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Randomized Clinical Trial of Adjuvant Mitomycin Plus Tegafur in Patients With Resected Stage III Gastric Cancer

Address reprint requests to Lluis Cirera, MD, Medical Oncology Unit, Hospital Mútua de Terrassa-Universitat de Barcelona, Plaça Dr Robert 5, 08221 Terrassa, Barcelona, Spain

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: The efficacy of adjuvant chemotherapy in gastric cancer is controversial. We conducted a phase III, randomized, multicentric clinical trial with the goal of assessing the efficacy of the combination of mitomycin plus tegafur in prolonging the disease-free survival and overall survival of patients with resected stage III gastric cancer.

PATIENTS AND METHODS: Patients with resected stage III gastric adenocarcinoma were randomly assigned, using sealed envelopes, to receive either chemotherapy or no further treatment. Chemotherapy was started within 28 days after surgery according to the following schedule: mitomycin 20 mg/m² intravenously (bolus) at day 1 of chemotherapy; 30 days later, oral tegafur at 400 mg bid daily for 3 months. Disease-free survival and overall survival were estimated using the Kaplan-Meier analysis and the Cox proportional hazards model.

RESULTS: Between January 1988 and September 1994, 148 patients from 10 hospitals in Catalonia, Spain, were included in the study. The median follow-up period was 37 months. The tolerability of the treatment was excellent. The overall survival and disease-free survival were higher in the group of patients treated with chemotherapy (P = .04 for survival and P = .01 for disease-free survival in the log-rank test). The overall 5-year survival rate and the 5-year disease-free survival rate were, respectively, 56% and 51% in the treatment group and 36% and 31% in the control group.

CONCLUSION: Our positive results are consistent with the results of recent studies; which conclude that there is a potential benefit from adjuvant chemotherapy in resected gastric cancer.

	INTRODUCTION

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GASTRIC CANCER IS a very aggressive disease, with a tumor doubling time of 40 to 80 days. Surgery is the treatment of choice, with less than 30% 5-year survival for patients with complete tumor resection.^1-3 Although the incidence of gastric cancer in Western countries has decreased progressively in recent decades, the prognosis of the disease has not changed in the last 30 years. Global survival to 5 years remains between 7% and 15%.^4-7

The efficacy of adjuvant chemotherapy in this disease is controversial. The results of trials performed to study its effects did not recommend its use.^8,9 On the other hand, in Japan, the administration of mitomycin and fluoropyrimidines has been considered standard adjuvant chemotherapy since the late 1970s.^10,11 However, the Japanese results have been criticized for the lack of randomized studies to confirm efficacy.^12,13

In 1983, a Western group reported the results of a randomized clinical trial showing a significant disease-free and overall survival advantage with the administration of high doses of adjuvant mitomycin, as a single agent, when administered within 4 weeks after complete resection in patients with stage II and III gastric cancer.¹⁴ These considerations prompted us to conduct a phase III, randomized, multicentric clinical trial, initiated in 1988, with the goal of assessing the efficacy of the combination of mitomycin plus tegafur in prolonging disease-free survival and overall survival of patients with resected, stage III gastric cancer.

	PATIENTS AND METHODS

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Patients
Patients were eligible for this study if they had undergone curative resection of a pathologically confirmed gastric adenocarcinoma in stage III (pT1-T3, N1-N2, M0; pT4a, N0-N2, M0 [according to the 1983 American Joint Committee on Cancer Classification])¹⁵; were 75 years old or younger; had a Karnofsky index equal to or greater than 70; had normal renal, liver, and bone marrow function; had no associated diseases contraindicating the administration of chemotherapy; and had provided informed consent. Surgical treatment consisted of complete resection of the tumor, defined as surgical margins free from disease and extended lymphadenectomy, ie, type R-2 resection (according to the Japanese Research Society for Gastric Cancer, 1981).¹⁶ A total of 10 hospitals in the area of Barcelona, Spain, participated in the study. The study was approved by the Institutional Review Board of the coordinating center (Hospital Mútua de Terrassa, Terrassa, Spain).

Chemotherapy
After surgery, patients were randomly assigned, with equal probability, to receive either chemotherapy or no further treatment. The randomization was administered at the coordinating center using sealed envelopes. Chemotherapy was started within 28 days after surgery and was administered according to the following schedule: mitomycin 20 mg/m² intravenously (bolus) at day 1 of chemotherapy; 30 days later, oral tegafur was initiated at 400 mg bid daily for 3 months. Toxic effects were evaluated using the World Health Organization criteria.¹⁷

Follow-Up Evaluation
The follow-up for all patients in both study arms consisted of a physical examination, laboratory tests, abdominal computed tomography scan every 6 months, and a yearly upper gastrointestinal endoscopy during the first and second year after surgery. After the second year, follow-up consisted of a physical examination, laboratory tests, and abdominal computed tomography scan annually, and an upper gastrointestinal endoscopy every 2 years. In addition, patients randomized to receive chemotherapy were given a physical examination and laboratory tests (hematology, liver-, and renal function) monthly during the 4 months of chemotherapy.

