treatment paradigms. The timely initiation of radiation, as well as surgery in selected cases, is critical to preserving neurological function, as well as achieving local tumor control and pain control. Future studies investigating surgical and radiation treatment for metastatic epidural cord compression are urgently needed.
Precis Epidural metastases occur in 5–10% of cancer patients and represent a neurological emergency. The timely initiation of radiation, as well as surgery in selected cases, is critical to preserving neurological function, as well as achieving local tumor control and pain control.
Keywords Spinal cord; epidural; metastases; cancer; neurologic deficit; paralysis; radiation; cauda equina
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Contact for correspondence and reprints: Tracy Batchelor, M.D., 55 Fruit Street, Yawkey 9E, Boston MA 02114, Phone: 617-643-1938, Fax: 617-643-2591, [email protected]. Conflict of interest disclosures M. Loreto Yanez and Julie Miller have no conflicts of interest Dedicated Author Contributions Dr. Yanez helped conceptualize the manuscript, gathered resources, assisted in writing the original draft and review and editing of final manuscript, and helped with visualization of the data in the form of tables and figures. Dr. Miller helped conceptualize the manuscript, gathered resources, assisted in writing the original draft as well as review and editing of final manuscript, and helped with visualization of the data in the form of tables and figures. Dr. Batchelor helped conceptualize the manuscript, gathered resources, assisted in review and editing of final manuscript, and helped with visualization of the data in the form of tables and figures, and provided funding.
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Introduction Many types of cancers can metastasize to the spine. There are three main sites of metastatic dissemination in the spine: epidural, leptomeningeal and intramedullary (Figure 1). In this article we review epidural metastases and the most worrisome complications: epidural spinal cord and cauda equina compression, which can lead to pain and irreversible neurological deficits. Metastatic epidural spinal cord compression (MESCC) occurs in approximately 5% of patients who die of cancer1.
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Epidural metastases originate in either the vertebral column (85%), the paravertebral tissues (10–15%) or the epidural space itself. The vertebral column is a very common site of bony metastases from cancer and eighty percent of vertebral epidural metastases are localized to the vertebral body, with fewer in the posterior arch2. The propensity of tumors to metastasize to the vertebral bodies is thought to be related to the highly vascular nature of bone marrow. A metastatic lesion in the vertebrae may then grow posteriorly and invade the epidural space, which is the area between the bone and the dura overlying the spinal cord (Figure 2, left panel). As the tumor grows in the epidural space, it encroaches on the thecal sac, compresses the spinal cord and also may occlude the venous plexus of the epidural space, leading to vasogenic edema in the white and gray matter which may cause additional damage by causing infarction of the spinal cord. Certain epidural metastases, such as those arising from prostate cancer, may disseminate through the Batson’s venous plexus. Epidural metastases that originate in the paravertebral tissues, such as lymphoma, can invade through the neural foramina into the epidural space (Figure 2, right panel)2. Rarely, some cancers may invade the epidural space without bony or paraspinal compromise.
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The majority of epidural metastases develop in the thoracic spine (60%), followed by the lumbosacral area and cervical spine (10%). Involvement of multiple spinal regions is not uncommon, occurring in 20–35% of patients3, and highlights the importance of imaging the entire spine (cervical, thoracic, lumbosacral) when screening for metastatic epidural disease. Similar to ESCC, when cancer metastasizes to the lumbosacral region, tumor growth and spread can result in compression of the cauda equina, a bundle of nerve roots extending from the most caudal portion of the spinal cord and involved in controlling the motor and sensory function of the lower extremities as well as bladder and bowel function.
Epidemiology
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The incidence of epidural metastases and epidural spinal cord compression is difficult to calculate due to the observation that some metastases to the epidural region are asymptomatic and are only incidentally diagnosed on radiologic examinations. Many times, however, epidural metastases come to medical attention after the development of pain and/or neurological symptoms. Approximately 5–10% of cancer patients will develop MESCC at some point during their disease course4. In adults, the most frequent cancers associated with MESCC are breast, lung or prostate cancer5. An autopsy study revealed that epidural spinal cord compression can be identified in approximately 5% of patients who die with cancer1. In hospitalized
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cancer patients the annual incidence of MESCC diagnosis is 3–4%6 and potentially on the rise as the incidence of MESCC in cancer patients rose from 4.4 to 6% between 1979 and 1985, based on the data from a Danish cancer referral center7. Although spinal cord compression related to epidural metastases can be the first sign of malignancy in up to 20% of cases, this neurological complication of cancer more commonly occurs in patients with previously diagnosed metastatic cancer. In cases where MESCC is the first manifestation of disease, the types of primary cancers (lung, unknown primary, multiple myeloma, non-Hodgkin lymphoma) is different than in cases in which the primary cancer was previously diagnosed3.
Presentation Author Manuscript
Patients with epidural metastases compressing the spinal cord or cauda equina present with neurological symptoms referable to the site(s) of the neuraxis that is being compressed. The most common symptom is progressive back pain, typically occurring 2–3 months before imaging and diagnosis3. The pain can be at any level along the spine, and may radiate to other body sites. The pain may worsen when the patient is recumbent due to distension of the epidural venous plexus, and possibly secondary to lower endogenous corticoid secretion during the night. The pain can be more intense during physical activity if there is vertebral column instability. Back pain arises when there is periosteal damage or invasion into the nearby soft tissue. Radicular pain evolves as tumor either invades or compresses the nerve roots, and may be enhanced during Valsalva maneuver. Rarely, MESCC can manifest as funicular pain in which the pain is falsely localized to the lower back or lower extremities, far below the site of compression for instance cervical cord compression presenting with sciatica-like leg pain8.
