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© 2002 American Society for Clinical Oncology 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 9104ByFrom the Osaka Prefectural Habikino Hospital, Osaka City General Medical Center, Kinki National Hospital for Chest Disease, and National Toneyama Hospital for Chest Disease, Osaka; Aichi Cancer Center, Aichi; Niigata Cancer Center Hospital, Niigata; National Cancer Center Hospital East, Chiba; Yokohama Municipal Citizen’s Hospital and Kanagawa Cancer Center, Kanagawa; and National Cancer Center Hospital and National Cancer Center Research Institute, Tokyo, Japan. Address reprint requests to Nagahiro Saijo, MD, Division of Internal Medicine, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan; email: nsaijo{at}ncc.go.jp
PURPOSE: To evaluate the optimal timing for thoracic radiotherapy (TRT) in limited-stage small-cell lung cancer (LS-SCLC), the Lung Cancer Study Group of the Japan Clinical Oncology Group conducted a phase III study in which patients were randomized to sequential TRT or concurrent TRT. PATIENTS AND METHODS: We treated 231 patients with LS-SCLC. TRT consisted of 45 Gy over 3 weeks (1.5 Gy twice daily), and the patients were randomly assigned to receive either sequential or concurrent TRT. All patients received four cycles of cisplatin plus etoposide every 3 weeks (sequential arm) or 4 weeks (concurrent arm). TRT was begun on day 2 of the first cycle of chemotherapy in the concurrent arm and after the fourth cycle in the sequential arm. RESULTS: Concurrent radiotherapy yielded better survival than sequential radiotherapy (P = .097 by log-rank test). The median survival time was 19.7 months in the sequential arm versus 27.2 months in the concurrent arm. The 2-, 3-, and 5-year survival rates for patients who received sequential radiotherapy were 35.1%, 20.2%, and 18.3%, respectively, as opposed to 54.4%, 29.8% and 23.7%, respectively, for the patients who received concurrent radiotherapy. Hematologic toxicity was more severe in the concurrent arm. However, severe esophagitis was infrequent in both arms, occurring in 9% of the patients in the concurrent arm and 4% in the sequential arm. CONCLUSION: This study strongly suggests that cisplatin plus etoposide and concurrent radiotherapy is more effective for the treatment of LS-SCLC than cisplatin plus etoposide and sequential radiotherapy.
SMALL-CELL LUNG cancer accounts for approximately 20% of all lung cancers,1 and it follows a more rapid clinical course than non–small-cell lung cancer. In contrast to non–small-cell lung cancer, however, small-cell lung cancer is very sensitive to cytotoxic agents and radiation therapy. Limited-stage small-cell lung cancer (LS-SCLC) is confined to the hemithorax, clinically, and thus the main treatment is radiotherapy and chemotherapy. A meta-analysis performed by Pignon et al2 showed that the addition of radiotherapy to combination chemotherapy significantly improved the survival for patients with LS-SCLC, but the optimal method of integrating thoracic radiotherapy (TRT) with chemotherapy remained undefined. During the 1980s, the cisplatin-etoposide regimen became the treatment of choice, because this combination seemed to offer better systemic therapy without intrinsic pulmonary toxicity. Because of this, pilot studies combining TRT with concurrent cisplatin plus etoposide therapy were performed.3-5 The results of the trials were encouraging: a 2-year survival rate of approximately 40% was obtained with acceptable toxicities. To evaluate the optimal timing for TRT in LS-SCLC, the Lung Cancer Study Group of the Japan Clinical Oncology Group (JCOG) conducted a phase III study in which patients were randomized to sequential TRT or concurrent TRT.
