1 Department of Internal Medicine, 2 Department of Surgery and 3 Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
Received 26 November 2001; revised 13 May 2002; accepted 29 May 2002
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Abstract |
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A phase III single-center randomized trial was performed in order to determine whether the addition of mitomycin C (MMC) and/or doxorubicin to 5-fluorouracil (5-FU) as adjuvant chemotherapy could influence survival in patients with curatively resected gastric cancer.
Patients and methods:
A total of 416 patients who had undergone curative resection for stage IBIIIB gastric adenocarcinoma were stratified according to the stage and type of surgery, and then randomized to receive one of the three chemotherapy regimens, 5-FU alone (F) or 5-FU and MMC (FM) or 5-FU, doxorubicin and MMC (FAM) within 5 weeks after surgery.
Results:
Of 416 patients registered, 395 (133 in F, 131 in FM and 131 in FAM) were assessable. Median follow-up duration was 91 months. Five-year overall survival rates were 67.2% for F, 67.0% for FM and 66.7% for FAM (P = 0.97). Five-year disease-free survival rates were 62.1% for F, 63.3% for FM and 62.5% for FAM (P = 0.83). Hematological toxicities were more frequent in the FM and FAM groups, whereas stomatitis was more common in the F group.
Conclusions:
Compared with adjuvant 5-FU alone, the addition of MMC and/or doxorubicin to 5-FU did not influence survival in patients with resected gastric cancer.
Key words: adjuvant chemotherapy, doxorubicin, 5-fluorouracil, gastric cancer, mitomycin C, phase III trial
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Introduction |
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The most effective treatment for gastric carcinoma is curative surgical resection of the primary tumor. However, a substantial number of patients eventually die of locoregional recurrences and/or distant metastases after curative resection. In an attempt to improve prognosis, a number of randomized trials investigating the role of adjuvant chemotherapy have been conducted. However, the efficacy of adjuvant chemotherapy is still controversial and varies between Western and Asian trials [3, 4]. Meta-analysis of Western trials did not demonstrate the benefit of adjuvant chemotherapy after curative resection [5]. Conversely, some Asian studies have demonstrated the efficacy of adjuvant chemotherapy after curative resection [610]. Based on these observations, adjuvant chemotherapy has been recommended in Asian countries. Moreover, Grau et al. [11] reported a positive result for adjuvant mitomycin C (MMC) from a randomized trial, and more recently a meta-analysis for Western trials also suggested that adjuvant chemotherapy conferred survival benefit compared with no-treatment controls [12]. Therefore, although adjuvant chemotherapy following surgery is not regarded as standard treatment in gastric cancer, it is important to reinforce efforts to find more effective adjuvant chemotherapy regimens.
Most studies performed before 1990 used less-effective chemotherapeutic agents, such as nitrosourea. In theory, the best regimen for adjuvant chemotherapy would be the one with the highest response in advanced gastric cancer. Since FAM [5-fluorouracil (5-FU), doxorubicin and MMC] was reported to be effective in advanced gastric carcinoma [13] these drugs have been considered as standard active agents for advanced gastric cancer. It is therefore reasonable to test whether these drugs can play a role as adjuvant therapy in resected gastric cancer.
In this study, we used a 5-FU-alone arm as treatment control and performed a randomized trial to determine whether MMC-containing (FM) and doxorubicin-containing (FAM) regimens could impact on survival when compared with 5-FU alone in resected gastric cancer.
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Patients and methods |
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To ensure equal distribution of prognostic factors among treatment groups, patients were stratified according to disease stage (stage IB, II, IIIA or IIIB) and the operation method (total or proximal gastrectomy versus distal subtotal gastrectomy) and then randomized to receive one of three chemotherapy regimens. Patients were assigned to one of the three arms by a computer-generated randomization.
Surgery
Curative resection was defined as en bloc removal of gastric tumor with macroscopically and microscopically free proximal and distal resection margins together with en bloc resection of the greater and lesser omentum and adherent organs, and extended lymphadenectomy (D-2 dissection) [14, 15].
Chemotherapy
Chemotherapy was started within 35 days after surgery according to the schedule (Table 1). The maximum doses per day were limited as follows: 5-FU 1000 mg, doxorubicin 50 mg, and MMC 15 mg.
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Follow-up evaluation
Patients were evaluated every 4 weeks for the first 12 months, every 3 months for the next 12 months, and every 6 months until the end of the fifth year, and yearly thereafter. Follow-up examinations included the patients general condition, body weight, performance status, physical examination, complete blood cell count, laboratory tests, chest X-ray (every 3 months for the first 2 years, and subsequently at every follow-up), and upper gastrointestinal tract series and abdominal ultrasonography (alternately, every 3 months for the first 2 years, and subsequently at every follow-up).
Statistical analysis
The primary end points of the study were overall survival (OS) and disease-free survival (DFS). OS and DFS were measured from the date of surgery. OS was defined as the time from surgery to the date of death from any cause and DFS was measured to the date of recurrence of gastric cancer. The sample size was calculated to ensure that the study had a power of 90% to detect a difference of 20% in the 5-year survival rate at the 5% level of significance (two-tailed). One hundred and twenty-eight patients in each arm were needed. It was assumed that the expected 5-year survival rate for the 5-FU-treated group was 45%.