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Motor weakness is another very common symptom, found in approximately 60–80% of MESCC patients5. Compression of the spinal cord will result in myelopathic or upper neuron signs, such as extensor weakness in the upper extremities and flexor weakness in the lower extremities, hyperreflexia, and the presence of the Babinski sign. Sensory deficits, such as hypoesthesia and paresthesias are less common than motor symptoms. A sensory level may be found 1 to 5 spinal levels above the point at which there is cord compression. Involvement of both upper and lower extremities suggests that the lesion in the cervical cord while motor signs affecting the bilateral legs only can result from compression in cervical, thoracic, lumbar cord or cauda equina.
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The cauda equina syndrome consists of a constellation of symptoms that includes back pain, "saddle" anesthesia in the gluteal and perineal regions, urinary retention, bowel incontinence and sciatic-like pain down one or both legs. This can be associated with variable motor or sensory deficits in the lower extremities. The syndrome arises when a metastatic epidural lesion compresses the cauda equina nerve roots below the level at which the spinal cord terminates, at approximately L1 (Figure 3).
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Prognosis The most important prognostic factor to regain ambulation after treatment of MESCC is the prior neurological status9–12. Once a patient has become non-ambulatory, it is uncommon to regain the ability to walk13. Therefore, recognition of early signs and symptoms, and making a prompt diagnosis is critical14. Cancer patients and their families should be educated about this neurological complication, since in most cases back pain precedes cord compression by weeks13.
Diagnosis
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MESCC is a neurological emergency. Given the above-mentioned relationship between neurological status and prognosis for recovery, it is critical to make an early diagnosis of epidural metastases before the development of neurological deficits. Unfortunately, the vast majority of patients with MESCC are diagnosed after the development of symptoms.
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While the clinical picture can raise suspicion, the definitive diagnosis of MESCC is made radiographically, typically by MRI. As noted above, multiple sites of epidural disease are seen in up to 35% of patients3 and therefore imaging of the entire spine is required. An MRI not only demonstrates the extent and configuration of epidural disease involvement, but also allows visualization of the degree of involvement of bony structures and surrounding soft tissue. Epidural metastases are best visualized with post-contrast imaging which allows for clear delineation of the border of the metastasis in most cases (Figure 4). Although MRI is informative, it is not definitive and it is important to note that cancer patients are often immunosuppressed from antineoplastic therapies and thus susceptible to infections, including vertebral osteomyelitis and epidural abscesses, both of which can have a similar radiologic appearance on MRI.
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Prior to wide-spread availability of MRI, radiologic diagnosis was often made with CT myelogram which is considered adequately sensitive for detection of MESCC and is still utilized in patients in whom MRI is contraindicated (Figure 5)15. It is more cumbersome because it requires lumbar puncture for injection of contrast dye into the subarachnoid space and may not be safe to perform in a variety of situations, including when there is significant mass effect from intracranial metastases, there is epidural spinal block or the patient is coagulopathic15. Thus, neurological or neurosurgical consultation is advised before performing a lumbar puncture on a patient with suspected MESCC. CT imaging does remain important during the course of evaluation for MESCC as it is a superior method to MRI for imaging bone, and providing critical information on bone integrity that is necessary for surgical planning, which applicable. Overall, metastatic spinal cord compression is a diagnosis that should not be missed. Therefore, it is important to have a high index of suspicion and obtain an MRI of the spine as soon as possible in a cancer patient with new or worsening back pain, particularly in the setting of weakness or paresthesias.
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Treatment The objective of treatment of MESCC is the prevention of or reversal of neurological deficits as well as pain control. One should evaluate the patient`s performance status, prognosis and tumor burden when deciding on an appropriate treatment strategy.
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Pain management is necessary in every patient. Liberal use of non-opioid and opioid analgesics, corticosteroids and neuropathic pain medications may be necessary to reduce pain. In non-ambulatory or partially ambulatory patients, the use of prophylactic anticoagulants for the prevention of venous thromboembolism (VTE) is recommended, although the risk of VTE in this particular patient population has not been adequately studied. Stool softeners, osmotic laxatives, high fiber diets and hydration can prevent or alleviate constipation secondary to limited mobility, the use of opioids and autonomic dysfunction.
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Corticosteroids are used in patients with neurological signs or symptoms of epidural compression despite limited documented evidence of benefit16. The optimal dosage of dexamethasone in MESCC is not well established, and reported loading doses range between 10–100 mg, followed by progressive tapering. Caution should be taken when higher doses of corticosteroids are used, since these drugs are associated with potentially serious adverse effects such as hyperglycemia, gastrointestinal perforation and psychosis. A typical recommendation is to use higher loading doses of corticosteroids in patients with paraplegia, then halving the dose every three days16. In patients with MESCC but minimal neurological symptoms or signs, a bolus of 10 mg of dexamethasone followed by 16 mg daily with subsequent tapering is a reasonable approach. Corticosteroids can be withheld in asymptomatic patients or in patients with small epidural lesions without spinal cord or cauda equina compression17.
