Treatment of Metastatic Spinal Cord Compression: Cepo Review and Clinical Recommendations

• long-course radiotherapy be administered to patients with inoperable spinal cord compression and good life expectancy. • decompressive surgery followed by long-course radiotherapy be offered to appropriate symptomatic mscc patients (including spinal instability, displacement of vertebral fragment); and • patients considered for surgery have a life expectancy of at least 3–6 months.


INTRODUCTION
According to recent Canadian statistics, an estimated 186,400 new cases of cancer and 75,700 deaths from cancer are expected in Canada in 2012 1 .In general, between 40% and 70% of patients with advanced solid tumours such as those of breast, prostate, and lung will develop bone metastases 2 .The spine is the most common site for bone metastasis, affecting up to 30% of cancer patients 3 .Overall, between 5% and 10% of cancer patients will develop metastatic spinal cord compression (mscc), an oncologic emergency requiring early diagnosis and immediate treatment 4,5 .Spinal cord damage including vascular injury, hemorrhage, white matter edema, and nerve damage such as demyelination and axonal damage, are frequently observed at the site of compression and cause symptoms such as back pain and motor or sensory deficits [6][7][8][9] .
The main objectives of mscc treatment are preservation or improvement of neurologic function (particularly walking capacity), pain relief, and preservation or improvement of quality of life 7 .The most-used treatment modalities are corticotherapy, radiotherapy, and surgery.

Background
Metastatic spinal cord compression (mscc) is an oncologic emergency that, unless diagnosed early and treated appropriately, can lead to permanent neurologic impairment.After an analysis of relevant studies evaluating the effectiveness of various treatment modalities, the Comité de l'évolution des pratiques en oncologie (cepo) made recommendations on mscc management.

Method
A review of the scientific literature published up to February 2011 considered only phase ii and iii trials that included assessment of neurologic function.A total of 26 studies were identified.

Recommendations
Considering the evidence available to date, cepo recommends that • cancer patients with mscc be treated by a specialized multidisciplinary team.• dexamethasone 16 mg daily be administered to symptomatic patients as soon as mscc is diagnosed or suspected.• high-loading-dose corticosteroids be avoided.
• histopathologic diagnosis and scores from scales evaluating prognosis and spinal instability be considered before treatment.• corticosteroids and chemotherapy with radiotherapy be offered to patients with spinal cord compression caused by myeloma, lymphoma, or germ cell tumour without sign of spinal instability or compression by bone fragment.• short-course radiotherapy be administered to patients with spinal cord compression and short life expectancy.

METHODS
The scientific literature published up to February 2011 was reviewed through a PubMed search using the keywords "metastatic spinal cord compression" (mesh), "neoplasm" (mesh), "cancer," "treatment," "surgery," "radiotherapy," and "corticotherapy."Only prospective studies including an evaluation of neurologic function, in the English or French language, were considered.Economic studies, retrospective studies, studies reporting only the results of unplanned subgroup analyses, studies on intradural or intramedullary spinal cord lesions, and those investigating treatment of relapses were not considered.Abstracts from relevant international conferences held in 2009 and 2010 were reviewed, and only those presenting results from randomized controlled trials were considered.Recommendations for clinical practice and expert consensus issued by relevant international organizations and cancer agencies were also identified.The level of evidence of selected studies and the strength of the author's recommendations were evaluated using the American Society of Clinical Oncology and the European Society for Medical Oncology grading system (Table i).The original guideline was developed by a Comité de l'évolution des pratiques en oncologie (cepo) subcommittee.The draft was reviewed by independent external experts and was finally adopted by the cepo.

