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Raltitrexed and the treatment of advanced colorectal cancer

Pharmacy Department, Guy's and St. Thomas' Hospital, London, England

Objective. Colorectal cancer is the second largest cause of death from malignant disease in Western countries. Although surgical resection is the preferred treatment in early disease, chemotherapy has an important role to play both as an adjunct to surgery and in the palliation of advanced disease. For many years 5-fluorouracil (5-FU) has been the only cyto toxic drug with significant activity in this condition and, recently, considerable effort has been directed toward enhancing its activity and finding better, alternative agents. Recently, raltitrexed (Tomudex; Zeneca Pharmaceuticals), the first of a new class of cytotoxic drugs, the selective, direct, thymidylate synthase inhibitors, received its first regulatory ap proval for the first-line treatment of advanced colo rectal cancer. The purpose of this review is to con sider the efficacy, toxicity, and resource implications of using this new antineoplastic agent, alongside developments that have been made in the more effective use of fluoropyrimidines, and the place of drug treatment in the management of colorectal cancer.

Data Sources. A variety of sources were used, including manual and on-line (Medline and Pharm- line) literature searching. Approved and other drug names were used as primary search terms, linked with colorectal cancer where limitation was required. The medical information department of Zeneca Pharma ceuticals also was used where appropriate.

Study Selection. Particular attention was di rected to randomized clinical trials, but nonrandom ized and preclinical studies were considered where appropriate.

Conclusions. Although colorectal cancer is in herently resistant to cytotoxic chemotherapy, such treatment now has an established role as an adjunct to surgery and in the palliation of advanced disease. The optimum 5-FU- based regimen has yet to be estab lished with certainty, although in advanced disease a four-times-weekly, 5-day regimen of 5-FU and low- dose folinic acid is probably the best of those fully evaluated to date. Raltitrexed seems to be as effective as this combination while having definite advantages in terms of toxicity and the resources required for its preparation and administration, although it remains to be seen to what extent these and other resource benefits will be offset by its higher cost and how its efficacy and tolerability will compare with other 5-FU- based regimens in ongoing clinical trials.

Key Words: Colorectal cancer • 5-fluorouracil; folinate • raltitrexed • chemotherapy.

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