Radiation therapy
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Before the development of modern surgical techniques of decompression and stabilization, radiation therapy was the preferred treatment used in patients with MESCC. The goal of radiation therapy in patients with MESCC is both to improve pain and to achieve local tumor control. Traditionally, radiation typically targeted the damaged vertebra in addition to 1–2 additional vertebrae above and below the site of epidural metastasis. Practitioners are moving away from this practice in the era of stereotactic body radiosurgery since there is < 5% incidence of local failure in adjacent unaffected vertebrae18.The urgency of radiation treatment in MESCC must be emphasized because, as noted above, the most critical prognostic factor for motor recovery is pre-treatment ambulatory status; prognosis is therefore heavily dependent on time to treatment. Irradiation in this palliative setting is usually well tolerated, but if many spinal segments are treated gastrointestinal symptoms and bone marrow suppression may develop. A variety of radiation dose schedules have been used, from single large fractions of 8 Gy to protracted courses of 40 Gy in 20 fractions. The available data suggest that similar palliation can be achieved by either short or protracted radiotherapy regimens in metastatic patients
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with short life expectancy19–23. Longer courses of radiation therapy might be appropriate for patients with longer life expectancy in order to maximize long-term local control. In a prospective clinical trial of short-course RT (8 Gy in 1 fraction or 20 Gy in 5 fractions) versus long-course RT (30 Gy in 10 fractions or 40 Gy in 20 fractions)21, there were no significant differences in functional outcome or overall survival. However, longer treatments conferred significantly better local control (77% versus 61%) and improved 12-month progression-free survival (72% versus 55%).
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Stereotactic body radiation therapy (SBRT) is a technique that precisely delivers radiation to a target, minimizing radiation exposure in adjacent normal tissue. This targeting allows for the treatment of spinal metastases at relatively high doses in close proximity to the spinal cord, in a single or in a limited number of dose fractions. There is up to a 15% risk of vertebral compression fracture after SBRT24, with higher risk noted in patients who received single doses > 20 Gy, or in vertebrae with preexisting fractures, spinal deformity or lytic bone lesions24. In cases where SBRT is being considered as a treatment, stability evaluation such as the SINS score should be taken into account to prevent the risk of fractures after the procedure, potentially unstable and unstable spines must be operated on before SBRT in these cases.
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Particle accelerators are not available in most centers but proton beams and other particle beams may be useful, considering the characteristics of their energy deposition (Bragg peak) leading to secondary protection of nearby organs at risk, such as the spinal cord. This may be particularly beneficial to patients who require higher radiation doses for radio-resistant tumors, for example melanomas. However, there is minimal data to support or refute the utility of proton radiation therapy in this setting and no consensus exists as to whether use of this radiation type is appropriate. Further studies are needed to address this question25.
Surgery Before the availability of modern radiation facilities and techniques, surgery in the form of a laminectomy was the only treatment employed for MESCC. After the incorporation of radiation into the management of MESCC, a prospective randomized clinical trial demonstrated no apparent benefit of routinely employing both a laminectomy and radiation26. Additionally, laminectomy alone was largely abandoned as a treatment for MESCC as the vast majority of epidural metastases are in the anteriorly located vertebral bodies which are not accessed by a posterior approach15 (Figure 6). Moreover, laminectomy may produce spinal instability by removing the posterior elements of the spine.
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The advent of anterior decompression with reconstruction and stabilization of the spinal column occurred in the 1980s and this surgical technique proved to be effective at maintaining neurological function and relieving pain. Both an uncontrolled surgical series and a meta-analysis demonstrated that this neurosurgical technique, with or without radiation therapy, was superior to radiotherapy alone. However, these studies contained highly selected patients, variable inclusion criteria, heterogeneous tumors, and imprecise outcomes and endpoints. A randomized trial was published by Patchell and colleagues in 2005 to definitively address the question of surgery versus radiation for MESCC. The study
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included anterior, decompressive surgery plus 30 Gy of fractionated radiation versus 30 Gy of fractionated radiation alone. The primary outcome was maintenance of ambulation. The trial included patients with spinal cord compression leading to neurological deficit or pain which had been present for 48 hours or less. Spinal cord compression was limited to a single area of involvement and patient life expectancy had to be greater than 3 months. Of note, patients with radiosensitive tumors, such as lymphoma, leukemia, myeloma and germ cell tumors, were excluded, as well as patients whose tumors compressed the cauda equina. The trial was stopped at interim analysis because significantly more patients in the surgical group were able to walk after treatment (odds ratio 6.2 [95%CI:0–19,8] p=0.001). In addition, ambulatory capacity was maintained for a longer period of time after surgery and radiotherapy than after radiotherapy alone (median 122 days versus 13 days)27. Interestingly, the outcomes for patients in the radiation-only arm were worse than historical controls, perhaps in part because a number of patients with spinal instability were included in this arm. Nevertheless, in a prospective cohort of patients with spinal metastases, quality of life as measured by the EQ-5D, VAS pain score and KPS improved rapidly after surgery and this improvement was maintained for up to 2 years28. Thus, the combination of surgery via anterior decompression followed by fractionated radiation is a reasonable approach for patients with MESCC who have spinal instability, favorable prognosis and limited disease burden.
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Tumor embolization is occasionally used prior to tumor resection to reduce intraoperative blood loss, which can be a major of cause of surgery-associated morbidity. This technique is often undertaken if the tumor has signs of hypervascularity or the vasculature is difficult to access, as long as the embolization procedure does not pose additional risk29. There is also evidence that embolization may decrease the time of the operation. A retrospective study of 46 patients with MESCC treated with pre-operative embolization showed a significant reduction in intraoperative blood loss30 though a randomized, prospective study of 45 patients found the decrease in blood loss to be notable only in a subgroup analysis of hypervascular tumors31. In this study, however, there was a significant decrease in surgical time, with median procedure time of 124 minutes in the control arm and 90 minutes in the embolization arm31.
Medical treatment
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Systemic therapies currently have a very limited role in the management of MESCC, though this may be changing in the near future with the increasing use of targeted therapies and immunotherapies. Given the acute presentation of MESCC, chemotherapy and other systemic treatments do not typically lead to a decrease in tumor size on a timeline that is rapid enough to preserve neurologic function. However, in cases where the tumor burden is small and symptoms are minimal, the use of select, fast-acting targeted agents may be feasible, particularly if the patient is not a suitable candidate for surgery or radiation. For instance, Li et al reported a partial response of a cervical metastatic lesion in a woman with presumed EGFR mutant lung adenocarcinoma following 4 months of erlotinib32. Other targeted therapies, such as BRAF inhibitors and ALK/ROS inhibitors may also prove to be useful when the tumors harboring these alterations respond quickly to the targeted agents, though experience with these scenarios have not been frequently reported in the literature. Oncology (Williston Park). Author manuscript; available in PMC 2016 December 19.