Patients The diagnosis of small-cell lung cancer was confirmed by the histologic or cytologic findings in all cases. Limited stage was defined as disease confined to one hemithorax with or without mediastinal node metastasis and with or without bilateral supraclavicular node metastasis. Additional eligibility criteria consisted of measurable or assessable disease, age less than 75 years, Eastern Cooperative Oncology Group performance status (PS)  2, adequate organ function, leukocyte count greater than 4,000/mm3, hemoglobin level greater than 11 g/dL, platelet count greater than 100,000/mm3, serum creatinine level less than 1.5 mg/dL, serum AST and ALT levels less than two times the upper limit of normal, serum bilirubin level less than 2.0 mg/dL, 24-hour creatinine clearance greater than 60 mL/min/m2, and arterial oxygen pressure greater than 70 mmHg. Patients with malignant pleural effusions or stage I disease by the tumor-node-metastasis staging method6 were ineligible. Patients with symptomatic cardiac disease or a history of myocardial infarction within the previous 3 months were excluded. Each patient underwent the following studies: chest radiography and fiberoptic bronchoscopy, complete blood count and biochemical tests, ECG, computed tomography scan of the thorax, abdomen, and brain, bone marrow aspiration biopsy, and a radionuclide bone scan. All patients were reassessed at the end of treatment in the same manner as at the time of enrollment.
Chemotherapy
Thoracic Radiotherapy After TRT, prophylactic whole-brain irradiation was administered to patients with a complete or near-complete response: a scar-like shadow on chest films but no positive cytology and/or bronchoscopic biopsy. The brain irradiation consisted of 24 Gy in 1.5-Gy fractions twice daily, 5 days per week.
Response and Toxicity Criteria
Study Design and Statistical Analysis Analysis of the trial data was based on the intention-to-treat principle. Duration of survival was measured from the date of randomization to the date of death or most recent follow-up. Progression-free survival was measured from the date of randomization to the date of the first observation of disease progression or death. If there was no progression or the patient had not died, progression-free survival was censored at the date of confirmation of no progression. Survival distributions were calculated by the Kaplan-Meier method9 and compared by using the log-rank test.10 Fisher’s exact test was used for comparisons of categorical data.11 Cox’s proportional hazards regression model was used to assess the impact on survival of treatment and important demographic factors, such as sex, Eastern Cooperative Oncology Group PS, age, and stage.12 All P values are based on two-sided test. The protocol was approved by the Clinical Trial Review Committee of JCOG before the study activation. In accordance with policies of the JCOG in 1991, oral or written consent was obtained from the patients or their families before randomization.
Patient Characteristics Between May 1991 and January 1995 a total of 231 patients with LS-SCLC being treated at 15 institutions were enrolled onto the study. Three patients in the sequential arm were ineligible, because of extensive disease in two patients and malignant lymphoma in one patient. These three patients were excluded from the primary analyses of overall survival, progression-free survival, and response. The characteristics of the 228 eligible patients are shown in Table 1, and they are well balanced between the arms.
Toxicity Documentation of toxicity data was not available for nine patients (seven in the sequential arm and two in the concurrent arm), which left 222 patients (110 in the sequential arm and 112 in the concurrent arm) assessable for toxicity. Hematologic and nonhematologic toxicities are summarized in Table 2. Myelosuppression was common in both arms but more severe in the concurrent arm. Leukopenia was much more frequent in the concurrent arm. Thrombocytopenia was infrequent and mild in both arms. Two patients in the concurrent arm died of sepsis. Grade 3 or 4 esophagitis occurred in 10 patients in the concurrent arm and four patients in the sequential arm, but none of these patients developed a permanent stricture. There were no marked differences in nonhematologic toxicity between the arms. There were three treatment-related deaths in the concurrent arm (sepsis in two patients and pyothorax in one patient) and four in the sequential arm (radiation pneumonitis in three patients and acute cardiac failure in one patient).
Tumor Response Table 3 shows tumor response according to treatment arm. The overall response rate was 92% (27% complete response rate and 65% partial response rate) in the sequential arm and 97% (40% complete response and 65% partial response) in the concurrent arm. There was a trend for a higher complete response rate in the concurrent arm (P = .07).
