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Originally published as JCO Early Release 10.1200/JCO.2005.11.940 on February 28 2005 © 2005 American Society of Clinical Oncology.
Radiation Therapy Alone for Spinal Cord Compression: Time to Improve Upon a Relatively Ineffective Status QuoDepartment of Radiation Oncology, University of Maryland Medical Center, Baltimore, MD
Division of Neurosurgery, University of Kentucky Medical Center, Lexington, KY Metastatic spinal cord compression (MSCC) is a common problem afflicting cancer patients. It affects 5% to 14% of all patients with cancer, and more than 20,000 cases are diagnosed annually in the United States.1-3 Once diagnosed, it is considered to be a medical emergency, and immediate intervention is required with high-dose corticosteroids and radiotherapy, with or without decompressive surgery. Without therapy, MSCC is a source of significant morbidity and mortality, causing pain, paralysis, incontinence, and an overall decline in quality of life. Even with aggressive therapy, results can often be unsatisfactory. Although most patients will die as a result of their underlying cancer within the first year of the diagnosis of MSCC, up to one third will survive beyond 1 year.4,5 Therefore, optimal therapy is required to maintain quality of life. Palliative radiotherapy has long been standard in the management of patients with MSCC, but the radiation oncologist is often faced with multiple competing and complex issues. The need to deliver a meaningful radiation dose to the tumor for adequate palliation must be balanced with the necessity of avoiding undue toxicity, the most serious of which is radiation myelopathy. Furthermore, the fractionation scheme must be weighed against the performance status and expected survival of the patient. These issues may explain the wide range of fractionation schemes reported in multiple retrospective analyses, with a total of 30 Gy in 3-Gy daily fractions for 10 days most frequently prescribed. In this issue of the Journal of Clinical Oncology, Maranzano et al6 report on a phase III, randomized, multicenter trial of two hypofractionation schemes, short course compared with split course, for patients with MSCC. Although there are multiple randomized trials on fractionation schemes for brain and bone metastases, to our knowledge this report is the first such trial for MSCC.7-9 The authors should be commended for completing such a difficult trial. Unfortunately, multiple problems are inherent in this study, and readers should be cautious before implementing the results in clinical practice.
The explanation of the selection criteria for short life expectancy ( One of the most controversial aspects of this study was the choice of the two treatment arms. The most common fractionation schedule used in patients with MSCC in the United States is 30 Gy in 3-Gy daily fractions for 10 days, without a planned break.13 The schedules adopted for the two arms are not considered standard; therefore, this study may be interpreted by some as a randomized phase II study, rather than a true phase III study. Furthermore, many radiation oncologists are hesitant to use the large fractions prescribed in this study in the CNS. The main determinant of late radiation injury is fraction size,14 and hypofractionated schedules have clearly been associated with toxicity in the brain.15 It is conceivable that the 13 patients who progressed to paraplegia without in-field recurrence may have suffered from late radiation-induced toxicity, even if not scored as late toxicity by the authors. The authors report seemingly impressive response rates, with pain, motor function, and sphincter control responses of 57%, 70%, and 89%, respectively. These numbers are undoubtedly a reflection of the inclusion of patients with favorable histology and by a definition of response that combines both stability and improvement. However, when one limits the definition of response to regaining motor function and sphincter control, the rates of success decrease to 29% and 14%, respectively. Multiple authors have advocated the use of adjunctive surgical decompression and stabilization to improve on results from radiation alone. At best, radiation for nonradiosensitive tumors typically only temporarily arrests the progression of tumor and does not stabilize the spine. Most importantly, surgery provides immediate cord decompression, whereas radiotherapy typically takes several days to work. In a large retrospective study from Memorial Sloan-Kettering Cancer Center (New York, NY), Wang et al16 reported that 75% of nonambulatory patients regained the ability to walk after a single-stage posterolateral transpedicular approach. Recently, Patchell et al17 reported on the first phase III randomized trial testing the efficacy of direct decompressive surgery in patients with MSCC. The study compared the standard 30 Gy in 3-Gy daily fractions, without a break, with decompressive and stabilization surgery within 24 hours of diagnosis followed by the same radiotherapy started within 2 weeks. The trial was terminated early at interim analysis when early-stopping rules were met regarding the primary end points of ambulatory rate and time ambulatory after treatment. Secondary end points evaluated motor and neurologic status, continence function, narcotic and corticosteroid usage, and survival. This trial definitively demonstrated the value of surgery for every end point at statistically significant levels. Regarding the primary end point of ambulation, the combined treatment had a median ambulation time of 126 days, compared with 35 days for radiation alone (P = .006). Furthermore, baseline ambulatory and nonambulatory