|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 24, No 21 (July 20), 2006: pp. 3388-3393 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.0542 Prognostic Factors for Local Control and Survival After Radiotherapy of Metastatic Spinal Cord Compression
From the Department of Radiation Oncology, University Hospital Hamburg-Eppendorf; Department of Radiotherapy, Medical Center Hamburg, Hamburg; Department of Radiation Oncology, University Hospital Schleswig-Holstein, Luebeck; Department of Radiotherapy, Siloah Hospital; Department of Radiation Oncology, Medical School, Hannover; Department of Radiation Oncology, St Josef Hospital, Ruhr University, Bochum; Department of Radiation Oncology, Philipps University, Marburg, Germany; Department of Radiation Oncology, Dr Bernard Verbeeten Institute, Tilburg; Department of Radiotherapy, Academic Medical Center, Amsterdam, the Netherlands; Department of Radiation Oncology, University Hospital, Sarajevo, Bosnia, and Herzegovina; Mount Vernon Centre for Cancer Treatment, Northwood, Middlesex, United Kingdom; and the Department of Radiation Oncology, Mayo Clinic Scottsdale, 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 evaluate potential prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression (MSCC).
PATIENTS AND METHODS: The following potential prognostic factors were investigated retrospectively in 1,852 patients irradiated for MSCC: age, sex, performance status, primary tumor, interval between tumor diagnosis and MSCC ( RESULTS: On univariate analysis, improved local control of MSCC was associated significantly with favorable histology (breast cancer, prostate cancer, lymphoma/myeloma), no visceral metastases, and long-course radiotherapy. On multivariate analysis, absence of visceral metastases and radiation schedule maintained significance. On univariate analysis, improved survival was associated significantly with female sex, favorable histology, no visceral or other bone metastases, good performance status, being ambulatory before radiotherapy, longer interval between tumor diagnosis and MSCC, and slower development of motor deficits before radiotherapy. Long-course radiotherapy showed a trend. On multivariate analysis, histology, visceral metastases, other bone metastases, ambulatory status before radiotherapy, interval between tumor diagnosis and MSCC, and time of developing motor deficits maintained significance. CONCLUSION: Poorer local control after radiotherapy for MSCC is associated with visceral metastases and short-course radiotherapy. Long-course radiotherapy seems preferable for patients with more favorable prognoses, given that these patients may live long enough to develop MSCC recurrences. Long-term survival after radiotherapy for MSCC may be predicted if several prognostic factors are considered.
Approximately 5% to 10% of cancer patients are estimated to develop metastatic spinal cord compression (MSCC) during the course of their disease.1 Radiotherapy (RT) and surgery are the most frequently applied treatment modalities.2 Because the indication for surgery of MSCC is usually limited to patients with involvement of one spinal segment who have a good performance status and an expected survival of more than 3 months, RT alone is still an important modality in the treatment of MSCC. Most MSCC patients have a limited life span of only a few months3-5 and will not live long enough to develop a recurrence or a progression of MSCC in the previously irradiated spinal region. However, a considerable proportion of MSCC patients live much longer, even a few years. These patients may develop an MSCC recurrence. Because of the limited indications for surgery, reirradiation is the primary treatment option for many of these recurrences.2 However, reirradiation may carry an increased risk of radiation myelopathy. To select the optimal treatment for the individual MSCC patient, prognostic factors are helpful in predicting the risk of local failure. For patients with a relatively high risk of developing a MSCC recurrence, the indication for surgery may be expanded beyond its suggested limitations. In addition to prediction of the local control, the prediction of the survival time is important, given that a longer survival is associated with a higher risk of a MSCC recurrence. This international multicenter study is the first study that focused on local control and survival after RT of MSCC. It investigated a variety of potential prognostic factors with respect to local control and survival to help define individually tailored treatment for MSCC patients.
A total of 1,852 patients irradiated for MSCC between January 1992 and October 2005 for MSCC were included in this retrospective analysis. The entire cohort includes unselected series of consecutive patients who were treated for MSCC at the contributing centers during a certain period of time. Short-course RT is the standard regimen in the contributing centers from The Netherlands, United Kingdom, and Bosnia Herzegovina, whereas long-course RT is the standard regimen in the German centers. Parts of the data have been previously reported.6 Additional criteria for inclusion were as follows: motor deficits of the lower extremities due to MSCC of the thoracic or the lumbar spine, no prior RT to the involved sites of the spine, confirmation of MSCC by computed tomography (CT) or magnetic resonance imaging (MRI), and administration of dexamethasone (12 to 32 mg/d) from the first day of RT for at least 1 week. The data were obtained from the patients, their general practitioners, treating oncologists, and patient files. The patients usually were presented to a neurosurgeon before RT to discuss the option of decompressive surgery, if indicated. Patient characteristics are summarized in Table 1.
