Evaluation of Adjuvant UFT for Gastric Cancer

ABSTRACT: In a trial of adjuvant chemotherapy with mitomycin and 5-FU followed by oral UFT for T1 and T2 gastric cancer after curative gastrectomy, there was no significant difference in survival between the treated and control (surgery alone) groups (5-year survival rate, 82.9% control vs 85.8% treated). Although not significantly different, 5-year survival for patients with T2 cancer was slightly higher in the treated group than in the control group (76.9% control vs 83.0% treated). This finding suggests that T2 cancer should remain the target of further trials of adjuvant chemotherapy. [ONCOLOGY 14(Suppl 9):82-86, 2000]

Introduction

Recent trials of adjuvant chemotherapy in Japan are characterized by regimens that consist of intravenous (IV) induction chemotherapy and oral administration of 5-FU (5-fluorouracil) or its derivatives.[1,2] The combination drug UFT (uracil and tegafur) is the most frequently employed anticancer drug in Japan where, until now, no previous trials have evaluated the survival benefits of oral chemotherapy alone. However, UFT had been used as part of maintenance chemotherapy after IV induction chemotherapy. Therefore, given its proven survival benefits and low toxicity profile,[3] orally administered UFT may prove convenient for treating patients at home.

From 1984 to 1998, the Gastric Cancer Surgical Study Group of the Japan Clinical Oncology Group (JCOG) conducted a series of three trials of adjuvant chemotherapy after curative gastrectomy.[4] These regimens were based mainly on various combinations of mitomycin (Mutamycin): mitomycin plus 5-FU (MF) and mitomycin plus 5-FU plus cytarabine (Ara-C, Cytosar) (MFC) with or without UFT (study 8801). The results of this study[5] led us to conduct a new trial, beginning in 1998, to evaluate the survival benefits of UFT alone after curative surgery for T2 gastric cancer with lymph node metastasis.

Patients and Methods

From 1988 to 1992, seven cancer centers in Japan participated in this randomized, controlled trial of curative gastrectomy, followed by IV mitomycin plus 5-FU followed by oral UFT, for serosa-negative gastric cancer. A total of 579 patients were allocated randomly to undergo surgery plus chemotherapy or surgery alone. Six patients were excluded because they did not meet the eligibility criteria.

Entry criteria were histologically proven adenocarcinoma, age £ 75 years, macroscopically serosa-negative cancer eradicated by curative gastrectomy and normal liver, kidney, and bone marrow functions. The chemotherapy consisted of IV mitomycin 1.4 mg/m² twice a week for 3 weeks plus 5-FU 166.7 mg/m² twice a week for 3 weeks; oral UFT 300 mg/day was then administered for 18 months. The control group received no additional therapy after surgery. The study design is shown in Figure 1. The primary end point was survival, although cause of death and type of recurrence were also studied.

Results

The distribution of main prognostic factors and the method of surgery across the two groups were almost identical, although the proportion of patients with absolute curative surgery was slightly higher in the treatment group (Table 1). Among the 573 eligible patients, 188 (32.8%) were in the pT1 category and 304 (53.1%) had no lymph node metastasis on microscopy. Toxicity was generally mild: leukocytopenia was observed in 9% of patients and throm-bocytopenia in 0.7%.

At a median follow-up of 72 months, the overall 5-year survival rate was 82.9% in the control group and 85.8% in the treatment group (Figure 2). Among T1 patients, 5-year survival was 94.9% in the control group and 92.0% in the treatment group (Figure 3). Survival for T2 patients in the control and treated groups was 76.9% and 83.0%, respectively (Figure 4). During follow-up, 39 (13.7%) patients in the control group and 29 (10.9%) in the treatment group suffered cancer recurrence.

Hematogenous metastasis was the most common type of recurrence in both groups, followed by peritoneal dissemination.

Conclusions

Due to a lack of evidence of any survival benefit, no standard adjuvant chemotherapy has been established for gastric cancer. However, a few recent meta-analyses of adjuvant chemotherapy trials[6,7,8] have revealed survival benefits in patients with locally advanced gastric cancer after curative gastrectomy for locally advanced gastric cancer (T2-T3). These results, reported in 1999, showed no survival benefit with the MF plus UFT regimen in postoperative T1-T2 gastric cancer, although a slightly higher survival rate was observed for the treatment group in the T2 subset. T2 cancer should remain the target of further adjuvant chemotherapy trials.

The response rate to UFT in advanced gastric cancer was 27%,[9] with no serious side effects observed. If oral administration of UFT could result in increased survival in postoperative patients with T2 cancer, it might be useful as an adjuvant to surgery in terms of improved quality of life for these patients.[10]

A new trial has been under way since 1997 by the National Surgical Adjuvant Study (NSAS) Group (Figure 5). The goal of this study is to accumulate 500 cases of T2 cancer with lymph node metastasis. Results of this study will provide important data for future trial designs of adjuvant chemotherapy for gastric cancer.

References:

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2. Sano T, Sasako M, Katai H, et al: Randomized controlled trials on adjuvant therapy for gastric cancer: Japanese experience, in Nakajima T, Yamaguchi T (eds): Multimodality Therapy for Gastric Cancer, pp 7-16. Tokyo, Springer Verlag, 1999.

3. Takiuchi H, Ajani JA: Uracil-tegafur in gastric carcinoma: A comprehensive review. J Clin Oncol 16:2877-2885, 1998.

4. Kitamura M, Nakajima T, Ohta K, et al: Adjuvant chemotherapy of gastric cancer: JCOG experience, in Nakajima T, Yamaguchi T (eds): Multimodality Therapy for Gastric Cancer, pp 32-41. Tokyo, Springer Verlag, 1999.

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6. Hermans J, Bonenkamp H: In reply to the editor. J Clin Oncol 12:879-880, 1994.

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8. Nakajima T, Ohta K, Ohyama S, et al: Meta-analysis of adjuvant chemotherapy trials for gastric cancer at the Cancer Institute Hospital, Tokyo, in Nakajima T, Yamaguchi T (eds): Multimodality Therapy for Gastric Cancer, pp 27-31. Tokyo, Springer Verlag, 1999.

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10. Hoff PM, Pazdur R, Benner SE, et al: UFT and leucovorin: A review of its clinical development and therapeutic potential in the oral treatment of cancer. Anticancer Drugs 9:479-490, 1998.