Corticotherapy
Three randomized controlled trials investigating the efficacy and toxicity of corticosteroids in the treatment of mscc met the selection criteria (Table ii, level ii evidence).Results showed that corticotherapy was associated with back pain reduction, but that it had no significant impact on ambulatory capacity or median overall survival.Vecht et al. 15 showed no difference between two intravenous loading doses of dexamethasone (10 mg and 100 mg) in terms of back pain relief, ambulatory capacity, and survival; however, the dose of corticosteroids seemed to correlate with the incidence of adverse events.Graham et al. 17 showed that severe treatment-related toxicities such as sepsis were reported with high-dose dexamethasone (96 mg daily) and that none were reported with low-dose treatment (16 mg daily).Sorensen et al. 16 also demonstrated that high-dose dexamethasone was associated with clinically significant adverse effects, including hypomania, psychosis with confusion, and gastric ulcer perforation.

Radiotherapy
Nine prospective trials assessing the efficacy and toxicity of radiotherapy in the treatment of mscc were identified (Table iii, level iii evidence).In those studies, fractionated radiation doses ranging from 16 Gy to 30 Gy were delivered.The pretreatment ambulatory rate varied from 31% to 100%, depending on the population being evaluated.Overall, radiotherapy helped to maintain or improve ambulation in 59%-100% of mscc patients.Aass and Fossa 26 showed a pretreatment ambulatory rate of 31% in hormone-resistant prostate cancer patients with mscc; subsequently, at 2 and 6 months after a median radiation dose of 30 Gy, 69% and 59% of patients had respectively maintained or regained their ambulatory capacity.Similarly, a split-course regimen (15 Gy in 3 fractions, stopped for 4 days, and then resumed with 15 Gy in 5 fractions only in responders) allowed 84% of breast cancer patients with mscc to maintain or regain their ability to walk 20 .
Patient prognosis at mscc diagnosis may affect clinical outcomes after radiotherapy.In this regard, Maranzano et al. 24 showed a pretreatment ambulation rate of 47% in mscc patients with poor prognosis (low radioresponsive primary tumour, paraplegic or paraparetic, poor performance status, poor life expectancy) and a post-radiotherapy (16 Gy in 2 fractions) total motor function response rate of 63%.In mscc patients with good prognosis (without neurologic deficit at diagnosis), a 30-Gy regimen resulted in an adequate motor function response for all patients 23 .
Overall, radiotherapy was associated with back pain relief in 67%-90% of mscc patients.The median overall survival ranged from 3.5 months to 26 months.Adverse events included vomiting, esophagitis, dysphagia, and skin reactions 23,24 .

