The combination of mitomycin C (MMC) and a fluorinated pyrimidine derivative has been evaluated as chemotherapy for colorectal cancer in Japan. Both types of agents have exhibited excellent antitumor effect when used alone against colorectal cancer. The effects of combining MMC and UFT (tegafur and uracil) were first illustrated when human colonic cancer cells were xenotransplanted into nude mice and then treated with MMC/UFT. On the basis of this study, adjuvant chemotherapy with combination MMC/UFT was expected to be effective in preventing postoperative recurrence. Accordingly, the Japanese Foundation for Multidisciplinary Treatment of Cancer conducted a multicenter clinical trial to investigate the usefulness of postoperative adjuvant chemotherapy with MMC/UFT following curative resection of rectal cancer.
Patients who satisfied the requirements were selected as study subjects. Patients who were intraoperatively judged as possible candidates for curative resection of rectal cancer were also considered as potential study subjects. Entry criteria included: T3 or T4 tumors (invading beyond the muscularis propria) and/or N1, N2, or N3 disease (metastasis to regional lymph nodes); younger than 70 years of age; no serious complications; no history of cancer therapy (surgery, radiotherapy, chemotherapy, or immunotherapy); no synchronous or metachronous multiple cancers; and adequate results of preoperative laboratory tests.
The MMC/UFT group received MMC 20 mg dissolved in 200 mL of a physiologic saline solution and sprinkled into the abdominal cavity or the operating field at the time of abdomen closure. In addition, intravenous MMC 6 mg/m2 was administered on day 7, and then 1, 2, 3, 4, 5, and 6 months after surgery. Oral UFT 400 mg/day (200 mg orally two times daily) was administered, beginning 3 weeks after surgery and continuing for 1 year. Patients in the control group received no anticancer drugs after surgery.
Registration was conducted by the central registration method, by which patients were registered by a telephone call to the Secretariat of the Japanese Foundation for Multidisciplinary Treatment of Cancer on the day of surgery before closing the surgical wound. Registered patients were randomly allocated to postoperative treatment with MMC/UFT (treatment group) or no drug therapy (control group).
Intergroup comparison of prognostic factors was conducted by the chi-square test and Kruskal-Wallis test on eligible patients. Eligible patients who tolerated surgery were analyzed for overall and disease-free survival, drug administration condition, laboratory test values, and adverse events. The survival and disease-free survival rates were calculated by the Kaplan-Meier method, and an intergroup comparison was made by the (stratified) log-rank test. A cumulative recurrence rate, by initial recurrence site, was calculated and analyzed in a manner similar to that for the survival rate. All statistical analyses were conducted by the Data Center of the Japanese Foundation for Multidisciplinary Treatment of Cancer, using a statistical package (SAS System ver. 6.04, SAS Institute Japan Ltd., Tokyo).
Nationwide, 117 institutions joined the study, for a total of 834 patients (416 in the MMC/UFT group and 418 in the control group. Subjects were registered during a period of 2 years and 11 months from February 1986 to December 1988.
There were 20 ineligible patients in each group, for a total of 40, or 4.8% of those registered. Ineligibility was due to macroscopically noncurative resection in 16 patients, ineligible disease stage in 12, ineligible cancer site in 5, inadequate laboratory test results in 3, multiple cancers in 3, and other reasons in 1.
Among the 794 eligible patients, no intergroup differences were observed in terms of sex, age, location of tumor, or Dukes classification (Table 1). Only three were lost to follow-up, with a total of 791 patients followed for survival status or death up to 5 years after surgery. One patient died within 30 days after surgery of postoperative complications, and the remaining 793 patients tolerated surgery.
Administration of MMC directly into the operating field was carried out in 98.0% of the patients. The planned seven doses of intravenous MMC were administered to 40% of the patients; 59% of patients received five or more doses. In 47.8% of patients, 80% or more of the planned total dose of UFT (173.6 g) was given.
In the MMC/UFT-treated group, anorexia was observed in 17% and nausea and vomiting in 9.6% of patients, representing a significant difference from the 10% anorexia and 5.8% nausea and vomiting seen in the control group. Diarrhea, however, was observed in 12.2% of patients in the MMC/UFT group and 11.8% in the control group, with no significant difference between the groups.
