Metastatic colorectal cancer: integrating irinotecan into combination and sequential chemotherapy

The chemotherapy of metastatic colorectal cancer (CRC) has undergone a succession of refinements. Through the biochemical modulation of 5-fluorouracil (5-FU) with folinic acid (FA), the use of infusional rather than bolus regimens and the combination of 5-FU/FA with other active agents (notably irinotecan), first-line response rates (RRs) of 40% can be achieved, with patients surviving up to 17 months. Significant benefits on survival are also seen with second-line chemotherapy. The question of how best to sequence combination chemotherapy was addressed in a recent trial in which patients were randomized to receive either an irinotecan-based combination with 5-FU/FA (FOLFIRI) followed by an oxaliplatin-based combination (FOLFOX), or the two regimens in the reverse order. In both arms, RRs were greater than 50% and median survival exceeded 20 months. The primary end point was time to progression after two lines of treatment, and this was not significantly different. However, the sequence FOLFIRI followed by FOLFOX appears preferable because of the better tolerability of FOLFIRI in first-line use. Use of the sequence FOLFIRI/FOLFOX is also supported by the greater chance of a second-line response with FOLFOX. Concern has been expressed about the safety of irinotecan combined with bolus 5-FU/FA. Infusional regimens have a better risk/benefit ratio than bolus regimens. However, the adverse event profile with both approaches is manageable, and irinotecan plus 5-FU/FA can be considered one standard of care in metastatic CRC.