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Volume 9, Issue 4, July-August 2011, Pages 121-124
Review
D. Andrew Loblaw BSc, MD, MSc, FRCPC, CIP
Abstract
Malignant epidural spinal cord compression is a dreaded complication of malignancy. Fortunately, it does not happen very often. Estimating the prognosis is critical to achieving a balance between effective therapy and the burden of treatment. Treatment can be individualized by reviewing simple prognosis scales. For patients with a poor prognosis, a single fraction of 8 Gy is just as effective as multiple fractions and much more convenient. Surgery and radiation should be considered for patients with a more positive prognosis. For patients not getting surgery, enrollment in clinical trials of single vs. multiple fractions of radiation should be a priority.
Article Outline
Malignant spinal cord compression (MSCC) is one of the most dreaded complications of metastatic cancer. MSCC can be divided into intradural (intramedullary and leptomeningeal) and extradural (Malignant Extradural Spinal Cord Compression [MESCC]).[1] Its natural history, if untreated, is usually one of relentless and progressive pain, paralysis, sensory loss, and sphincter dysfunction.[2]
A population-based study of cancer patients reported that 2.5% (n = 3,458) of all cancer patients who died from their disease between 1990 and 1995 had at least one admission for MSCC.[3] The incidence of MSCC varied widely by primary cancer site, from 7.9% in patients with myeloma to 0.2% in patients with pancreatic cancer.[3]
In 1998 and again in 2005, our group published evidence-based clinical practice guidelines for the diagnosis and management of MESCC.[2] and [4] The latter guideline was formally developed and approved through Cancer Care Ontario's Program in Evidence-Based Care (PEBC). The PEBC recommends that the guidelines be reviewed regularly and updated when potentially practice-changing data have been published. Since the last guideline, several randomized control trials have been published but, to our knowledge, no evidence-based guidelines have been issued.
Our objective was to review the literature published since the last guideline and summarize the data specifically pertaining to an optimal dose strategy for patients with MESCC treated with radiotherapy (with or without surgery). The literature search strategy was adopted from the initial review in 2005.[4] Where the data were available, the summary focused on prospective studies.
Prognosis
A number of reports have been published to define the prognosis of patients with MESCC. Our group's research indicated that the prognosis overall was poor, with a median survival of 2.9 months after the diagnosis of MESCC.[3] One of the strongest predictors of overall survival (OS) in our population-based study was tumor histology. Non-small-cell lung cancer had the worst median OS (1.5 months), and myeloma had the best median OS (6.7 months).
Other groups have shown quite a dramatic OS difference between patients who are able to ambulate posttreatment and patients who are not able to ambulate posttreatment. Maranzano et al[5] documented a threefold difference in OS (10 vs. three months) based on ambulatory status posttreatment. In the Italian randomized studies, patients with favorable histology (breast, prostate, lymphoma, seminoma, or myeloma) and no abnormal neurology qualified for the good-prognosis group (the remaining patients were considered to have a poor prognosis).[6] and [7]
Rades and colleagues have published a number of studies identifying several prognostic factors that were identified in several multivariate analyses.[8], [9], [10] and [11] In a multicenter, international retrospective study of 1,852 patients treated with radiotherapy, the following factors were independently prognostic: histology, visceral metastases, other bone metastases, ambulatory status before radiotherapy, interval between tumor diagnosis and MESCC, and time of developing motor deficits.[9]
Rades, and colleagues went on to lead the development of a prognostic scoring system based on these factors and this patient data set. Total scores ranged between 20 and 45 points, and patients were divided into five groups. The six-month OS ranged from 4% to 99% (P < 0.001), with median OS estimated to range between two and 62 months from the worst to the best prognostic group (see [Table 1] and [Table 2]).
Adapted from Rades et al.9
| PROGNOSTIC FACTOR | SCORE |
|---|---|
| Type of tumor | |
| Myeloma/lymphoma | 9 |
| Breast cancer | 8 |
| Prostate cancer | 7 |
| Other tumors | 4 |
| Lung cancer | 3 |
| Other bone metastasesa | |
| No | 8 |
| Yes | 2 |
| Visceral metastasesa | |
| No | 8 |
| Yes | 2 |
| Tumor diagnosis to MESCC | |
| >15 months | 7 |
| ≤15 months | 4 |
| Ambulatory status pretreatment | |
| Ambulatory | 7 |
| Nonambulatory | 3 |
| Time to develop motor deficits before treatment | |
| >14 days | 8 |
| 8–14 days | 6 |
| 1–7 days | 3 |
Surgical Management of MESCC
A multi-institutional, randomized control trial by Patchell et al[12] randomized 101 patients with magnetic resonance imaging–confirmed MESCC (cauda equina lesions excluded) to receive decompressive surgical resection with radiation 14 days later or radiation (RT) alone of 30 Gy in 10 fraction treatments. All patients were directed to receive dexamethasone 100 mg bolus + 96 mg daily (dose reduced for patients with relative contraindications to high-dose steroids). Patients were stratified by institution, tumor type, ambulatory status, and spinal stability; 38% of accrued patients had spinal instability.
