Management of colorectal cancer - Defining the role of raltitrexed

In Europe and the US > 300 000 cases of advanced colorectal cancer are diagnosed each year, and it is the third most common type of cancer after breast/prostate and lung cancers, The lifetime risk of developing colorectal cancer increases with genetic predisposition or a family history of colorectal cancer. The 5-year survival rate varies depending on the stage at which colorectal cancer is diagnosed. Advanced colorectal cancer (stage IV, Duke's D) has a 5-year survival rate of <5%. Screening and early detection can significantly increase the likelihood of survival. Treatment of early colorectal cancer relies on surgery and/or chemotherapy. Patients with stage I to II (Duke's A to B) colorectal cancer have a good prognosis, with a > 70% survival rate at 5 years. While the management of advanced colorectal cancer also encompasses these options, treatment is largely palliative. Fluorouracil is currently the gold standard for treatment of advanced colorectal cancer. However, despite its widespread use it is associated with a relatively low tumor response rate (< 15%), drug regimens are complex and toxicities are significant. Raltitrexed, a specific thymidylate synthase inhibitor, has been approved for the treatment of advanced colorectal cancer. As first-line therapy it has similar efficacy to fluorouracil in terms of tumor response rates (approximately 14 to 19%) and overall survival duration (approximately 10 to 11 months), although disease progression may be sooner with raltitrexed. However, in an effort to further increase survival duration, raltitrexed has been administered concomitantly with fluorouracil or oxaliplatin therapy as first- or second-line therapy with promising preliminary results. In comparative clinical trials, leukopenia and mucositis were more commonly associated with fluorouracil than with raltitrexed monotherapy. In contrast, elevated transaminase levels. which were not clinically significant, and anemia were more common with the raltitrexed regimen. Higher drug acquisition costs for raltitrexed than for fluorouracil are partially offset by reduced pharmacy resource utilization, lower drug administration costs and reduced costs relating to the management of chemotherapy-induced adverse events. Overall treatment-related costs were slightly higher for raltitrexed than for fluorouracil administered according to the Mayo regimen, but lower than either the Lokich or De Gramont regimens. Early comparative quality-of-life assessments favoured raltitrexed over fluorouracil: however, comparisons at 15 weeks failed to show any clear preference in favor of either treatment. Palliative improvements occurred in patients who responded to treatment or those who had disease stabilization in both treatment groups. Conclusions: Raltitrexed is a first-line treatment option for the management of advanced colorectal cancer and offers a more convenient administration regimen than traditional fluorouracil infusion regimens. Available data suggest that it may have lower overall treatment costs than some but not all fluorouracil regimens: however, formal cost-effectiveness comparisons (in terms of cost per clinical outcome) are not available. Preliminary results from trials of combination therapy with raltitrexed and either fluorouracil or oxaliplatin are promising, however, further data on raltitrexed combination therapy are necessary to better determine its place in the management of advanced colorectal cancer.