Correlative analysis of plasma SN-38 levels and DPD activity with outcomes of FOLFIRI regimen for metastatic colorectal cancer with UGT1A1 *28 and *6 wild type and its implication for individualized chemotherapy. Issue 3 (4th March 2017)

• Record Type: Journal Article
• Authors: Cai, Xun; Tian, Chuan; Wang, Liwei; Zhuang, Rongyuan; Zhang, Xiaowei; Guo, Yuanbiao; Lu, Hongmin; Wang, Hui; Li, Xiaoyu; Gao, Junwei; Li, Qi; Wang, Chungang
• Is Part Of: Cancer biology & therapy. Volume 18:Issue 3(2017)
• Page Start: 186
• Page End: 193
• Publication Date: 2017-03-04
• Subjects: Colonic neoplasm -- dihydropyrimidine dehydrogenase -- drug metabolism -- genetic polymorphism -- Irinotecan -- rate-limiting enzyme -- uridine diphosphate glucuronosyltransferase; 616.99406
• DOI: 10.1080/15384047.2017.1294286
• Languages: English
• ISSNs: 1538-4047

Abstract

ABSTRACT: It remains uncertain whether there is an correlation between clinical pharmacokinetic parameters and outcomes for metastatic colorectal cancer especially with UGT1A1 *28 and *6 wild type (*1/*1-*1/*1) for serious events associated with Irinotecan are largely excluded. This study retrospectively analyzed the relationship between Irinotecan metabolite levels and outcomes of UGT1A1 *1/*1-*1/*1 genotype arrangement. Blood samples (n = 244) were collected for analysis of plasma DPD activity (before first chemotherapy) and SN-38 levels (1.5 and 49 hour after CPT-11 administration). Clinical variables such as toxicity and outcomes were then assessed. Of the *1/*1 -*1/*1 genotype combination, the median progression free survival of the CSN-38 1.5 h > 50.24 ng/ml subset was remarkably longer than that of the CSN-38 1.5 h ≤ 50.24 ng/ml subset. However, there were no differences between the CSN-38 49 h > 15.25 ng/ml subgroup and the ≤ 15.25 ng/ml group. It was lower DPD activity that responsible for the relatively higher incidence of bone marrow hypocellular, diarrhea, and oral mucositis in the CSN-38 1.5 h > 50.24 ng/ml and CSN-38 49 h > 15.25 ng/ml subsets. Therefore, plasma SN-38 levels is related to outcomes for UGT1A1 *1/*1-*1/*1 genotype, to improve efficacy, patients with CSN-38 1.5 h lower than 50.24 ng/ml, CPT-11 dosage could be added in next chemmotherapy on SN-38 plasma level monitoring. Additionally, in patients with DPD activity below 3.18 before treatment, appropriate reduction of 5-FU dose could be considered to minimize the incidence of adverse events.