TY - JOUR
T1 - Impact of UGT1A1 genetic polymorphism on toxicity in unresectable pancreatic cancer patients undergoing FOLFIRINOX
AU - Shirasu, Hiromichi
AU - Todaka, Akiko
AU - Omae, Katsuhiro
AU - Fujii, Hirofumi
AU - Mizuno, Nobumasa
AU - Ozaka, Masato
AU - Ueno, Hideki
AU - Kobayashi, Satoshi
AU - Uesugi, Kazuhiro
AU - Kobayashi, Noritoshi
AU - Hayashi, Hideyuki
AU - Sudo, Kentaro
AU - Okano, Naohiro
AU - Horita, Yosuke
AU - Kamei, Keiko
AU - Yukisawa, Seigo
AU - Kobayashi, Marina
AU - Fukutomi, Akira
N1 - Funding Information:
H. Fujii received a research grant from Yakult Honsha, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, Eisai, Merck, and Kyowa-Hakko Kirin. N. Mizuno received research grants from Zeria Pharmaceutical, Taiho Pharmaceutical, Merck Serono, AstraZeneca, NanoCarrier, Eisai, and MSD, and received honoraria from Yakult Honsha, Taiho Pharmaceutical, Novartis, Pfizer, and Kyowa-Hakko Kirin. H. Ueno received research grant and honoraria from Yakult Honsha. S. Kobayashi received honoraria from Yakult Honsha. N. Okano received research grants from Yakult Honsha and Daiichi Sankyo. A. Todaka received honoraria from Yakult Honsha and Daiichi Sankyo. A. Fukutomi received honoraria from Yakult Honsha and Daiichi Sankyo. The study was designed under the responsibility of Shizuoka Industrial Foundation Pharma Valley Center, in conjunction with the steering committee; the study was funded by Yakult Honsha, Daiichi Sankyo, and Shizuoka Industrial Foundation Pharma Valley Center. Shizuoka Industrial Foundation Pharma Valley Center collected and analyzed the data and contributed to the interpretation of the study. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication. All other authors have declared no conflicts of interest.
Publisher Copyright:
© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
PY - 2019/2
Y1 - 2019/2
N2 - Studies have indicated an association between UDP-glucuronosyltransferase-1A1 (UGT1A1) genetic polymorphisms and irinotecan-induced toxicity. We undertook this study to investigate the association between UGT1A1 genetic polymorphisms and toxicity in patients treated with the FOLFIRINOX (comprising oxaliplatin, irinotecan, fluorouracil, and leucovorin) chemotherapy regimen in the JASPAC 06 study. Patients screened for UGT1A1*6 and UGT1A1*28, and treated with either the original FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 200 mg/m2, bolus 5-fluorouracil [5-FU] 400 mg/m2, and continuous 5-FU 2400 mg/m2) or a modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 200 mg/m2, and continuous 5-FU 2400 mg/m2) as first-line chemotherapy were included. Of 199 patients eligible for this analysis, 79 patients were treated with the original FOLFIRINOX regimen and 120 patients were treated with the modified FOLFIRINOX regimen. In the original FOLFIRINOX group, 54 were UGT1A1 WT, and 25 were UGT1A1 heterozygous type (−/*6, 12 patients; −/*28, 13 patients). In the modified FOLFIRINOX group, 64 were UGT1A1 WT and 56 were UGT1A1 heterozygous type (−/*6, 33 patients; −/*28, 23 patients). In the original FOLFIRINOX group, the incidence of diarrhea was significantly higher among patients with UGT1A1 heterozygous type than among those with UGT1A1 WT and the incidence of leukopenia and diarrhea was significantly higher among patients with UGT1A1 −/*6 than among those with UGT1A1 −/*28. Patients with UGT1A1 heterozygous type, especially those with UGT1A1 −/*6, tended to show a higher incidence rate of severe adverse events, but this was not statistically significant. However, for patients who received the modified FOLFIRINOX, there was no difference in the frequency of adverse events due to UGT1A1 status. In conclusion, patients with heterozygous UGT1A1 polymorphisms treated with the original FOLFIRINOX regimen experienced severe toxicity more frequently than patients with WT UGT1A1.
AB - Studies have indicated an association between UDP-glucuronosyltransferase-1A1 (UGT1A1) genetic polymorphisms and irinotecan-induced toxicity. We undertook this study to investigate the association between UGT1A1 genetic polymorphisms and toxicity in patients treated with the FOLFIRINOX (comprising oxaliplatin, irinotecan, fluorouracil, and leucovorin) chemotherapy regimen in the JASPAC 06 study. Patients screened for UGT1A1*6 and UGT1A1*28, and treated with either the original FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 200 mg/m2, bolus 5-fluorouracil [5-FU] 400 mg/m2, and continuous 5-FU 2400 mg/m2) or a modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 200 mg/m2, and continuous 5-FU 2400 mg/m2) as first-line chemotherapy were included. Of 199 patients eligible for this analysis, 79 patients were treated with the original FOLFIRINOX regimen and 120 patients were treated with the modified FOLFIRINOX regimen. In the original FOLFIRINOX group, 54 were UGT1A1 WT, and 25 were UGT1A1 heterozygous type (−/*6, 12 patients; −/*28, 13 patients). In the modified FOLFIRINOX group, 64 were UGT1A1 WT and 56 were UGT1A1 heterozygous type (−/*6, 33 patients; −/*28, 23 patients). In the original FOLFIRINOX group, the incidence of diarrhea was significantly higher among patients with UGT1A1 heterozygous type than among those with UGT1A1 WT and the incidence of leukopenia and diarrhea was significantly higher among patients with UGT1A1 −/*6 than among those with UGT1A1 −/*28. Patients with UGT1A1 heterozygous type, especially those with UGT1A1 −/*6, tended to show a higher incidence rate of severe adverse events, but this was not statistically significant. However, for patients who received the modified FOLFIRINOX, there was no difference in the frequency of adverse events due to UGT1A1 status. In conclusion, patients with heterozygous UGT1A1 polymorphisms treated with the original FOLFIRINOX regimen experienced severe toxicity more frequently than patients with WT UGT1A1.
KW - FOLFIRINOX
KW - UGT1A1
KW - chemotherapy
KW - pancreatic cancer
KW - toxicity
UR - http://www.scopus.com/inward/record.url?scp=85058238012&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058238012&partnerID=8YFLogxK
U2 - 10.1111/cas.13883
DO - 10.1111/cas.13883
M3 - Article
C2 - 30447099
AN - SCOPUS:85058238012
VL - 110
SP - 707
EP - 716
JO - Cancer Science
JF - Cancer Science
SN - 1347-9032
IS - 2
ER -
