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© 2003 American Society for Clinical Oncology Randomized Phase III Trial of Fluorouracil Alone Versus Fluorouracil Plus Cisplatin Versus Uracil and Tegafur Plus Mitomycin in Patients With Unresectable, Advanced Gastric Cancer: The Japan Clinical Oncology Group Study (JCOG9205)
From the Division of Gastrointestinal Oncology/Digestive Endoscopy, National Cancer Center Hospital East, Kashiwa; Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo; Department of Internal Medicine, National Shikoku Cancer Center, Matsuyama; Department of Internal Medicine, Yamagata Prefectural Central Hospital, Yamagata; Department of Surgery, Fukui Prefectural Center for Adult Disease, Fukui; Department of Internal Medicine, Saku Central Hospital, Nagano; Department of Internal Medicine, Mitoyo General Hospital, Kagawa; and JCOG Data Center, Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo, Japan. Address reprint requests to Atsushi Ohtsu, MD, Division of Gastrointestinal Oncology/Digestive Endoscopy, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577 Japan; email: aohtsu{at}east.ncc.go.jp.
Purpose: To compare fluorouracil (FU) alone with FU plus cisplatin (FP) and with uracil and tegafur plus mitomycin (UFTM) for patients with advanced gastric cancer in a prospective, randomized, controlled trial. Patients and Methods: A total of 280 patients with advanced gastric cancer were randomly allocated and analyzed for survival, response, and toxicity. The survival curves were compared between groups by log-rank test on an intent-to-treat basis. Results: At the interim analysis, the UFTM arm showed a significantly inferior survival with higher incidences of hematologic toxic effects than did control arm FU alone, and the registration to UFTM was terminated. Both investigational regimens, FP and UFTM, had a significantly higher incidence of hematologic toxic effects than FU alone, although the effects were manageable. The overall response rates of the FU-alone, FP, and UFTM arms were 11%, 34%, and 9%, respectively. The median progression-free survival was 1.9 months with FU alone, 3.9 months with FP, and 2.4 months with UFTM, respectively. Although FP demonstrated a higher response rate (P < .001) and longer progression-free survival than did FU alone (P < .001), no differences in overall survival were observed between the arms. The median survival times and 1-year survival rates were 7.1 months and 28% with FU, 7.3 months and 29% with FP, and 6.0 months and 16% with UFTM, respectively. Conclusion: Neither investigational regimen, FP nor UFTM, showed a survival advantage as compared with FU alone. FU alone will remain a reference arm in our future trial for advanced gastric cancer.
GASTRIC CANCER remains one of the major causes of cancer death worldwide. Despite a remarkably improving survival trend through early detection and curative surgery, approximately 50,000 deaths from gastric cancer were observed in Japan in 1997.1 Unresectable advanced or recurrent gastric cancer still both have a poor prognosis. Some randomized trials demonstrated that a fluorouracil (FU)-based regimen provides superior survival in patients with advanced gastric cancer when compared with the best supportive care.2–4 This survival advantage appears to be marginal, however, and no standard regimens have yet been established. Before this study, the Japan Clinical Oncology Group (JCOG) had undertaken four phase II studies for advanced gastric cancer, including one randomized study.5–8 At first, a randomized study comparing tegafur plus mitomycin with tegafur and uracil (UFT) plus mitomycin was carried out.5 That study demonstrated a higher response rate in UFT plus mitomycin (UFTM) than in tegafur plus mitomycin, whereas no survival differences were observed between the two arms. Subsequently, we conducted three studies of a platinum-based combination consisting of doxifluridine plus cisplatin (CDDP),6 etoposide plus doxorubicin plus CDDP (EAP),7 and FU plus CDDP (FP).8 Despite a high response rate and favorable survival, approximately 10% of treatment-related deaths occurred in the EAP study.7 These substantial toxic effects also were reported in another study.9 Consequently, we did not accept this EAP regimen for future study. Both the doxifluridine plus CDDP and FP regimens showed similar response and survival results.6,8 After completing these three studies, we planned to undertake a randomized phase III trial to establish a standard regimen. As we were planning the randomized trial, we learned of a published, randomized, controlled trial comparing FU alone with a three-drug combination regimen consisting of FU, doxorubicin, and mitomycin. That study revealed no survival advantage in the combination regimen as compared with FU alone.10 Therefore, we decided to use FU alone as a control arm in our phase III study. On the basis of results of our phase II studies, as well as the widespread use of UFTM in Japan and FP use worldwide, we adopted both regimens for the investigational arms in our phase III study. In most Japanese studies at that time, only patients who had not received any prior adjuvant chemotherapy were accepted onto phase II/III studies, a policy we also adopted for this study. The primary end point of this study was overall survival; namely, whether one or both investigational arms showed a significantly prolonged survival as compared with the control arm of FU alone. The secondary end points were response rates, toxic effects, and progression-free survival.
