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Journal of Clinical Oncology, Vol 23, No 32 (November 10), 2005: pp. 8270a-8272 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.3522
Radiotherapy Alone or Surgery in Spinal Cord Compression? The Choice Depends on Accurate Patient Selection
Radiation Oncology Center, Azienda Ospedaliera, Terni, Italy To the Editor: We read with great interest the editorial by Kwok, Regine, and Patchell,1 in which they suggest caution in implementing the results in clinical practice of our phase III randomized clinical trial on hypofractionated radiotherapy in metastatic spinal-cord compression (MSCC).2 We feel obliged to reply by answering point by point to the major reported criticisms. As stated in the paper, only MSCC patients with a short life expectancy entered onto the trial. The majority of patients (229; 83%) had low Karnofsky performance status (KPS) and the remaining 47 (17%) enrolled with a good KPS, and had poor life expectancy and bad prognosis for the presence of unfavorable histologies. Although 30 Gy in 3-Gy daily fractions represents the most common fractionation schedule used in patients with MSCC in the United States, the optimal radiotherapy (RT) regimen for treating MSCC is still unknown and many schedules are reported in the literature.3 In some published trials, 4 to 5 Gy daily for 3 days followed by 4 days of rest, and then five to 16 daily doses of 2 to 3 Gy have been administered with both good results and tolerance.4-8 Studies concerning RT for patients with painful bone metastases have shown that low fraction regimens and high single doses have a clinical outcome similar to more protracted regimens, also in patients with vertebral metastases.9 Considering that higher RT doses per fraction is one of the possible factors that may be associated with radiation-induced late spinal cord morbidity, in our previous trials we adopted different hypofractionation regimens on the basis of the patient's life expectancy.3,8 A safer fractionation of 3 to 30 Gy in 10 fractions over 2 weeks was administered to patients with a long life expectancy (approximately 15% of observed cases). Split-course RT of three fractions of 5 Gy each, 4 days of rest, and then five fractions of 3 Gy each, to a total dose of 30 Gy in 2 weeks, was adopted for patients with short life expectancy.8 In recent phase II trial, we have proved the feasibility and effectiveness of a short-course RT (two fractions 8 Gy) in the patients with less than 6 months of life.3 With this background, this prospective randomized phase III trial was performed to compare the aforementioned split-course regimen with the short-course RT in patients with MSCC and short life expectancy. Other MSCC patients who did not enter onto the study, underwent to 3 to 30 Gy regimen. We agree with Kwok, Regine, and Patchell in being worried about radiation-induced myelopathy (RIM) that may result in heavy neurologic deficits. Of 465 MSCC patients submitted to RT at our center between 1988 and 1997, 13 living patients treated with the aforementioned split- or short-course regimens survived for 2 years or more were reviewed to evaluate RIM. This trial, the only one published on RIM in long-term–surviving MSCC patients, showed an excellent spinal cord tolerance to the hypofractionated RT schedules adopted, with only one case of suspected RIM.10 Furthermore, three randomized Medical Research Council trials on non–small-cell lung cancer have shown the effectiveness of two fractions 8.5 Gy RT in the palliation of symptoms caused by thoracic disease. This regimen has given the same outcome and toxicity as three other regimens used for comparison. Only one of 550 patients submitted to this hypofractionation schedule presented a suspected RIM.11-13 Recently Macbeth14 encourage a wider use of 8 Gy x 2 fractionation in palliative RT.
