Uridine diphosphate glucuronosyl transferase 1 family polypeptide A1 gene (UGT1A1) polymorphisms are associated with toxicity and efficacy in irinotecan monotherapy for refractory pancreatic cancer

Cancer Chemother Pharmacol. 2013 Jan;71(1):85-92. doi: 10.1007/s00280-012-1981-0. Epub 2012 Sep 29.

Abstract

Purpose: 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.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Phytogenic / adverse effects
  • Antineoplastic Agents, Phytogenic / therapeutic use*
  • Camptothecin / adverse effects
  • Camptothecin / analogs & derivatives*
  • Camptothecin / therapeutic use
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / therapeutic use
  • Disease Progression
  • Drug Combinations
  • Female
  • Glucuronosyltransferase / genetics*
  • Humans
  • Irinotecan
  • Male
  • Middle Aged
  • Oxonic Acid / therapeutic use
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Polymorphism, Genetic*
  • Prospective Studies
  • Salvage Therapy / methods
  • Survival Rate
  • Tegafur / therapeutic use
  • Treatment Outcome

Substances

  • Antineoplastic Agents, Phytogenic
  • Drug Combinations
  • Deoxycytidine
  • S 1 (combination)
  • Tegafur
  • Oxonic Acid
  • Irinotecan
  • gemcitabine
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • Camptothecin