Patient Eligibility All patients had to have histologically proven unresectable or recurrent gastric cancer with measurable or assessable lesions and had to be younger than 75 years of age. Patients also were required to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or better, the ability to take oral agents, no prior history other than surgery, and to fulfill the following criteria: WBC count  4,000/µL, hemoglobin 9.5 g/dL, platelets 100,000/µL, AST and ALT within three times the upper limit, bilirubin  2.0 mg/dL, serum blood urea nitrogen 25 mg/dL, creatinine 1.5 mg/dL, creatinine clearance 50 mL/min, and life expectancy of 8 weeks or longer. Patients with serious complications, active carcinoma at other sites, or large amounts of ascites were excluded. In the beginning of the study, in accordance with a 1992 JCOG policy, written informed consent was obtained from patients or from their family members. Over the course of the study, as doctors began to discuss the cancer diagnosis with patients rather than just with their family members, the informed consent procedure was changed to obtain the consent from patients themselves. This study protocol was approved by the Clinical Trial Review Committee of JCOG and by institutional review boards of each participating institution.
Randomization
Treatment Schedule
The FP regimen comprised continuous-infusion FU 800 mg/m2/d along with a 30-minute infusion of CDDP 20 mg/m2/d with adequate hydration for 5 consecutive days.8 Cycles were repeated every 4 weeks for up to six courses; the subsequent courses were administered without CDDP in the same schedule as the FU-alone regimen. The dose of FU was reduced to 600 mg/m2/d if one of the following toxic effects occurred during the previous course: grade 2 or lower stomatitis, diarrhea, or thrombocytopenia or grade 3 or lower leukopenia or bilirubinemia. If the serum creatinine level elevated to
The UFTM regimen administered was same as in the previous study.5 UFT 375 mg/m2/d bid was given by oral administration, with weekly bolus infusion of mitomycin 5 mg/m2. Both agents were suspended until recovery from toxicity, followed by 25% dose reduction in the subsequent course if one of the following toxic effects occurred: WBC count < 2,000/mm3, platelets < 75,000/mm3, or creatinine
Evaluations We adopted the Japanese response criteria proposed by the Japanese Research Society for Gastric Cancer.11 According to these criteria, the response for unmeasurable primary tumors was assessed by the same criteria on the basis of roentgenographic and endoscopic findings, as published previously.8 For measurable lesions, these Japanese criteria were the same as the standard definitions of World Health Organization response criteria. Objective responses were confirmed by central review at regular group meetings. Toxicity was evaluated using JCOG Toxicity Criteria.12 These criteria were based on the National Cancer Institute Common Toxicity Criteria.
Study Design and Statistical Analysis
Comparison of patient characteristics, toxicity, and response rates between groups were calculated by
Because of an immature infrastructure in clinical trials, the first statistically formal interim analysis was actually carried out in December 1995, 3 years after initiation of the study. The analysis revealed a significantly inferior survival in the UFTM arm than in the FU-alone control arm and less possibility of significant survival prolongation in the UFTM arm than in the FU-alone arm. On the basis of this result, the monitoring committee recommended the termination of enrollment onto the UFTM arm. After discontinuation of enrollment to the UFTM arm, random allocation to the remaining two arms continued. The second formal analysis was carried out after the final follow-up. Between September 1992 and March 1997, a total of 280 patients (FU alone, 105; FP, 105; and UFTM, 70) were enrolled onto the study from 31 institutions. Approximately one half of the patients (139/280) were registered from three institutions. All patients registered were eligible and were included in the analysis of survival, progression-free survival, and response rates on intention-to-treat basis. However, one patient in the FU-alone arm and three patients each in the FP and the UFTM arms were not included in the analysis for toxicity because they did not receive chemotherapy. The average follow-up time was 8.9 months in the FU-alone arm, 10.1 months in the FP arm, and 7.6 months in the UFTM arm.
