Adjuvant chemotherapy has been shown to alter the natural history of patients with resected colon cancer. Two regimens (fluorouracil [5-FU] plus levamisole (Ergamisol) and 5-FU plus leucovorin) have been found most
ABSTRACT: Adjuvant chemotherapy has been shown to alter the natural history of patients with resected colon cancer. Two regimens (fluorouracil [5-FU] plus levamisole (Ergamisol) and 5-FU plus leucovorin) have been found most successful in prolonging disease-free and overall survival. When these two regimens were directly compared in randomized clinical trials, it appeared that a small disease-free survival and overall survival advantage had emerged in favor of 5-FU plus leucovorin. This advantage, in conjunction with an increased understanding of the mechanism of leucovorin’s biochemical modulation of 5-FU, makes this regimen a logical choice for studies designed to further optimize and augment the clinical efficacy of chemotherapy for colon cancer. The introduction of oral tegafur and uracil (UFT) and the demonstration of significant antitumor activity with the combination of oral UFT and oral leucovorin, provide an excellent opportunity to optimize treatment with 5-FU plus leucovorin. The National Surgical Adjuvant Breast and Bowel Project has recently implemented a new clinical trial (Protocol C-06) comparing oral UFT plus leucovorin with 5-FU plus leucovorin in the treatment of patients with resected stage II and III colon cancer. The rationale for the design of the trial, inclusion and exclusion criteria, treatment regimens, and statistical considerations are reviewed.[ONCOLOGY 11(Suppl 10):44-47,1997]
During the last quarter of this century, many randomized trials have been conducted evaluating the often potential benefit of adjuvant therapy in patients with resected colon cancer. Not until recently, however, has the value of such therapy been established clearly.[2-5] Of particular interest, while most chemotherapy regimens that failed to produce a substantial benefit were based on fluorouracil (5-FU), it was regimens that combined fluorouracil with other agents that finally resulted in significant alterations in the natural history of the disease.
Two strategies have been most successful in prolonging both the disease-free and the overall survival of patients with resected colon cancer. The first approach was to combine fluorouracil with levamisole (Ergamisol). The mechanism by which levamisole augments the cytotoxicity of fluorouracil remains unclear. However, trials by the North Central Cancer Treatment Group and, subsequently, by the Intergroup,[3,4] have demonstrated significantly prolonged disease-free and overall survival of patients with resected stage III colon cancer who received adjuvant fluorouracil/levamisole compared with those treated by surgery alone. Subsequent to the dissemination of these results in 1990, a National Institutes of Health consensus panel recommended fluorouracil/levamisole as standard adjuvant therapy for patients with stage III colon cancer being treated outside clinical trials. The second encouraging treatment approach exploits the biochemical modulation of fluorouracil by leucovorin. This modulation occurs primarily as a result of an increase in formation and stability of the fluorodeoxyuridylate-thymidylate synthase complex in the presence of 5-10 methylene tetrahydrofolate. This interaction results in a covalent ternary complex with consequent inhibition of thymidylate synthase, ultimately affecting the cytotoxic activity of fluorouracil. In the clinical setting, the superiority of modulated fluorouracil over fluorouracil alone has been demonstrated in patients with metastatic colon cancer.[7-9] In 1993, results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-03 trial demonstrated a significant benefit in terms of disease-free and overall survival for patients with stage II and III colon cancer who received fluorouracil/leucovorin, compared with those receiving the MOF regimen (semustine vincristine[Oncovin]/fluorouracil). In addition, results from other smaller trials [10-13] that used different doses and schedules further substantiated the benefits of treatment with fluorouracil/leucovorin for patients with resected stage II and III colon cancer.
As a result of the demonstrated activity of the fluorouracil/levamisole and fluorouracil/leucovorin regimens, a direct comparison of the two regimens was deemed necessary. Two large-scale clinical trials, one by the National Surgical Adjuvant Breast and Bowel Project (C-04) and one by the Intergroup (INT 0089), were designed to compare fluorouracil/levamisole with fluorouracil/leucovorin and, further, to assess whether a combination of all three drugs would confer any additional benefit over that achieved with either two-drug regimen. Initial results from the C-04 trial  demonstrated no statistically significant differences in disease-free or overall survival among the three groups compared simultaneously. Pair-wise comparison, however, showed small, borderline statistically significant disease-free survival and 5-year survival advantages associated with fluorouracil/leucovorin compared with fluorouracil/levamisole. A similar, although statistically nonsignificant, trend favoring fluorouracil/leucovorin over fluorouracil/levamisole also has emerged in the preliminary results from the INT 0089 trial.
