|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 24, No 24 (August 20), 2006: pp. 3815-3816 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.2827
Thoracic Radiation Therapy in Limited Stage Small-Cell Lung Cancer: Timing Is Everything...Isn't It?University of Missouri/Ellis Fischel Cancer Center, Columbia, MO Over the last 20 years, there have been three significant advances in the treatment of limited-stage small-cell lung cancer. These are the inclusion of thoracic radiation therapy (TRT) to decrease local recurrences,1 the routine use of prophylactic cranial radiation (PCI) in complete responders to minimize CNS metastases,2 and the use of twice-daily TRT3 to improve survival. Each of these changes in therapy is associated with a small improvement in survival, and there are unresolved controversies associated with all three. Twice-daily TRT has never caught on, perhaps because of the inconvenience to patients and facilities or because of the high incidence of esophagitis, which, although largely reversible, is distinctly more severe than the usual adverse effects associated with standard TRT. PCI may cause late neuropsychological adverse effects, the prospect of which frightens some patients and physicians. The use of TRT is generally accepted without debate, but the issue of its timing, early or late, remains disputed, perhaps because there is so little progress on other fronts that there is little else to discuss. In this issue, Spiro et al4 of the London Lung Cancer Group have attempted to replicate the National Cancer Institute of Canada (NCIC) study that found a significant advantage with early TRT (administered with cycle 2 of chemotherapy) compared with late TRT (administered with cycle 6).4,5 The entry criteria for both of these trials were similar, and the staging in both series did not routinely include computed tomography scans of the thorax and brain. In fact, less than 50% of patients in the London study had brain scans at any time. In addition, Spiro et al4 did not routinely perform the pulmonary function tests and bone marrow sampling required by the NCIC. Patients in both studies had to be younger than 75 years of age and could have an Eastern Cooperative Oncology Group performance status of up to 3. The chemotherapy was the same in the NCIC and London studies, with cyclophosphamide, doxorubicin, and vincristine every 3 weeks alternating with etoposide and cisplatin (EP), for a total of six cycles. TRT was administered with the first EP cycle in one arm and with the third EP cycle (cycle 6) in the second arm. TRT consisted of 40 Gy in 15 fractions over 3 weeks using cobalt or a linear accelerator. PCI, at a dose of 25 Gy in 10 fractions over 2 weeks, was administered to responding patients after the completion of TRT and chemotherapy. The two groups were balanced according to baseline characteristics. Unlike the NCIC study, the study by Spiro et al4 showed no difference between the two arms, with median survival times of 13.7 and 15.1 months in the early and late arms, respectively. By comparison, in the NCIC study, the median survival times were 21.2 and 16 months in the early and late arms, respectively. Only 69% of the patients in the early arm of the study by Spiro et al4 received all six courses of chemotherapy compared with 80% of the patients in the late arm (P = .003), possibly because of increased toxicity on the early arm, which was similar to the results of a Cancer and Leukemia Group B study, which found no advantage for early compared with late TRT.6 In their meta-analysis of eight trials comparing timing of TRT, there was a trend toward benefit from the optimal delivery of chemotherapy with early TRT. The study by Spiro et al4 can be criticized for its inadequate staging, at least by contemporary standards; the inclusion of patients with a performance score of 3; and the exclusion of patients older than age 75 years, which may be considered by some to be age discrimination. Nevertheless, they have otherwise replicated the NCIC trial and obtained differing results, further potentially prolonging the debate over the timing of TRT in small-cell lung cancer. Why was it necessary to repeat the NCIC trial? Although many studies have been performed to address this timing question, these trials have used different chemotherapy or radiation therapy schemes administered at markedly different times. Radiation has been administered once daily, twice daily, or by split course and at doses ranging from 40 to 54 Gy. The chemotherapy has been similarly diverse in the choice of drugs and the length of treatment. Many trials have had small numbers of patients, permitting detection of only major differences. Meta-analyses struggle with which studies to include and the definitions of early (weeks 1 to 8) and late (weeks 6 to 16) TRT.7 Earlier this year in the Journal of Clinical Oncology, De Ruysscher et al8 used a meta-analysis technique and concluded that the time from the start of any treatment until the end of TRT was the most important predictor of outcome, with a significantly higher 5-year survival in the arms that had a shorter time from the start of any treatment until the end of TRT. The accompanying editorial by Brade and Tannock9 found the hypothesis that neoadjuvant chemotherapy may induce resistance to subsequent radiation through repopulation in limited-stage small-cell lung cancer to be consistent with the evidence but not conclusive. They suggested that those treatment strategies helpful in other cancers, such as the use of the epidermal growth factor receptor cetuximab with radiation therapy in head and neck cancer or the dose-dense therapy used in the adjuvant therapy of breast cancer and the therapy of non-Hodgkin's lymphomas, may be helpful. What can now be concluded about the timing of TRT in limited-stage small-cell lung cancer? If one uses modern cisplatin-based chemotherapy in adequate doses with appropriate radiation therapy doses and ports, the timing of TRT is probably not a critical factor, although we do know that sequential radiotherapy is inferior to concurrent therapy.10 Our failures in limited-stage small-cell lung cancer can be traced to the failure of current chemotherapy and radiation therapy regimens and not to the timing of their use. The only way to settle the timing issue definitively is to perform a large randomized trial requiring hundreds of patients, which would be a waste of resources. In addition, where else in oncology does the timing of radiation therapy by a period of about 6 weeks make a clinically important difference? The real need is to develop novel, more effective therapies to treat systemic disease. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. ACKNOWLEDGMENTS Portions of this research were supported by National Cancer Institute Grant No. CA-12046 (Cancer and Leukemia Group B). REFERENCES 1. Pignon J-P, Arrigada R, Ihde DC, et al: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327: 1618-1624, 1992[Abstract] 2. Arriagada R, Le Chevalier T, Borie F, et al: Prophylactic cranial irradiation for patients with small cell lung cancer in remission. J Natl Cancer Inst 87: 183-190, 1995 3. Turrisi AT III, Kim K, Blum R, et al: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340: 265-271, 1999 4. Spiro SG, James LE, Rudd RM, et al: Early compared with late radiotherapy in combined-modality treatment for limited-disease small-cell lung cancer: A London Lung Cancer Group multicenter randomized clinical trial. J Clin Oncol 24: 3823-3830, 2006 5. Murray N, Coy P, Pater JL, et al: Importance of timing for thoracic irradiation in the combined modality treatment of limited stage small-cell lung cancer. J Clin Oncol 11: 336-344, 1993 6. Perry MC, Herndon JE II, Eaton WL, et al: Thoracic radiation therapy added to chemotherapy for small cell lung cancer: An update of Cancer and Leukemia Group B study 8083. J Clin Oncol 16: 2466-2467, 1998[Abstract] 7. Fried DB, Morris DE, Poole C, et al: Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol 22: 4837-4845, 2004 8. De Ruysscher D, Pijls-Johannesma M, Bentzen S, et al: Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small cell lung cancer. J Clin Oncol 24: 1057-1063, 2006 9. Brade AM, Tannock IF: Scheduling of radiation and chemotherapy for limited-stage small-cell lung cancer: Repopulation as a cause for treatment failure? J Clin Oncol 24: 1020-1022, 2006 10. Takada M, Fukuoka M, Kawahara M, et al: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: Results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 20: 3054-3060, 2002 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
|
