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Journal of Clinical Oncology, Vol 25, No 1 (January 1), 2007: pp. 50-56 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.7155 Outcome After Radiotherapy Alone for Metastatic Spinal Cord Compression in Patients With Oligometastases
From the Department of Radiation Oncology, University Hospital Schleswig-Holstein, Luebeck; Department of Radiation Oncology, University Hospital Hamburg-Eppendorf, Hamburg; Department of Radiation Oncology, Dr. Bernard Verbeeten Institute, Tilburg; Department of Radiation Oncology, St Josef Hospital, Ruhr University, Bochum; Department of Radiation Oncology, Medical School, Hannover, Germany; Department of Radiotherapy, Academic Medical Center, Amsterdam, the Netherlands; Department of Radiation Oncology, University Hospital, Sarajevo, Bosnia and Herzegovina; and the Department of Radiation Oncology, Mayo Clinic, Scottsdale, AZ Address reprint requests to Dirk Rades, MD, Department of Radiation Oncology, University Hospital Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, D-23538 Luebeck, Germany; e-mail: Rades.Dirk{at}gmx.net
Purpose: To investigate outcome and prognosis of metastatic spinal cord compression (MSCC) patients with oligometastatic disease treated with radiotherapy alone. Patients and Methods: Oligometastatic disease was defined as involvement of three or fewer vertebrae and lack of other bone or visceral metastases. Five hundred twenty-one patients with oligometastatic disease and MSCC were evaluated for functional outcome, ambulatory status, local control of MSCC, and survival. Furthermore, seven potential prognostic factors were investigated. Results: Motor function improved in 40% (n = 207), remained stable in 54% (n = 279), and deteriorated in 7% (n = 35) of patients. Fifty-eight (54%) of 107 nonambulatory patients became ambulatory, and 388 (94%) of 414 ambulatory patients remained ambulatory. Improved functional outcome was significantly associated with tumor type and slower development of motor deficits (> 14 days). Local control at 1, 2, and 3 years was 92%, 88%, and 78%, respectively. Improved local control was significantly associated with long-course radiotherapy. Survival at 1, 2, and 3 years was 71%, 58%, and 50%, respectively. Better survival was significantly associated with tumor type, ambulatory status, slower development of motor deficits, and long-course radiotherapy. Patients who developed motor deficits slowly (onset > 14 days before initiating treatment) were further analyzed. In this subgroup, the best results were observed for myeloma/lymphoma and breast cancer patients. No patient had progression of motor deficits. One hundred percent (myeloma/lymphoma) and 99% (breast cancer) of patients were ambulatory after radiotherapy. One-year local control was 100% and 98%, 1-year survival was 94% and 89%. Conclusion: Given the limitations of a retrospective review, improved outcome of patients with oligometastatic MSCC was associated with myeloma/lymphoma and breast cancer, slower development of motor deficits, and a more prolonged course of radiation.
Cancer patients with oligometastatic disease have a better prognosis than patients with more wide-spread metastases.1 The definition of oligometastases varies in the literature. The number of metastases varied between two and three, four or fewer, and five or fewer metastases.1-7 In this study of patients with metastatic spinal cord compression (MSCC), we defined oligometastatic disease as an involvement of three or fewer vertebrae and absence of further bone or visceral metastases. This is the first study that focuses on MSCC patients with oligometastatic disease. It investigates the outcome after radiotherapy alone and aims to define significant prognostic factors regarding post-treatment motor function, local control of MSCC, and overall survival. A clear understanding of prognostic factors can be helpful in selecting the optimal treatment for the individual MSCC patient. A recently published randomized trial with 101 patients found that decompressive surgery followed by radiotherapy resulted in better functional outcome and survival than radiotherapy alone.8 However, if MSCC patients with oligometastases do very well with radiotherapy alone, they may not require surgery.
