Seventeen studies were included in the review. Methodological quality varied between trials
First-line irinotecan combination therapy (seven RCTs, n = 4,343): irinotecan plus 5-FU compared to 5-FU alone (four RCTs, n = 3,536) improved overall survival by between two and four months (HR 0.84, 955 CI 0.76, 0.93, p = 0.0007) and progression-free survival by between two and three months (p < 0.00001). Subgroup analysis showed that overall survival was significantly better with combination therapy with 5-FU infusion (HR 0.84, 95% CI: 0.75, 0.94, p = 0.003) but not with 5-FU bolus. There was no significant difference between irinotecan plus 5-FU compared to oxaliplatin combinations (four RCTs, n = 2,942). Subgroup analysis showed better overall survival when 5-FU was delivered by bolus (HR 0.70, p = 0.032, 95% CI not reported).
Irinotecan second-line monotherapy (two RCTs, n = 546): one RCT (n = 267) found that irinotecan was significantly more effective than 5-FU in prolonging overall survival and progression-free survival; a second (n = 279) found that irinotecan plus best supportive care was significantly more effective than best supportive care alone.
First-line oxaliplatin combination therapy (four RCTs n =3,007): there was no significant difference in overall survival between oxaliplatin plus 5-FU and 5-FU alone, but progression-free survival was significantly better in the combination group (HR 0.75, 95% CI: 0.69, 0.82, p < 0.00001).
Second-line oxaliplatin combination therapy (one RCT, n = 83): there was no statistically significant difference in overall survival between combination therapy and 5-FU alone in overall or progression-free survival.
Raltitrexed (four RCTs, n = 2,308): there were no significant differences between raltitrexed and 5-FU for first-line treatment in overall survival or progression-free survival, but in two trials raltitrexed treatments were halted due to excess toxic deaths.
Sequencing of treatment (two RCTs n = 2,355): one study found that staged treatment (5-FU then irinotecan) was inferior to other treatment plans, while 5-FU then irinotecan plus 5-FU was as effective as 5-FU then oxaliplatin plus 5-FU.
Irinotecan or oxaliplatin with 5-FU for downstaging patients with unresectable liver metastases (three RCTs, 8 non RCTs): response rates were between 47.5 per cent and 56 per cent for patients treated with irinotecan plus 5-FU; for oxaliplatin plus 5-FU rates were between 50 per cent and 54 per cent; where they were compared there was no significant difference between the groups. Resection rates were between 9 per cent and 35 per cent for irinotecan and between 7 per cent and 51 per cent for oxaliplatin.
Results for response rates and quality of life were also reported for each comparison.