The authors reported that patients undergoing surgery in addition to radiotherapy (30 Gy/10) were more likely to retain or maintain their ambulatory status longer compared to patients receiving radiotherapy alone (84% vs. 57%, P = 0.001). In addition, patients assigned to the combined-modality arm experienced a longer period of ambulation (122 vs. 13 days, P = 0.003), urinary continence (74% vs. 57%, P = 0.005), duration of continence (median 157 vs. 17 days, P = 0.016), and functional status (maintenance of Frankel and American Spinal Injury Association scores, P = 0.001). There was a difference in survival favoring the combined-modality arm (median 126 vs. 100 days, P = 0.033).
Surgery is associated with significant morbidity, which needs to be considered when deciding between surgery and radiation for medically operable patients with a single area of compression and no spinal instability or bony compression. Minimally-invasive techniques may decrease the morbidity of the procedure, shorten the recovery period, and maintain the procedure's efficacy.[13] Despite this, it would be reasonable to select patients for surgery who have the longest life expectancy (groups D and E of the MESCC prognostic scale).[10]
Within two weeks of surgery, patients should have postoperative RT of 30 Gy in 10 fractions, per the Patchell et al trial.[12]
Optimal Dose Fractionation Schedule
Poor-Prognosis Patients
Maranzano and colleagues[6] and [7] have conducted and reported two randomized control trials addressing the question of a dose fractionation schedule for poor prognosis patients. These patients were defined as having poor-histology tumors (melanoma or lung, sarcoma, gastrointestinal, head and neck, or kidney) or good-histology tumors with any functional impairment or poor performance status. It may be reasonable to extrapolate the results of these trials to the MESCC prognosis groups A, B, and C.[10]
The first study, reported in 2005, randomized 300 patients 1:1 to a split course of radiation (15 Gy in three fractions, 4-day break, then 15 Gy in five fractions) or hypofractionated radiotherapy (8 Gy in two fractions, one week apart).[6] All patients were given dexamethasone 16 mg daily during RT, tapered off posttreatment. Patients were assessed for ability to ambulate (with/without assistance), duration of ambulation, bladder function, OS, toxicity, and pain relief. There were 276 analyzable patients, and the median follow-up (presumably of survivors) was 33 months. There were no significant differences in any of these outcomes (Table 3).
Adapted from Maranzano et al6 and Maranzano et al.[7]
The Italian group's second study, reported in 2009, randomized 327 poor-prognosis patients (as above) to 16 Gy in two fractions over one week vs. 8 Gy for one fraction.[7] Dexamethasone 16 mg/day was given to both groups. There were 303 analyzable patients; median follow-up was not reported (but appears to be approximately five months from the Kaplan-Meier plots). Again, no significant differences were reported between the treatment arms for ambulation, duration of ambulation, bladder control, pain response, and OS (see Table 3). Of note, there was a nonsignificant trend toward greater in-field failures favoring the two-fraction arm in this study (2.5% vs. 6.0%, P = 0.12).
Good-Prognosis Patients
For patients who are ineligible for surgery and have a good prognosis for their MESCC, clinical trials are needed to determine the role of dose-escalating RT to improve outcomes.
A prospective, international nonrandomized study of 231 patients (SCORE-1 study) treated with different RT schedules concluded that longer fractionation schemes were predictive of progression-free survival (12 months 72% vs. 55%, P = 0.034) and local control (12 months 77% vs. 61%, P = 0.032) and that the RT schedule held up on a multivariate analysis.[14] There was no relationship between length of RT scheme and OS or motor status posttreatment. Patients were not selected but tended to be a better-prognosis group than usually reported (median OS five months).
In their retrospective prognostic study, Rades et al[10] reported that longer fractionation schemes were associated with improved OS. In another prospective study by Rades et al,[15] 40 Gy in 20 fractions did not improve functional outcomes or ambulatory status compared to 30 Gy in 10 fractions. Confirmation in a prospective randomized control trial should be done to determine whether this is true or whether there are patient selection factors that explain the observations. In sum, there are insufficient data to support dose escalation above 8 Gy in good-prognosis patients.
An international consortium of trialists is running a trial of one vs. multiple fractions of RT (SCORAD) for all prognosis patients; patients should be entered if possible to confirm the benefit of longer vs. shorter fractionation treatments.
Conclusions
MESCC is a dreaded complication of malignancy and, fortunately, not common. Despite many patients being identified early with no or minimal functional losses, their prognosis is poor. A single fraction of 8 Gy is just as effective as multiple fractions for poor-prognosis patients. For good-prognosis patients, surgery and radiation should be considered. For patients not getting surgery, enrollment in clinical trials of single vs. multiple fractions of radiation should be a priority.
References [Pub Med ID in brackets]
1 T.N. Byrne, Spinal cord compression from epidural metastases, N Engl J Med 327 (9) (1992), pp. 614–619.
2 D.A. Loblaw and N.J. Laperiere, Emergency treatment of malignant extradural spinal cord compression: an evidence-based guideline, J Clin Oncol 16 (4) (1998), pp. 1613–1624.
3 D.A. Loblaw, N.J. Laperriere and W.J. Mackillop, A population-based study of malignant spinal cord compression in Ontario, Clin Oncol 15 (4) (2003), pp. 211–217.