The small disease-free and overall survival advantages suggested for fluorouracil/leucovorin by the C-04 and INT 0089 trials, as well as an increased understanding of the mechanism of leucovorins biochemical modulation of fluorouracil, give this combination a clear advantage, defining it as the regimen of choice to be pursued for optimization and augmentation of its clinical efficacy.
In the National Surgical Adjuvant Breast and Bowel Project C-05 trial, further modulation of the fluorouracil/leucovorin regimen involved the addition of alpha interferon, a modification that had previously shown increased activity in patients with advanced colorectal carcinoma. Results from the C-05 trial are not yet available but may ultimately provide information as to the most advantageous avenue for additional modulation of the fluorouracil/leucovorin combination.
During the period that we await results of the C-05 and other relevant clinical trials, another important treatment approach is being tested that involves an attempt to optimize the fluorouracil/leucovorin regimen. The introduction of Ftorafur (or tegafur) (an oral prodromal drug of fluorouracil) provides an excellent opportunity to optimize treatment with fluorouracil/leucovorin. The combination of oral tegafur and uracil (UFT) and oral leucovorin has demonstrated significant clinical antitumor activity in patients with advanced colorectal carcinoma.[17,18] The National Surgical Adjuvant Breast and Bowel Project has recently implemented a new clinical trial (protocol C-06) comparing oral UFT/leucovorin with fluorouracil/leucovorin in the treatment of patients with stage II and III carcinoma of the colon. Following stratification according to number of positive nodes, patients with resected stage II and III colon cancer are randomized to treatment with either fluorouracil/leucovorin or UFT/leucovorin (Figure 1). The fluorouracil/leucovorin regimen is given for 3 cycles. Each cycle consists of leucovorin (500 mg/m2 over 2 hours) and intravenous fluorouracil 500 mg/m2 (bolus, 1 hour after the beginning of the leucovorin infusion), both given weekly for six doses, with a 2-week rest period between cycles. The UFT/leucovorin regimen consists of five 28-day cycles of oral UFT 300 mg/m2/day, in three divided doses every 8 hours, and oral leucovorin 90 mg/day, also in three divided doses every 8 hours. There is a 7-day rest period between cycles.
Inclusion and exclusion criteria for the study are generally similar to those in previous NSABP colon protocols and are summarized in Table 1. The primary aim of the study is to compare UFT/leucovorin and fluorouracil/leucovorin in terms of their relative efficacy in prolonging disease-free survival and overall survival. Secondary aims include evaluating the prognostic significance of several biomarkers (alone or in combination) for disease-free survival and overall survival and evaluating the relationship of these biomarkers to each other and to patient and tumor characteristics. The following biomarkers will be evaluated in paraffin block material obtained from patients entered in the C-06 study: DNA mismatch repair gene mutations, p53 oncogene mutations, allelic loss of the DCC (deleted colon cancer) gene, proliferation status, and thymidylate synthase levels. In addition, this study will compare the quality of life of patients treated with fluorouracil/leucovorin with that of patients treated with UFT/leucovorin. Quality of life assessment is helpful in weighing the risks and benefits of treatment options when differences in disease-free and overall survival rates among the treatment groups are small. It is particularly important when the treatments are associated with similar disease-free and overall survival, but different toxicities. Two quality of life questionnaires will be used. The first questionnaire will be administered after the patients sign the informed consent, but before they are randomized. Thereafter it will be administered on day 1 of each chemotherapy cycle (after cycle 1), and again at 1 year after randomization. This schedule is designed to capture longitudinally the difference in symptoms and treatment burden between the two regimens. The second questionnaire will be administered to both treatment groups after the consent form is signed, but before randomization, and then on day 1 of cycle 3 for the fluorouracil/leucovorin-treated group, and on day 1 of cycle 4 for the UFT/leucovorin-treated group. It will be administered again 1-year after randomization. This second questionnaire is designed to provide a more detailed comparison of the on-therapy quality of life of patients accrued to the C-06 study.