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On the other hand, traditional chemotherapies like platinum-based agents used in non-small cell lung cancer (NSCLC) have not demonstrated the ability to stabilize or shrink spinal cord metastases33. Immunotherapy utilizing programmed cell death-1 receptor (PD-1) or programmed cell death ligand-1 (PD-L1) blockade may have a future role in the management of MESCC secondary to specific cancer types, including melanoma and NSCLC. Interestingly, radiation treatment can activate the immune system, often making immunotherapies more effective34. Initiation of PD-1 or PD-L1 inhibitors at the time of radiation could provide additional symptom relief and prolonged tumor stabilization. However, at present, there is limited evidence to support routine use of systemic therapies for MESCC and more studies are needed.
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Conclusion
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Acknowledgments
Metastatic epidural metastases occur in 5–10% of cancer patients and represent a neurological emergency. The diagnosis should be suspected in any cancer patient with back pain or new neurological symptoms and requires prompt diagnostic evaluation to avoid serious and irreversible neurological deficits. Contrast-enhanced MRI of the entire spine should be obtained in patients in whom a diagnosis of MESCC is suspected. Timely treatment with radiation, as well as surgery in selected cases, is critical to preserving neurological function as well as achieving local tumor control and pain control. Medical treatments include pain management with analgesics and corticosteroids. Future studies of surgical and radiation treatments for metastatic epidural cauda equina compression are urgently needed.
Tracy Batchelor has the following disclosures: Pharmaceutical Consulting (Merck & Co., Inc., Kirin Pharmaceuticals, Novartis, Proximagen/Upsher, Agenus, Roche, Oxigene, Cavion, Foundation Medicine, Accerta) CME Lectures/Material (Up to Date, Inc., Research to Practice, Oakstone Medical Publishing, Imedex) Other Consulting (Champions Biotechnology) Research Support (Pfizer, Astra Zeneca, Millenium)
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Anatomy and location of spinal metastases. Metastases can be found arising in the vertebral body or intervertebral foramen, from the dura, in the subarachnoid space or within the spinal cord (intramedullary). Lesions in the vertebral body or surrounding soft tissues can lead to epidural invasion. Illustration credit: @Christy Krames. Figure reproduced with permission.
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Figure 2.
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Epidural spinal cord compression. Left panel: Metastatic tumor arising in vertebral body extending into the epidural space, between the dura and bony spinal column. As it grows, the tumor can exert increasing pressure on the spinal cord. Right panel: Metastatic tumor extending through the intraventricular foramen. Illustration by Carol Donner reproduced with permission from Spinal Cord Compression: An Obstructive Oncologic Emergency by Maryjo Osowski, RN, MSN, AOCN, Medscape Education http://www.medscape.org/ multispecialty.
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Figure 3.
Spinal cord and cauda equina. The spinal cord terminates at approximately L1, with the nerve roots arising from L2-S5 forming a bundle nerves which comprises the cauda equine. Figure credit: Buckyball Design, Melissa Thomas Baum. Reproduced with permission.
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Sagittal post-contrast T1 on left and axial T1 on right demonstrating a mass extending from posterior vertebral body at level of L1 (arrow) without evidence of spinal cord compression.
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Figure 5.
Depiction of Laminectomy. The lamina connects the spinous process with the pedicles. During laminectomy, a portion of the lamina is removed. Figure credit: BruceBlaus https:// en.wikipedia.org/wiki/Laminectomy.
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Table 1
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Comparison of different radiation schedules and results.20–22 Rades D., et al. (retrospective)
Rades D., et al. (match paired analysis)
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Maranzano E., et al (randomized)
Radiation schedules compared (# of patients)
Regain of ambulation in previously nonambulatory patients (%)
Post-treatment ambulatory rates (%)
In field recurrence rates at 2 years (%)
1 × 8Gy (261)
25%
69%
24%
5 × 4Gy (279)
26%
68%
26%
10 × 3Gy (274)
26%
63%
14%
15 × 2,5Gy (233)
24%
66%
9%
20 × 2Gy (257)
30%
74%
7%
Radiation Schedules compared
Improvement of motor function
In field reIrradiation at 1 year %
1 × 8Gy (121)
17%
30%
5 × 4 Gy (121)
19%
22%
Radiation schedules compared
Regain of ambulation in previously nonambulatory patients (%)
Post-treatment ambulatory rates
In field recompression after treatment
1 × 8Gy
16%
62%
6%
2 × 8Gy
26%
69%
2.50%
Author Manuscript Author Manuscript Oncology (Williston Park). Author manuscript; available in PMC 2016 December 19.
Oncology (Williston Park). Author manuscript; available in PMC 2016 December 19. Published in final edited form as: Oncology (Williston Park). 1990 April ; 4(4): 47–58.
