基于胸苷酸合成酶和二氢嘧啶脱氢酶表达，采用5-氟尿嘧啶和亚叶酸或奥沙利铂和伊立替康对晚期结直肠癌进行个体化化疗的II期研究。

Phase II study of tailored chemotherapy for advanced colorectal cancer with either 5-fluouracil and leucovorin or oxaliplatin and irinotecan based on the expression of thymidylate synthase and dihydropyrimidine dehydrogenase.

作者信息

Smorenburg C H, Peters G J, van Groeningen C J, Noordhuis P, Smid K, van Riel A M G H, Dercksen W, Pinedo H M, Giaccone G

机构信息

Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.

出版信息

Ann Oncol. 2006 Jan;17(1):35-42. doi: 10.1093/annonc/mdj046. Epub 2005 Oct 26.

DOI:10.1093/annonc/mdj046

PMID:16251201

Abstract

BACKGROUND

Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are essential enzymes for 5-fluorouracil (5-FU) metabolism. In patients with advanced colorectal cancer (ACRC), retrospective studies have shown that low expression levels of TS and DPD correlated with response to 5-FU. We performed a prospective study in which the choice of first-line chemotherapy with either 5-FU or a non-5-FU containing regimen was based on TS and DPD expression.

PATIENTS AND METHODS

Fresh-frozen samples of metastases were obtained from 58 previously untreated patients with ACRC. mRNA expression of TS and DPD was quantified using an RT-PCR assay. Patients with low tumor expression of both TS and DPD received weekly bolus 5-FU/leucovorin (LV) 500 mg/m2 (group A); patients with high TS and/or DPD received 3-weekly oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2 (group B). After progression, cross-over to the alternative regimen was attempted.

RESULTS

Of 53 eligible patients, 31 had tumors with both low TS and low DPD, and were treated in group A. A response was observed in 11 patients [35%; 95% confidence interval (CI) 19% to 54%]. Cross-over to second-line oxaliplatin/irinotecan resulted in a partial response in two out of 16 patients (13%; 95% CI 1% to 38%). In group B, four out of 22 patients responded (18%; 95% CI 5% to 40%), while no responses were observed in 12 patients after cross-over to 5-FU/LV (0%; 95% CI 0% to 28%).

CONCLUSIONS

Prospective selection of 5-FU/LV chemotherapy based on low TS and DPD expression in patients with ACRC did not confirm the high response rates reported in retrospective studies. The procedure of obtaining metastatic tissue and quantitation of enzymes appeared feasible but cumbersome. Before assessing the clinical utility of a predictive marker in a randomized trial, future studies should focus on prospective validation of the assay in a large and well defined population.

摘要

背景

胸苷酸合成酶（TS）和二氢嘧啶脱氢酶（DPD）是5-氟尿嘧啶（5-FU）代谢的关键酶。在晚期结直肠癌（ACRC）患者中，回顾性研究表明TS和DPD的低表达水平与对5-FU的反应相关。我们进行了一项前瞻性研究，其中一线化疗选择5-FU或不含5-FU的方案是基于TS和DPD的表达。

患者和方法

从58例先前未接受治疗的ACRC患者中获取转移灶的新鲜冷冻样本。使用逆转录聚合酶链反应（RT-PCR）测定法对TS和DPD的mRNA表达进行定量。TS和DPD肿瘤表达均低的患者接受每周一次大剂量5-FU/亚叶酸钙（LV）500mg/m²（A组）；TS和/或DPD高表达的患者接受每3周一次奥沙利铂85mg/m²和伊立替康200mg/m²（B组）。病情进展后，尝试交叉使用替代方案。

结果

在53例符合条件的患者中，31例患者的肿瘤TS和DPD均低，在A组接受治疗。11例患者观察到缓解[35%；95%置信区间（CI）19%至54%]。交叉使用二线奥沙利铂/伊立替康后，16例患者中有2例出现部分缓解（13%；95%CI 1%至38%）。在B组中，22例患者中有4例缓解（18%；95%CI 5%至40%），而12例患者交叉使用5-FU/LV后未观察到缓解（0%；95%CI 0%至28%）。