A total of 521 patients with involvement of three or fewer vertebrae and lack of further bone or visceral metastases were included in this retrospective analysis. The search for metastases included at least abdominal ultrasound, chest x-ray and/or computed tomography (CT), bone scan, and spinal imaging consisting of whole-spine magnetic resonance imaging (MRI) in the vast majority of patients. More than 95% of the patient files were additionally reviewed by the principal investigator (D.R.) to achieve uniformity in the analysis across the institutions involved.
All patients were irradiated for MSCC between January 1992 and October 2005. They received either short-course radiotherapy with one dose of 8 Gy in 1 day (n = 97) or 5 x 4 Gy given in 1 week (five 4 Gy fractions per week; n = 113), or long-course radiotherapy with 10 x 3 Gy given in 2 weeks (five 3 Gy fractions per week; n = 107), 15 x 2.5 Gy given in 3 weeks (five 2.5 Gy fractions per week; n = 71), or 20 x 2 Gy given in 4 weeks (five 2 Gy fractions per week; n = 133). The biologic effectiveness of radiation schedules depends on total dose and dose per fraction. A comparison of radiation schedules with different total doses and doses per fraction can be performed with the Equivalent Dose in 2-Gray Fractions (EQD2). The EQD2 is calculated with the equation EQD2 = D x [(d + The selection of the radiation regimen was based on institutional policy. Each series of patients from a contributing center represents an unselected series, uniformly treated with either short-course long-course radiotherapy over a certain period of time. Further criteria for inclusion were motor deficits resulting from MSCC, no prior radiotherapy to the involved spine, confirmation of MSCC by CT or MRI, and administration of dexamethasone (12 to 32 mg/d) from day 1 of radiotherapy for at least 1 week. Data were obtained from patients, general practitioners, treating oncologists, and patient files. Most of the data were from the patients' medical records (follow-up notes). The patients were generally seen at 1 and 3 months after radiotherapy. Thereafter, the patients were regularly seen approximately every 6 months and when motor function deteriorated. Additional data, in particular regarding the time of death, were obtained from general practitioner contact. The patients were usually presented to a neurosurgeon before radiotherapy to discuss the option of decompressive surgery. Patient characteristics are summarized in Table 1.
Irradiation was performed with 6- to 10-MV linear accelerators or cobalt-60 units. Depending on the depth of the spinal cord according to CT scans or MRI, irradiation was delivered through a single posterior field (depth  6 cm) or parallel opposed fields (depth > 6 cm). The dose was prescribed to the midplane (parallel opposed fields) or to the spinal cord (single posterior field). Treatment volumes encompassed one healthy vertebra above and below the metastatic lesions. Motor function was evaluated before radiotherapy and at 1, 3, and 6 months after radiotherapy with a five-point scale10: 0, normal strength; 1, ambulatory without aid; 2, ambulatory with aid; 3, not ambulatory; and 4, paraplegia. Improvement of motor function was defined as a change of at least 1 point. Local failure of MSCC was defined as recurrence of motor deficits resulting from MSCC in the previously irradiated spinal region if radiotherapy led to an improvement in motor function or as progression of motor deficits if radiotherapy resulted in no change of motor deficits. The diagnosis was confirmed by spinal CT or MRI. Time to local failure was measured from the end of radiotherapy.
The following potential prognostic factors were evaluated for treatment outcome: age ( Patients were followed until death or for at least 6 months. The median follow-up was 12 months (range, 2 to 96 months) in the entire cohort and 14 months (range, 6 to 96 months) in surviving patients. The surviving patients were censored at the time of their last follow-up. Thirty-two patients were lost to follow-up within 12 months. One hundred seventy-one patients died during the period of follow-up after a median of 9 months (range, 2 to 61 months). The potential prognostic factors for functional outcome were included in a multivariate analysis that was performed with the ordered logit model because the data for functional outcome are ordinal (–1 = deterioration, 0 = no change, 1 = improvement). The Bonferroni correction for multiple comparisons was used to adjust the P values derived from the ordered logit model. Because seven potential prognostic factors were investigated, P values less than .007 were considered significant, representing an alpha level less than .05. Local control and survival rates were calculated using the Kaplan-Meier method.11 Differences between Kaplan-Meier curves were determined with the log-rank test. Actuarial local control and survival rates are reported at 1, 2, and 3 years after radiotherapy. The prognostic factors found significant in the univariate analyses (P < .05) were included in multivariate analyses (Cox proportional hazards model).
