PMID- 32829105
OWN - NLM
STAT- MEDLINE
DCOM- 20210121
LR  - 20210121
IS  - 1879-0852 (Electronic)
IS  - 0959-8049 (Linking)
VI  - 138
DP  - 2020 Oct
TI  - Determination of the UGT1A1 polymorphism as guidance for irinotecan dose 
      escalation in metastatic colorectal cancer treated with first-line bevacizumab 
      and FOLFIRI (PURE FIST).
PG  - 19-29
LID - S0959-8049(20)30398-1 [pii]
LID - 10.1016/j.ejca.2020.05.031 [doi]
AB  - AIM: Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism plays 
      a crucial role in the increased susceptibility of patients to irinotecan and its 
      toxicity. This study is a multicenter, randomised clinical trial comparing the 
      clinical outcomes and adverse events (AEs) in metastatic colorectal cancer (mCRC) 
      patients treated with bevacizumab plus FOLFIRI with or without UGT1A1 genotyping 
      and irinotecan dose escalation as the first-line therapy. METHODS: The control 
      group received conventional biweekly FOLFIRI plus bevacizumab without UGT1A1 
      genotyping, whereas the study group received the same regimen with irinotecan 
      dose escalation based on UGT1A1 genotyping. The primary end-point was 
      progression-free survival (PFS), and secondary end-points were overall response 
      rate (ORR), disease control rate (DCR), overall survival (OS), AEs and 
      metastasectomy rate. RESULTS: Over a median follow-up of 26.0 months (IQR, 
      17.0-35.0 months), study group (n = 107) was superior to the control group 
      (n = 106) in PFS, OS, ORR, DCR, and metastasectomy rate (all P < 0.05). 
      Furthermore, there were no significant differences in AEs >/= grade III between the 
      two groups, even with the 1.36-fold increase in the relative dose intensity of 
      irinotecan in the study group. Dose escalation of irinotecan, an independent 
      factor of ORR (P < 0.001) and DCR (P = 0.006), improved PFS in mCRC patients with 
      wild-type and mutant KRAS (P = 0.007 and P = 0.019, respectively). CONCLUSION: 
      The current study revealed that mCRC patients, regardless of KRAS gene status, 
      with UGT1A1 genotyping can tolerate escalated doses of irinotecan and potentially 
      achieve a more favourable clinical outcome without significantly increased 
      toxicities. CLINICAL TRIAL REGISTRATION: NCT02256800.
CI  - Copyright (c) 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.
FAU - Tsai, Hsiang-Lin
AU  - Tsai HL
AD  - Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical 
      University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department 
      of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical 
      University, Kaohsiung, Taiwan. Electronic address: chunpin870132@yahoo.com.tw.
FAU - Huang, Ching-Wen
AU  - Huang CW
AD  - Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical 
      University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department 
      of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical 
      University, Kaohsiung, Taiwan. Electronic address: baseball5824@yahoo.com.tw.
FAU - Lin, Yi-Wen
AU  - Lin YW
AD  - Division of Colorectal Surgery, Department of Surgery, Tainan Municipal Hospital, 
      Tainan, Taiwan. Electronic address: linyiewen@yahoo.com.tw.
FAU - Wang, Jui-Ho
AU  - Wang JH
AD  - Division of Colorectal Surgery, Department of Surgery, Kaohsiung Veterans General 
      Hospital, Kaohsiung, Taiwan. Electronic address: rayhowang@gmail.com.
FAU - Wu, Chang-Chieh
AU  - Wu CC
AD  - Division of Colorectal Surgery, Department of Surgery, Keelung Branch, 
      Tri-Service General Hospital, Keelung, Taiwan. Electronic address: 
      doc20276@gmail.com.
FAU - Sung, Yung-Chuan
AU  - Sung YC
AD  - Division of Medical Oncology, Department of Internal Medicine, Taipei Cathay 
      General Hospital, Taipei, Taiwan. Electronic address: yungchuans@cgh.org.tw.
FAU - Chen, Tzu-Liang
AU  - Chen TL
AD  - Division of Colorectal Surgery, Department of Surgery, Taichung China Medical 
      University Hospital, Taichung, Taiwan. Electronic address: golfma22@gmail.com.