Patient Characteristics
Compliance and Safety Profile The median number of courses actually administered in the FU-alone and the FP arms was two (range, one to 13) and three (range, one to 11), respectively, and the median administration of mitomycin in the UFTM arm was six times (range, one to 23). The most frequent reason patients came off-protocol was disease progression in all three arms. The next most frequent reason was toxic effects, which were experienced more frequently in the FP and the UFTM arms than in the FU-alone arm. Patients’ refusal of the treatment also was observed more in the FP arm (25%) than in the FU-alone (7%) and UFTM (7%) arms.
Adverse events in each arm are listed in Table 2
According to information from the off-treatment forms at the failure of the first-line treatment, at least 149 patients (53%) received second-line chemotherapy regimens: 60 (57%), 55 (52%), and 34 (49%) patients in the FU-alone, FP, and UFTM arms, respectively. The most frequent second-line treatment regimen in all three arms (administered to approximately 40% of patients) was a combination of methotrexate and FU. We adopted this same regimen in our second-line phase II study, which was carried out in parallel with this phase III study. The next most frequent second-line regimens were CDDP-containing regimens such as FP or a combination of irinotecan (CPT-11) and CDDP. According to information collected from off-treatment forms, these latter regimens were administered in less than 15% of the patients in all three arms.
Response
Survival The progression-free survival curves are drawn in Fig 1  . The median progression-free survival times were 1.9 months (95% CI, 1.3 to 2.7) in the FU-alone arm, 3.9 months (95% CI, 3.1 to 4.8) in the FP arm, and 2.4 months (95% CI, 1.3 to 3.2) in the UFTM arm. Patients in the FP group demonstrated significantly longer progression-free survival than did patients in the FU-alone group (P < .001).
The median survival times were 7.1 months (95% CI, 5.8 to 8.2) in the FU-alone arm, 7.3 months (95% CI, 6.0 to 9.7) in the FP arm, and 6.0 months (95% CI, 4.6 to 7.4) in the UFTM arm (Fig 2 ). There were no significant differences between the arms with respect to overall survival (P = .34 for FU alone v FP, P = .11 for FU alone v UFTM). One- and two-year survival rates in the FU-alone and FP arms were equivalent: 28% and 7%, respectively, in the FU-alone arm and 29% and 7%, respectively, in the FP arm. The one- and 2-year survival rates were lower in the UFTM arm: 16% and 4%, respectively.
In this study, the median survival times in the FP and UFTM arms were 7.3 and 5.8 months, respectively, which were similar to those in the previous study (7 and 6 months, respectively).5,9 The failure to demonstrate survival advantages in these investigational arms seemed to be caused by our underestimation of expected survival in the FU-alone control arm. On the basis of our previous experiences with this regimen (data not shown), we had expected a 6-month survival rate of 35% in the control arm. Contrary to our expectations, the control regimen provided a median survival of 7.1 months, which was equivalent to that in the FP arm, and even had a superior survival than the UFTM arm at the interim analysis. The median progression-free survival in the UFTM arm was slightly longer than that in the FU-alone arm; nevertheless, overall survival in the UFTM arm was inferior to the FU-alone arm. This discrepancy might be caused by prolonged hematologic toxicity from mitomycin, which would delay the initiation of second-line treatment. These conclusions seem to be similar to those mentioned by O’Connell.13 Although patients treated with the UFTM demonstrated an inferior survival at the interim analysis than did those treated with the FU alone, there were no significant differences between the two arms at the final analysis. This difference may result from the small sample size caused by the discontinued enrollment to the UFTM arm. However, we believe that our decision to terminate enrollment to the UFTM arm was appropriate, based on generally accepted scientific and ethical principles. As for comparing the FP arm with the FU-alone arm, although FP demonstrated a significantly longer progression-free survival than did FU alone, no significant differences were observed in overall survival between the two arms. These phenomena also were observed in other randomized studies. A Korean phase III study14 revealed that FP provided a significantly longer time to progression but no superiority in overall survival as compared with FU alone. A North Central Cancer Treatment Group trial15 also did not show a significant survival advantage in three-drug combination regimens as compared with FU alone. In our study, one factor that may have affected our ability to determine the difference in