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

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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/m2) 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.

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Abbreviations

APC:

Advanced pancreatic cancer

UGT1A1:

Uridine diphosphate glucuronosyl transferase 1 family polypeptide A1 gene

TTP:

Time to progression

OS:

Overall survival

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Acknowledgments

The authors thank two medical technologists Hiromitsu Yokota and Makiko Kurihara (Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo) for genotyping of UGT1A1 and a research coordinator Miyuki Tsuchida (Clinical Research Support Center, The University of Tokyo Hospital) for supporting data collection.

Conflict of interest

None.

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Authors and Affiliations

  1. Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Naminatsu Takahara, Yousuke Nakai, Hiroyuki Isayama, Takashi Sasaki, Tsuyoshi Hamada, Rie Uchino, Suguru Mizuno, Koji Miyabayashi, Dai Mohri, Kazumichi Kawakubo, Hirofumi Kogure, Natsuyo Yamamoto, Naoki Sasahira, Kenji Hirano, Hideaki Ijichi, Minoru Tada & Kazuhiko Koike

  2. Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Yumiko Satoh, Daiya Takai & Yutaka Yatomi

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  1. Naminatsu Takahara
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Correspondence to Hiroyuki Isayama.

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Takahara, N., Nakai, Y., Isayama, H. et al. 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 71, 85–92 (2013). https://doi.org/10.1007/s00280-012-1981-0

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