ABSTRACT
For nearly 40 years, 5-fluorouracil (5-FU) was the sole cytotoxic agent with significant activity in advanced colorectal cancer.1,2 During the 1970s and 1980s, elucidation of the complex biochemical pathways that 5-FU follows in cells and its mechanisms of action (thymidylate synthase inhibition, and DNA and RNA incorporation) has led to the development of several biochemical modulation strategies designed to enhance the cytotoxic effects of the drug. Amongst many, the prevalent standard is the addition of folinic acid (FA, leucovorin), which results in an increased response rate, but results of metaanalyses have failed to show increased survival when it is added to bolus 5-FU.3 Modulation with methotrexate, N-phosphonoacetyl-L-aspartate (PALA) or levamisole has led to very modest gains compared with 5-FU/FA.4,5 The development of hybrid regimens, combining bolus and infusional administration and biochemical modulators, has led to increased response rates and 2-3 months’ increase in time to progression.6-8 Besides 5-FU modulation, most attempts to improve systemic treatment have consisted of empirically adding drugs to 5-FU.1,2
Nitrosoureas were extensively studied as an addition to 5-FU schedules. Response rates of 10-15% have been reported for carmustine (BCNU), lomustine (CCNU), chlorozotocin, and semustine (methylCCNU). The addition of semustine to 5-FU (MOF-or MF-type regimens) resulted in response rates ranging from 4% to 40%. Most of these responses were partial and lasted less than 6 months.2,8 Nitrosoureas were definitively abandoned because of the lack of difference in time-related parameters and the risk of secondary leukaemia.9 Attempts to substitute or add other agents did not result in clinically meaningful differences.2,10 The addition of cisplatin to 5-FU has been evaluated based on preclinical studies demonstrating synergy between these two agents. Although initial phase II studies produced response rates of
30-40%, several randomized trials have subsequently failed to demonstrate any advantage of the combination over 5-FU alone in terms of time to progression or survival.11,12
During the last 10 years, we have seen the emergence of two new active antitumour agents with mechanisms of action independent of thymidylate synthase inhibition (TSI); irinotecan (CPT-11) and oxaliplatin.