patients who had surgery and radiation had one half the likelihood of being nonambulatory, compared with those who had radiation alone. For nonambulatory patients, the combined-treatment patients had a significant higher chance of regaining the ability to walk after therapy (56% v 19%; P = .03). Thus, the radiation-alone arm in the study by Patchell et al17 had overall poor results for ambulatory and nonambulatory patients, similar to the current study. Contrary to the conclusions drawn by Maranzano et al,6 both of these studies clearly demonstrate that hypofractionation schedules of radiation alone for MSCC (including 30 Gy in 3-Gy daily fractions) are of limited effectiveness; in the case of the trial by Maranzano et al,6 they are also perhaps associated with unacceptable toxicity. These prospective data challenge the accepted standard status quo of radiation alone in the management of MSCC. A trial evaluating a more effective dose-escalation scheme must be performed to improve on the poor results of radiotherapy alone for the majority of patients with MSCC. On the basis of biologic modeling, a total dose of 39, 42, and 45 to 48 Gy at 3-Gy daily fractions would be associated with a much better chance of tumor control, but with an expected risk of radiation myelopathy of less than 1%, less than 5%, and approximately 5%, respectively. One of these total dose-escalation schemes could then be compared with the standard of 30 Gy in 3-Gy daily fractions. It is only through such clinical trials that we can answer the question of the utility of dose-escalation to improve the quality of life for the majority of patients with MSCC who are not surgical candidates. Such a trial is currently under development within the Radiation Therapy Oncology Group. Authors’ Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES 1. Byrne TN: Spinal cord compression from epidural metastases. N Engl J Med 327:614-619, 1992[Medline] 2. Quinn JA, DeAngelis LM: Neurologic emergencies in the cancer patient. Semin Oncol 27:311-321, 2000[Medline] 3. Nelson KA, Walsh D, Abdullah O, et al: Common complications of advanced cancer. Semin Oncol 27:34-44, 2000 4. Maranzano E, Latini P, Checcaglini F, et al: Radiation therapy in metastatic spinal cord compression: A prospective analysis of 105 consecutive patients. Cancer 67:1311-1317, 1991[CrossRef][Medline] 5. Hirabayashi H, Ebara S, Kinoshita T, et al: Clinical outcome and survival after palliative surgery for spinal metastases: Palliative surgery in spinal metastases. Cancer 97:476-484, 2003[CrossRef][Medline]
6. Maranzano E, Bellavita R, Rossi R, et al: Short-course versus split-course radiotherapy in metastatic spinal cord compression: Results of a phase III, randomized, multicenter trial. J Clin Oncol 23:3358-3365, 2005 7. Murray KJ, Scott C, Greenberg HM, et al: A randomized phase III study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: A report of the Radiation Therapy Oncology Group (RTOG) 9104. Int J Radiat Oncol Biol Phys 39:571-574, 1997[CrossRef][Medline] 8. Hartsell W, Scott C, Watkins Bruner D, et al: Phase III randomized trial of 8 Gy in 1 fraction vs. 30 Gy in 10 fractions for palliation of painful bone metastases: Preliminary Results of RTOG 97-14—Proc Am Soc Ther Radiol Oncol. Int J Radiat Oncol Biol Phys 57:S124, 2003[Medline] 9. Hoskin PJ, Price P, Easton D, et al: A prospective randomised trial of 4 Gy or 8 Gy single doses in the treatment of metastatic bone pain. Radiother Oncol 23:74-78, 1992[CrossRef][Medline] 10. Gaspar L, Scott C, Rotman M, et al: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:745-751, 1997[CrossRef][Medline]
11. Chau I, Norman AR, Cunningham D, et al: Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer: Pooled analysis from three multicenter, randomized, controlled trials using individual patient data. J Clin Oncol 22:2395-2403, 2004
12. Le Chevalier T, Brisgand D, Soria JC, et al: Long term analysis of survival in the European randomized trial comparing vinorelbine/cisplatin to vindesine/cisplatin and vinorelbine alone in advanced non-small cell lung cancer. Oncologist 6:8-11, 2001 (suppl 1)
13. Loblaw DA, Laperriere NJ: Emergency treatment of malignant extradural spinal cord compression: An evidence-based guideline. J Clin Oncol 16:1613-1624, 1998 14. Hall EJ: Radiobiology for the Radiologist. Philadelphia, PA, Lippincott Williams & Williams, 2000 15. DeAngelis LM, Mandell LR, Thaler HT, et al: The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery 24:798-805, 1989[CrossRef][Medline] 16. Wang JC, Boland P, Mitra N, et al: Single-stage posterolateral transpedicular approach for resection of epidural metastatic spine tumors involving the vertebral body with circumferential reconstruction: Results in 140 patients. J Neurosurg Spine 1:287-298, 2004[Medline] 17. Patchell RA, Tibbs PA, Regine WF, et al: A randomized trial of direct decompressive surgical resection in the treatment of spinal cord compression caused by metastasis. Proc Am Soc Clin Oncol 22:1, 2003 (abstr 2) Related Article
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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6 months) of the study patients is incomplete. One can form the interpretation that the main criterion for inclusion was unfavorable histology alone, or favorable histology with neurologic dysfunction or poor performance status. However, this study has included groups of patients who might be anticipated to live significantly longer than 6 months. For example, one of the most significant predictors of short survival for patients with metastatic cancer is poor performance status; yet, 17% of patients in this study had Karnofsky performance status of 80 to 100.