Treatment Delivery and Dose-Intensity One hundred (88%) of the 114 eligible patients in the sequential arm and 98 (86%) of the 114 in the concurrent arm completed four cycles of chemotherapy. The median chemotherapy interval was 21 days in the sequential arm and 28 days in the concurrent arm. Planned and actual dose-intensities are shown in Table 4. The actual dose-intensity as a proportion of the planned dose-intensity was greater than 90% in both arms. Actual dose-intensities for both cisplatin and etoposide were 1.3 times higher in the sequential arm. More than 80% of patients in both arms completed thoracic radiotherapy of 45 Gy.
Survival The formal final analysis of the study was performed in May 1998, and updated survival follow-up was performed on August 2000. Figure 1 shows the updated survival curves for eligible patients analyzed on August 2000. The median survival time of all eligible patients was 19.7 months in the sequential arm (95% confidence interval [CI], 15.8 to 23.3 months) and 27.2 months (95% CI, 18.4 to 31.0 months) in the concurrent arm. The 2-, 3-, and 5-year survival rates were 35.1%, 20.2%, and 18.3%, respectively, in the sequential arm versus 54.4%, 29.8%, and 23.7% in the concurrent arm (P = .097 for eligible patients and .086 for all randomized patients by log-rank test). Overall survival in the concurrent arm tended to be superior to that in the sequential arm. After adjustments for the prognostic factors performance status, age, and stage, by Cox proportional hazards regression model, the hazard ratio for death in the concurrent arm to death in the sequential arm was 0.70 (95% CI, 0.52 to 0.94, P = .02) (Table 5).
Progression-Free Survival Figure 2 shows the estimated progression-free survival distribution of eligible patients at the analysis on May 1998. Progression-free survival in the concurrent arm was also superior to that in the sequential arm. The distribution of the first progression sites was similar in both the arms (Table 6). Brain metastasis was experienced as the first progression in 27% of the patients in the sequential arm and 19% in the concurrent arm. The first local failure rate within the thorax was low, only 18% in both arms.
The standard treatment for LS-SCLC is combined-modality therapy consisting of TRT and systemic chemotherapy. However, there have been many unresolved problems with regard to combined therapy: the radiation dose, fractionation, chemotherapy regimen, and the timing of TRT. With regard to fractionation, Turrisi et al13 had determined that accelerated hyperfractionation, which is the same method used in this study, was superior to standard fractionation in an intergroup phase III study. Early administration of TRT may eliminate localized populations of chemotherapy-resistant tumor cells that might be responsible for treatment failure if permitted to disseminate systemically. This would be an obvious advantage of early administration of TRT. Although concurrent use of the two modalities seemed to be more effective, many doxorubicin-based or cyclophosphamide-based regimens could not be combined with full doses of TRT concurrently because of increased pulmonary toxicity. Cisplatin plus etoposide was found to be the optimal regimen for combination with concurrent TRT, since it hardly accelerates toxicity at all and there is no recall phenomenon.14-16 The median survival time for patients treated with this regimen and concurrent twice-daily TRT in the various phase II studies has been 18 to 22 months.4,17,18 A 50% increase in median survival from 1219 to 18 months was considered a clinically significant survival improvement. In view of this, we conducted a phase III study of sequential versus concurrent TRT combined with cisplatin plus etoposide for patients with LS-SCLC. Comparison of overall- and progression-free survival in this study suggested that concurrent radiotherapy was more advantageous than sequential radiotherapy, but the difference was not statistically significant (P = .097). In view of the baseline characteristics, there seemed to be a slight imbalance in PS and stage between the arms; however, adjustment with Cox regression analysis suggested a greater benefit of concurrent radiotherapy than simple comparison. We think that the imbalance in baseline characteristics would result in a more conservative