4 D.A. Loblaw, J. Perry, A. Chambers and N.J. Laperriere, Systematic review of the diagnosis and management of malignant extradural spinal cord compression: the Cancer Care Ontario Practice Guidelines Initiative's Neuro-Oncology Disease Site Group, J Clin Oncol 23 (9) (2005), pp. 2028–2037.
5 E. Maranzano, P. Latini, F. Checcaglini, S. Ricci, B.M. Panizza, C. Aristei, E. Perrucci, S. Beneventi, E. Corgna and M. Tonato, Radiation therapy in metastatic spinal cord compression: A prospective analysis of 105 consecutive patients, Ann Neurol 3 (1991), pp. 40–51.
6 E. Maranzano, R. Bellavita, R. Rossi, V. De Angelis, A. Frattegiani, R. Bagnoli, M. Mignogna, S. Beneventi, M. Lupattelli, P. Ponticelli, G.P. Biti and P. Latini, Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized, multicenter trial, J Clin Oncol 23 (15) (2005), pp. 3358–3365.
7 E. Maranzano, F. Trippa, M. Casale, S. Costantini, M. Lupattelli, R. Bellavita, L. Marafioti, S. Pergolizzi, A. Santacaterina, M. Mignogna, G. Silvano and V. Fusco, 8Gy single-dose radiotherapy is effective in metastatic spinal cord compression: results of a phase III randomized multicentre Italian trial, Radiother Oncol 93 (2) (2009), pp. 174–179.
8 D. Rades, F. Heidenreich and J.H. Karstens, Final results of a prospective study of the prognostic value of the time to develop motor deficits before irradiation in metastatic spinal cord compression, Int J Radiat Oncol Biol Phys 53 (4) (2002), pp. 975–979.
9 D. Rades, F. Fehlauer, R. Schulte, T. Veninga, L.J. Stalpers, H. Basic, A. Bajrovic, P.J. Hoskin, S. Tribius, I. Wildfang, V. Rudat, R. Engenhart-Cabilic, J.H. Karstenssf, W. Alberti, J. Dunst and S.E. Schild, Prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression, J Clin Oncol 24 (21) (2006), pp. 3388–3393.
10 D. Rades, V. Rudat, T. Veninga, L.J. Stalpers, P.J. Hoskin and S.E. Schild, Prognostic factors for functional outcome and survival after reirradiation for in-field recurrences of metastatic spinal cord compression, Cancer 113 (5) (2008), pp. 1090–1096. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (12)
11 D. Rades, L.J. Stalpers, T. Veninga, R. Schulte, P.J. Hoskin, N. Obralic, A. Bajrovic, V. Rudat, R. Schwarz, M.C. Hulshof, P. Poortmans and S.E. Schild, Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression, J Clin Oncol 23 (15) (2005), pp. 3366–3375.
12 R.A. Patchell, P.A. Tibbs, W.F. Regine, R. Payne, S. Saris, R.J. Kryscio, M. Mohiuddin and B. Young, Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial, Lancet 366 (9486) (2005), pp. 643–648.
13 H. Akram and J. Allibone, Spinal surgery for palliation in malignant spinal cord compression, Clin Oncol (R Coll Radiol) 22 (9) (2010), pp. 792–800.
14 D. Rades, M. Lange, T. Veninga, V. Rudat, A. Bajrovic, L.J. Stalpers, J. Dunst and S.E. Schild, Preliminary results of spinal cord compression recurrence evaluation (SCORE-1) study comparing short-course versus long-course radiotherapy for local control of malignant epidural spinal cord compression, Int J Radiat Oncol Biol Phys 73 (1) (2009), pp. 228–234.
15 D. Rades, F. Fehlauer, L.J. Stalpers, I. Wildfang, O. Zschenker, S.E. Schild, H.J. Schmoll, J.H. Karstens and W. Alberti, A prospective evaluation of two radiotherapy schedules with 10 versus 20 fractions for the treatment of metastatic spinal cord compression: final results of a multicenter study, Cancer 101 (11) (2004), pp. 2687–2692.
Conflict of Interest Disclosure: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Vitae
Dr. Loblaw and G. Mitera are from the Department of Radiation Oncology at the Sunnybrook Health Sciences Centre in Toronto, Canada
Volume 9, Issue 4, July-August 2011, Pages 121-124
Review
D. Andrew Loblaw BSc, MD, MSc, FRCPC, CIP
Abstract
Malignant epidural spinal cord compression is a dreaded complication of malignancy. Fortunately, it does not happen very often. Estimating the prognosis is critical to achieving a balance between effective therapy and the burden of treatment. Treatment can be individualized by reviewing simple prognosis scales. For patients with a poor prognosis, a single fraction of 8 Gy is just as effective as multiple fractions and much more convenient. Surgery and radiation should be considered for patients with a more positive prognosis. For patients not getting surgery, enrollment in clinical trials of single vs. multiple fractions of radiation should be a priority.
