Fluorinated pyrimidine derivatives and mitomycin (Mutamycin) (MMC) have played a central role in chemotherapy for gastric cancer in Japan. In one randomized study, supported in part by a grant in Aid for Cancer Research (62s-1), the combined use of UFT (tegafur and uracil) and MMC, known as UFTM, was compared with a control regimen of combination tegafur/MMC (FTM). The response rate among evaluable patients in the UFTM group was 25.3% (20 of 79 patients), which was significantly superior to the 7.8% (seven of 90) achieved in the FTM group (P = .04). Although the median survival time was 180 days in both groups, patients in the UFTM group were found to have a significant advantage over those in the FTM group (P = .0398) after adjustment for major prognostic factors. UFTM therapy has therefore been considered standard chemotherapy for advanced gastric cancer in Japan.
Recently, combination therapies including cisplatin (Platinol) (CDDP), have been investigated and are reported to produce a high response rate. Among these combinations, CDDP plus fluorouracil (5-FU), known as FP, has been shown to exhibit a synergistic effect in some laboratory studies, as well as excellent clinical results in patients with gastric cancer.[3-5] From the viewpoint of improving the patients quality of life, we considered that it would be helpful to investigate the use of CDDP combined with an oral preparation in place of the intravenous 5-FU used in the FP regimen. Since it can be administered to outpatients, we expected that UFT plus CDDP (UFTP therapy) would have advantages. We obtained very interesting results from a laboratory study and a pilot clinical study of UFTP, and, based on these results, a phase II study is now under way.
To evaluate the effectiveness of chemotherapies for advanced gastric cancer, we established an experimental peritoneum model of gastrointestinal cancer by intraperitoneal transplantation of experimental mouse tumor Colon 26 PMF-15. This model was used to compare the effect on survival of four therapeutic approaches: no treatment (control), UFTM, FP, and UFTP. Both median and maximal survival times were longest for those in the UFTP group, followed in descending order by the FP, UFTM, and control groups. Significant survival differences were observed between the UFTP and control groups (P < .001) and between the UFTP and UFTM groups (P = .021). The reduction in body weight was small in the UFTP and FP groups compared with the UFTM and control groups, indicating that overall well being based on time-course changes in body weight were better in the former groups than in the latter.
In this study, the UFTP regimen suppressed tumor growth, prolonged the survival of mice and maintained these mice in relatively good condition. Therefore, UFTP therapy was expected to be clinically effective.
A pilot study was conducted to evaluate the antitumor effect and safety of UFTP therapy in patients with advanced gastric cancer. The subjects of the study had histologically and cytologically confirmed gastric cancer with measurable or evaluable lesions. Other eligibility criteria included age between 15 and 74 years, performance status of 0-2, and no prior therapyor prior therapy followed by a complete washout period. Patients also were required to have sufficient major organ function, including bone marrow (WBC
³ 4,000/mm3, platelet
³ 100,000/mm3), hepatic functions (AST, APT
£ 100 U, total bilirubin
£ 3.0 mg/dL) and renal function (serum creatinine level
£ 1.5 mg/dL, creatinine clearance
³70 mL/min). Finally, patients had to have a life expectancy of 12 weeks or longer and have no severe complications. All patients gave informed consent.
Treatment consisted of intravenous CDDP 30 mg/m2 administered for 8 hours/d on days 1-3 and a single oral UFT dose of 400 mg/m2/d administered on days 1 through 28. Treatment cycles were repeated every 28 days until evidence of disease progression or unacceptable toxicity. Antitumor effects were evaluated according to the Response Assessment of Chemotherapy for Gastric Carcinoma. Primary gastric tumors are strictly evaluated by x-ray and endoscopy and classified into three subtypes: (a) measurable, (b) not measurable but evaluable, and (c) diffusely infiltrating lesions. Of the 16 registered patients, 14 were evaluable for response. Extramural review revealed an overall response rate of 42.9% (95% confidence interval, 21.4% to 67.4%), with a 41.7% (5 out of 12) response rate for primary lesions (Table 1). The median survival time was 11.4 months.
To evaluate these data, we summarized the results of a recently reported phase II study of combination therapies including fluorinated pyrimidine derivatives and CDDP (Table 2). Although the present study was exploratory, the antitumor effects and excellent median survival time were comparable with those of the phase II studies.
