Toshifumi Yamaguchi1,2,3, Satoru Iwasa4, Hirokazu Shoji4, Yoshitaka Honma4, Atsuo Takashima4, Ken Kato4, Tetsuya Hamaguchi5, Kazuhide Higuchi6, Narikazu Boku4. 1. Cancer Chemotherapy Center, Osaka Medical College Hospital, 2-7 Daigaku machi, Takatsuki, Osaka, 569-8686, Japan. yamagu.toshifumi@gmail.com. 2. Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigaku machi, Takatsuki, Osaka, 569-8686, Japan. yamagu.toshifumi@gmail.com. 3. Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. yamagu.toshifumi@gmail.com. 4. Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. 5. Department of Gastrointestinal Oncology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. 6. Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigaku machi, Takatsuki, Osaka, 569-8686, Japan.
Abstract
BACKGROUND: While uridine diphosphate glucuronosyltransferase (UGT) 1A1 is a key enzyme in the metabolism of irinotecan, relationship between UGT1A1 genotype and safety and efficacy of irinotecan monotherapy in patients with advanced gastric cancer is not clarified. METHODS: Efficacy and safety in advanced gastric cancer patients, who were tested for UGT1A1*6 and *28 genotype and treated with irinotecan monotherapy as third-line treatment from 2009 to 2014, were evaluated according to the UGT1A1*6 and *28 genotypes. RESULTS: Among 74 patients of the subjects, the genotypes of UGT1A1 were wild-type (WT) in 37 patients (50%), single heterozygosity (SH) in 27 (36.5%) and double heterozygosity or homozygosity (Homo/DH) in 10 (13.5%). The initial dose of irinotecan was reduced in 10 patients (27%) with WT, in 9 (33%) with SH, and in 7 (70%) with Homo/DH. Median overall survival was 6.9 months, 6.3 months, and 2.8 months in the WT, SH and Homo/DH genotypes, associated with median time to treatment failure of 2.4 months, 2.3 months, and 1.3 months, respectively. Among 36 patients with measurable lesion, disease control rates were 47.6%, 41.7% and 33.3% in the WT, SH and Homo/DH genotypes. Grade 3 or higher adverse events of special interest were neutropenia (13%, 22%, and 64% for the WT, SH and Homo/DH genotypes), febrile neutropenia (2%, 7%, and 50%) and diarrhea (6%, 5%, and 21%). CONCLUSIONS: The UGT1A1 polymorphism may be related to the clinical outcomes of irinotecan monotherapy as the third-line treatment for advanced gastric cancer.
BACKGROUND: While uridine diphosphate glucuronosyltransferase (UGT) 1A1 is a key enzyme in the metabolism of irinotecan, relationship between UGT1A1 genotype and safety and efficacy of irinotecan monotherapy in patients with advanced gastric cancer is not clarified. METHODS: Efficacy and safety in advanced gastric cancerpatients, who were tested for UGT1A1*6 and *28 genotype and treated with irinotecan monotherapy as third-line treatment from 2009 to 2014, were evaluated according to the UGT1A1*6 and *28 genotypes. RESULTS: Among 74 patients of the subjects, the genotypes of UGT1A1 were wild-type (WT) in 37 patients (50%), single heterozygosity (SH) in 27 (36.5%) and double heterozygosity or homozygosity (Homo/DH) in 10 (13.5%). The initial dose of irinotecan was reduced in 10 patients (27%) with WT, in 9 (33%) with SH, and in 7 (70%) with Homo/DH. Median overall survival was 6.9 months, 6.3 months, and 2.8 months in the WT, SH and Homo/DH genotypes, associated with median time to treatment failure of 2.4 months, 2.3 months, and 1.3 months, respectively. Among 36 patients with measurable lesion, disease control rates were 47.6%, 41.7% and 33.3% in the WT, SH and Homo/DH genotypes. Grade 3 or higher adverse events of special interest were neutropenia (13%, 22%, and 64% for the WT, SH and Homo/DH genotypes), febrile neutropenia (2%, 7%, and 50%) and diarrhea (6%, 5%, and 21%). CONCLUSIONS: The UGT1A1 polymorphism may be related to the clinical outcomes of irinotecan monotherapy as the third-line treatment for advanced gastric cancer.