Raltitrexed: optimism and reality.
BACKGROUND
Raltitrexed was developed as a direct and specific inhibitor of thymidylate synthase. Early clinical trials showed similar activity to 5-fluorouracil (5-FU), mainly in metastatic colorectal cancer (MCRC).


METHODS
Pharmacokinetics are summarized and Phase III adjuvant and MCRC trials of raltitrexed are reviewed.


RESULTS
Response rates and overall survival with raltitrexed in MCRC are equivalent to 5-FU. Pooled analysis showed relapse free survival was 1 month longer with 5-FU compared with raltitrexed. Grade 3+ toxicity rates with raltitrexed compare favorably with 5-FU. Unexpectedly, however, treatment-related mortality (TRM) was greater with raltitrexed, mainly due to protocol violations. TRM was also greater in the adjuvant trial, leading to its discontinuation. In spite of excess TRM, much of which could have been avoided, overall survival was the same as with 5-FU. Quality of life was variously reported as better or inferior to 5-FU.


CONCLUSIONS
The simple once every 3 week regimen of raltitrexed has not fulfilled its promise. Meanwhile, the field change in MCRC management has left little space for raltitrexed. Withdrawal of the sponsor's support has left raltitrexed without the level of continuing investigation afforded to 5-FU. The use of raltitrexed in Canada is limited to patients exhibiting intolerance - mucosal, hematological and cardiac - to 5-FU.
Wilson
Kenneth S
KS
Vancouver Island Centre, Department of Medicine, Victoria, British Columbia, Canada. KWilson@bccancer.bc.ca
Malfair Taylor
Suzanne C
SC
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D006801:Humans; D011799:Quinazolines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D013876:Thiophenes / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution
D000964:Antimetabolites, Antineoplastic; D011799:Quinazolines; D013876:Thiophenes; D013940:Thymidylate Synthase; C068874:raltitrexed