survival between the FU and the FP arms was the possible imbalance of prognostic factors between arms. Although statistically insignificant, the distribution of macroscopically scirrhous-type, liver, and peritoneal metastasis, which are possible predictive factors for worse prognosis, was rather frequent in the FP arm. In fact, use of the multivariate Cox analysis to adjust these factors revealed significant differences in the survival between the FU-alone and FP arms. These survival differences, however, may result from chance in conducting subgroup analysis and have only limited influence on interpretation of the primary conclusion of the study. After we obtained final results from this study, discussions were held about which regimen should be the reference arm in the next phase III study. Some investigators insisted that FP should be the reference arm because this regimen had a higher response rate and longer progression-free survival than did the FU alone. It was noted, however, that there was a higher incidence of toxic effects in the FP arm than in the FU-alone arm and that 25% of the patients in the FP arm refused to continue treatment. In addition, there were no remarkable differences between the two arms in the rate of patients receiving second-line treatment. Because the primary end point of this study was overall survival, and FU alone showed almost equivalent survival to FP and patients experienced less toxicity, we chose FU alone as the reference arm in our next study. There have been many reports of randomized phase III studies in patients with advanced gastric cancer. In Europe, a combination of high-dose methotrexate, FU, and doxorubicin (FAMTX) demonstrated a significantly superior response rate and survival than did a combination of FU, doxorubicin, and mitomycin (FAM) in a European Organization for Research and Treatment of Cancer (EORTC) phase III trial.16 The response rate and median survival after FAMTX treatment were 41% and 9.7 months, respectively. The subsequent EORTC phase III study, however, did not prove any superiority of FAMTX over FP or over a combination of etoposide and FU/leucovorin.17 The objective response rate and median survival of patients receiving FAMTX declined to 12% and 6.7 months, respectively, which seemed to be comparable to rates in the FAM arm in the former study. Another published randomized trial from the United Kingdom compared FAMTX with a combination of epirubicin, cisplatin, and FU (ECF).18 That study demonstrated a response rate and survival in the ECF arm significantly superior to that in the FAMTX arm. That study, however, included approximately 40% of patients with esophageal or esophagogastric cancer, and the median survival of patients treated with FAMTX was only 5.7 months. In addition, the median survival of 8.9 months shown in the ECF arm was similar to that in the FAMTX arm in the first EORTC study. On the basis of these results, there seems to be no progress in survival outcomes during the last decade. A regimen must overcome the threshold of approximately 9 months for overall survival and should probably confer close to 12 months in a well-designed study to be considered a new standard of care, as mentioned by Ajani.19 In considering the next study, there were some discussions about whether to pursue regimens with a high response rate or those with long tumor stabilization. One might argue that less-toxic regimens, such as FU alone in this study, have an effect of long tumor stabilization. Our current results, however, did not show such evidence, because the progression-free survival of patients receiving FU alone was significantly shorter than those receiving FP. Therefore, we plan to pursue a regimen with high response rate and with favorable feasibility for long-term administration. Recently, new agents such as CPT-11 and S-1, a new oral fluoropyrimidine, have been developed in Japan. CPT-11 was initially combined with CDDP.20 This combination regimen yielded a response rate of 48% in all 44 patients and 59% in 29 chemotherapy-naive patients and a median survival of 322 days.21 S-1 also was active in a single-agent phase II study,22 with a response rate of 49%, median survival of 250 days, and good treatment compliance. Another study also showed similar results.23 On the basis of these Japanese results, JCOG has already initiated a three-arm randomized trial comparing FU alone with CPT-11 plus CDDP and with S-1 alone. This study requires a large sample size of 450 patients, and its primary end point is overall survival. We still believe that overall survival is the most reliable and reasonable end point for future studies. A new standard regimen should demonstrate a significant prolongation of overall survival as compared with FU alone and should exceed the current median threshold of survival of 9 months.