Article Outline
Malignant spinal cord compression (MSCC) is one of the most dreaded complications of metastatic cancer. MSCC can be divided into intradural (intramedullary and leptomeningeal) and extradural (Malignant Extradural Spinal Cord Compression [MESCC]).[1] Its natural history, if untreated, is usually one of relentless and progressive pain, paralysis, sensory loss, and sphincter dysfunction.[2]
A population-based study of cancer patients reported that 2.5% (n = 3,458) of all cancer patients who died from their disease between 1990 and 1995 had at least one admission for MSCC.[3] The incidence of MSCC varied widely by primary cancer site, from 7.9% in patients with myeloma to 0.2% in patients with pancreatic cancer.[3]
In 1998 and again in 2005, our group published evidence-based clinical practice guidelines for the diagnosis and management of MESCC.[2] and [4] The latter guideline was formally developed and approved through Cancer Care Ontario's Program in Evidence-Based Care (PEBC). The PEBC recommends that the guidelines be reviewed regularly and updated when potentially practice-changing data have been published. Since the last guideline, several randomized control trials have been published but, to our knowledge, no evidence-based guidelines have been issued.
Our objective was to review the literature published since the last guideline and summarize the data specifically pertaining to an optimal dose strategy for patients with MESCC treated with radiotherapy (with or without surgery). The literature search strategy was adopted from the initial review in 2005.[4] Where the data were available, the summary focused on prospective studies.
Prognosis
A number of reports have been published to define the prognosis of patients with MESCC. Our group's research indicated that the prognosis overall was poor, with a median survival of 2.9 months after the diagnosis of MESCC.[3] One of the strongest predictors of overall survival (OS) in our population-based study was tumor histology. Non-small-cell lung cancer had the worst median OS (1.5 months), and myeloma had the best median OS (6.7 months).
Other groups have shown quite a dramatic OS difference between patients who are able to ambulate posttreatment and patients who are not able to ambulate posttreatment. Maranzano et al[5] documented a threefold difference in OS (10 vs. three months) based on ambulatory status posttreatment. In the Italian randomized studies, patients with favorable histology (breast, prostate, lymphoma, seminoma, or myeloma) and no abnormal neurology qualified for the good-prognosis group (the remaining patients were considered to have a poor prognosis).[6] and [7]
Rades and colleagues have published a number of studies identifying several prognostic factors that were identified in several multivariate analyses.[8], [9], [10] and [11] In a multicenter, international retrospective study of 1,852 patients treated with radiotherapy, the following factors were independently prognostic: histology, visceral metastases, other bone metastases, ambulatory status before radiotherapy, interval between tumor diagnosis and MESCC, and time of developing motor deficits.[9]
Rades, and colleagues went on to lead the development of a prognostic scoring system based on these factors and this patient data set. Total scores ranged between 20 and 45 points, and patients were divided into five groups. The six-month OS ranged from 4% to 99% (P < 0.001), with median OS estimated to range between two and 62 months from the worst to the best prognostic group (see [Table 1] and [Table 2]).
Adapted from Rades et al.9
| PROGNOSTIC FACTOR | SCORE |
|---|---|
| Type of tumor | |
| Myeloma/lymphoma | 9 |
| Breast cancer | 8 |
| Prostate cancer | 7 |
| Other tumors | 4 |
| Lung cancer | 3 |
| Other bone metastasesa | |
| No | 8 |
| Yes | 2 |
| Visceral metastasesa | |
| No | 8 |
| Yes | 2 |
| Tumor diagnosis to MESCC | |
| >15 months | 7 |
| ≤15 months | 4 |
| Ambulatory status pretreatment | |
| Ambulatory | 7 |
| Nonambulatory | 3 |
| Time to develop motor deficits before treatment | |
| >14 days | 8 |
| 8–14 days | 6 |
| 1–7 days | 3 |
Surgical Management of MESCC
A multi-institutional, randomized control trial by Patchell et al[12] randomized 101 patients with magnetic resonance imaging–confirmed MESCC (cauda equina lesions excluded) to receive decompressive surgical resection with radiation 14 days later or radiation (RT) alone of 30 Gy in 10 fraction treatments. All patients were directed to receive dexamethasone 100 mg bolus + 96 mg daily (dose reduced for patients with relative contraindications to high-dose steroids). Patients were stratified by institution, tumor type, ambulatory status, and spinal stability; 38% of accrued patients had spinal instability.
The authors reported that patients undergoing surgery in addition to radiotherapy (30 Gy/10) were more likely to retain or maintain their ambulatory status longer compared to patients receiving radiotherapy alone (84% vs. 57%, P = 0.001). In addition, patients assigned to the combined-modality arm experienced a longer period of ambulation (122 vs. 13 days, P = 0.003), urinary continence (74% vs. 57%, P = 0.005), duration of continence (median 157 vs. 17 days, P = 0.016), and functional status (maintenance of Frankel and American Spinal Injury Association scores, P = 0.001). There was a difference in survival favoring the combined-modality arm (median 126 vs. 100 days, P = 0.033).