Surgery
Six prospective studies assessing the efficacy of various surgical techniques (such as cytoreduction, vertebrectomy, and laminectomy) in the treatment of mscc were reviewed (Table v, level iii evidence).Four studies reported specifically on vertebrectomy (using a posterolateral, transpedicular, posterolateral, or anterior approach) and showed that between 80% and 100% of patients maintained or regained their ambulatory capacity after the intervention [31][32][33]35 . In  study investigating the efficacy of surgical decompression according to the location of the tumour in the spinal canal, the postoperative ambulatory rate after vertebrectomy was twice the rate after laminectomy (80% vs. 39%) 31 .Median overall survivals of 7.7 months and 16 months were observed after vertebrectomy in two studies 31,33 .Overall, back pain relief rate exceeded 90% in the selected studies.
Surgical complications including wound infections and dehiscence, spinal stabilization problems, pulmonary complications, and severe bleeding were reported [31][32][33][34][35] .The mean operative blood loss for patients undergoing decompressive and reconstructive surgery was lower with posterolateral vertebrectomy (1514 mL) than with posterior (2277 mL), anterior (4278 mL), or a combined approach (8300 mL).Two observational studies assessing the effectiveness of unspecified surgical interventions (en bloc excision, cytoreduction, palliative, and decompression surgery) showed maintenance of ambulatory capacity in 64%-80% of patients, back pain relief in 71% of patients, and a median overall survival ranging from 12 months to 13 months 34,36 .Medical and surgical complications such as cerebrospinal fluid leakage, thoracic duct injury, dysphagia, neurologic deterioration, wound infection, spinal instability, and gastrointestinal hemorrhage were reported in those studies 34,36 .After laminectomy, results showed that 39%-44% of patients maintained ambulation; reported complications included deterioration of neurologic function and delayed wound healing 31,37 .
A meta-analysis and two randomized controlled trials compared the efficacy of surgery followed by radiotherapy with radiotherapy alone for the management of mscc (Table vi) 3,37,38 .A meta-analysis by Klimo et al. included data from twenty-four surgical (n = 999) and four radiation oncology articles (n = 543), reporting mostly uncontrolled studies (Level i evidence) 3 .Results showed that, compared with patients treated with radiotherapy alone, those treated with surgery followed by radiotherapy had an increased likelihood of remaining ambulant (relative risk: 1.28; 95% confidence interval: 1.20 to 1.37; p < 0.001) and of regaining ambulatory function (relative risk: 1.99; 95% confidence interval: 1.63 to 2.44; p < 0.001).Surgery plus radiotherapy was also associated with better pain relief (90% vs. 70%) and higher 1-year survival (41% vs. 24%).However, a higher recurrence rate (8% vs. 2.4%) was shown in the surgery group 3 .In a phase iii trial, Young et al. showed no statistically significant difference in effectiveness between laminectomy followed by postoperative radiotherapy and radiotherapy alone in terms of ambulation rate (44% vs. 54%) and back pain relief (50% vs. 46%, level ii evidence) 37 .No specific complication or premature death was reported in the surgery group.However, an early mortality rate of 24% was observed in the radiotherapy-alone group 37 .On the other hand, a phase iii trial by Patchell et al. showed that, after treatment with decompressive surgery followed by radiotherapy (compared with radiotherapy alone), a significantly higher proportion of patients kept their ambulatory capacity (84% vs. 57%; odds ratio: 6.2; 95% confidence interval: 2.0 to 19.8; p = 0.001) and retained that ability for a significantly longer median period (122 days vs. 13 days, p = 0.003, level ii evidence) 38 .No patient diagnosed with lymphoma, myeloma, or germ cell tumours were included in the study.A significantly increased median survival was reported in the surgery-plus-radiotherapy group (126 days vs. 100 days; relative risk: 0.60; 95% confidence interval: 0.38 to 0.96; p = 0.033).Substantial reductions in the median doses of dexamethasone (mean daily equivalent: 1.6 mg vs. 4.2 mg, p = 0.0093) and analgesics (0.4 mg vs. 4.8 mg, p = 0.002) were also reported in the surgery-plus-radiotherapy group than in the radiotherapy-alone group 38 .