Diagnosis and treatment of epidural metastases M. Loreto Yáñez, M.D.1, Julie J. Miller, M.D., Ph.D.2, and Tracy T. Batchelor, M.D.2,3,4 1Department
of Radiation Oncology, Fundación Arturo López Pérez, Santiago, Chile
2Department
of Neurology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
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3Department
Radiation Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
4Division
of Hematology/Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
Abstract
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Epidural metastases occur in 5–10% of cancer patients and represent a neurological emergency. Patients most commonly present with acute onset of motor weakness, and restoration of neurologic function is critically dependent on prompt diagnosis and treatment. In this review, we discuss the clinical, epidemiological and radiologic features associated with epidural metastases and resulting spinal cord compression. We further review current treatment paradigms. The timely initiation of radiation, as well as surgery in selected cases, is critical to preserving neurological function, as well as achieving local tumor control and pain control. Future studies investigating surgical and radiation treatment for metastatic epidural cord compression are urgently needed.
Precis Epidural metastases occur in 5–10% of cancer patients and represent a neurological emergency. The timely initiation of radiation, as well as surgery in selected cases, is critical to preserving neurological function, as well as achieving local tumor control and pain control.
Keywords Spinal cord; epidural; metastases; cancer; neurologic deficit; paralysis; radiation; cauda equina
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Contact for correspondence and reprints: Tracy Batchelor, M.D., 55 Fruit Street, Yawkey 9E, Boston MA 02114, Phone: 617-643-1938, Fax: 617-643-2591, [email protected]. Conflict of interest disclosures M. Loreto Yanez and Julie Miller have no conflicts of interest Dedicated Author Contributions Dr. Yanez helped conceptualize the manuscript, gathered resources, assisted in writing the original draft and review and editing of final manuscript, and helped with visualization of the data in the form of tables and figures. Dr. Miller helped conceptualize the manuscript, gathered resources, assisted in writing the original draft as well as review and editing of final manuscript, and helped with visualization of the data in the form of tables and figures. Dr. Batchelor helped conceptualize the manuscript, gathered resources, assisted in review and editing of final manuscript, and helped with visualization of the data in the form of tables and figures, and provided funding.
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Introduction Many types of cancers can metastasize to the spine. There are three main sites of metastatic dissemination in the spine: epidural, leptomeningeal and intramedullary (Figure 1). In this article we review epidural metastases and the most worrisome complications: epidural spinal cord and cauda equina compression, which can lead to pain and irreversible neurological deficits. Metastatic epidural spinal cord compression (MESCC) occurs in approximately 5% of patients who die of cancer1.
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Epidural metastases originate in either the vertebral column (85%), the paravertebral tissues (10–15%) or the epidural space itself. The vertebral column is a very common site of bony metastases from cancer and eighty percent of vertebral epidural metastases are localized to the vertebral body, with fewer in the posterior arch2. The propensity of tumors to metastasize to the vertebral bodies is thought to be related to the highly vascular nature of bone marrow. A metastatic lesion in the vertebrae may then grow posteriorly and invade the epidural space, which is the area between the bone and the dura overlying the spinal cord (Figure 2, left panel). As the tumor grows in the epidural space, it encroaches on the thecal sac, compresses the spinal cord and also may occlude the venous plexus of the epidural space, leading to vasogenic edema in the white and gray matter which may cause additional damage by causing infarction of the spinal cord. Certain epidural metastases, such as those arising from prostate cancer, may disseminate through the Batson’s venous plexus. Epidural metastases that originate in the paravertebral tissues, such as lymphoma, can invade through the neural foramina into the epidural space (Figure 2, right panel)2. Rarely, some cancers may invade the epidural space without bony or paraspinal compromise.
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The majority of epidural metastases develop in the thoracic spine (60%), followed by the lumbosacral area and cervical spine (10%). Involvement of multiple spinal regions is not uncommon, occurring in 20–35% of patients3, and highlights the importance of imaging the entire spine (cervical, thoracic, lumbosacral) when screening for metastatic epidural disease. Similar to ESCC, when cancer metastasizes to the lumbosacral region, tumor growth and spread can result in compression of the cauda equina, a bundle of nerve roots extending from the most caudal portion of the spinal cord and involved in controlling the motor and sensory function of the lower extremities as well as bladder and bowel function.
Epidemiology
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The incidence of epidural metastases and epidural spinal cord compression is difficult to calculate due to the observation that some metastases to the epidural region are asymptomatic and are only incidentally diagnosed on radiologic examinations. Many times, however, epidural metastases come to medical attention after the development of pain and/or neurological symptoms. Approximately 5–10% of cancer patients will develop MESCC at some point during their disease course4. In adults, the most frequent cancers associated with MESCC are breast, lung or prostate cancer5. An autopsy study revealed that epidural spinal cord compression can be identified in approximately 5% of patients who die with cancer1. In hospitalized
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cancer patients the annual incidence of MESCC diagnosis is 3–4%6 and potentially on the rise as the incidence of MESCC in cancer patients rose from 4.4 to 6% between 1979 and 1985, based on the data from a Danish cancer referral center7. Although spinal cord compression related to epidural metastases can be the first sign of malignancy in up to 20% of cases, this neurological complication of cancer more commonly occurs in patients with previously diagnosed metastatic cancer. In cases where MESCC is the first manifestation of disease, the types of primary cancers (lung, unknown primary, multiple myeloma, non-Hodgkin lymphoma) is different than in cases in which the primary cancer was previously diagnosed3.
Presentation Author Manuscript
Patients with epidural metastases compressing the spinal cord or cauda equina present with neurological symptoms referable to the site(s) of the neuraxis that is being compressed. The most common symptom is progressive back pain, typically occurring 2–3 months before imaging and diagnosis3. The pain can be at any level along the spine, and may radiate to other body sites. The pain may worsen when the patient is recumbent due to distension of the epidural venous plexus, and possibly secondary to lower endogenous corticoid secretion during the night. The pain can be more intense during physical activity if there is vertebral column instability. Back pain arises when there is periosteal damage or invasion into the nearby soft tissue. Radicular pain evolves as tumor either invades or compresses the nerve roots, and may be enhanced during Valsalva maneuver. Rarely, MESCC can manifest as funicular pain in which the pain is falsely localized to the lower back or lower extremities, far below the site of compression for instance cervical cord compression presenting with sciatica-like leg pain8.