Statistical Analysis
The sample size was calculated to ensure that the study had a power of 80% to detect a difference of 20% in the 5-year survival rate with an alfa error of 0.05. It was assumed that the expected 5-year survival rate for the control group was 35% to 40%.¹⁸ Differences in age and in the frequency of individual prognostic factors were assessed with the Student's t and the ² tests. Kaplan-Meier analysis and the log-rank test were used to evaluate differences in survival and disease-free survival.¹⁹ The size of the treatment effect was assessed with the Cox proportional hazards regression¹⁹ and the number of patients needed to treat to avoid an adverse outcome (NNT).²⁰ The NNT is an estimate of the number of patients, who would not have achieved a desired outcome with the control regimen, that would need to be treated for one of them to achieve a desired outcome. The NNT is the inverse of the difference between the event rate in the experimental group and the event rate in the control group. All P values were two-sided.

	RESULTS

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Between January 1988 and September 1994, 156 patients were admitted to the study from the 10 participant hospitals. Eight patients were found not to have stage III cancer after pathologic review and were excluded from the analysis. Of the 148 eligible patients, the control group included 72, and the treatment group included 76. All patients received the treatment to which they were randomized. The cut-off date for statistical analysis was January 1, 1998. Figure 1 shows the flow diagram of patients through the stages of the trial.

View larger version (29K): [in this window] [in a new window]   Fig 1. Flow diagram of patients through the stages of the clinical trial.

At baseline, the two groups were similar in demographic characteristics, tumor size, tumor histology, and surgical technique (Table 1). There was a larger percentage of patients with affected nodes in the control group (93%) compared with the treatment group (80%), both overall and by the N1 and N2 nodal categories. However, these differences did not reach statistical significance (P = .07).

Toxicity
The tolerability of the treatment was excellent. Side effects were generally mild or moderate, and no modification of the treatment regimen was required in any patient (Table 2). There was a single episode of grade III neurocerebellar toxicity that was self-limited to 10 days. Four patients (5%) from the chemotherapy group did not complete the treatment, three patients by choice and one because of intercurrent viral hepatic infection.

Survival and Disease-Free Survival
Table 3 lists the overall results for the outcome variables after a median follow-up period of 37 months (range, 3 to 122 months). There were more deaths and more patients with disease progression in the control arm than in the treatment arm. Overall 5-year survival and disease-free survival rates were higher in the treatment arm than in the control arm. Five patients (two in the control arm and three in the treatment arm) died because of cardiovascular disease. Table 4 lists the relapse sites. The Kaplan-Meier curves were statistically significant and showed a higher overall survival and disease-free survival in the group of patients treated with chemotherapy (Fig 2).

View larger version (14K): [in this window] [in a new window]   Fig 2. Kaplan-Meier survival and disease-free survival curves by therapeutic options.

The estimated hazard ratio for the treatment group, when compared with the control group, was 0.60 (95% confidence interval (CI), 0.39 to 0.93) for mortality and 0.55 (95% CI, 0.36 to 0.85) for relapse. These results remained the same after adjusting for grade of nodal infiltration. The NNT to avoid a death during the first 5 years was 5 (NNT = 1/[0.56 - 0.36]), and the NNT to avoid a relapse was 4 (NNT = 1/[0.55 - 0.31]).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In this study of patients with resected stage III gastric cancer, we found that adjuvant chemotherapy with a single dose of mitomycin (20 mg/m² intravenously) and oral tegafur at 400 mg bid daily for 3 months significantly improved survival and disease-free survival. There was a greater percentage of patients with infiltrated nodes in the control group, but chemotherapy was shown to be effective when controlling for this difference. The fact that death and relapse can be avoided by one in five and one in four patients, respectively, when compared with the control group, suggests that this chemotherapy regime is clinically cost-effective.