The following investigators and institutions participated in this study: T. Imamura, MD, Sapporo Kosei Hospital, Sapporo; H. Honma, MD, National Sapporo Hospital, Sapporo; Y. Tsuji, MD, Tonan Hospital, Sapporo; H. Sasagawa, MD, Rumoi Municipal Hospital, Rumoi; S. Matsumoto, MD, Asahikawa Red-Cross Hospital, Asahikawa; T. Ishii, MD, National Hakodate Hospital, Hakodate; Y. Sakata, MD, Aomori Prefectural Hospital, Aomori; A. Kanou, MD, Iwate Prefectural Hospital, Morioka; H. Saito, MD, Yamagata Prefectural Hospital, Yamagata; H. Komatsu, MD, Yonezawa Municipal Hospital, Yonezawa; A. Nakamura, MD, Asahi General Hospital, Asahi; A. Ohtsu, MD, National Cancer Center Hospital East, Kashiwa; Y. Shimada, MD, National Cancer Center Hospital, Tokyo; M. Matsuoka, MD, Misyuku Hospital, Tokyo; T. Goya, MD, Kyorin University Hospital, Tokyo; A. Hijikata, MD, Ohashi Hospital, Toho University, Tokyo; Y. Kuraishi, MD, Jikei University Hospital, Tokyo; W. Koizumi, MD, East Hospital, Kitasato University, Sagamihara; Y. Miyata, MD, Saku Central Hospital, Nagano; N. Yamamichi, MD, Fukui Prefectural Center for Adult Disease, Fukui; H. Iwase, MD, National Nagoya Hospital, Nagoya; K. Morise, MD, Nagoya University Hospital, Nagoya; M. Hayakawa, MD, Meitetsu Hospital, Nagoya; T. Sasai, MD, National Okayama Hospital, Okayama; S. Mukai, MD, Kure Kyosai Hospital, Kure; N. Ikeda, MD, Mitoyo General Hospital, Kagawa; K. Kawai, MD, Kagawa Prefectural Hospital, Takamatsu; Y. Shiotani, MD, Sakaide Municipal Hospital, Sakaide; and I. Hyodo, MD, National Shikoku Cancer Center, Matsuyama.
We thank Professor Yasuo Ohashi (Tokyo University) for planning the study design; Miyuki Niimi, PhD (JCOG Data Center) for data management; and all participants who contributed to this study.
This work was supported by Grant-in-Aid (5S-1, 8S-1, 11S-3, 11S-4) from the Ministry of Health, Labour, and Welfare, Japan. Presented in part at the Thirty-fifth Annual Meeting of the American Society of Clinical Oncology, 1999.
1. Health and Welfare Statistics Association: The movement of population.J Health Welfare Stat 46 (Suppl):41–72, 1999 2. Murad AM, Santiago FF, Petroianu A, et al: Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer 72:37–41, 1993[CrossRef][Medline]
3. Glimelius B, Hotfmann K, Haglund U, et al: Initial or delayed chemotherapy with best supportive care in advanced gastric cancer. Ann Oncol 5:189–190, 1994 4. Pyrhonen S, Kuitumen T, Nyandoto P, et al: Randomized comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus best supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 71:587–591, 1995[Medline] 5. Kurihara M, Izumi T, Yoshida S, et al: A cooperative randomized study on tegafur plus mitomycin C in the treatment of advanced gastric cancer. Jpn J Cancer Res 82:613–620, 1991[CrossRef][Medline] 6. Koizumi W, Kurihara M, Sasai T, et al: A phase II study of combination therapy with 5'-deoxy-5-fluorouridine and cisplatin in the treatment of advanced gastric cancer with primary foci. Cancer 72:658–662, 1993[CrossRef][Medline] 7. Shimada Y, Yoshida S, Ohtsu A, et al: A phase II study of EAP (etoposide, adriamycin and cisplatin) in the patients with advanced gastric cancer: Multi-institutional study. J Jpn Soc Cancer Ther 26:280, 1991 (abstract 227) 8. Ohtsu A, Shimada Y, Yoshida S, et al: Phase II study of protracted infusional 5-fluorouracil combined with cisplatinum for advanced gastric cancer: Report from the Japan Clinical Oncology Group (JCOG). Eur J Cancer 30A:2091–2093, 1994[CrossRef][Medline]
9. Kelsen D, Atiq OT, Saltz L, et al: FAMTX versus etoposide, doxorubicin, and cisplatin: A random assignment trial in gastric cancer. J Clin Oncol 10:541–548, 1992
10. Cullinan SA, Moertel CG, Fleming TR, et al: A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluorouracil versus fluorouracil and doxorubicin versus fluorouracil, doxorubicin, and mitomycin. JAMA 253:2061–2067, 1985 11. Japanese Research Society for Gastric Cancer: Japanese classification of gastric carcinoma. (English edition). Nishi M, Omori Y, and Miwa Y (eds). Part IV. Response assessment of chemotherapy for gastric carcinoma. Kanehara Syuppan, Tokyo, 1995, pp 89–100