Surgery is associated with significant morbidity, which needs to be considered when deciding between surgery and radiation for medically operable patients with a single area of compression and no spinal instability or bony compression. Minimally-invasive techniques may decrease the morbidity of the procedure, shorten the recovery period, and maintain the procedure's efficacy.[13] Despite this, it would be reasonable to select patients for surgery who have the longest life expectancy (groups D and E of the MESCC prognostic scale).[10]
Within two weeks of surgery, patients should have postoperative RT of 30 Gy in 10 fractions, per the Patchell et al trial.[12]
Optimal Dose Fractionation Schedule
Poor-Prognosis Patients
Maranzano and colleagues[6] and [7] have conducted and reported two randomized control trials addressing the question of a dose fractionation schedule for poor prognosis patients. These patients were defined as having poor-histology tumors (melanoma or lung, sarcoma, gastrointestinal, head and neck, or kidney) or good-histology tumors with any functional impairment or poor performance status. It may be reasonable to extrapolate the results of these trials to the MESCC prognosis groups A, B, and C.[10]
The first study, reported in 2005, randomized 300 patients 1:1 to a split course of radiation (15 Gy in three fractions, 4-day break, then 15 Gy in five fractions) or hypofractionated radiotherapy (8 Gy in two fractions, one week apart).[6] All patients were given dexamethasone 16 mg daily during RT, tapered off posttreatment. Patients were assessed for ability to ambulate (with/without assistance), duration of ambulation, bladder function, OS, toxicity, and pain relief. There were 276 analyzable patients, and the median follow-up (presumably of survivors) was 33 months. There were no significant differences in any of these outcomes (Table 3).
Adapted from Maranzano et al6 and Maranzano et al.[7]
The Italian group's second study, reported in 2009, randomized 327 poor-prognosis patients (as above) to 16 Gy in two fractions over one week vs. 8 Gy for one fraction.[7] Dexamethasone 16 mg/day was given to both groups. There were 303 analyzable patients; median follow-up was not reported (but appears to be approximately five months from the Kaplan-Meier plots). Again, no significant differences were reported between the treatment arms for ambulation, duration of ambulation, bladder control, pain response, and OS (see Table 3). Of note, there was a nonsignificant trend toward greater in-field failures favoring the two-fraction arm in this study (2.5% vs. 6.0%, P = 0.12).
Good-Prognosis Patients
For patients who are ineligible for surgery and have a good prognosis for their MESCC, clinical trials are needed to determine the role of dose-escalating RT to improve outcomes.
A prospective, international nonrandomized study of 231 patients (SCORE-1 study) treated with different RT schedules concluded that longer fractionation schemes were predictive of progression-free survival (12 months 72% vs. 55%, P = 0.034) and local control (12 months 77% vs. 61%, P = 0.032) and that the RT schedule held up on a multivariate analysis.[14] There was no relationship between length of RT scheme and OS or motor status posttreatment. Patients were not selected but tended to be a better-prognosis group than usually reported (median OS five months).
In their retrospective prognostic study, Rades et al[10] reported that longer fractionation schemes were associated with improved OS. In another prospective study by Rades et al,[15] 40 Gy in 20 fractions did not improve functional outcomes or ambulatory status compared to 30 Gy in 10 fractions. Confirmation in a prospective randomized control trial should be done to determine whether this is true or whether there are patient selection factors that explain the observations. In sum, there are insufficient data to support dose escalation above 8 Gy in good-prognosis patients.
An international consortium of trialists is running a trial of one vs. multiple fractions of RT (SCORAD) for all prognosis patients; patients should be entered if possible to confirm the benefit of longer vs. shorter fractionation treatments.
Conclusions
MESCC is a dreaded complication of malignancy and, fortunately, not common. Despite many patients being identified early with no or minimal functional losses, their prognosis is poor. A single fraction of 8 Gy is just as effective as multiple fractions for poor-prognosis patients. For good-prognosis patients, surgery and radiation should be considered. For patients not getting surgery, enrollment in clinical trials of single vs. multiple fractions of radiation should be a priority.
References [Pub Med ID in brackets]
1 T.N. Byrne, Spinal cord compression from epidural metastases, N Engl J Med 327 (9) (1992), pp. 614–619.
2 D.A. Loblaw and N.J. Laperiere, Emergency treatment of malignant extradural spinal cord compression: an evidence-based guideline, J Clin Oncol 16 (4) (1998), pp. 1613–1624.
3 D.A. Loblaw, N.J. Laperriere and W.J. Mackillop, A population-based study of malignant spinal cord compression in Ontario, Clin Oncol 15 (4) (2003), pp. 211–217.
4 D.A. Loblaw, J. Perry, A. Chambers and N.J. Laperriere, Systematic review of the diagnosis and management of malignant extradural spinal cord compression: the Cancer Care Ontario Practice Guidelines Initiative's Neuro-Oncology Disease Site Group, J Clin Oncol 23 (9) (2005), pp. 2028–2037.
5 E. Maranzano, P. Latini, F. Checcaglini, S. Ricci, B.M. Panizza, C. Aristei, E. Perrucci, S. Beneventi, E. Corgna and M. Tonato, Radiation therapy in metastatic spinal cord compression: A prospective analysis of 105 consecutive patients, Ann Neurol 3 (1991), pp. 40–51.
6 E. Maranzano, R. Bellavita, R. Rossi, V. De Angelis, A. Frattegiani, R. Bagnoli, M. Mignogna, S. Beneventi, M. Lupattelli, P. Ponticelli, G.P. Biti and P. Latini, Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized, multicenter trial, J Clin Oncol 23 (15) (2005), pp. 3358–3365.
