title: 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.
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 hlower 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.
authors.affiliation: a Department of Oncology , Shanghai General Hospital, Nanjing Medical University , Shanghai , China.|b Department of Oncology , Shanghai General Hospital, Shanghai Jiaotong University School of Medicine , Shanghai , China.
authors.forename: Xun
authors.initials: X
authors.lastname: Cai
authors.affiliation: c Department of Nuclear Medicine , People's Hospital of Guizhou Province , Guiyang , China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Tian
authors.affiliation: a Department of Oncology , Shanghai General Hospital, Nanjing Medical University , Shanghai , China.|b Department of Oncology , Shanghai General Hospital, Shanghai Jiaotong University School of Medicine , Shanghai , China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Wang
authors.affiliation: d Department of Oncology , Zhongshan Hospital, Shanghai Medical College, Fudan University , Shanghai , China.
authors.forename: Rongyuan
authors.initials: R
authors.lastname: Zhuang
authors.affiliation: e Department of Medical Oncology , Shanghai Cancer Center, Shanghai Medical College, Fudan University , Shanghai , China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: f Department of Traditional Chinese Medicine , Ruijin Hospital, Medical College, Shanghai Jiaotong University , Shanghai , China.
authors.forename: Yuanbiao
authors.initials: Y
authors.lastname: Guo
authors.affiliation: g Department of Oncology , Renji Hospital, Medical College, Shanghai Jiaotong University , Shanghai , China.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Lu
authors.affiliation: h Department of Oncology , Shanghai Tenth People's Hospital, Shanghai Tongji University , Shanghai , China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: i Department of Clinical Pharmacy , Shanghai General Hospital, Shanghai Jiaotong University School of Medicine , Shanghai , China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Li
authors.affiliation: i Department of Clinical Pharmacy , Shanghai General Hospital, Shanghai Jiaotong University School of Medicine , Shanghai , China.
authors.forename: Junwei
authors.initials: J
authors.lastname: Gao
authors.affiliation: a Department of Oncology , Shanghai General Hospital, Nanjing Medical University , Shanghai , China.|b Department of Oncology , Shanghai General Hospital, Shanghai Jiaotong University School of Medicine , Shanghai , China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.affiliation: j Department of Radiotherapy , Shanghai General Hospital, Shanghai Jiaotong University School of Medicine , Shanghai , China.
authors.forename: Chungang
authors.initials: C
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D015179:Colorectal Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D055815:Young Adult; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D002955:Leucovorin; D000099148:UGT1A1 Enzyme
keywords: Colonic neoplasm; Irinotecan; dihydropyrimidine dehydrogenase; drug metabolism; genetic polymorphism; rate-limiting enzyme; uridine diphosphate glucuronosyltransferase