estimation of the benefit of concurrent radiotherapy in the intent-to-treat primary analysis. One of the major reasons that this study could not demonstrate a statistically significant result was a relatively small sample size of 220 patients. The design called for a 50% increase in median survival from 12 to 18 months. Actually, median survival times in both arms were greater than 18 months. The United States Intergroup study required over 400 patients and took many years to show a significant advantage in twice-daily thoracic radiotherapy.13 However, accrual of 65 to 75 patients per year was the limit of our study group at the time. Another reason may be the difference in chemotherapy intervals between two arms. The chemotherapy was given at 4-week intervals in the concurrent arm and at 3-week intervals in the sequential arm. An increase in the chemotherapy interval from 3 weeks to 4 weeks results in a decrease in dose-intensity of 33% in the concurrent arm, which may be responsible for the unusual shape of the survival curves. One might accept a 4-week interval only for the first cycle to mitigate the toxicity of concurrent chemoradiotherapy. However, we had considered that chemotherapy by 3-week intervals could not be administered for subsequent chemotherapy courses based on the results of our previous study.20 Interestingly, local control was the same in both arms, yet survival was better in the concurrent arm. It may suggest two hypotheses: (1) local control is achieved earlier in the concurrent arm, preventing distant dissemination beyond the confines of the radiation field, and (2) clinical ability to assess local control is still poor in both arms. The fact that there was more brain metastasis in the sequential arm (Table 6) may support hypothesis 1. Hematologic toxicity and esophagitis were more severe in the concurrent arm; however, there was no increase in pulmonary toxicity in the concurrent arm. Treatment was well tolerated by most patients, and the frequency of radiation esophagitis in this study was lower than previously reported. In other studies, chemotherapy was administered in 3-week cycles in the concurrent arm. The 4-week cycle of cisplatin plus etoposide with concurrent radiotherapy seemed to reduce the frequency of radiation esophagitis. Five randomized trials of thoracic irradiation timing in LS-SCLC, including this study,21-24 have been reported, and three of them,21,22 including this study, have shown the superiority of early thoracic irradiation over delayed thoracic irradiation. The two studies23,24 that failed to show the superiority of early thoracic irradiation used cyclophosphamide-based chemotherapy, and the decrease in dose-intensity because of the accelerated toxicity of the combined-modality therapy may be the main reason for this. Long-term survival after early irradiation consistently exceeds 20% at 5 years, 21,22 and delayed irradiation has never approached the 20% long-term survival milestone. The data available from these trials strongly suggest the superiority of early irradiation over delayed irradiation. However, the possibility that concurrent radiotherapy in the middle of chemotherapy course (eg, with the third cycle of chemotherapy) is equally or more effective than immediate concurrent radiotherapy is still remains to be investigated. The 24% 5-year survival in this study was impressive and consistent with the 26% reported by Turrisi et al13 in a large intergroup trial. The results of the two trials have updated the recommendation for treatment of patients with LS-SCLC to cisplatin plus etoposide and early, concurrent, twice-daily thoracic radiotherapy. This combined-modality treatment yielded a median survival time of 23 to 27 months and 24% to 26% long-term survivors.
Supported in part by Grants-in-Aid for Cancer Research 2S-1, 5S-1, 8S-1, 11S-2, and 11S-4 and by the Second Term Comprehensive 10-Year Strategy for Cancer Control, all from the Ministry of Health, Labor, and Welfare. We thank JCOG Data Center (Miyuki Niimi, Naoki Ishizuka, and their colleagues) and other participating institutions: Osaka Adult and Cancer Center (Harumichi Ikegami), Nagasaki Municipal Hospital (Seishin Nakano), National Nishi-Gunma Hospital (Ryusei Saitou), Tochigi Cancer Center (Kiyoshi Mori), and Hyogo Medical Center for Adults (Katsuki Takada).
