Uridine diphosphate glucuronosyl transferase 1 family polypeptide A1 gene (UGT1A1) polymorphisms are associated with toxicity and efficacy in irinotecan monotherapy for refractory pancreatic cancer.
OBJECTIVE
The aim of this study was to evaluate the efficacy and safety of irinotecan monotherapy in patients with advanced pancreatic cancer (APC).


METHODS
Patients with APC refractory to gemcitabine and S-1 were included. Irinotecan (100 mg/m(2)) was administered on days 1, 8, and 15 every 4 weeks until disease progression or unacceptable toxicity was observed. The relationship between uridine diphosphate glucuronosyl transferase 1 family polypeptide A1 gene (UGT1A1) polymorphisms and clinical outcomes was evaluated.


RESULTS
Between January 2007 and December 2011, 231 cycles were delivered in 56 patients. Irinotecan was administered as second-line chemotherapy in 35.7% of patients and as third-line chemotherapy or later in 64.3%. A partial response was achieved in two (3.6%) and stable disease in 23 patients (41.0%), giving a disease control rate of 44.6%. The median time to progression (TTP) and overall survival (OS) were 2.9 (95% confidence interval [CI] 1.8-3.5) months and 5.3 (95% CI 4.5-6.8) months, respectively. Median survival from the first-line chemotherapy was 19.5 (95% CI 15.3-23.8) months. Major grade 3/4 adverse events included neutropenia (28.6%), anemia (12.5%), and anorexia (10.7%). Patients with *6 and/or *28 allele(s) (n = 15) were associated with grade 3/4 neutropenia and anorexia but showed longer TTP (5.3 vs. 1.8 months; p = 0.05), and OS (8.0 vs. 4.8 months; p = 0.09) than those without *6 and/or *28 (n = 29).


CONCLUSIONS
Salvage chemotherapy with irinotecan was moderately effective and well-tolerated in patients with APC refractory to gemcitabine and S-1. UGT1A1 polymorphisms were associated with toxicity and efficacy.
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Naminatsu
N
Takahara
Yousuke
Y
Nakai
Hiroyuki
H
Isayama
Takashi
T
Sasaki
Yumiko
Y
Satoh
Daiya
D
Takai
Tsuyoshi
T
Hamada
Rie
R
Uchino
Suguru
S
Mizuno
Koji
K
Miyabayashi
Dai
D
Mohri
Kazumichi
K
Kawakubo
Hirofumi
H
Kogure
Natsuyo
N
Yamamoto
Naoki
N
Sasahira
Kenji
K
Hirano
Hideaki
H
Ijichi
Minoru
M
Tada
Yutaka
Y
Yatomi
Kazuhiko
K
Koike
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018450:Disease Progression; D004338:Drug Combinations; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D010094:Oxonic Acid / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D016879:Salvage Therapy / Q000379:methods; D015996:Survival Rate; D005641:Tegafur / Q000627:therapeutic use; D016896:Treatment Outcome; D000093542:Gemcitabine; D000099148:UGT1A1 Enzyme
D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D003841:Deoxycytidine; D004338:Drug Combinations; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D010094:Oxonic Acid; D005641:Tegafur; D000093542:Gemcitabine; D000099148:UGT1A1 Enzyme; C079198:S 1 (combination)