The combination of uracil and tegafur(Drug information on tegafur) (UFT) in a 4:1 molar concentration was developed by Fujii et al. Tegafur is a 5-fluorouracil (5-FU) prodrug and uracil competes with 5-FU as a substrate for dihydropyrimidine dehydrogenase, an enzyme that enhances the catabolism of 5-FU. In preclinical studies, the coadministration of uracil with tegafur enhanced the concentration of 5-FU in tumors and increased antineoplastic activity.[2-6] Phase I and II trials in patients with advanced cancer and metastatic colon cancer indicate that UFT administered orally with the biochemical modulator calcium folinate(Drug information on calcium folinate) for more than 28 days resulted in response rates of 25% to 43% and a toxicity profile acceptable for the adjuvant setting.[7-9]
Since the National Institutes of Health Consensus Development Conference on adjuvant therapy for colorectal cancer, the National Surgical Adjuvant Breast and Bowel Project (NSABP) has undertaken two large clinical trials designed to evaluate the role of adjuvant therapy in patients with resected Dukes B and C colon cancer. In NSABP Protocol C-04, 5-FU/levamisole (Ergamisol) was compared with 5-FU/calcium folinate and 5-FU/levamisole/calcium folinate. Initial results from this study demonstrated no statistically significant differences in disease-free survival or overall survival among the three groups. Tests for pair-wise comparison, however, suggested a small disease-free survival and overall survival benefit for 5-FU/calcium folinate compared with 5-FU/levamisole. In NSABP Protocol C-05, 5-FU/calcium folinate was compared with 5-FU/calcium folinate/interferon alfa-2a.[10,11] This trial demonstrated no disease-free survival or overall survival benefit but increased toxicity for 5-FU/calcium folinate/interferon alfa-2a compared with 5-FU/calcium folinate.
The C-04 trial, in conjunction with the NSABP Protocol C-03 (demonstrating superiority with the 5-FU/calcium folinate regimen over the semustine [MeCCNU]/vincristine [Oncovin]/5-FU [MOF] regimen) and the recently reported Intergroup trial (comparing 5-FU/levamisole with 5-FU/calcium folinate), has challenged the primacy of 5-FU/levamisole as the standard adjuvant therapy for resected Dukes C colon cancer, and has provided information supporting the use of 5-FU/calcium folinate not only for Dukes C, but also for Dukes B patients.[12,13]
The existing evidence concerning the oral regimen of UFT plus oral calcium folinate (Orzel) indicating activity in the treatment of metastatic colon cancer led us to explore the role of this option in the adjuvant setting. To this end, in February 1997, the NSABP implemented Protocol C-06, a prospective, randomized trial designed to compare the efficacy of 5-FU/calcium folinate with that of UFT plus oral calcium folinate in the treatment of patients with stage II or III colon cancer.
Patients and Methods
Patient eligibility in C-06 necessitates a life expectancy of 10 years; Eastern Cooperative Oncology Group performance status of 0, 1, or 2; adequate hematologic function (leukocyte count > 4,000/µL and platelet count ³ 100,000/µL); adequate renal and hepatic function (normal serum creatinine, alanine aminotransferase, aspartate aminotransferase, and total bilirubin); and resected American Joint Committee on Cancer (AJCC) stage II (T3,4, N0, M0; modified Astler-Coller B2, B3) or stage III (any T, N1,2,3, M0) colon cancer.
For the purposes of this study, a colon tumor is defined as located above the peritoneal reflection on surgical exploration or more than 15 cm from the anal verge on endoscopy. The presence of more than one synchronous colon cancer does not preclude the patients involvement in the study, as long as the eligibility is based on the more advanced primary tumor. Involvement of adjacent structures (eg, bladder, small intestine, ovary) by direct extension of the primary tumor is acceptable, as long as the surgical margins are tumor-free and surgical en bloc resection is deemed to be curative by the surgeon.
Specific exclusion criteria include the presence of free perforation (as manifested by free air or fluid in the abdomen), a history of prior colon or rectal cancer, prior chemotherapy or radiotherapy for the present malignancy, and a history of prior noncolonic malignancy unless the patient has been disease-free for 10 years or more (excluding basal and squamous cell carcinoma of the skin and carcinoma in situ of the cervix). Informed consent is required from all patients.
Following stratification based on the number of involved lymph nodes, patients are randomly assigned to treatment with either 5-FU/calcium folinate or UFT plus oral calcium folinate (Figure 1). The 5-FU/calcium folinate regimen is given for three cycles of calcium folinate (500 mg/m² over 2 hours) and intravenous 5-FU (500 mg/m² bolus, 1 hour after beginning calcium folinate), both given weekly for six doses, with a 2-week rest period between cycles. The UFT plus oral calcium folinate regimen consists of five 28-day cycles of oral UFT 300 mg/m²/d in three divided doses (q8h). There is a 7-day rest period between cycles. The drug dose is calculated before the onset of each cycle, and body surface area determination is based on the actual body weight (up to a maximum of 2 m² for any patient).