DISCUSSION
Metastatic spinal cord compression is an oncologic emergency which, unless diagnosed early and treated promptly, can lead to permanent neurologic impairment and can seriously affect a patient's quality of life 5 .Opinions regarding the aggressiveness of the interventions to be used in this palliative context are Some argue for a more aggressive approach; others favour supportive care.The most frequently used therapeutic modalities for mscc are corticotherapy, radiotherapy, and surgery.The primary objective of corticotherapy is reduction of edema and inflammation in the area of spinal cord compression.More than 80% of metastatic cancer patients manifest pain that is caused directly by tumour infiltration into adjacent organs and structures or from the development of peritumoural edema.
The efficacy of corticotherapy in the management of mscc has been demonstrated in terms of pain relief and motor function [15][16][17] .The use of adjuvant highdose steroid in addition to conventional radiotherapy has been shown to be beneficial, but was associated with an increased incidence of severe adverse events.Indeed, high-dose dexamethasone (>96 mg daily) has been associated with serious toxicities such as severe psychoses, gastric ulcer bleeding, rectal bleeding, gastrointestinal perforation, and sepsis 4,7,39 .To summarize, the available evidence demonstrates that high-dose corticosteroid does not appear to be more effective than low-dose treatment, and that dexamethasone at a total daily dose of 16 mg is effective and safe for the treatment of mscc.
Twelve prospective studies evaluating effectiveness of radiotherapy for the management of mscc were reviewed 12,[18][19][20][21][22][23][24][25][26][27][28] .The use of radiotherapy has been shown to reduce back pain and to maintain or restore ambulatory capacity.Radiotherapy-related toxicities such as vomiting, esophagitis, dysphagia, and skin reactions have been reported 23,24 .Five studies of various radiation regimens showed no difference in terms of back pain relief, of posttreatment maintenance, improvement, or regain of ambulation, and of toxicities 12,[27][28][29][30] .However, Rades et al. 12 demonstrated that long-course radiotherapy was associated with improved local control of spinal metastasis.Similar results have been observed in retrospective studies 40,41 .According to the evidence evaluated, radiotherapy appears to be effective for the maintenance and restoration of ambulatory function and for back pain relief in mscc patients.Shortcourse radiotherapy (including split-course) has the advantage of being faster and less time-consuming for the patient; however, long-course radiotherapy allows for better local control at the site of the spinal cord compression.
Six prospective studies assessing the effectiveness of surgery followed by radiotherapy showed that surgery was associated with significant improvements in ambulatory capacity and back pain relief [31][32][33][34][35][36] .Results showed that vertebrectomy combined with spinal stabilization was an effective a No data on post-treatment pain relief rate are available.However, the authors showed that use of corticosteroids (p = 0.0093) and opioid analgesics (p = 0.002) were significantly reduced in the surgery group.Pts = patients; rt = radiotherapy; na = not available; rr = relative risk; ci = confidence interval.
Current OnCOlOgy-VOlume 19, number 6, DeCember 2012 Copyright © 2012 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).surgical approach.However, that technique was associated with morbidities such as pulmonary, hemorrhagic, and wound complications [31][32][33][34][35][36] .Despite the reports of increased complications, surgery has been shown to significantly improve quality of life over a period of 6-9 months after treatment [42][43][44] .No randomized controlled trial comparing surgical approaches for the treatment of mscc was identified.Such a comparison is difficult to make because surgical technique is linked directly to the location of the metastasis.In that regard, the use of laminectomy alone for lesions that are not posteriorly located is considered suboptimal because it could potentially lead to spinal instability.