Improvement of motor function occurred in 40% of the patients (n = 207), no further progression of motor deficits in 54% (n = 279), and deterioration of motor function in 7% (n = 35). Of 107 nonambulatory patients, 54 patients (51%) regained the ability to walk within 1 month of radiotherapy, and an additional four patients (3%) between 1 and 3 months of radiotherapy. Of 414 ambulatory patients, 388 patients (94%) remained ambulatory. The fraction of patients remaining ambulatory after radiotherapy was 88%. The impact of the potential prognostic factors is shown in Tables 1 and 2. Improved functional outcome was significantly associated with tumor type (myeloma/lymphoma) and slower development of motor deficits before radiotherapy (> 14 days). A trend was observed for an interval between tumor diagnosis and MSCC more than 15 months and ambulatory status. The radiation schedule had no significant impact.
Local failure of MSCC was observed in 52 patients (10%) after a median of 8 months (range, 2 to 62 months). The actuarial local control rates at 1, 2, and 3 years were 92%, 88%, and 78%, respectively. The potential prognostic factors are summarized in Table 3. On univariate analysis, better local control was significantly associated with favorable tumor type (myeloma/lymphoma, breast cancer) and long-course radiotherapy. On multivariate analysis, long-course radiotherapy maintained significance (risk ratio [RR], 0.30; 95% CI, 0.16 to 0.52; P < .001). Tumor type lost significance (RR, 1.02; 95% CI, 0.84 to 1.22; P = .852).
Of the 52 patients who developed local failure of MSCC, 38 patients (73%) underwent reirradiation. Eight patients (15%) underwent surgery, two patients (4%) received chemotherapy, and four patients (8%) received no treatment. Reirradiation was performed with 1 x 8 Gy (n = 13), 5 x 3 Gy (n = 12), 5 x 4 Gy (n = 7), 10 to 12 x 2 Gy (n = 5), or 17 x 1.8 Gy (n = 1). Thirty-two of the reirradiated patients were initially treated with short-course radiotherapy, and six patients with long-course radiotherapy. A second course of long-course radiotherapy with a total dose more than 20 Gy was administered in one patient (15 x 2.5 Gy plus 17 x 1.8 Gy after 10 months; cumulative EQD2 = 69.2 Gy). Improvement of motor function occurred in 42% (22 of 52) of all patients treated for local failure of MSCC, in 45% (17 of 38) after reirradiation, and in 50% (four of eight) after surgery. One of two patients treated with chemotherapy and zero of four patients without treatment improved. For the entire cohort, the actuarial survival rates at 1, 2, and 3 years were 71%, 58%, and 50%, respectively. The impact of the potential prognostic factors on survival is shown in Table 4. On univariate analysis, better survival was significantly associated with favorable tumor type (myeloma/lymphoma, breast cancer), a longer interval between tumor diagnosis and MSCC (> 15 months), ambulatory status, slower development of motor deficits (> 14 days), and long-course radiotherapy. On multivariate analysis, the following prognostic factors maintained significance: tumor type (RR, 1.19; 95% CI, 1.07 to 1.32; P < .001), ambulatory status (RR, 0.47; 95% CI, 0.34 to 0.67; P < .001), slower development of motor deficits (RR, 0.66; 95% CI, 0.54 to 0.80; P < .001), and long-course radiotherapy (RR, 0.63; 95% CI, 0.47 to 0.86; P = .004). Interval between tumor diagnosis and MSCC lost significance (RR, 0.87; 95% CI, 0.75 ro 1.03; P = .092).