Irradiation was performed with 6- to 10-MV linear accelerators or cobalt-60 units. Irradiation was delivered through a single posterior field or parallel opposed fields depending on the depth of the spinal cord according to CT scans or MRI. According to the radiation technique, the dose was prescribed to the midplane (parallel opposed fields) or to the anterior part of the vertebral body (single posterior field). Treatment volumes were the same in each institution and usually encompassed one normal vertebra above and below the metastatic lesions. If the lesions of the thoracic spine also involved parts of the cervical spine, two normal vertebrae above the metastatic lesions were included. Motor function and ambulatory status were evaluated before RT, and up to 24 months after RT. Motor function was evaluated with a 5-point scale7: grade 0, normal strength; grade 1, ambulatory without aid; grade 2, ambulatory with aid; grade 3, not ambulatory; and grade 4, paraplegia. Improvement of motor function was defined as a change of at least one point. Local control of MSCC was defined as no recurrent motor deficits as a result of progressive or recurrent MSCC in the previously irradiated spinal region. The diagnosis of progression or recurrence of MSCC was confirmed by spinal CT or MRI. Recurrence of MSCC was defined either as a recurrence of motor deficits if RT led to an improvement in motor function or as a progression of motor deficits if RT resulted in no change of motor deficits. Time to recurrence was measured from the end of RT.
The following potential prognostic factors were evaluated with respect to local control of MSCC: age (
Local control and survival rates were calculated using the Kaplan-Meier method.9 The differences between Kaplan-Meier curves were determined with the log-rank test (univariate analysis). Actuarial local control and survival rates are given for 1, 2, and 3 years after RT. The Bonferroni correction for multiple comparisons was used to adjust the P values derived from the univariate analyses to determine which factors were significant, and these factors were then evaluated in the multivariate analyses using the Cox proportional hazards model. Because 11 separate analyses have been performed (one analysis for each of the 11 investigated potential prognostic factors), P < .0045 was considered significant, representing
A recurrence of MSCC in the irradiated site was observed in 144 patients (8%) after a median interval of 7 months (range, 2 to 62 months). The potential prognostic factors in relation to freedom from recurrence are summarized in Table 2 (univariate analysis) and in Table 3 (multivariate analysis). On univariate analysis, better local control was associated significantly with a favorable histology (breast cancer, prostate cancer, and myeloma/lymphoma), absence of visceral metastases, and long-course RT. On multivariate analysis, absence of visceral metastases and long-course RT maintained significance (Table 3).
Of the 144 patients who developed a recurrence of MSCC in the preirradiated site, 104 patients (72%) received reirradiation. Fifteen patients (10%) received surgery, six patients (4%) received chemotherapy, and nineteen patients (13%) received no treatment. Reirradiation was more frequently applied after short-course RT (91 of 98 patients; 93%) than after long-course RT (13 of 46 patients; 28%; P < .001). The improvement rate of all the patients who were treated for MSCC recurrence was 35% (51 of 144 patients). Improvement of motor function was observed in 40 of 104 patients (39%) after reirradiation, and in 10 of 15 patients (67%) after surgery. Only one of six patients (17%) treated with chemotherapy and 0 of 19 patients (0%) without any treatment improved. Results of reirradiation in relation to the applied fractionation schedules are summarized in Table 4.
The median follow-up of the entire cohort was 7 months (range, 0 to 110 months) after RT. The median follow-up in survivors was 14 months (range, 6 to 110 months). The impact of the potential prognostic factors on survival is shown in Table 5 (univariate analysis) and in Table 6 (multivariate analysis). On univariate analysis, better survival was significantly associated with female sex, a better performance status, favorable histology, involvement of only one to two vertebrae, absence of other bone metastases at the time of RT, absence of visceral metastases at the time of RT, a longer interval between tumor diagnosis and MSCC, being ambulatory before RT, and a slower development of motor deficits before RT (Table 5). Long-course RT was significantly associated with survival by the log-rank test (P = .017) if one considered P < .05 significant, but was not considered significant after the Bonferroni correction for multiple comparisons. On multivariate analysis, favorable histology, absence of other bone metastases and absence of visceral metastases at the time of RT, a longer interval between tumor diagnosis and MSCC, being ambulatory before RT, and a slower development of motor deficits before RT maintained significance (Table 6).
