A UGT1A1 genotype-guided dosing study of modified FOLFIRINOX in previously untreated patients with advanced gastrointestinal malignancies.
Academic Medical Centers
Adult
Age Factors
Aged
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Biliary Tract Neoplasms
/ drug therapy
Disease-Free Survival
Dose-Response Relationship, Drug
Drug Administration Schedule
Female
Fluorouracil
/ therapeutic use
Gastrointestinal Neoplasms
/ drug therapy
Genotype
Glucuronosyltransferase
/ genetics
Humans
Irinotecan
/ therapeutic use
Leucovorin
/ therapeutic use
Male
Maximum Tolerated Dose
Middle Aged
Molecular Targeted Therapy
/ methods
Oxaliplatin
/ therapeutic use
Pancreatic Neoplasms
/ drug therapy
Prognosis
Retrospective Studies
Risk Assessment
Sex Factors
Stomach Neoplasms
/ drug therapy
Survival Analysis
Treatment Outcome
UGT1A1
biliary tract cancer
gastric cancer
irinotecan
pancreatic cancer
Journal
Cancer
ISSN: 1097-0142
Titre abrégé: Cancer
Pays: United States
ID NLM: 0374236
Informations de publication
Date de publication:
15 05 2019
15 05 2019
Historique:
received:
11
07
2018
revised:
30
10
2018
accepted:
02
11
2018
pubmed:
16
1
2019
medline:
12
2
2020
entrez:
16
1
2019
Statut:
ppublish
Résumé
FOLFIRINOX (5-fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) is an effective but toxic therapy for pancreatic cancer. UGT1A1 (UDP glucuronosyltransferase 1A1) eliminates the active metabolite of irinotecan. Polymorphisms reduce UGT1A1 activity, leading to toxicity. The primary objective was to determine the dose-limiting toxicity (DLT) rate in cycle 1 of modified FOLFIRINOX (mFOLFIRINOX) using genotype-guided dosing of irinotecan for the most common UGT1A1 genotypes (*1/*1, *1/*28) in advanced gastrointestinal malignancies, with expansion in pancreatic and biliary tract cancers. 5-FU (2400 mg/m In cohort 1, DLTs (most commonly febrile neutropenia, fatigue, diarrhea) occurred in 2/15 (13%), 3/16 (19%), and 4/10 (40%) patients with *1/*1, *1/*28, and *28/*28 genotypes, respectively. In cohort 2, 6/19 (32%) pancreatic and 4/19 (21%) biliary tract cancer patients experienced DLTs (most commonly fatigue, diarrhea, nausea/vomiting). In cohort 2, upper confidence limits of DLT rates exceeded 33%. Response rates were 38% in pancreatic and 21% in biliary tract cancers. On the basis of our prespecified criteria, tolerability of UGT1A1 genotype-guided mFOLFIRINOX was not established in pancreatic and biliary tract cancers. However, this regimen was effective.
Sections du résumé
BACKGROUND
FOLFIRINOX (5-fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) is an effective but toxic therapy for pancreatic cancer. UGT1A1 (UDP glucuronosyltransferase 1A1) eliminates the active metabolite of irinotecan. Polymorphisms reduce UGT1A1 activity, leading to toxicity. The primary objective was to determine the dose-limiting toxicity (DLT) rate in cycle 1 of modified FOLFIRINOX (mFOLFIRINOX) using genotype-guided dosing of irinotecan for the most common UGT1A1 genotypes (*1/*1, *1/*28) in advanced gastrointestinal malignancies, with expansion in pancreatic and biliary tract cancers.
METHOD
5-FU (2400 mg/m
RESULTS
In cohort 1, DLTs (most commonly febrile neutropenia, fatigue, diarrhea) occurred in 2/15 (13%), 3/16 (19%), and 4/10 (40%) patients with *1/*1, *1/*28, and *28/*28 genotypes, respectively. In cohort 2, 6/19 (32%) pancreatic and 4/19 (21%) biliary tract cancer patients experienced DLTs (most commonly fatigue, diarrhea, nausea/vomiting). In cohort 2, upper confidence limits of DLT rates exceeded 33%. Response rates were 38% in pancreatic and 21% in biliary tract cancers.
CONCLUSION
On the basis of our prespecified criteria, tolerability of UGT1A1 genotype-guided mFOLFIRINOX was not established in pancreatic and biliary tract cancers. However, this regimen was effective.
Substances chimiques
folfirinox
0
Oxaliplatin
04ZR38536J
Irinotecan
7673326042
UGT1A1 enzyme
EC 2.4.1.-
Glucuronosyltransferase
EC 2.4.1.17
Leucovorin
Q573I9DVLP
Fluorouracil
U3P01618RT
Types de publication
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1629-1636Informations de copyright
© 2019 American Cancer Society.