Survival rates were lower than local control rates. During the period of follow-up, 120 (23%) of 521 patients died without experiencing progression of motor deficits during irradiation or recurrence of MSCC after radiotherapy. These 120 patients remained oligometastatic for a limited period of time and died after a median of 9 months (range, 4 to 61 months) due to metastatic disease.
Acute toxicity did not exceed grade 0 to 1 according to Common Toxicity Criteria 2.0.12 Late toxicity such as myelopathy was not diagnosed after primary irradiation or reirradiation. Assuming a The strongest predictors for functional outcome were tumor type and time of developing motor deficits. To define patients with an extraordinarily good prognosis, the patients with the slowest development of motor deficits (> 14 days) were analyzed separately. The data of this subset of patients in total and in relation to the different tumor types are summarized in Table 5. The results were most favorable in myeloma/lymphoma patients, followed by breast cancer patients.
Treatment results related to the functional scores before radiotherapy10 are summarized in Table 6. The preradiotherapy functional score was not included in the analyses described in Tables 1 through 4, because it correlated with the ambulatory status (1 to 2 = ambulatory, 3 to 4 = not ambulatory) and was, therefore, a confounding factor. A better functional score before radiotherapy was associated with improved functional outcome, local control, and survival.
This is the first study that focused on irradiation of MSCC in patients with oligometastatic disease. These patients have a better prognosis than patients with more extensive metastases.1 Regarding functional outcome after radiotherapy, 40% of the patients in this study showed an improvement of motor function, which is a much better result than the 27% observed in our previous study of 1,304 patients which included patients with oligometastases and more widespread metastases.13 In this study, 51% of the nonambulatory patients regained walking ability within 1 month after radiotherapy compared with 26% in the previous report. The ambulatory rates after radiotherapy were 88% and 68%, respectively, for those with oligometastasis versus all MSCC patients. Oligometastatic disease appears associated with better functional outcome than more widespread metastatic disease. In the present study, improved functional outcome was significantly associated with favorable tumor type and slower development of motor deficits before radiotherapy. A trend was observed for a longer interval between tumor diagnosis and MSCC and ambulatory status. These findings are in accordance with the literature.13-17 Local control of MSCC in the present series was slightly better than in our recently published series, which also included patients with multiple metastases.18 The 1-year local control rates were 92% and 89%, and the 2-year local control rates 88% and 84%, respectively. In the present study, the radiation schedule was the only significant predictor of local control. Long-course radiotherapy provided better local control. This may be explained by the higher total radiation doses (30 to 40 v 8 to 20 Gy) and the higher EQD2 (32.5 to 40 v 12 to 23.3 Gy) of the long-course protocols. Some physicians hesitate to offer patients reirradiation because of concerns about myelopathy, which may be more of an issue after long-course radiotherapy including higher doses such as 30 to 40 Gy. Local control may be further improved with administration of bisphosphonates such as zoledronic acid, which have been demonstrated to reduce skeletal complications in patients with bone metastases including vertebral body metastasis.19-21 MSCC patients with oligometastatic disease have a relatively favorable survival prognosis after radiotherapy alone. Survival in this series was much better than in our previous series, which also included patients with extensive metastases.17 The 1-year survival rates were 71% and 43%, and the 2-year survival rates 58% and 32% for those with oligometastasis versus all MSCC patients. MSCC patients with relatively favorable survival prognoses such as patients with oligometastatic disease are at a greater risk of developing a recurrence of MSCC because they live longer. Thus, long-course radiotherapy appears a better option for oligometastatic patients than short-course radiotherapy, as it is associated with better local control and survival. In the present study, survival was positively associated with ambulatory status, slower development of motor deficits, favorable tumor type, and long-course radiotherapy. The prognostic value of