FAU - Wang, Hwei-Ming
AU  - Wang HM
AD  - Division of Colorectal Surgery, Department of Surgery, Taichung China Medical 
      University Hospital, Taichung, Taiwan. Electronic address: phillipwhm@gmail.com.
FAU - Tang, Hsiu-Chin
AU  - Tang HC
AD  - Division of Colorectal Surgery, Department of Surgery, Tainan Sin-Lan Hospital, 
      Tainan, Taiwan. Electronic address: schoetz.tang@gmail.com.
FAU - Chen, Joe-Bin
AU  - Chen JB
AD  - Division of Colorectal Surgery, Department of Surgery, Taichung Veterans General 
      Hospital, Taichung, Taiwan. Electronic address: jbchen@vghtc.gov.tw.
FAU - Ke, Tao-Wei
AU  - Ke TW
AD  - Division of Colorectal Surgery, Department of Surgery, Taichung China Medical 
      University Hospital, Taichung, Taiwan. Electronic address: ketaowei@gmail.com.
FAU - Tsai, Chang-Sung
AU  - Tsai CS
AD  - Division of Medical Oncology, Department of Internal Medicine, Tainan Municipal 
      Hospital, Tainan, Taiwan. Electronic address: chonsonechai@gmail.com.
FAU - Huang, Hsuan-Yuan
AU  - Huang HY
AD  - Division of Colorectal Surgery, Department of Surgery, Changhua Christian 
      Hospital, Changhua, Taiwan. Electronic address: 107431@cch.org.tw.
FAU - Wang, Jaw-Yuan
AU  - Wang JY
AD  - Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical 
      University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department 
      of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical 
      University, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College 
      of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: 
      cy614112@ms14.hinet.net.
LA  - eng
SI  - ClinicalTrials.gov/NCT02256800
PT  - Comparative Study
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20200820
PL  - England
TA  - Eur J Cancer
JT  - European journal of cancer (Oxford, England : 1990)
JID - 9005373
RN  - 0 (KRAS protein, human)
RN  - 2S9ZZM9Q9V (Bevacizumab)
RN  - 7673326042 (Irinotecan)
RN  - EC 2.4.1.- (UGT1A1 enzyme)
RN  - EC 2.4.1.17 (Glucuronosyltransferase)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - Q573I9DVLP (Leucovorin)
RN  - U3P01618RT (Fluorouracil)
RN  - XT3Z54Z28A (Camptothecin)
RN  - IFL protocol
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse 
      effects
MH  - Bevacizumab/*administration & dosage/adverse effects
MH  - Camptothecin/administration & dosage/adverse effects/*analogs & derivatives
MH  - Colorectal Neoplasms/*drug therapy/genetics/mortality/pathology
MH  - Female
MH  - Fluorouracil/administration & dosage/adverse effects
MH  - Genotype
MH  - Glucuronosyltransferase/*genetics
MH  - Humans
MH  - Irinotecan/*administration & dosage/adverse effects
MH  - Leucovorin/administration & dosage/adverse effects
MH  - Male
MH  - Middle Aged
MH  - Neoplasm Metastasis
MH  - Outcome Assessment, Health Care
MH  - *Polymorphism, Genetic
MH  - Proto-Oncogene Proteins p21(ras)/genetics
OTO - NOTNLM
OT  - Bevacizumab
OT  - Dose escalation
OT  - FOLFIRI
OT  - First-line treatment
OT  - Irinotecan
OT  - Metastatic colorectal cancer
OT  - UGT1A1 polymorphism
COIS- Conflict of interest statement The authors have declared that no conflicts of 
      interest exist.
EDAT- 2020/08/24 06:00
MHDA- 2021/01/22 06:00
CRDT- 2020/08/24 06:00
PHST- 2020/02/25 00:00 [received]
PHST- 2020/05/08 00:00 [revised]
PHST- 2020/05/21 00:00 [accepted]
PHST- 2020/08/24 06:00 [pubmed]
PHST- 2021/01/22 06:00 [medline]
PHST- 2020/08/24 06:00 [entrez]
AID - S0959-8049(20)30398-1 [pii]
AID - 10.1016/j.ejca.2020.05.031 [doi]
PST - ppublish
SO  - Eur J Cancer. 2020 Oct;138:19-29. doi: 10.1016/j.ejca.2020.05.031. Epub 2020 Aug 
      20.