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Motor weakness is another very common symptom, found in approximately 60–80% of MESCC patients5. Compression of the spinal cord will result in myelopathic or upper neuron signs, such as extensor weakness in the upper extremities and flexor weakness in the lower extremities, hyperreflexia, and the presence of the Babinski sign. Sensory deficits, such as hypoesthesia and paresthesias are less common than motor symptoms. A sensory level may be found 1 to 5 spinal levels above the point at which there is cord compression. Involvement of both upper and lower extremities suggests that the lesion in the cervical cord while motor signs affecting the bilateral legs only can result from compression in cervical, thoracic, lumbar cord or cauda equina.
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The cauda equina syndrome consists of a constellation of symptoms that includes back pain, "saddle" anesthesia in the gluteal and perineal regions, urinary retention, bowel incontinence and sciatic-like pain down one or both legs. This can be associated with variable motor or sensory deficits in the lower extremities. The syndrome arises when a metastatic epidural lesion compresses the cauda equina nerve roots below the level at which the spinal cord terminates, at approximately L1 (Figure 3).
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Prognosis The most important prognostic factor to regain ambulation after treatment of MESCC is the prior neurological status9–12. Once a patient has become non-ambulatory, it is uncommon to regain the ability to walk13. Therefore, recognition of early signs and symptoms, and making a prompt diagnosis is critical14. Cancer patients and their families should be educated about this neurological complication, since in most cases back pain precedes cord compression by weeks13.
Diagnosis
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MESCC is a neurological emergency. Given the above-mentioned relationship between neurological status and prognosis for recovery, it is critical to make an early diagnosis of epidural metastases before the development of neurological deficits. Unfortunately, the vast majority of patients with MESCC are diagnosed after the development of symptoms.
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While the clinical picture can raise suspicion, the definitive diagnosis of MESCC is made radiographically, typically by MRI. As noted above, multiple sites of epidural disease are seen in up to 35% of patients3 and therefore imaging of the entire spine is required. An MRI not only demonstrates the extent and configuration of epidural disease involvement, but also allows visualization of the degree of involvement of bony structures and surrounding soft tissue. Epidural metastases are best visualized with post-contrast imaging which allows for clear delineation of the border of the metastasis in most cases (Figure 4). Although MRI is informative, it is not definitive and it is important to note that cancer patients are often immunosuppressed from antineoplastic therapies and thus susceptible to infections, including vertebral osteomyelitis and epidural abscesses, both of which can have a similar radiologic appearance on MRI.
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Prior to wide-spread availability of MRI, radiologic diagnosis was often made with CT myelogram which is considered adequately sensitive for detection of MESCC and is still utilized in patients in whom MRI is contraindicated (Figure 5)15. It is more cumbersome because it requires lumbar puncture for injection of contrast dye into the subarachnoid space and may not be safe to perform in a variety of situations, including when there is significant mass effect from intracranial metastases, there is epidural spinal block or the patient is coagulopathic15. Thus, neurological or neurosurgical consultation is advised before performing a lumbar puncture on a patient with suspected MESCC. CT imaging does remain important during the course of evaluation for MESCC as it is a superior method to MRI for imaging bone, and providing critical information on bone integrity that is necessary for surgical planning, which applicable. Overall, metastatic spinal cord compression is a diagnosis that should not be missed. Therefore, it is important to have a high index of suspicion and obtain an MRI of the spine as soon as possible in a cancer patient with new or worsening back pain, particularly in the setting of weakness or paresthesias.
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Treatment The objective of treatment of MESCC is the prevention of or reversal of neurological deficits as well as pain control. One should evaluate the patient`s performance status, prognosis and tumor burden when deciding on an appropriate treatment strategy.
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Pain management is necessary in every patient. Liberal use of non-opioid and opioid analgesics, corticosteroids and neuropathic pain medications may be necessary to reduce pain. In non-ambulatory or partially ambulatory patients, the use of prophylactic anticoagulants for the prevention of venous thromboembolism (VTE) is recommended, although the risk of VTE in this particular patient population has not been adequately studied. Stool softeners, osmotic laxatives, high fiber diets and hydration can prevent or alleviate constipation secondary to limited mobility, the use of opioids and autonomic dysfunction.
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Corticosteroids are used in patients with neurological signs or symptoms of epidural compression despite limited documented evidence of benefit16. The optimal dosage of dexamethasone in MESCC is not well established, and reported loading doses range between 10–100 mg, followed by progressive tapering. Caution should be taken when higher doses of corticosteroids are used, since these drugs are associated with potentially serious adverse effects such as hyperglycemia, gastrointestinal perforation and psychosis. A typical recommendation is to use higher loading doses of corticosteroids in patients with paraplegia, then halving the dose every three days16. In patients with MESCC but minimal neurological symptoms or signs, a bolus of 10 mg of dexamethasone followed by 16 mg daily with subsequent tapering is a reasonable approach. Corticosteroids can be withheld in asymptomatic patients or in patients with small epidural lesions without spinal cord or cauda equina compression17.