ambulatory status and tumor type for survival was described previously.13,14,22-24 The negative impact of a faster development of motor deficits reflects the increased growth rate of more aggressive tumors. The improved survival after long-course radiotherapy can be explained by the fact that a recurrence of MSCC, which is more frequent after short-course radiotherapy, may lead to neurologic debility and visceral metastasis resulting in poorer survival. Furthermore, patients unable to walk due to MSCC recurrence have a greater risk of life-threatening complications such as pneumonia. To better define a favorable subset of oligometastatic MSCC patients treated with radiotherapy alone, a subgroup analysis was performed including only the patients with the most favorable prognostic factors. The patients who had the slowest development of motor deficits (> 14 days) were investigated for treatment outcome. Only 1% of these patients showed deterioration of motor function after radiotherapy, 96% were ambulatory after treatment, 76% of the nonambulatory patients regained the ability to walk, almost 100% of the ambulatory patients maintained the ability to walk. Median survival was 60 months, 5-year local control 65%. The results are quite favorable when compared with those of other MSCC patients. Because the tumor type was the other significant prognostic factor for functional outcome, the data were evaluated with regard to the different tumor types (Table 5). The best results were observed for myeloma/lymphoma patients and breast cancer patients. These subsets of patients appear adequately treated with radiotherapy alone. Patients with oligometastatic disease who show a faster development of motor deficits (1 to 14 days) or have a primary tumor different from myeloma/lymphoma and breast cancer may be considered for decompressive surgery followed by radiotherapy. Patchell et al8 performed a phase III trial comparing radiotherapy alone to radiotherapy plus surgery for MSCC. Significantly more patients in the radiotherapy plus surgery group (42 of 50; 84%) than in the radiotherapy alone group (29 of 51; 57%) were able to walk after treatment (P = .001). Patients treated with radiotherapy plus surgery also retained the ability to walk significantly longer than did those with radiotherapy alone (median, 122 v 13 days; P = .003). Additionally, the median survival was 125 days after in the surgery plus radiotherapy compared with 100 days after radiotherapy alone (P = .03). The present study differs in many regards from the Patchell study. The Patchell study was a small (N = 101) phase III trial that excluded favorable histologies such as myeloma and lymphoma but included patients with extensive metastases. The present study was a larger retrospective analysis of patients with oligometastases that included both unfavorable and favorable radiosensitive histologies. Thus, both studies are not directly comparable but provide complementary information. Additional prospective trials for MSCC treatment are required, including a study comparing radiotherapy alone versus surgery plus radiotherapy in patients with oligometastatic disease. Possibly, a subset of patients in whom surgery can be avoided can be identified.25,26 In conclusion, MSCC patients with oligometastatic disease have an extraordinarily good prognosis regarding functional outcome, ambulatory status, local control of MSCC, and survival when compared with other MSCC patients. The best results were observed for myeloma/lymphoma and breast cancer patients with a development of motor deficits more than 14 days. Given the limitations of a retrospective review, the results of the present study suggest that surgical intervention may not be needed in oligometastatic patients, in particular in those patients with favorable radiosensitive tumors and slow development of motor deficits.
The authors indicated no potential conflicts of interest.
Conception and design: Dirk Rades, Steven E. Schild Administrative support: Juergen Dunst Provision of study materials or patients: Dirk Rades, Theo Veninga, Lukas J.A. Stalpers, Hiba Basic, Volker Rudat, Johann H. Karstens Collection and assembly of data: Dirk Rades, Theo Veninga, Lukas J.A. Stalpers, Hiba Basic, Volker Rudat, Johann H. Karstens, Steven E. Schild Data analysis and interpretation: Dirk Rades, Volker Rudat, Juergen Dunst, Steven E. Schild Manuscript writing: Dirk Rades, Juergen Dunst, Steven E. Schild Final approval of manuscript: Dirk Rades, Theo Veninga, Lukas J.A. Stalpers, Hiba Basic, Volker Rudat, Johann H. Karstens, Juergen Dunst, Steven E. Schild
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
/ß)/2 Gy + 