A meta-analysis and two phase iii studies evaluating the efficacy of surgery followed by radiotherapy compared with radiotherapy alone were selected 3,37,38 .The ground-breaking study by Patchell et al. 38 showed that, compared with patients treated with radiotherapy alone, those treated with direct decompressive surgery radiotherapy combined significantly better outcomes in terms of motor capacity, survival, and use of corticosteroids and analgesics.However, that study elicited criticisms from the scientific community (among others) for patient selection bias.The study included only patients who were more likely to benefit from surgery and excluded patients with very radiosensitive tumours.The two patient groups also differed in the delay between diagnosis of the primary tumour and development of mscc, suggesting a difference in tumour biology in favour of the surgery group.It has also been suggested that the proportion of patients with vertebral body collapse might explain the poorer outcomes observed in the radiotherapy-alone group 45 .Indeed, it has been shown that, when treated with primary radiotherapy, patients with vertebral instability or vertebral bone fragment experienced less neurologic improvement than did those presenting compression from a soft-tissue mass 46 .Clinical guidelines and expert consensus recommend that patients presenting with unstable spine should be treated with surgery followed by radiotherapy to decompress and stabilize the spine 13,[47][48][49][50][51][52] .Meanwhile, the study by Young et al. 37 showed no difference in post-treatment ambulatory function and pain relief in patients treated using laminectomy and radiotherapy compared with radiotherapy alone.The absence of significant differences and the lack of statistical power were attributed to the small number of patients recruited.
Altogether, studies have shown that each treatment modality is effective in reducing back pain and maintaining the ambulatory capacity of mscc patients.Surgery followed by radiotherapy seems to be beneficial, especially for patients who are medically operable and have specific characteristics such as being symptomatic, having an expected survival of more than 3 months, and having only one level of spinal cord compression.The criterion for life expectancy set in the study by Patchell et al. is debatable.In fact, tools available to date for assessment of expected survival do not allow for such a level of precision, and an assessment of life expectancy of at least 6 months would probably be more appropriate.
A clinical challenge in the management of mscc remains, and that challenge consists in identifying patients who will benefit most from each treatment.The patient's prognosis must be evaluated, and various classification systems can be used to predict survival [53][54][55][56] .In general, these tools consider the patient's performance status and primary tumour type, the presence of visceral metastases, and pretreatment ambulatory status.The scoring system by Tokuhashi et al. 54 is simple, practical and provides a reasonably good estimate of patient's prognosis based on the evaluation of various clinical parameters.The Tokuhashi tool has been validated in various cohorts of patients (breast, kidney, lung, and liver cancers), showing reliable and reproducible evaluation of survival [57][58][59][60][61] .Recently, Fisher et al. 62 published a novel comprehensive classification system for spinal instability in neoplastic disease that can guide clinicians in identifying when patients may benefit from surgical consultation.
Finally, the histopathology of the primary tumour can also influence the therapeutic decision.For instance, it has been shown that patients presenting with mscc derived from myeloma, lymphoma, breast, or prostate cancer have an initial response rate to radiotherapy of up to 80%; patients with pulmonary or renal tumour or melanoma are generally considered to have radioresistant tumours 11,63,64 .