7 E. Maranzano, F. Trippa, M. Casale, S. Costantini, M. Lupattelli, R. Bellavita, L. Marafioti, S. Pergolizzi, A. Santacaterina, M. Mignogna, G. Silvano and V. Fusco, 8Gy single-dose radiotherapy is effective in metastatic spinal cord compression: results of a phase III randomized multicentre Italian trial, Radiother Oncol 93 (2) (2009), pp. 174–179.
8 D. Rades, F. Heidenreich and J.H. Karstens, Final results of a prospective study of the prognostic value of the time to develop motor deficits before irradiation in metastatic spinal cord compression, Int J Radiat Oncol Biol Phys 53 (4) (2002), pp. 975–979.
9 D. Rades, F. Fehlauer, R. Schulte, T. Veninga, L.J. Stalpers, H. Basic, A. Bajrovic, P.J. Hoskin, S. Tribius, I. Wildfang, V. Rudat, R. Engenhart-Cabilic, J.H. Karstenssf, W. Alberti, J. Dunst and S.E. Schild, Prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression, J Clin Oncol 24 (21) (2006), pp. 3388–3393.
10 D. Rades, V. Rudat, T. Veninga, L.J. Stalpers, P.J. Hoskin and S.E. Schild, Prognostic factors for functional outcome and survival after reirradiation for in-field recurrences of metastatic spinal cord compression, Cancer 113 (5) (2008), pp. 1090–1096. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (12)
11 D. Rades, L.J. Stalpers, T. Veninga, R. Schulte, P.J. Hoskin, N. Obralic, A. Bajrovic, V. Rudat, R. Schwarz, M.C. Hulshof, P. Poortmans and S.E. Schild, Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression, J Clin Oncol 23 (15) (2005), pp. 3366–3375.
12 R.A. Patchell, P.A. Tibbs, W.F. Regine, R. Payne, S. Saris, R.J. Kryscio, M. Mohiuddin and B. Young, Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial, Lancet 366 (9486) (2005), pp. 643–648.
13 H. Akram and J. Allibone, Spinal surgery for palliation in malignant spinal cord compression, Clin Oncol (R Coll Radiol) 22 (9) (2010), pp. 792–800.
14 D. Rades, M. Lange, T. Veninga, V. Rudat, A. Bajrovic, L.J. Stalpers, J. Dunst and S.E. Schild, Preliminary results of spinal cord compression recurrence evaluation (SCORE-1) study comparing short-course versus long-course radiotherapy for local control of malignant epidural spinal cord compression, Int J Radiat Oncol Biol Phys 73 (1) (2009), pp. 228–234.
15 D. Rades, F. Fehlauer, L.J. Stalpers, I. Wildfang, O. Zschenker, S.E. Schild, H.J. Schmoll, J.H. Karstens and W. Alberti, A prospective evaluation of two radiotherapy schedules with 10 versus 20 fractions for the treatment of metastatic spinal cord compression: final results of a multicenter study, Cancer 101 (11) (2004), pp. 2687–2692.
Conflict of Interest Disclosure: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Vitae
Dr. Loblaw and G. Mitera are from the Department of Radiation Oncology at the Sunnybrook Health Sciences Centre in Toronto, Canada
Volume 9, Issue 4, July-August 2011, Pages 121-124
Review
D. Andrew Loblaw BSc, MD, MSc, FRCPC, CIP
Abstract
Malignant epidural spinal cord compression is a dreaded complication of malignancy. Fortunately, it does not happen very often. Estimating the prognosis is critical to achieving a balance between effective therapy and the burden of treatment. Treatment can be individualized by reviewing simple prognosis scales. For patients with a poor prognosis, a single fraction of 8 Gy is just as effective as multiple fractions and much more convenient. Surgery and radiation should be considered for patients with a more positive prognosis. For patients not getting surgery, enrollment in clinical trials of single vs. multiple fractions of radiation should be a priority.
Article Outline
Malignant spinal cord compression (MSCC) is one of the most dreaded complications of metastatic cancer. MSCC can be divided into intradural (intramedullary and leptomeningeal) and extradural (Malignant Extradural Spinal Cord Compression [MESCC]).[1] Its natural history, if untreated, is usually one of relentless and progressive pain, paralysis, sensory loss, and sphincter dysfunction.[2]
A population-based study of cancer patients reported that 2.5% (n = 3,458) of all cancer patients who died from their disease between 1990 and 1995 had at least one admission for MSCC.[3] The incidence of MSCC varied widely by primary cancer site, from 7.9% in patients with myeloma to 0.2% in patients with pancreatic cancer.[3]
In 1998 and again in 2005, our group published evidence-based clinical practice guidelines for the diagnosis and management of MESCC.[2] and [4] The latter guideline was formally developed and approved through Cancer Care Ontario's Program in Evidence-Based Care (PEBC). The PEBC recommends that the guidelines be reviewed regularly and updated when potentially practice-changing data have been published. Since the last guideline, several randomized control trials have been published but, to our knowledge, no evidence-based guidelines have been issued.
Our objective was to review the literature published since the last guideline and summarize the data specifically pertaining to an optimal dose strategy for patients with MESCC treated with radiotherapy (with or without surgery). The literature search strategy was adopted from the initial review in 2005.[4] Where the data were available, the summary focused on prospective studies.
