When used as first-line therapy, the combination of either irinotecan or oxaliplatin with an infusional fluorouracil and folinic acid (FU/FA) regimen appears to extend median progression-free survival by 23 months compared with FU/FA alone, although with increased toxicity; irinotecan has also been shown to extend overall survival. However, raltitrexed appears to reduce both progression-free and overall survival compared with FU/FA. When used as second-line treatment, irinotecan monotherapy appears to extend median progression-free survival by approximately 1 month and overall survival by approximately 2 months compared with FU/FA alone, again at the cost of increased toxicity. Preliminary data suggest that, as second-line treatment, oxaliplatin plus 5FU may extend median progression-free survival compared with either 5FU or irinotecan monotherapy.