Vancouver Island Centre, Department of Medicine, Victoria, British Columbia, Canada.
Expert Opin Drug Metab Toxicol. 2009 Nov;5(11):1447-54. doi: 10.1517/17425250903307455.
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).
Pharmacokinetics are summarized and Phase III adjuvant and MCRC trials of raltitrexed are reviewed.
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.
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.
雷替曲塞是一种胸苷酸合成酶的直接且特异性抑制剂，早期临床试验显示其与氟尿嘧啶（5-FU）具有相似的活性，主要用于转移性结直肠癌（MCRC）。
总结了雷替曲塞的药代动力学特征，并对其 III 期辅助治疗和 MCRC 临床试验进行了回顾。
MCRC 患者应用雷替曲塞的缓解率和总生存率与 5-FU 相当。汇总分析显示，5-FU 组无疾病进展生存时间比雷替曲塞组长 1 个月。雷替曲塞的 3 级以上毒性发生率与 5-FU 相比具有优势。然而，出乎意料的是，雷替曲塞治疗相关死亡率（TRM）较高，主要是由于违反方案。辅助治疗试验中的 TRM 也较高，导致该试验终止。尽管 TRM 过高，其中大部分是可以避免的，但总生存率与 5-FU 相同。生活质量的报告结果各异，有些报告认为优于 5-FU，有些则认为劣于 5-FU。
雷替曲塞每 3 周一次的简单治疗方案并未如其承诺的那样有效。与此同时，MCRC 治疗领域的变化使得雷替曲塞的应用空间有限。由于赞助商停止支持，雷替曲塞的继续研究水平已不如 5-FU。在加拿大，雷替曲塞仅用于对 5-FU 不耐受（黏膜、血液和心脏毒性）的患者。