Prognosis
A number of reports have been published to define the prognosis of patients with MESCC. Our group's research indicated that the prognosis overall was poor, with a median survival of 2.9 months after the diagnosis of MESCC.[3] One of the strongest predictors of overall survival (OS) in our population-based study was tumor histology. Non-small-cell lung cancer had the worst median OS (1.5 months), and myeloma had the best median OS (6.7 months).
Other groups have shown quite a dramatic OS difference between patients who are able to ambulate posttreatment and patients who are not able to ambulate posttreatment. Maranzano et al[5] documented a threefold difference in OS (10 vs. three months) based on ambulatory status posttreatment. In the Italian randomized studies, patients with favorable histology (breast, prostate, lymphoma, seminoma, or myeloma) and no abnormal neurology qualified for the good-prognosis group (the remaining patients were considered to have a poor prognosis).[6] and [7]
Rades and colleagues have published a number of studies identifying several prognostic factors that were identified in several multivariate analyses.[8], [9], [10] and [11] In a multicenter, international retrospective study of 1,852 patients treated with radiotherapy, the following factors were independently prognostic: histology, visceral metastases, other bone metastases, ambulatory status before radiotherapy, interval between tumor diagnosis and MESCC, and time of developing motor deficits.[9]
Rades, and colleagues went on to lead the development of a prognostic scoring system based on these factors and this patient data set. Total scores ranged between 20 and 45 points, and patients were divided into five groups. The six-month OS ranged from 4% to 99% (P < 0.001), with median OS estimated to range between two and 62 months from the worst to the best prognostic group (see [Table 1] and [Table 2]).
Adapted from Rades et al.9
| PROGNOSTIC FACTOR | SCORE |
|---|---|
| Type of tumor | |
| Myeloma/lymphoma | 9 |
| Breast cancer | 8 |
| Prostate cancer | 7 |
| Other tumors | 4 |
| Lung cancer | 3 |
| Other bone metastasesa | |
| No | 8 |
| Yes | 2 |
| Visceral metastasesa | |
| No | 8 |
| Yes | 2 |
| Tumor diagnosis to MESCC | |
| >15 months | 7 |
| ≤15 months | 4 |
| Ambulatory status pretreatment | |
| Ambulatory | 7 |
| Nonambulatory | 3 |
| Time to develop motor deficits before treatment | |
| >14 days | 8 |
| 8–14 days | 6 |
| 1–7 days | 3 |
Surgical Management of MESCC
A multi-institutional, randomized control trial by Patchell et al[12] randomized 101 patients with magnetic resonance imaging–confirmed MESCC (cauda equina lesions excluded) to receive decompressive surgical resection with radiation 14 days later or radiation (RT) alone of 30 Gy in 10 fraction treatments. All patients were directed to receive dexamethasone 100 mg bolus + 96 mg daily (dose reduced for patients with relative contraindications to high-dose steroids). Patients were stratified by institution, tumor type, ambulatory status, and spinal stability; 38% of accrued patients had spinal instability.
The authors reported that patients undergoing surgery in addition to radiotherapy (30 Gy/10) were more likely to retain or maintain their ambulatory status longer compared to patients receiving radiotherapy alone (84% vs. 57%, P = 0.001). In addition, patients assigned to the combined-modality arm experienced a longer period of ambulation (122 vs. 13 days, P = 0.003), urinary continence (74% vs. 57%, P = 0.005), duration of continence (median 157 vs. 17 days, P = 0.016), and functional status (maintenance of Frankel and American Spinal Injury Association scores, P = 0.001). There was a difference in survival favoring the combined-modality arm (median 126 vs. 100 days, P = 0.033).
Surgery is associated with significant morbidity, which needs to be considered when deciding between surgery and radiation for medically operable patients with a single area of compression and no spinal instability or bony compression. Minimally-invasive techniques may decrease the morbidity of the procedure, shorten the recovery period, and maintain the procedure's efficacy.[13] Despite this, it would be reasonable to select patients for surgery who have the longest life expectancy (groups D and E of the MESCC prognostic scale).[10]
Within two weeks of surgery, patients should have postoperative RT of 30 Gy in 10 fractions, per the Patchell et al trial.[12]
Optimal Dose Fractionation Schedule
Poor-Prognosis Patients
Maranzano and colleagues[6] and [7] have conducted and reported two randomized control trials addressing the question of a dose fractionation schedule for poor prognosis patients. These patients were defined as having poor-histology tumors (melanoma or lung, sarcoma, gastrointestinal, head and neck, or kidney) or good-histology tumors with any functional impairment or poor performance status. It may be reasonable to extrapolate the results of these trials to the MESCC prognosis groups A, B, and C.[10]
The first study, reported in 2005, randomized 300 patients 1:1 to a split course of radiation (15 Gy in three fractions, 4-day break, then 15 Gy in five fractions) or hypofractionated radiotherapy (8 Gy in two fractions, one week apart).[6] All patients were given dexamethasone 16 mg daily during RT, tapered off posttreatment. Patients were assessed for ability to ambulate (with/without assistance), duration of ambulation, bladder function, OS, toxicity, and pain relief. There were 276 analyzable patients, and the median follow-up (presumably of survivors) was 33 months. There were no significant differences in any of these outcomes (Table 3).