Acute toxicity was mild or absent in all patients. Late radiation toxicity such as myelopathy did not occur after primary irradiation or reirradiation.
The life expectancy of most MSCC patients is quite short, with reported median survival of only a few months.3-5 However, about one third of the MSCC patients have a better survival prognosis and live long enough to develop a recurrence of MSCC within the initially treated region of the spinal cord. There are little data available regarding recurrences of MSCC. The major goal of this study was to define prognostic factors predicting local control and survival in MSCC patients treated with RT. This study suggests two significant prognostic factors for local control of MSCC in the multivariate analysis. Absence of visceral metastases and the administration of long-course RT (10 x 3 Gy, 15 x 2.5 Gy, or 20 x 2 Gy) instead of short-course RT (1 x 8 Gy or 5 x 4 Gy) were associated with better local control. The presence of visceral metastases at the time of RT reflects a more advanced and more aggressive tumor, which is likely to be associated with a worse prognosis.
The fact that significantly more MSCC recurrences were observed after short-course RT than after long-course RT may be explained by the higher total radiation doses given in the long-course protocols (30 to 40 v 8 to 20 Gy). However, the biologic effectiveness of a radiation schedule depends on both total dose and dose per fraction. A comparison of radiation schedules that include different total doses and doses per fraction can be performed with the equivalent dose in 2-Gy fractions (EQD2). The EQD2 is calculated with the equation EQD2 = D x [(d + When MSCC recurred, most patients were treated with spinal reirradiation, which led to an improvement of motor deficits in 39% of the patients and to no further progression of motor dysfunction in another 47% of the patients. Surgery, which is considered appropriate only for the minority of MSCC patients, resulted in improvement of motor function in 67% of the patients. Thus, whenever possible, surgery should be performed, which is in accordance with the study of Patchell et al2 performed for primary treatment of MSCC. Acute toxicity was mild or absent in all patients. Late radiation-related toxicity such as myelopathy was not observed after primary or reirradiation. Thus, both short-course RT and long-course RT seem safe. However, late toxicity may be underreported due to the retrospective nature of this study. Patients with a poor expected survival would benefit from a shorter course of radiation because a shorter overall treatment time creates less burden for debilitated patients resulting from multiple daily trips to the radiation oncology department and positioning on the treatment couch. Furthermore, a shorter program substantially reduces the cost of therapy, and has been reported as effective for painful bone metastases.12 However, MSCC patients with a comparably good survival prognosis are at a greater risk of developing a recurrence of MSCC. Thus, short-course RT may be a poorer option for these patients than long-course RT, given that it seems associated with poorer local control of MSCC. Accurate understanding of prognostic factors predicting survival of MSCC patients can facilitate the selection of an appropriate radiation schedule (short-course v long-course RT) for the individual patient. In this study, survival was associated significantly with the presence of visceral metastases and other bone metastases at the time of RT, the ambulatory status before RT, the interval between tumor diagnosis and MSCC, the time of developing motor deficits before RT, and the type of primary tumor. Furthermore, there was a trend for better survival after long-course RT rather than short-course RT. The impact of the presence of visceral metastases or other bone metastases on survival has been described previously.3,13 Some authors described the ambulatory status before RT as a significant prognostic factor for survival after RT of MSCC.5,14-16 The negative prognostic impact of a shorter interval between tumor diagnosis and MSCC likely reflects the faster growth of more aggressive tumors. The velocity of tumor growth may also be reflected by the dynamic of the development of motor deficits before RT. Faster progression of motor deficits was associated significantly with poorer survival than a slower progression of motor dysfunction. The prognostic impact of the type of primary tumor on survival in MSCC patients has been described previously. Favorable histologies such as breast cancer, myeloma/lymphoma, and prostate cancer are associated with better survival prognosis than other histologies, whereas in lung cancer patients, survival is extraordinarily poor.3,13,15 A potential survival benefit of longer-course RT with higher total doses has been suggested in a retrospective series of 34 colorectal cancer patients developing MSCC.16 In the study of Patchell et al2 that compared surgery followed by RT versus RT alone in 101 MSCC patients, the combined modality resulted in both better local control and better survival. This can be explained by the fact that a recurrence of MSCC may lead to visceral metastasis, resulting in a worse survival. Furthermore, patients who are unable to walk due to MSCC are at a higher risk to develop complications such as pneumonia, which may lead to death, especially in cancer patients with suppressed immune systems. However, when interpreting the survival analysis of our series, one has to be aware that an inherent bias might have been introduced due to the retrospective nature of the study. Furthermore, because a proportional hazards model has been used for the multivariate analyses, the effects of variables such as baseline performance status, which almost surely are nonproportional, could only be interpreted as averages over the period of analysis.