In Japan, where the incidence of the disease remains high, improvements in global survival have been the result of, according to most authors, screening campaigns, early diagnosis, radical surgery with extensive lymphadenectomy, and the administration of adjuvant chemotherapy with mitomycin and fluoropyrimidines.^21-24 In 1977, a Japanese group reported a statistically significant survival advantage in patients given postoperative intermittent mitomycin.²⁵ Nakajima²⁶ reported that mitomycin produced a significant survival advantage in patients with serosal and/or nodal involvement. When adding tegafur to mitomycin, he obtained similar results to using mitomycin alone.^27,28 In 1983, in a randomized Western trial, significant improvement in disease-free survival and overall survival were reported with the administration of four courses of high-dose mitomycin (20 mg/m²) in resected stage II to III gastric cancer patients.¹⁴ These results remained significant after 10 years of follow-up.²⁹ Severe toxicity caused by mitomycin was observed in all studies and resulted in decreases in survival in a subset of patients in one of them.²⁶ Although none of the previous trials have been confirmed by other European or United States studies, mitomycin was recommended as adjuvant chemotherapy within 6 weeks after surgery.^21,30

We based the dose of mitomycin on a previous Western experience.¹⁴ To achieve less toxicity, we used a single high-dose of mitomycin within the recommended timing.^21,30 Tegafur is a highly lipophilic prodrug that is slowly metabolized in vivo into fluorouracil.^31-40 Tegafur (1-tetrahydro-2-furanyl) has 100% bioavailability and a half-life of 6 to 17 hours. We used 800 mg/day administered as two fractionated daily doses, as was done in some Japanese studies,^11,36 so as to not exceed the daily dose of the drug (1 g/m²), which can cause an increase in neurologic and gastrointestinal toxicity.^37-40 The duration of treatment (3 months), with a total dose of 72 grams, seemed adequate for the natural evolution of the disease. Treatment was well-tolerated and associated with mild or moderate toxicity. The hemolytic-uremic syndrome, which has been reported with the administration of high doses of mitomycin,⁴¹ was not seen in any of our patients, probably as a result of the use of a single dose of this drug.

The most frequent relapses occurred at the local and peritoneal sites, with the incidence of hepatic metastases being lower in the treatment group. These findings are similar to those reported in other studies.^29,42,43 According to some authors, systemic chemotherapy can exercise a protective effect with regard to distant metastases, but not at the tumor bed.^21,29,43 For this reason, intraperitoneal chemotherapy has been administered in conjunction with systemic chemotherapy in some studies.^44,45

In our study, the 5-year survival of 56% of patients in chemotherapy was higher than a previous Spanish trial with a 5-year survival rate of 41% in patients treated with mitomycin alone¹⁴ and similar to a randomized Japanese clinical trial with a 5-year survival rate of 60% in patients treated with mitomycin and oral fluorouracil.⁴⁶ In a recently published randomized Spanish clinical trial, mitomycin and tegafur resulted in a 5-year survival rate of 67% versus 44% in patients treated with mitomycin alone.⁴⁷ The large 5-year survival rate observed in our control patients can be explained by the inclusion of patients with a good prognosis who would be assigned to stages I and II according to the 1993 American Joint Committee on Cancer classification.⁴⁸

Although gastric cancer has been shown to be relatively chemosensitive, with a 15% to 60% response rate to therapy in advanced stages of the disease,^49-54 the efficacy of adjuvant chemotherapy is still controversial. Of the two published reviews found on this topic, one was a narrative review that presented important methodologic limitations.⁸ The second review showed a positive treatment effect (odds ratio = 0.88), but the CI for the odds ratio included the null value by a small margin (0.72 to 1.08).⁹ A very recent review from the University of Ottawa (Earle, personal communication, May, 1998) concluded that adjuvant chemotherapy may be associated with a small survival benefit (odds ratio for death 0.81, 95% CI, 0.67 to 0.98) in patients with resected gastric carcinoma.

The positive results of our study are consistent with the results of recent studies, which conclude that there is a potential benefit from adjuvant chemotherapy in resected gastric cancer.^43,46,47 There is a need for an updated, systematic review of adjuvant chemotherapy in gastric cancer to determine whether there is enough evidence to support its use or whether more clinical trials are needed.

	ACKNOWLEDGMENTS

 
We thank Ramón Esbrí, Montse Rué, and Marta Roqué for their assistance in the statistical analysis and John Paul Glutting for his assistance with the manuscript.

	NOTES

 
Grupo Cooperativo para el estudio del Cáncer Gástrico de los Hospitales Comarcales de Catalunya (The Catalan County Hospitals Cooperative Group on Gastric Cancer).

Medical Oncology Units of: Hospital Mútua de Terrassa, Terrassa; Hospital Arnau de Vilanova, Lleida; Hospital General de Vic, Vic; Hospital del Mar, Barcelona; Consorci Hospitalari de Mataró, Mataró; Hospital de Terrassa, Terrassa; Hospital General de Granollers, Granollers; Corporació Sanitària Parc Taulí, Sabadell; Hospital General de Manresa, Manresa; Hospital-Residència Sant Camil, Sant Pere de Ribes, Spain.

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Submitted March 4, 1999; accepted July 21, 1999.

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