In terms of hematologic and hepatic toxicities, decreases in leukocyte, platelet count, and hemoglobin level were more frequently observed in the MMC/UFT group than in the control group (Table 2). In the treatment group, leukopenia and thrombopenia grades 3 or higher were seen in 0.5% and 1.5% of patients, respectively. There were no differences between the groups in elevation of aspartate aminotransferase or alanine aminotransferase.
The 5-year overall survival rates were 70.3% for patients in the MMC/UFT group and 66.3% for those in the control group, with no significant difference between the groups. Analysis by Dukes classification showed no significant differences between groups in patients classified as Dukes A, B, or C/D (Table 3).
The 5-year disease-free survival rates were 69.1% for the MMC/UFT group and 59.3% for the control group, a significantly better result in the MMC/UFT group. According to analysis by Dukes classification, there were no significant differences between the two groups for patients staged at Dukes A, and better results were observed in the MMC/UFT group for all other stages, with a significant advantage seen for those at Dukes C/D (Table 4).
The rate of local recurrence within 5 years after surgery was significantly lower in the MMC/UFT group as a whole compared with the control group. The hepatic and pulmonary recurrence rates also were slightly lower in the MMC/UFT group, but the difference was not significant. In the Dukes C patients, no difference in hepatic recurrence was observed between treatment groups, but the local and pulmonary recurrence rates were significantly lower for the MMC/UFT-treated patients (Table 5).
The Group of Research for Colorectal Cancer Treatment (Kajitani Group) supported by the Ministry of Health and Welfare, the Cooperative Study of Surgical Adjuvant Chemotherapy for Colorectal Cancer, and the Colorectal Cancer Chemotherapy Study Group evaluated the comparative effectiveness of postoperative combination MMC and oral fluorinated pyrimidine derivatives (fluorouracil, tegafur) vs surgery alone as treatment of colorectal cancer. These studies showed that adjuvant chemotherapy could prevent disease recurrences, especially for those with rectal cancer.[2,3] Since similar results were obtained in the present study of MMC/UFT, combined therapy using MMC and a fluorinated pyrimidine derivative is considered effective postoperative adjuvant chemotherapy for rectal cancer. Conversely, none of these studies provide clear results relating to colon cancer. It may be noted, however, that comparison of postoperative MMC/tegafur vs MMC/UFT in patients with colon cancer showed that both disease-free and overall survival rates were higher in the MMC/UFT-treated group. The combined use of MMC and UFT is therefore expected to have a preventive effect on recurrence of colon cancer.
To evaluate whether higher daily doses of UFT would enhance its antitumor effects, patients with advanced colorectal cancer were treated with a daily dose of UFT 600 mg (200 mg orally three times daily), administered for 5 consecutive days, followed by two drug-free days (weekly-5 method). Intravenous MMC 6 mg/m2 was administered at 2-week intervals. A response rate of 38.5% (5/13 patients) was obtained in these previously untreated patients, and the incidence of gastrointestinal toxicities was 8% (2/26 patients). Further study of this therapeutic method as postoperative adjuvant chemotherapy is warranted.
At present, National Surgical Adjuvant Study of Colorectal Cancer, organized as a consigned study by the Ministry of Health and Welfare, is conducting a randomized controlled trial in which surgery alone is being compared with surgery followed by UFT (400 mg/m2/day by the weekly-5 method) to investigate the merits of single-agent UFT in patients with Dukes C colorectal cancer.
1. Takahashi Y, Kikuchi R, Ueno M, et al: Effect of combination of UFT and MMC (UFT-M Therapy) on human colonic cancer xenotransplanted in nude mice. Jpn J Cancer Chemother 14:1345-1347, 1987.
2. Nishida O, Uchino J, Kikuchi K, et al: Cooperative study of surgical adjuvant chemotherapy for colorectal cancer (third report). Jpn J Cancer Chemother 20:101-108, 1993.
3. The Colorectal Cancer Chemotherapy Study Group of Japan: Five-year results of a randomized controlled trial of adjuvant chemotherapy for curatively resected colorectal carcinoma. Jpn J Clin Oncol 25:91-103, 1995.
4. Okuda M, Teramoto T, Watanabe M, et al: Adjuvant chemotherapy with mitomycin C, tegafur and UFT for colorectal cancer. J Jpn Soc Coloproctol 48:129-136, 1995.
5. Ikeda E, Kodaira S, Teramoto T, et al: Optimal dosage of UFT + MMC combination chemotherapy for advanced colorectal cancer. Jpn J Cancer Chemother 23:1291-1298, 1996.