Another important support on the feasibility of the hypofractionated RT can be derived by the radiobiology. The effect of an RT schedule on tumor control and on late toxicity depends on both the total dose and the dose per fraction. Each schedule adopted can be compared with the equivalent dose in 2-Gy fraction (EQD2), which is calculated using the equation As reported in our article,2 responders were considered either those patients who retained or regained the ability to walk. This definition of response, shared by the majority of authors, can be acceptable because untreated MSCC patients generally deteriorate and develop neurologic dysfunction.3-7 Also the authors of the editorial have adopted these criteria in defining response in their recent trial.17 So, we do not understand the reason for which they argume against our results and want to limit the percentage of response to only patients who have improved after RT. The good response rate found in our trial is probably due to the early diagnosis and prompt treatment (in 67% of cases, MSCC was diagnosed and treated when patients were ambulant, and 90% of patients maintained this function).2 Considering that the pretreatment ambulatory function is the main determinant for post-treatment gait function, an important message we would like reinforce is the importance of the early diagnosis that can be obtained prescribing MRI or CT for all cancer patients with back pain, osteolysis and/or positive bone scan, even in the absence of clinical neurologic signs of MSCC.2,18 The best or most effective treatment for MSCC patients is still not defined, and the choice between surgery plus RT or RT alone is debatable. In fact, the two published randomized studies comparing surgery plus RT versus RT alone do not conclusively clarify what is the treatment of choice.5,17 Young's trial5 has shown no difference between laminectomy plus RT and RT alone; however, too few patients were enrolled and simple laminectomy is generally considered an inappropriate surgical approach. The other trial was closed at an interim analysis that showed a significant better response rate in the surgical group.17 In our opinion, these data give not a sufficient evidence in favor of surgery plus RT for two important reasons. First, this last randomized study cannot be considered good evidence to recommend surgery plus RT in all MSCC patients because it was available only as an abstract and was closed before reaching the established sample size. Second, in the clinical practice, only a minority of MSCC patients are eligible for surgery: Low KPS, old age, systemic progressive disease, and so on are characteristics that can prevent a surgical approach. Also, the authors of this editorial reported in their abstract that only patients with a single site of cord compression and an expected survival of at least 3 months were enrolled in their phase III trial.17 In conclusion, early diagnosis and a prompt treatment are very important for patients with MSCC. In the clinical practice, the best therapeutic approach might be discussed for each patient between surgeon and radiation oncologist. There are situations in which surgery is surely indicated before RT, but there is not convincing evidence that surgery must be performed for all MSCC patients. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Kwok Y, Regine FW, Patchell RA: Radiation therapy alone for spinal cord compression: Time to improve upon a relatively ineffective status quo. J Clin Oncol 23:3308-3310, 2005
2. 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 3. Maranzano E, Latini P, Perrucci E, et al: Short-course radiotherapy (8 Gy x 2) in metastatic spinal cord compression: An effective and feasible treatment. Int J Radiat Oncol Biol Phys 38:1037-1044, 1997[CrossRef][Medline] 4. Greenberg HS, Kim JB, Posner JB: Epidural spinal cord compression from metastatic tumour: Diagnosis and treatment. Ann Neurol 3:40-51, 1980 5. Young RF, Post EM, King GA: Treatment of spinal epidural metastases: Randomised prospective comparison of laminectomy and radiotherapy. J Neurosurg 53:741-748, 1980[Medline]
6. Kim RY, Spencer SA, Meredith RF, et al: Extradural spinal cord compression: Analysis of factors determining functional prognosis—Prospective study. Radiology 176:279-282, 1990 7. Leviov M, Dale J, Stein M, et al: The management of metastatic spinal cord compression: A radiotherapeutic success ceiling. Int J Radiat Oncol Biol Phys 27:231-234, 1993[Medline] 8. 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] 9. Wu JS, Wong R, Johnston M, et al: Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys 55:594-605, 2003[CrossRef][Medline] 10. Maranzano E, Bellavita R, Floridi P, et al: Radiation-induced myelopathy in long-term metastatic spinal cord compression patients after hypofractionated radiotherapy: A clinical and magnetic resonance imaging analysis. Radiother Oncol 60:281-288, 2001[CrossRef][Medline] 11. Report to the Medical Research Council by its Lung Cancer Working Party: Inoperable non-small cell lung cancer: A Medical Research Council randomized trial of palliative radiotherapy with two fractions or ten fractions. Br J Cancer 63:265-270, 1991[Medline] 12. Bleehen NM, Girling DJ, Machin D, et al: A Medical Research Council randomized trial of palliative radiotherapy with two fractions or a single fraction in patients with inoperable non-small cell lung cancer and poor performance status. Br J Cancer 65:934-941, 1992[Medline] 13. British Medical Research Council Lung Cancer Working Party: Randomized trial of two radiotherapy policies for patients with inoperable non-small cell lung cancer and good performance status. Lung Cancer 11:S138, 1994 (suppl 1; abstr 504) 14. Macbeth F: Letter to the Editor. Radiother Oncol 64:119, 2002[CrossRef][Medline] 15. Barendsen GW: Dose fractionation, dose rate and iso-effect relationship for normal tissue responses. Int J Radiat Oncol Biol Phys 8:1981-1997, 1982[Medline] 16. Emami B, Lyman J, Brown A, et al: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 21:109-122, 1991[Medline] 17. Regine WF, Tibbs PA, Young A, et al: Metastatic spinal cord compression: A randomized trial of direct decompressive surgical resection plus radiotherapy vs. radiotherapy alone. Int J Radiat Oncol Biol Phys 57:S125, 2003 (abstr 3)[CrossRef]
18. Loblaw DA, Laperriere NJ: Emergency treatment of malignant extradural spinal cord compression: An evidence-based guideline. J Clin Oncol 16:1613-1624, 1998 Related Reply
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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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derived from the linear-quadratic model.
/ß ratio of 2 Gy, resulting in an EQD2 of 45 Gy and 40 Gy for the split-course (5 Gy x 3; 3 Gy x 5) and short-course (8 Gy x 2) schedules, respectively. Thus, whatever of these two RT regimens are adopted, relevant late toxicity appears to be extremely unlikely. 