Radiation therapy
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Before the development of modern surgical techniques of decompression and stabilization, radiation therapy was the preferred treatment used in patients with MESCC. The goal of radiation therapy in patients with MESCC is both to improve pain and to achieve local tumor control. Traditionally, radiation typically targeted the damaged vertebra in addition to 1–2 additional vertebrae above and below the site of epidural metastasis. Practitioners are moving away from this practice in the era of stereotactic body radiosurgery since there is < 5% incidence of local failure in adjacent unaffected vertebrae18.The urgency of radiation treatment in MESCC must be emphasized because, as noted above, the most critical prognostic factor for motor recovery is pre-treatment ambulatory status; prognosis is therefore heavily dependent on time to treatment. Irradiation in this palliative setting is usually well tolerated, but if many spinal segments are treated gastrointestinal symptoms and bone marrow suppression may develop. A variety of radiation dose schedules have been used, from single large fractions of 8 Gy to protracted courses of 40 Gy in 20 fractions. The available data suggest that similar palliation can be achieved by either short or protracted radiotherapy regimens in metastatic patients
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with short life expectancy19–23. Longer courses of radiation therapy might be appropriate for patients with longer life expectancy in order to maximize long-term local control. In a prospective clinical trial of short-course RT (8 Gy in 1 fraction or 20 Gy in 5 fractions) versus long-course RT (30 Gy in 10 fractions or 40 Gy in 20 fractions)21, there were no significant differences in functional outcome or overall survival. However, longer treatments conferred significantly better local control (77% versus 61%) and improved 12-month progression-free survival (72% versus 55%).
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Stereotactic body radiation therapy (SBRT) is a technique that precisely delivers radiation to a target, minimizing radiation exposure in adjacent normal tissue. This targeting allows for the treatment of spinal metastases at relatively high doses in close proximity to the spinal cord, in a single or in a limited number of dose fractions. There is up to a 15% risk of vertebral compression fracture after SBRT24, with higher risk noted in patients who received single doses > 20 Gy, or in vertebrae with preexisting fractures, spinal deformity or lytic bone lesions24. In cases where SBRT is being considered as a treatment, stability evaluation such as the SINS score should be taken into account to prevent the risk of fractures after the procedure, potentially unstable and unstable spines must be operated on before SBRT in these cases.
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Particle accelerators are not available in most centers but proton beams and other particle beams may be useful, considering the characteristics of their energy deposition (Bragg peak) leading to secondary protection of nearby organs at risk, such as the spinal cord. This may be particularly beneficial to patients who require higher radiation doses for radio-resistant tumors, for example melanomas. However, there is minimal data to support or refute the utility of proton radiation therapy in this setting and no consensus exists as to whether use of this radiation type is appropriate. Further studies are needed to address this question25.
Surgery Before the availability of modern radiation facilities and techniques, surgery in the form of a laminectomy was the only treatment employed for MESCC. After the incorporation of radiation into the management of MESCC, a prospective randomized clinical trial demonstrated no apparent benefit of routinely employing both a laminectomy and radiation26. Additionally, laminectomy alone was largely abandoned as a treatment for MESCC as the vast majority of epidural metastases are in the anteriorly located vertebral bodies which are not accessed by a posterior approach15 (Figure 6). Moreover, laminectomy may produce spinal instability by removing the posterior elements of the spine.
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The advent of anterior decompression with reconstruction and stabilization of the spinal column occurred in the 1980s and this surgical technique proved to be effective at maintaining neurological function and relieving pain. Both an uncontrolled surgical series and a meta-analysis demonstrated that this neurosurgical technique, with or without radiation therapy, was superior to radiotherapy alone. However, these studies contained highly selected patients, variable inclusion criteria, heterogeneous tumors, and imprecise outcomes and endpoints. A randomized trial was published by Patchell and colleagues in 2005 to definitively address the question of surgery versus radiation for MESCC. The study
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included anterior, decompressive surgery plus 30 Gy of fractionated radiation versus 30 Gy of fractionated radiation alone. The primary outcome was maintenance of ambulation. The trial included patients with spinal cord compression leading to neurological deficit or pain which had been present for 48 hours or less. Spinal cord compression was limited to a single area of involvement and patient life expectancy had to be greater than 3 months. Of note, patients with radiosensitive tumors, such as lymphoma, leukemia, myeloma and germ cell tumors, were excluded, as well as patients whose tumors compressed the cauda equina. The trial was stopped at interim analysis because significantly more patients in the surgical group were able to walk after treatment (odds ratio 6.2 [95%CI:0–19,8] p=0.001). In addition, ambulatory capacity was maintained for a longer period of time after surgery and radiotherapy than after radiotherapy alone (median 122 days versus 13 days)27. Interestingly, the outcomes for patients in the radiation-only arm were worse than historical controls, perhaps in part because a number of patients with spinal instability were included in this arm. Nevertheless, in a prospective cohort of patients with spinal metastases, quality of life as measured by the EQ-5D, VAS pain score and KPS improved rapidly after surgery and this improvement was maintained for up to 2 years28. Thus, the combination of surgery via anterior decompression followed by fractionated radiation is a reasonable approach for patients with MESCC who have spinal instability, favorable prognosis and limited disease burden.
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Tumor embolization is occasionally used prior to tumor resection to reduce intraoperative blood loss, which can be a major of cause of surgery-associated morbidity. This technique is often undertaken if the tumor has signs of hypervascularity or the vasculature is difficult to access, as long as the embolization procedure does not pose additional risk29. There is also evidence that embolization may decrease the time of the operation. A retrospective study of 46 patients with MESCC treated with pre-operative embolization showed a significant reduction in intraoperative blood loss30 though a randomized, prospective study of 45 patients found the decrease in blood loss to be notable only in a subgroup analysis of hypervascular tumors31. In this study, however, there was a significant decrease in surgical time, with median procedure time of 124 minutes in the control arm and 90 minutes in the embolization arm31.