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, 1,500 total patients need to be accrued. Patients will be stratified by institution and by the number of positive lymph nodes (0, 1-3, or more than 3). Because the interest in UFT/leucovorin is generated by the possibility that this formulation may be less toxic and easier to administer than fluorouracil/leucovorin, there will be interest in the UFT/leucovorin regimen, even if the therapy turns out to have a 5-year survival rate equivalent to that of fluorouracil/leucovorin. The overall goal of this study is to determine the most appropriate course of action, based on patient survival. Possible study conclusions include (1) determining that the fluorouracil/leucovorin regimen leads to the best survival and should be the regimen of choice, (2) concluding that the UFT/leucovorin regimen leads to the best survival and should be the regimen of choice, or (3) establishing that the survival patterns of patients treated with either of the two regimens are similar, and that the choice of treatment should be based on other factors, such as toxicity, ease of administration, and cost.
1. Buyse M, Zeleniuch-Jacquotte A, Chalmers TC: Adjuvant therapy of colorectal cancer: Why we still dont know. JAMA 259:3751-3758, 1988.
2. Laurie JA, Moertel CG, Fleming TR, et al: Surgical adjuvant therapy of large bowel carcinoma: An evaluation of levamisole and the combination of levamisole and 5-fluorouracil. J Clin Oncol 7:1447-1457, 1989.
3. Moertel CG, Fleming TR, McDonald TS, et al: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322:352-358, 1990.
4. Moertel CG, Fleming TR, McDonald TS, et al: Fluorouracil plus levamisole after resection of stage III colon carcinoma: A final report. Ann Intern Med 122:321-326, 1995.
5. Wolmark N, Rockette H, Fisher B, et al: The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: Results from National Surgical Adjuvant Breast and Bowel Project Protocol C-03. J Clin Oncol 11: 1879-1887, 1993.
6. NIH Consensus Conference: Adjuvant therapy for patients with colon and rectal cancer. JAMA 264:1444-1450, 1990.
7. Piedbois P, Buyse M, Rustum Y, et al for the Adjuvant Colorectal Cancer Meta-Analysis Project: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: Evidence in terms of response rate. J Clin Oncol 10:896-903, 1992.
8. Poon MA, OConnell MJ, Moertel CG, et al: Biochemical modulation of fluorouracil: Evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 7:1407-1418, 1989.
9. Poon MA, OConnell MJ, Wieand HS, et al: Biochemical modulation of fluorouracil with leucovorin: Confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol 9:1967-1972, 1991.
10. OConnell MJ, Mailliard JA, Kahn MJ, et al: A controlled trial of 5-fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 15:246-250, 1997.
11. Erlichman C, Marsoni S, Seitz JF, et al: Event-free and overall survival is increased by FUFA in resected B and C colon cancer: A prospective pooled analysis of 3 randomized trials [abstract]. Proc Am Soc Clin Oncol 13:194, 1994.
12. Francini G, Petroli R, Marsili S, et al: Folinic acid plus 5-fluorouracil as adjuvant chemotherapy in colon cancer [abstract]. Proc Am Soc Clin Oncol 13:196, 1994.
13. International Multicenter Pooled Analysis of Colon Cancer Trials (IMPACT) Investigators: Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet 345:939-944, 1995.
14. Wolmark N, Rockette H, Mamounas EP, et al: The relative efficacy of 5-FU + leucovorin (FU + LV), 5-FU + levamisole (FU + LEV), and 5-FU + leucovorin + levamisole (FU + LV + LEV) in patients with Dukes B and C carcinoma of the colon: First report of NSABP C-04. [abstract]. Proc Am Soc Clin Oncol 15:205, 1996.
15. Haller DG, Catalano PJ, MacDonald JS, et al: Fluorouracil (FU), leucovorin (LV) and levamisole (LEV) adjuvant therapy for colon cancer: Preliminary results of INT 0089 [abstract]. Proc Am Soc Clin Oncol 15:211, 1996.
16. Grem JL, Jordan E, Robson ME, et al: Phase II study of fluorouracil, leucovorin, and interferon Alfa-2a in metastatic colorectal cancer. J Clin Oncol 11:1737-1745, 1993.
17. Pazdur R, Lassere Y, Rhodes V, et al: Phase II trial of uracil and tegafur plus oral leucovorin: An effective oral regimen in the treatment of metastatic colorectal carcinoma. J Clin Oncol 12:2296-2300, 1994.
18. Saltz LB, Leichman CG, Young CW, et al: A fixed-ratio combination of uracil and Ftorafur (UFT) with low-dose leucovorin. Cancer 75:782-785, 1995.