1. Elias AD: Small cell lung cancer: State-of-the-art therapy in 1996. Chest 112: 251S-258S, 1997 2. Pignon JP, Arriagada 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] 3. Frytak S, Shaw E, Eagan R: Accelerated hyperfractionated split course thoracic radiotherapy and infusion cisplatin based chemotherapy for small-cell lung cancer. Lung Cancer 7: 157, 1991 (suppl, abstr)
4. Johnson BE, Bridges JD, Sobczeck M, et al: Patients with limited-stage small-cell lung cancer treated with concurrent twice-daily chest radiotherapy and etoposide/cisplatin followed by cyclophosphamide, doxorubicin, and vincristine. J Clin Oncol 14: 806-813, 1996 5. Turrisi AT III: Platinum combined with radiation therapy in small cell lung cancer: Focusing like a laser beam on crucial issues. Semin Oncol 21: 36-42, 1994[Medline] 6. Hermanek P, Sobin Le: TNM Classification of Malignant Tumors, ed 4 . Berlin, Germany, Springer-Verlag, 1987 7. World Health Organization: Handbook for Reporting Results of Cancer Treatment (WHO Offset Publication No. 48). Geneva, Switzerland, World Health Organization, 1979 8. Rubinstein LV, Gail MH, Santner TJ: Planning the duration of a comparative clinical trial with loss to follow-up and a period of continued observation. J Chronic Dis 34: 469-479, 1981[CrossRef][Medline] 9. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef] 10. Peto R, Pike M: Conservatism of the approximation S(O-E)2/E in the log-rank test for survival data or tumour incidence data. Biometrics 29: 759-784, 1973 11. Cox D, Snell E: Analysis of binary data, ed 2 . London, United Kingdom, Chapman & Hall, 1989 12. Cox DR: Regression models and life table. J R Stat Soc B 34: 181-220, 1972
13. 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
14. Bunn PA Jr, Lichter AS, Makuch RW, et al: Chemotherapy alone or chemotherapy with chest radiation therapy in limited stage small cell lung cancer: A prospective, randomized trial. Ann Intern Med 106: 655-662, 1987
15. Greco FA, Brereton HD, Kent H, et al: Adriamycin and enhanced radiation reaction in normal esophagus and skin. Ann Intern Med 85: 294-298, 1976 16. Perez CA, Einhorn L, Oldham RK, et al: Randomized trial of radiotherapy to the thorax in limited small-cell carcinoma of the lung treated with multiagent chemotherapy and elective brain irradiation: A preliminary report. J Clin Oncol 2: 1200-1208, 1984[Abstract] 17. McCracken JD, Janaki LM, Crowley JJ, et al: Concurrent chemotherapy/radiotherapy for limited small-cell lung carcinoma: A Southwest Oncology Group study. J Clin Oncol 8: 892-898, 1990[Abstract] 18. Turrisi AT, Glover DJ, Mason BA: A preliminary report: Concurrent twice-daily radiotherapy plus platinum-etoposide chemotherapy for limited small cell lung cancer. Int J Radiat Oncol Biol Phys 15: 183-187, 1988[Medline]
19. Fukuoka M, Furuse K, Saijo N, et al: Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst 83: 855-861, 1991
20. Ariyoshi Y, Fukuoka M, Saijo N, et al: Concurrent cisplatin-etoposide chemotherapy plus thoracic radiotherapy for limited-stage small cell lung cancer. Jpn J Clin Oncol 24: 275-281, 1994
21. Jeremic B, Shibamoto Y, Acimovic L, et al: Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: A randomized study. J Clin Oncol 15: 893-900, 1997
22. 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: The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11: 336-344, 1993 23. Perry MC, Eaton WL, Propert KJ, et al: Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med 316: 912-918, 1987[Abstract] 24. Work E, Nielsen OS, Bentzen SM, et al: Randomized study of initial versus late chest irradiation combined with chemotherapy in limited-stage small-cell lung cancer: Aarhus Lung Cancer Group. J Clin Oncol 15: 3030-3037, 1997[Abstract] Submitted December 14, 2001; accepted April 15, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