Adapted from Maranzano et al6 and Maranzano et al.[7]
The Italian group's second study, reported in 2009, randomized 327 poor-prognosis patients (as above) to 16 Gy in two fractions over one week vs. 8 Gy for one fraction.[7] Dexamethasone 16 mg/day was given to both groups. There were 303 analyzable patients; median follow-up was not reported (but appears to be approximately five months from the Kaplan-Meier plots). Again, no significant differences were reported between the treatment arms for ambulation, duration of ambulation, bladder control, pain response, and OS (see Table 3). Of note, there was a nonsignificant trend toward greater in-field failures favoring the two-fraction arm in this study (2.5% vs. 6.0%, P = 0.12).
Good-Prognosis Patients
For patients who are ineligible for surgery and have a good prognosis for their MESCC, clinical trials are needed to determine the role of dose-escalating RT to improve outcomes.
A prospective, international nonrandomized study of 231 patients (SCORE-1 study) treated with different RT schedules concluded that longer fractionation schemes were predictive of progression-free survival (12 months 72% vs. 55%, P = 0.034) and local control (12 months 77% vs. 61%, P = 0.032) and that the RT schedule held up on a multivariate analysis.[14] There was no relationship between length of RT scheme and OS or motor status posttreatment. Patients were not selected but tended to be a better-prognosis group than usually reported (median OS five months).
In their retrospective prognostic study, Rades et al[10] reported that longer fractionation schemes were associated with improved OS. In another prospective study by Rades et al,[15] 40 Gy in 20 fractions did not improve functional outcomes or ambulatory status compared to 30 Gy in 10 fractions. Confirmation in a prospective randomized control trial should be done to determine whether this is true or whether there are patient selection factors that explain the observations. In sum, there are insufficient data to support dose escalation above 8 Gy in good-prognosis patients.
An international consortium of trialists is running a trial of one vs. multiple fractions of RT (SCORAD) for all prognosis patients; patients should be entered if possible to confirm the benefit of longer vs. shorter fractionation treatments.
Conclusions
MESCC is a dreaded complication of malignancy and, fortunately, not common. Despite many patients being identified early with no or minimal functional losses, their prognosis is poor. A single fraction of 8 Gy is just as effective as multiple fractions for poor-prognosis patients. For good-prognosis patients, surgery and radiation should be considered. For patients not getting surgery, enrollment in clinical trials of single vs. multiple fractions of radiation should be a priority.
References [Pub Med ID in brackets]
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2 D.A. Loblaw and N.J. Laperiere, Emergency treatment of malignant extradural spinal cord compression: an evidence-based guideline, J Clin Oncol 16 (4) (1998), pp. 1613–1624.
3 D.A. Loblaw, N.J. Laperriere and W.J. Mackillop, A population-based study of malignant spinal cord compression in Ontario, Clin Oncol 15 (4) (2003), pp. 211–217.
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8 D. Rades, F. Heidenreich and J.H. Karstens, Final results of a prospective study of the prognostic value of the time to develop motor deficits before irradiation in metastatic spinal cord compression, Int J Radiat Oncol Biol Phys 53 (4) (2002), pp. 975–979.
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10 D. Rades, V. Rudat, T. Veninga, L.J. Stalpers, P.J. Hoskin and S.E. Schild, Prognostic factors for functional outcome and survival after reirradiation for in-field recurrences of metastatic spinal cord compression, Cancer 113 (5) (2008), pp. 1090–1096. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (12)
11 D. Rades, L.J. Stalpers, T. Veninga, R. Schulte, P.J. Hoskin, N. Obralic, A. Bajrovic, V. Rudat, R. Schwarz, M.C. Hulshof, P. Poortmans and S.E. Schild, Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression, J Clin Oncol 23 (15) (2005), pp. 3366–3375.
12 R.A. Patchell, P.A. Tibbs, W.F. Regine, R. Payne, S. Saris, R.J. Kryscio, M. Mohiuddin and B. Young, Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial, Lancet 366 (9486) (2005), pp. 643–648.
13 H. Akram and J. Allibone, Spinal surgery for palliation in malignant spinal cord compression, Clin Oncol (R Coll Radiol) 22 (9) (2010), pp. 792–800.
14 D. Rades, M. Lange, T. Veninga, V. Rudat, A. Bajrovic, L.J. Stalpers, J. Dunst and S.E. Schild, Preliminary results of spinal cord compression recurrence evaluation (SCORE-1) study comparing short-course versus long-course radiotherapy for local control of malignant epidural spinal cord compression, Int J Radiat Oncol Biol Phys 73 (1) (2009), pp. 228–234.
15 D. Rades, F. Fehlauer, L.J. Stalpers, I. Wildfang, O. Zschenker, S.E. Schild, H.J. Schmoll, J.H. Karstens and W. Alberti, A prospective evaluation of two radiotherapy schedules with 10 versus 20 fractions for the treatment of metastatic spinal cord compression: final results of a multicenter study, Cancer 101 (11) (2004), pp. 2687–2692.
Conflict of Interest Disclosure: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Vitae
Dr. Loblaw and G. Mitera are from the Department of Radiation Oncology at the Sunnybrook Health Sciences Centre in Toronto, Canada