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Postoperative Adjuvant Chemotherapy With Mitomycin C and U
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Postoperative Adjuvant Chemotherapy With Mitomycin C and
UFT for Rectal Cancer
Review Article [1] | September 02, 1997 | Gastrointestinal Cancer [2]
By Susumu Kodaira, MD [3]
To evaluate the significance of postoperative adjuvant chemotherapy using mitomycin C (MMC) and
UFT (tegafur and uracil) in combination, the Japanese Foundation for Multidisciplinary Treatment of
Cancer conducted a prospective randomized controlled trial with 834 patients who had undergone
curative resection for rectal cancer (T3 or T4 tumors and/or N1, N2, or N3 disease). The patients
were randomly allocated to a treatment group (MMC/UFT, 416 patients) and a control group (surgery
only, 418 patients). For patients in the treatment group, 20 mg of MMC was sprinkled on the
operating field upon completion of surgery. MMC was intravenously injected at 6 mg/m2 on day 7,
and then each month after surgery for 6 months. UFT was administered orally at 400 mg/day for 1
year. Although no difference was observed in the 5-year survival rate between the two groups, the
5-year disease-free survival rate in the MMC/UFT group was 69.1%, which was significantly higher
than in the control group (59.3%, P = .005). The 5-year cumulative local recurrence rate was
significantly lower in the MMC/UFT group (11.6%) than in the control group (19.0%) (P = .0071). We
conclude that the adjuvant use of long-term oral UFT and intermittent intravenous MMC improves
the disease-free survival rate of patients with curatively resected rectal cancer. [ONCOLOGY
11(Suppl 10):40-43, 1997]
Introduction
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.[1] 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 and Methods
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.
Treatment Schedule
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.
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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).
Statistical Analysis
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).
Results
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.
Complications and Adverse Events
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.
Survival
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).
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Recurrence Rate by Initial Recurrence Site
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).
Discussion
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.[4] 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).[5] 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.
References:
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.
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[3] http://www.cancernetwork.com/authors/susumu-kodaira-md
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