CONCLUSIONS AND RECOMMENDATIONS
Management of mscc aims at pain relief, ambulation maintenance or improvement, and preservation of quality of life.Considering the evidence available to date, the cepo recommends that • patients with an established diagnosis of cancer presenting with spinal cord compression be treated by a specialized multidisciplinary team (medical oncologists, radiation oncologists, and neurosurgeons or orthopaedic surgeons specializing in spinal cord decompression and reconstruction surgery) (grade D recommendation).• corticotherapy consisting of dexamethasone 16 mg daily be immediately administered to symptomatic patients as soon as a spinal cord compression is diagnosed or suspected (grade B recommendation).• high-loading-doses of corticosteroids (for example, 100 mg) be avoided (grade B recommendation).• histopathologic diagnosis and scores on objective scales for prognosis (for example, Tokuhashi) and spinal instability (for example, Fisher) be considered before a therapeutic decision is made (grade D recommendation).
• corticotherapy and chemotherapy with radiotherapy be offered to patients with spinal cord compression caused by myeloma, lymphoma, or germ cell tumour without sign of spinal instability or spinal cord compression by bone fragment (grade B recommendation).Based on these recommendations, the cepo proposes an algorithm for the treatment of mscc (Figure 1).

ACKNOWLEDGMENTS
The cepo is a group of specialists in oncology that reports to the Direction québécoise de cancérologie of the Ministère de la Santé et des Services sociaux.The Direction québécoise de cancérologie provided financial support for the work reported in this article, which is an adaptation of cepo's original clinical practice guideline published in August 2011, freely available in its French version at http://www.msss.gouv.qc.ca/cancer.
The cepo thanks Ghassan Boubez md, Hôpital Notre-Dame (chum); Carolyn Freeman md, Montreal General Hospital (muhc); Alain Jodoin md, Hôpital du figure 1 Treatment algorithm proposed by the Comité de l'évolution des pratiques en oncologie (cepo) for metastatic spinal cord compression (mscc).In the process of deciding on the appropriate treatment, some criteria may be more important than others.a If surgery is contraindicated, long-course radiotherapy may be offered (30 • short-course radiotherapy (8 Gy in 1 fraction or 20 Gy in 5 fractions) be administered to patients with spinal cord compression and poor life expectancy (Tokuhashi score 0-8) (grade B recommendation).• long-course radiotherapy (30 Gy in 10 fractions, 37.5 Gy in 15 fractions, or Gy in 20 fractions) be administered to patients with inoperable spinal cord compression and good life expectancy (Tokuhashi score 9-15) (grade B recommendation).• decompressive surgery (including spinal stabilization) followed by long-course radiotherapy (30 Gy in 10 fractions, or more) be offered to patients diagnosed with symptomatic spinal cord compression.Patients presenting a spinal cord compression at a single level, with incomplete motor deficit within 48 hours of presentation, and a good performance status are appropriate candidates.Additional criteria in favour of surgery include spinal instability or displacement of a vertebral fragment (grade B recommendation).• patients considered for surgery must have a life expectancy of at least 3-6 months (grade D recommendation).
figure1 Treatment algorithm proposed by the Comité de l'évolution des pratiques en oncologie (cepo) for metastatic spinal cord compression (mscc).In the process of deciding on the appropriate treatment, some criteria may be more important than others.a If surgery is contraindicated, long-course radiotherapy may be offered(30 Gy in 10 fractions, 37.5 Gy in 15 fractions, or 40 Gy in 20 fractions).b For these patients, long-course radiotherapy (30 Gy in 10 fractions, 37.5 Gy in 15 fractions, or 40 Gy in 20 fractions) also constitutes a valuable option.mri = magnetic resonance imaging; fr = fraction.

table i
Levels of evidence and grades of recommendations a 14Evidence demonstrated by means of case series without controls a Adapted from Cook et al.14.e481CurrentOnCOlOgy-VOlume 19, number 6, DeCember 2012 Copyright © 2012 Multimed Inc. Folowing publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).table ii Results of corticotherapy trials for treatment of metastatic spinal cord compression (level ii evidence) a Percentage of patients that did not report pain relief after treatment.b At day 28, 80% of patients were evaluable for functional outcomes [(A) 10 of 11, (B) 6 of 9].Outcomes were measured depending on ambulation definition (Functional Independence measure, Barthel Index) c Pain evaluated using the Visual Analogue Pain Scale.e482 Current OnCOlOgy-VOlume 19, number 6, DeCember 2012 Copyright © 2012 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

table iii
Results of radiotherapy trials for treatment of metastatic spinal cord compression (level iii evidence)No data on pain relief after surgery are available.However, the authors reported a significant decrease in pain after surgery, based on a visual analog scale score(7.94 vs. 4.3).
a Patient without neurologic deficit.bSplit-course:15Gy in 3 fractions, then 4 days' rest, then 15 Gy in 5 fractions.cDatanotavailable in the publication, but authors stated that a significant reduction was observed after treatment (p < 0.001).dMedian survival for ambulant patients; post-treatment ambulant patients have better survival than non-ambulant patients (p < 0.001).Pts = patients; na = non available.e483Current OnCOlOgy-VOlume 19, number 6, DeCember 2012 Copyright © 2012 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).aSplit course: 15 Gy in 3 fractions, then 15 Gy in 5 fractions.bOf the study cohort, 24 patients were lost to follow up or died prematurely.Those patients were not included in the analysis.cShort course: 8 Gy in 1 fraction or 20 Gy in 5 fractions.dNo data on post-treatment ambulatory status are available.Published data demonstrated that, compared with short-course treatment, long-course treatment provided better 1-year local control of metastases recurrence (p = 0.005).eLong course: 30 Gy in 10 fractions, 37.5 Gy in 15 fractions, or 40 Gy in 20 fractions.Current OnCOlOgy-VOlume 19, number 6, DeCember 2012 Copyright © 2012 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).a e485 Current OnCOlOgy-VOlume 19, number 6, DeCember 2012 Copyright © 2012 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

table vi
Results of the comparison between surgery and radiotherapy for treatment of metastatic spinal cord compression