Benson A B
Clinical Investigations Program, Northwestern University Chicago, Illinois, USA.
Oncology (Williston Park). 1998 Oct;12(10 Suppl 7):28-34.
The treatment of advanced colorectal cancer has been evaluated in a series of randomized trials, including infusional and modulated 5-fluorouracil (5-FU), and three meta-analyses encompassing trials of 5-FU plus leucovorin, continuous-infusion 5-FU, and intra-arterial fluoropyrimidines. A Southwest Oncology Group seven-arm phase II trial suggested that infusional 5-FU produced the most favorable toxicity spectrum and the longest survival, warranting further investigation in phase III trials. In a randomized phase III five-arm trial conducted by the Eastern Cooperative Oncology Group and the Cancer and Leukemia Group B, significant toxicity differences noted among the arms favored high-dose infusional 5-FU. In addition, the trial showed that 5-FU modulated by leucovorin or interferon was not more effective than 5-FU given as a 24-hour high-dose infusion weekly, and N-(phosphonacetyl)-L-aspartic acid did not enhance the activity of the weekly infusional 5-FU. Oral leucovorin provided no advantage over IV dosing. There was a significant difference in survival for patients with nonmeasurable disease (16.9 months) compared to those with measurable disease (12.6 months, P = .001). The Advanced Colorectal Cancer Meta-analysis Project demonstrated a response advantage for patients receiving 5-FU plus leucovorin (23%) compared to those receiving bolus 5-FU (11%, P = 10(-7); however, there was no survival advantage of 5-FU plus leucovorin over 5-FU alone (P = 0.57). The Meta-Analysis Group in Cancer showed that continuous-infusion 5-FU resulted in a statistically significantly higher response rate than bolus 5-FU (22% vs 14%, P = .0002). Overall survival also favored continuous-infusion 5-FU (P = .04). Continuous-infusion 5-FU was less toxic than bolus treatment. Data from six select randomized trials comparing hepatic intra-arterial infusion of FUDR to systemic therapy demonstrated a significant difference favoring intra-arterial therapy. Future directions for the treatment of advanced colorectal cancer include ongoing trials comparing low-dose vs high-dose infusional 5-FU, intra-arterial FUDR, leucovorin and dexamethasone vs systemic leucovorin plus 5-FU and proposed trials evaluating the dihydropyrimidine dehydrogenase inhibitor eniluracil plus oral 5-FU. Other drugs of interest include UFT, capecitabine, thymidylate synthase inhibitors, oxaliplatin, and irinotecan combinations.
一系列随机试验对晚期结直肠癌的治疗进行了评估，包括输注式和调整剂量的5-氟尿嘧啶（5-FU），以及三项荟萃分析，涵盖了5-FU加亚叶酸、持续输注5-FU和动脉内氟嘧啶的试验。西南肿瘤协作组的一项七臂II期试验表明，输注式5-FU产生的毒性谱最有利，生存期最长，值得在III期试验中进一步研究。在东部肿瘤协作组和癌症与白血病B组进行的一项随机III期五臂试验中，各治疗组之间显著的毒性差异表明高剂量输注式5-FU更具优势。此外，该试验表明，由亚叶酸或干扰素调整的5-FU并不比每周一次24小时高剂量输注的5-FU更有效，N-（膦酰乙酰）-L-天冬氨酸也没有增强每周输注式5-FU的活性。口服亚叶酸与静脉给药相比没有优势。不可测量疾病患者的生存期（16.9个月）与可测量疾病患者（12.6个月，P = 0.001）存在显著差异。晚期结直肠癌荟萃分析项目表明，接受5-FU加亚叶酸的患者（23%）与接受推注5-FU的患者相比有反应优势（11%，P = 10^-7）；然而，5-FU加亚叶酸与单独使用5-FU相比没有生存优势（P = 0.57）。癌症荟萃分析组表明，持续输注5-FU的反应率在统计学上显著高于推注5-FU（22%对14%，P = 0.0002）。总生存期也有利于持续输注5-FU（P = 0.04）。持续输注5-FU的毒性低于推注治疗。六项比较肝动脉内输注氟尿苷与全身治疗的选定随机试验的数据表明，动脉内治疗具有显著优势。晚期结直肠癌治疗的未来方向包括正在进行的比较低剂量与高剂量输注式5-FU、动脉内氟尿苷、亚叶酸和地塞米松与全身亚叶酸加5-FU的试验，以及拟进行的评估二氢嘧啶脱氢酶抑制剂依诺拉西加口服5-FU的试验。其他有兴趣的药物包括优福定、卡培他滨、胸苷酸合成酶抑制剂、奥沙利铂和伊立替康联合用药。