In conclusion, better local control of MSCC was associated significantly with the absence of visceral metastases at the time of RT and with the long-course RT instead of short-course RT. Thus, for patients with a good survival prognosis, long-course RT seems preferable. Survival may be influenced by several prognostic factors. For patients with visceral metastases or other bone metastases at the time of RT, primary tumors other than breast cancer, prostate cancer, and myeloma/lymphoma, inability to walk before RT, a short interval between tumor diagnosis and MSCC (
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Loblaw DA, Laperriere NJ: Emergency treatment of malignant extradural spinal cord compression: An evidence-based guideline. J Clin Oncol 16:1613-1624, 1998 2. Patchell R, Tibbs PA, Regine WF, et al: Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: A randomised trial. Lancet 366:643-648, 2005[CrossRef][Medline] 3. Maranzano E, Latini P: Effectiveness of radiation therapy without surgery in metastatic spinal cord compression: Final results from a prospective trial. Int J Radiat Oncol Biol Phys 32:959-967, 1995[CrossRef][Medline] 4. Sørensen PS, Børgesen SE, Rohde K, et al: Metastatic epidural spinal cord compression. Cancer 65:1502-1508, 1990[CrossRef][Medline] 5. Hoskin PJ, Grover A, Bhana R: Metastatic spinal cord compression: Radiotherapy outcome and dose fractionation. Radiother Oncol 68:175-180, 2003[CrossRef][Medline] 6. Rades D, Stalpers LJA, Veninga T, et al: Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression in a series of 1304 patients. J Clin Oncol 23:3366-3375, 2005 7. Tomita T, Galicich JH, Sundaresan N: Radiation therapy for spinal epidural metastases with complete block. Acta Radiol Oncol 22:135-143, 1983[Medline] 8. Rades D, Heidenreich F, Karstens JH: 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 53:975-979, 2002[CrossRef][Medline] 9. Kaplan EL, Meier P: Non parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 10. Barendsen GW: Dose fractionation, dose rate and iso-effect relationships for normal tissue responses. Int J Radiat Oncol Biol Phys 8:1981-1997, 1982[Medline] 11. Joiner MC, Van der Kogel AJ: The linear-quadratic approach to fractionation and calculation of isoeffect relationships, in Steel GG (ed): Basic Clinical Radiobiology. New York, NY, Oxford University Press, 1997, pp 106-112 12. Van den Hout WB, Van der Linden YM, Steenland E, et al: Single- versus multiple-fraction radiotherapy in patients with painful bone metastases: Cost-utility analysis based on a randomized trial. J Natl Cancer Inst 95:222-229, 2003 13. Prasad D, Schiff D: Malignant spinal cord compression. Lancet Oncol 6:15-24, 2005[Medline] 14. Maranzano E, Latini P, Perrucci E, et al: Short-course radiotherapy (8 Gyx2) in metastatic spinal cord compression: An effective and feasible treatment. Int J Radiat Oncol Biol Phys 38:1037-1044, 1997[CrossRef][Medline] 15. Helweg-Larsen S, Sørensen PS, Kreiner S: Prognostic factors in metastatic spinal cord compression: A prospective study using multivariate analysis of variables influencing survival and gait function in 153 patients. Int J Radiat Oncol Biol Phys 46:1163-1169, 2000[CrossRef][Medline] 16. Brown PD, Stafford SL, Schild SE, et al: Metastatic spinal cord compression in patients with colorectal cancer. J Neurooncol 44:175-180, 1999[CrossRef][Medline] Submitted November 22, 2005; accepted May 12, 2006.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
15 v > 15 months), number of involved vertebrae (one to two v 
three), other bone metastases, visceral metastases, pretreatment ambulatory status, time of developing motor deficits before radiotherapy (faster, 1 to 14 v slower, > 14 days), and radiation schedule (short-course v long-course radiotherapy). 
< .05. The prognostic factors found to be significant in the univariate analysis (P < .0045) were included in a multivariate analysis, which was performed with the Cox proportional hazards model. 
