Although the authors state that 25 RCTs and 1 meta-analysis were included in the review, only 24 trials are listed in the five groupings of treatments. The authors performed a subgroup analysis on 11 RCTs where data were available for stage II patients only (n = 2,766).
Although the overall trial results showed a survival benefit for adjuvant treatments, the benefit was not significant for stage II patients.
In trials of 5-FU with levamisole, the survival rate among patients who received 5-FU plus levamisole was significantly greater than that among patients who received 5-FU alone (p = 0.02) or who underwent observation alone (p = 0.045). Of two follow-up trials, 1 did not confirm results and the second could only find a 30% to 40% reduction in the rates of recurrence and death for stage III patients.
In trials of 5-FU modulated by leucovorin, one trial (n = 1,493) found a significant reduction in the rate of recurrence among patients who received 5-FU plus leucovorin compared with control patients (hazard ratio 0.65, 95% CI: 0.54, 0.78; p < 0.0001). After a median follow-up of 3.5 years, there was also a reduction in the risk of death favouring treatment (hazard ratio 0.76, 95% CI: 0.61, 0.96); p = 0.018). However the benefits were confined to patients with stage III disease. The survival rate at 3 years was 76% versus 64% favouring treatment among patients with stage III disease, and 90% versus 88% among those with stage II disease. Similar results were reported in a second trial (n = 239) and in preliminary results from a third trial (n = 309).
In trials of chemotherapy administered by PVI, one trial reported a significant improvement in 5-year survival rates in the treatment group (78% treatment group alive versus 57% observation group alive for all patients, and for patients with stage II colon cancer 95% survival in the treatment group versus 65% in the observation group). In a subgroup analysis, the benefit was limited to patients with stage II colon cancer and stage III rectal cancer. These findings could not be reproduced in a further 8 trials.
In trials of adjuvant therapy without an observation control arm, a significant improvement was found among patients treated with 5-FU and leucovorin. In 1 trial, the survival benefit was mainly in patients with stage III colon cancer (27% relative reduction in the death rate), with a smaller reduction (8%) in stage II patients. The OR for death among patients receiving chemotherapy by portal vein infusion (PVI) was 0.62, 95% CI: 0.35, 1.11).
A meta-analysis of 11 trials for stage II colon cancer patients only, comparing adjuvant treatment with observation, indicated no significant reduction in the OR for death (OR = 0.83, 95% CI: 0.62, 1.10).
The toxic effects of 5-flourouracil (5-FU) with either levamisole or leucovorin, or both, were mild to moderate and consisted mostly of stomatitis, diarrhea and myelosuppression; 5% of patients required hospitalisation. 5-FU plus levamisole was associated with transient neurotoxic effects in 18% of patients. Toxic effects associated with PVI were mild, rare and consisted of leukopenia and diarrhea; 1% of patients experienced bowel perforation.