Survival probabilities were estimated by the life-table method and survival comparison was made by use of the generalized Wilcoxon test. The Cox proportional hazards model was used to find significant prognostic factors. Backward regression was used to find the most significant factors, and variables were eliminated by likelihood-ratio statistics based on conditional parameter estimates. Comparison of three groups based on patient characteristics was performed using the ANOVA method for continuous data and the chi-square test for discrete data. The SPSS program for Windows (Release 9.0.0) was used for analysis.
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Results |
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Patients characteristics
Of the 395 patients, 133 made up the 5-FU group, 131 the FM group and 131 the FAM group. Median age of all patients was 53 (range 2175) and male to female ratio was 295:100. The three groups were well balanced for sex, age, stage and type of surgery (Table 2).
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Relapse
One hundred and thirty-six of 395 patients (34.4%) eventually relapsed and 120 patients died of disease relapse. Around 30% of patients had locoregional relapse and the remaining 70% experienced peritoneal or distant metastasis. There was no significant difference in rate and pattern of relapse among treatment groups (Table 3). During follow-up, 137 of 395 patients died. Seventeen patients died without evidence of relapse. Causes of these deaths included the following: five from bowel obstruction, three from other malignancy (prostate carcinoma, lung carcinoma and acute leukemia), three from cardiovascular diseases, and two from infections which were not related to chemotherapy (sepsis and pulmonary tuberculosis). The causes of the deaths of the remaining four patients could not be evaluated because cause of death information was not available.
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Discussion |
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In Asia, the strategy for adjuvant therapy seems to be different from that of the West [4]. Some studies, mostly from Japan, demonstrated a benefit for adjuvant chemotherapy, mainly MMC-containing regimens [610], and there was a tendency to think that a surgery-alone group as the control arm may be considered ethically inappropriate. As a result, postoperative chemotherapy is usually recommended and a treatment control is commonly used. Based on the positive results of a recent meta-analysis in the Western [12] and Asian [610] trials, the approach of finding more effective regimens seems to be important for improving prognosis in resected gastric cancer.
In this study, we used 5-FU alone as a control arm instead of no treatment because 5-FU alone was reported to be marginally effective as a single agent and well tolerated in patients with advanced gastric cancer. Since FAM was found to be an active chemotherapy regimen in advanced gastric cancer in the 1970s [13], doxorubicin and MMC have been considered active drugs for advanced gastric cancer [18]. Clinical trials on the FAM regimen in an adjuvant setting have been tested, but no statistically significant benefit was found between treated patients and controls [1921]; but there have been encouraging results regarding MMC in the Western and Asian trials. Grau et al. [11] reported positive results with adjuvant MMC and Nakajima et al. [6] also demonstrated the benefit of single-agent MMC as an adjuvant chemotherapy. Therefore, we thought that a randomized trial was required to demonstrate whether the addition of MMC and/or doxorubicin may impact on survival as compared with 5-FU alone in Korean patients with resected gastric cancer.
In this study, we did not see significant survival differences between treatment groups. At the time this study was designed, we assumed that the expected 5-year survival rate of patients with gastric carcinoma in the control arm was 45%. The conclusion is based on the assumption of the initial study design. However, the actual 5-year OS rate of this study (67.2%) was higher than expected. The difference between expected and actual survival rates may be due to improved surgical technique or stage migration with early detection of gastric cancer. We calculated the power with the actual number of patients enrolled in this study based on a 5-year OS rate of 60% for the control arm to detect a difference of 10% at the 5% level of significance (two-tailed). The power is about 22%. With an assumption of 60% 5-year survival in the control arm, 376 patients in each arm are needed to detect a difference of 10% at the 5% level of significance with a power of 80% (two-tailed). To reach a conclusion of adequate statistical power, a large multicenter study is recommended.
According to TNM stage, 5-year OS were 91.3% for stage IB, 76.2% for stage II, 66.5% for stage IIIA and 48.7% for stage IIIB. These survival rates are generally higher than the survival rates reported in Western studies, but similar to Japanese results [2225]. The difference in survival rates between Japanese and Western studies may be due to the difference in surgical techniques used in Japan and the West [26], or due to the initiation time of adjuvant chemotherapy, which is earlier in Japanese studies than Western studies. In our study, the standard surgical procedure was gastrectomy with extended lymphadenectomy, similar to Japanese studies. But, the initiation time of adjuvant chemotherapy was similar to the Western studies, mean 29.5 days. So the difference in surgical procedure between Japan and the West may be a more important cause of the difference in the survival rate. But other causes of the difference may be possible, such as the difference in the biological characteristics of the tumor itself.
In conclusion, the addition of MMC and/or doxorubicin to 5-FU for adjuvant chemotherapy did not prolong the survival of patients with resected gastric cancer in our trial. A multicenter clinical trial with a larger number of patients is recommended.
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Acknowledgements |
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Footnotes |
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References |
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