Five RCTs were included in the review (n=1,421 patients, range 200 to 420). Three trials had a high percentage of cross-over rates (range 57 to 71.3% from the fluorouracil/leucovorin group to the fluorouracil/LV plus oxaliplatin or irinotecan). One trial reported a high level of salvage surgery in both the fluorouracil/leucovorin (21%) and fluorouracil/leucovorin/oxaliplatin groups (32%). Two trials were multi-centred.
Efficacy: Fluorouracil/leucovorin/oxaliplatin was significantly more effective than fluorouracil/leucovorin chemotherapy for response rate (OR 4.02, 95% CI 2.37 to 6.82; I2=64.7%; five RCTs) and progression-free survival (OR not reported; five RCTs), but not significant for overall survival (four RCTs).
Toxicity: The incidence of grade 3 or 4 toxicities was significantly higher in the fluorouracil/leucovorin/oxaliplatin group than the fluorouracil/leucovorin group for neutropenia (OR 21.69, 95% CI 4.82 to 97.50; I2=48.9%; five RCTs), thrombocytopenia (OR 3.97, 95% CI 1.32 to 11.93; I2=23.5%; five RCTs), vomiting (OR 2.24, 95% CI 1.27 to 3.95; I2=1.7%; four RCTs), and neurological toxicity (OR 37.84, 95% CI 9.37 to 152.86; I2=0%; four RCTs), but not significant for anaemia (I2=0%; three RCTs), nausea (I2=49%; four RCTs), or diarrhoea (I2=89.5%; five RCTs). Toxicity related dose modification (OR 6.22, 95% CI 3.44 to 11.25; I2=37.8%; two RCTs) and toxicity related discontinuation (OR 3.13, 95% CI 1.36 to 7.19; I2=55.1%; four RCTs) were significantly higher in the fluorouracil/leucovorin/oxaliplatin group compared with the fluorouracil/leucovorin group.
Sensitivity analyses: Exclusion of two trials where chemotherapy was given as a second-line or third-line treatment did not significantly change the odds ratio for the response rate. For toxicity, the exclusion of two trials where treatment was over five days, significantly altered one result, giving a significantly higher diarrhoea rate in the fluorouracil/leucovorin/oxaliplatin group compared with the fluorouracil/leucovorin group (OR 2.96, 95% CI 1.77 to 4.97; I2=0%; three RCTs).