For patients assigned to receive 5-FU/calcium folinate, a complete blood count is performed prior to each weekly treatment and hepatic and renal function tests every 8 weeks prior to each cycle. For patients assigned to receive UFT plus oral calcium folinate, complete blood counts are assessed weekly and renal and hepatic function tests are performed every 5 weeks prior to each cycle. Carcinoembryonic antigen levels are determined postoperatively, prior to randomization, and at 6-month intervals. A history and physical examination is performed prior to each treatment. Chest x-ray and barium enema or endoscopy are done at baseline (as clinically indicated), and annually. If the patient is polyp-free, the endoscopy is repeated every 3 years.
The primary aim of the study is to compare the relative efficacy of the two regimens in prolonging disease-free and overall survivals. Secondary aims include evaluating the prognostic significance of specific biomarkers (DNA mismatch repair gene mutations, p53 oncogene mutations, allelic loss of the deleted colon cancer gene, proliferation status, and thymidylate synthase levels) for disease-free survival and overall survival, and the relationship of biomarkers to each other and to tumor and patient characteristics.
Quality-of-life assessments are performed (using two quality-of-life questionnaires) on patients assigned to both regimens. If any differences in disease-free survival or overall survival between the two regimens exist, these questionnaires may be helpful in determining risks and benefits. The first questionnaire is administered before randomization, before each cycle of chemo- therapy, and 1 year after randomization. This is to determine longitudinal differences in symptoms and treatment burdens between the two treatments. The second is administered before randomization, at 15 weeks, and again at 1 year after randomization. This questionnaire is used to provide a more detailed comparison of on-therapy quality of life.
The trial is designed to accrue 1,452 eligible patients, at a projected rate of 600 patients per year. Assuming a 3% rate of ineligibility, a total of 1,500 patients need to be accrued. Patients are stratified by institution and by number of positive lymph nodes (0, 1 to 3, > 3). Because phase I and II data indicate that UFT plus oral calcium folinate is well tolerated, there will be interest in this regimen even if this therapy turns out to have a 5-year overall survival rate similar to that of 5-FU/calcium folinate.
Between February 1997 and March 1998, 691 patients were accrued to NSABP protocol C-06, 344 assigned to receive 5-FU/calcium folinate and 347 assigned to receive UFT plus oral calcium folinate. Six patients were considered ineligible in the former group, and seven in the latter group. As shown in Table 1, the treatment arms were well balanced for age, gender, race, Dukes stage, and tumor location. The unknown categories for race, Dukes classification, and tumor location categories refer to data forms not yet received, not yet processed, or undergoing medical review at the NSABP Biostatistical Center.
Toxicity has been assessed in 224 patients for this interim analysis assigned to 5-FU/calcium folinate, and 249 patients assigned to UFT plus oral calcium folinate. To date, an average of 1.9 cycles of 5-FU/calcium folinate per patient and 3.0 cycles of UFT plus oral calcium folinate per patient have been delivered. As shown in Table 2, grade ³ 3 granulocytopenia occurred in one patient receiving UFT plus oral calcium folinate and one patient in the 5-FU/calcium folinate group. Grade ³ 3 thrombocytopenia occurred in one patient treated with UFT plus oral calcium folinate, but none treated with 5-FU/calcium folinate. Sepsis occurred in 1% of patients receiving 5-FU/calcium folinate but was not reported in the group receiving UFT plus oral calcium folinate. Grade ³ 3 nausea or vomiting occurred in 14 (6%) and 13 (6%), of patients receiving 5-FU/calcium folinate; and 14 (6%) and 6 (< 3%) of patients receiving UFT plus oral calcium folinate. Diarrhea of grade ³ 3 occurred in 63 (28%) 5-FU/calcium folinatetreated patients, and 64 (26%) UFT plus oral calcium folinate-treated patients.
Transient abnormalities in liver function were observed in a few patients, predominantly in the UFT plus oral calcium folinate arm. Three deaths occurred in the 5-FU/calcium folinate group while on protocol (two cardiac deaths and one pulmonary embolus), two of which (one cardiac failure and the pulmonary embolus) are considered to be treatment-related. There were no deaths associated with the UFT plus oral calcium folinate arm.
This interim analysis indicates that the toxicities seen in patients with resected stage II or III colon cancer assigned to adjuvant combination chemotherapy with either UFT plus oral calcium folinate or 5-FU/calcium folinate are similar and that both regimens are well tolerated. Enrollment in this multi-institutional trial concluded as of March 31, 1999. If the final comparison of the toxicity profiles of these two regimens is similar to that of this interim analysis, and UFT plus oral calcium folinate is found to offer overall survival benefits similar to or greater than those of 5-FU/calcium folinate, based on its efficacy and ease of administration UFT plus oral calcium folinate could be established as a new treatment standard for the adjuvant therapy of these patients.