In terms of safety, however, World Health Organization grade 3 or higher toxicity was more common than anticipated (Table 3), with grade 3 digestive symptoms such as anorexia developing in five of 14 patients (35.7%), nausea and vomiting in two of 14 (14.3%), diarrhea in three of 14 (21.4%), and myelosuppression in three of 14 (21.4%). Upper digestive symptoms such as anorexia and nausea and vomiting, considered attributable to the divided administration of CDDP, were both more common and prolonged in comparison with their incidence and duration associated with other CDDP administration schedules. Evaluation of UFT dose intensity showed that the relative performance according to course was calculated at 0.7 to 0.75 and that the dosage of UFT was slightly high. Although this therapy was quite useful in terms of effectiveness, feasibility problems remained, and some modification of the administration schedule was thought to be required.
Based on the results of the pilot study, the following modifications were made: CDDP was administered as a single high-dose application, a standard administration schedule for CDDP monotherapy for gastric cancer in Japan. This administration schedule can reduce the inpatient period to 3 days for hydration. Based on results of a phase II study of UFTP in lung cancer, a resting period was established to follow each course of UFT administration, and the daily dose of UFT was reduced slightly to 360 mg/m2. Finally, on the basis of a study evaluating timing and combination therapy, timing for the combined use of the drugs was changed so that UFT was administered prior to and following CDDP administration. This change is expected to elicit a more synergistic antitumor effect.
With the expectation that toxicity would be reduced while retaining the benefits evident in the pilot study of fluorinated pyrimidines plus CDDP, the 28-day treatment course comprised oral UFT 360 mg/m2 in one dose administered for 21 days consecutively, beginning on day 1 and then suspended for 7 days before being repeated. CDDP is administered by intravenous infusion at 80 mg/m2 on day 8 and repeated every 28 days. A phase II study of this regimen is now under way with antitumor effect as a primary end point. Survival and quality of life will also be evaluated, which is important in planning a phase III study. The present regimen is expected to be tolerable and to provide a survival benefit for outpatients. If expectations are met, this will become a standard regimen for the treatment of advanced gastric cancer.
1. Kurihara M, Izumi T, Yoshida S, et al: A cooperative randomized study on tegafur plus mitomycin C versus combined tegafur and uracil plus mitomycin C in the treatment of advanced gastric cancer. Jpn J Cancer Res 82:613-620, 1991.
2. Leichman L, Berry BT: Cisplatin therapy for adenocarcinoma of the stomach. Semin Oncol 18:25-33, 1991.
3. Rougier PH, Ducreux M, Mahjoubi M, et al: Efficacy of combined 5-fluorouracil and cis-Platinum in advanced gastric carcinomas. A phase II trial with prognostic factor analysis. Eur J Cancer 30A:1263-1269, 1994.
4. Ohtsu A, Shimada Y, Yoshida Y, et al: Phase II study of protracted infusional 5-fluorouracil combined with cis-Platinum for advanced gastric cancer: Report from the Japan Clinical Oncology Group (JCOG). Eur J Cancer 30A:2091-2093, 1994.
5. Kurihara M: Relationship between quality of life and survival in patients undergoing two therapeutic regimens with 5-DFUR and CDDP for inoperable advanced gastric cancerReport of a phase II study. Proc Soc Survival Time Studies on Cancer Patients 13:39-42, 1993.
6. Kurihara M, Uchida J, Fujioka A, et al: Effect of combination therapy with UFT plus cisplatin (UFTP) on the survival of mice in the experimental model for widespread metastasis in the peritoneal cavity of gastrointestinal cancer using Colon 26 PMF-15 cells. Anticancer Res 17:2217-2222, 1997.
7. Sato A, Hasegawa K, Kurihara M, et al: Combination chemotherapy with tegafur-uracil (UFT) and cisplatin (CDDP) for advanced gastric cancer (in Japanese). Jpn J Cancer Chemother 22:1355-1362, 1995.
8. Japanese Research Society for Gastric Cancer: Criteria for evaluating efficacy of chemotherapy in the treatment of gastric cancer. Part IV: Response assessment of chemotherapy of gastric carcinoma, in Nishi M, Omori Y, Miwa K (eds): Japanese Classification of Gastric Carcinoma. First English ed, pp 90-100. Tokyo, Kanehara Schuppan, 1995.
9. Ichinose Y, Takanasi N, Yano T, et al: A phase II study of oral tegafur and uracil plus cisplatin in patients with inoperable nonsmall cell lung cancer. Cancer 75:2677-2680, 1995.
10. Yamada Y, Saito H, Oie S, et al: Experimental study of the effect of combined treatment of UFT with CDDP on human solid tumor xenografts in nude mice (in Japanese). Jpn J Cancer Chemother 17:1327-1331, 1990.