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Direct and specific thymidylate synthase inhibitors, such as raltitrexed ('Tomudex', formerly ZD1694), provide a promising new therapeutic approach to the treatment of advanced colorectal cancer. Two international phase III trials (studies 3 and 12) compared raltitrexed (3 mg/m2) with 5-fluorouracil plus low-dose leucovorin or plus high-dose leucovorin, respectively. Study 3 included a 15.5-month follow-up for efficacy and a 26-month follow-up for survival. Results of an interim analysis for study 12 are presented. Objective tumour response rates for each treatment group were comparable in both studies 3 (P=0.48) and 12 (P=0.896). The median time to progression was similar between treatments in study 3 (P=0.44), but was significantly longer for 5-fluorouracil + leucovorin compared with raltitrexed in study 12 (5.1 versus 3.9 months, P=0.005). The median survival (raltitrexed versus 5-fluorouracil + leucovorin) was comparable in both studies 3 (10.1 versus 10.2 months, P=0.42) and 12 (10.7 versus 11.8 months, P=0.36). Palliative benefits were similar between treatments in both studies. A third phase III trial (study 10), carried out in North America, demonstrated a statistically significantly longer median survival for 5-fluorouracil + leucovorin compared with raltitrexed (12.7 months versus 9.7 months; P=0.01). However, the possible unfamiliarity of the clinicians with raltitrexed and the early discontinuation of a 4 mg/m2 raltitrexed arm due to toxicity may have led to an unconscious investigator bias in this trial, leading to a non-protocol-led withdrawal of patients from the study. Overall, raltitrexed is comparable with standard 5-fluorouracil + leucovorin therapy in terms of response rates and overall survival, and has a more convenient dose schedule.

Original publication




Conference paper

Publication Date



8 Suppl 2


S11 - S15


Animals, Antimetabolites, Antineoplastic, Clinical Trials, Phase III as Topic, Colorectal Neoplasms, Quinazolines, Thiophenes