The literature search identified 30 RCTs.
Two of 3 RCTs reported improved survival rates with 5-FU plus semustine or mitomycin C (MMC) compared with no treatment (observation) after surgical resection. Three trials reported a benefit in both overall and disease-free survival with 5-FU plus levamisole compared with observation after surgery. In 2 trials, levamisole alone did not produce a survival benefit compared with observation. One trial reported improved disease-free, but not overall, survival rates with oral HCFU (1-hexylcarbamoyl-5-fluorouracil) compared with observation. In 3 trials of 5-FU plus leucovorin, disease-free and overall survival rates were improved compared with observation. Nine trials compared PVI of 5-FU with observation after surgery. In 2 of the trials, for which data were available for stage III patients only, improved overall survival was reported. There was a trend in all studies favouring PVI. One trial reported a survival benefit for stage III and IV patients who received oral HCFU maintenance therapy for 1 year compared with no maintenance therapy. In a trial comparing MMC plus oral HCFU with MMC alone, a survival benefit was reported in the combined treatment group; however, the stages of cancer were unevenly distributed among the treatment groups. Only 1 study tested monoclonal antibody; a benefit was reported for both overall and disease-free survival. A meta-analysis of 10 trials comparing adjuvant therapy with observation in patients with stage III disease detected a significant reduction in odds ratio for death (OR=0.69; 95% CI: 0.57,0.85), with an absolute improvement in survival of 4% to 13%. When trials were separated according to the type of treatment given, the significant ORs were for 5-FU plus either levamisole (OR=0.61; 95% CI: 0.46,0.80) or leucovorin (OR=0.51; 95% CI: 0.36,0.73). Three recently reported trials comparing various combinations of 5-FU plus leucovorin, with or without levamisole, showed similar improvements in disease-free and overall survival.