12. Tobinai K, Kohno A, Shimada Y, et al: Toxicity grading criteria of the Japan Clinical Oncology Group. Jpn J Clin Oncol 23:250–257, 1993
13. O’Connell MJ: Etoposide, doxorubicin, and cisplatin chemotherapy for advanced gastric cancer: An old lesson revisited. J Clin Oncol 10:515–516, 1992 14. Kim NK, Park YS, Heo DS, et al: A phase III randomized study of 5-fluorouracil and cisplatin versus 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouracil alone in the treatment of advanced gastric cancer. Cancer 71:3813–3818, 1993[CrossRef][Medline] 15. Cullinan SA, Moertel CG, Wieand HS, et al: Controlled evaluation of three drug combination regimens versus fluorouracil alone for the therapy of advanced gastric cancer. J Clin Oncol 12:412–416, 1994[Abstract] 16. Wils JA, Klein HO, Wagener JT, et al: Sequential high-dose methotrexate and fluorouracil combined with doxorubicin—A step ahead in the treatment of advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Group. J Clin Oncol 9:827–831, 1991[Abstract]
17. Vanhoefer U, Rougier P, Wilke H, et al: Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Group. J Clin Oncol 18:2648–2657, 2000
18. Webb A, Cunningham D, Scarffe H, et al: Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15:261–267, 1997
19. Ajani JA: Standard chemotherapy for gastric carcinoma: Is it a myth? J Clin Oncol 18:4001–4003, 2000
20. Shirao K, Shimada Y, Kondoh H, et al: Phase I–II study of irinotecan hydrochloride combined with cisplatin in patients with advanced gastric cancer. J Clin Oncol 15:921–927, 1997
21. Boku N, Ohtsu A, Shimada Y, et al: Phase II study of a combination of irinotecan and cisplatin against metastatic gastric cancer. J Clin Oncol 17:319–323, 1999 22. Sakata Y, Ohtsu A, Horikoshi N, et al: Late phase II study of novel oral fluoropyrimidine anticancer drug S-1 (1M tegafur-0.4M gimestat-1M otastat potassium) in advanced gastric cancer patients. Eur J Cancer 34:1715–1720, 1998[CrossRef][Medline] 23. Koizumi W, Kurihara M, Nakano S, et al: Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced gastric cancer. Oncology 58:191–197, 2000[CrossRef][Medline] Submitted April 18, 2002; accepted September 12, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
and ß error of 0.05 and 0.2, respectively. In this study design, FU was the control arm and was compared with two other arms. These calculations required a sample size of 309 patients from 31 participating institutions, for a total of 103 patients in each arm. The planned duration of accrual was 3 years, and planned follow-up time was 1 year after the last patient registration. Interim analysis was planned 1 year after the initiation of the study and every 6 months thereafter until the final analysis, using O’Brien-Fleming methods. 
2 test. All patients registered were included in the survival analysis on an intention-to-treat basis. Overall survival was calculated from the date of registration to the date of death from cause or to the last contact date, using the Kaplan-Meier method. Progression-free survival was calculated from the date of registration to the date of documented disease progression or the date of death from any cause if there was no disease progression beforehand. If there was no documented disease progression and if the patient had not died, data on progression-free survival were censored on the date that the absence of progression was confirmed. If a patient died without information on progression, data on progression-free survival were censored on the last date on which progression could be ruled out by the review of follow-up forms. Survival and progression-free survival curves were calculated by the Kaplan-Meier method and compared by the log-rank test. 