Medical treatment
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Systemic therapies currently have a very limited role in the management of MESCC, though this may be changing in the near future with the increasing use of targeted therapies and immunotherapies. Given the acute presentation of MESCC, chemotherapy and other systemic treatments do not typically lead to a decrease in tumor size on a timeline that is rapid enough to preserve neurologic function. However, in cases where the tumor burden is small and symptoms are minimal, the use of select, fast-acting targeted agents may be feasible, particularly if the patient is not a suitable candidate for surgery or radiation. For instance, Li et al reported a partial response of a cervical metastatic lesion in a woman with presumed EGFR mutant lung adenocarcinoma following 4 months of erlotinib32. Other targeted therapies, such as BRAF inhibitors and ALK/ROS inhibitors may also prove to be useful when the tumors harboring these alterations respond quickly to the targeted agents, though experience with these scenarios have not been frequently reported in the literature. Oncology (Williston Park). Author manuscript; available in PMC 2016 December 19.
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On the other hand, traditional chemotherapies like platinum-based agents used in non-small cell lung cancer (NSCLC) have not demonstrated the ability to stabilize or shrink spinal cord metastases33. Immunotherapy utilizing programmed cell death-1 receptor (PD-1) or programmed cell death ligand-1 (PD-L1) blockade may have a future role in the management of MESCC secondary to specific cancer types, including melanoma and NSCLC. Interestingly, radiation treatment can activate the immune system, often making immunotherapies more effective34. Initiation of PD-1 or PD-L1 inhibitors at the time of radiation could provide additional symptom relief and prolonged tumor stabilization. However, at present, there is limited evidence to support routine use of systemic therapies for MESCC and more studies are needed.
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Conclusion
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Acknowledgments
Metastatic epidural metastases occur in 5–10% of cancer patients and represent a neurological emergency. The diagnosis should be suspected in any cancer patient with back pain or new neurological symptoms and requires prompt diagnostic evaluation to avoid serious and irreversible neurological deficits. Contrast-enhanced MRI of the entire spine should be obtained in patients in whom a diagnosis of MESCC is suspected. Timely treatment with radiation, as well as surgery in selected cases, is critical to preserving neurological function as well as achieving local tumor control and pain control. Medical treatments include pain management with analgesics and corticosteroids. Future studies of surgical and radiation treatments for metastatic epidural cauda equina compression are urgently needed.
Tracy Batchelor has the following disclosures: Pharmaceutical Consulting (Merck & Co., Inc., Kirin Pharmaceuticals, Novartis, Proximagen/Upsher, Agenus, Roche, Oxigene, Cavion, Foundation Medicine, Accerta) CME Lectures/Material (Up to Date, Inc., Research to Practice, Oakstone Medical Publishing, Imedex) Other Consulting (Champions Biotechnology) Research Support (Pfizer, Astra Zeneca, Millenium)
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Anatomy and location of spinal metastases. Metastases can be found arising in the vertebral body or intervertebral foramen, from the dura, in the subarachnoid space or within the spinal cord (intramedullary). Lesions in the vertebral body or surrounding soft tissues can lead to epidural invasion. Illustration credit: @Christy Krames. Figure reproduced with permission.
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Figure 2.
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Epidural spinal cord compression. Left panel: Metastatic tumor arising in vertebral body extending into the epidural space, between the dura and bony spinal column. As it grows, the tumor can exert increasing pressure on the spinal cord. Right panel: Metastatic tumor extending through the intraventricular foramen. Illustration by Carol Donner reproduced with permission from Spinal Cord Compression: An Obstructive Oncologic Emergency by Maryjo Osowski, RN, MSN, AOCN, Medscape Education http://www.medscape.org/ multispecialty.
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Figure 3.
Spinal cord and cauda equina. The spinal cord terminates at approximately L1, with the nerve roots arising from L2-S5 forming a bundle nerves which comprises the cauda equine. Figure credit: Buckyball Design, Melissa Thomas Baum. Reproduced with permission.
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Author Manuscript Author Manuscript Figure 4.
Author Manuscript
Sagittal post-contrast T1 on left and axial T1 on right demonstrating a mass extending from posterior vertebral body at level of L1 (arrow) without evidence of spinal cord compression.
Author Manuscript Oncology (Williston Park). Author manuscript; available in PMC 2016 December 19.
Yáñez et al.
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Author Manuscript Author Manuscript Author Manuscript Author Manuscript
Figure 5.
Depiction of Laminectomy. The lamina connects the spinous process with the pedicles. During laminectomy, a portion of the lamina is removed. Figure credit: BruceBlaus https:// en.wikipedia.org/wiki/Laminectomy.
Oncology (Williston Park). Author manuscript; available in PMC 2016 December 19.
Yáñez et al.
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Table 1
Author Manuscript
Comparison of different radiation schedules and results.20–22 Rades D., et al. (retrospective)
Rades D., et al. (match paired analysis)
Author Manuscript
Maranzano E., et al (randomized)
Radiation schedules compared (# of patients)
Regain of ambulation in previously nonambulatory patients (%)
Post-treatment ambulatory rates (%)
In field recurrence rates at 2 years (%)
1 × 8Gy (261)
25%
69%
24%
5 × 4Gy (279)
26%
68%
26%
10 × 3Gy (274)
26%
63%
14%
15 × 2,5Gy (233)
24%
66%
9%
20 × 2Gy (257)
30%
74%
7%
Radiation Schedules compared
Improvement of motor function
In field reIrradiation at 1 year %
1 × 8Gy (121)
17%
30%
5 × 4 Gy (121)
19%
22%
Radiation schedules compared
Regain of ambulation in previously nonambulatory patients (%)
Post-treatment ambulatory rates
In field recompression after treatment
1 × 8Gy
16%
62%
6%
2 × 8Gy
26%
69%
2.50%
Author Manuscript Author Manuscript Oncology (Williston Park). Author manuscript; available in PMC 2016 December 19.
