BACKGROUND: Neutropenia and diarrhea are the common dose-limiting toxicities of irinotecan, and uridine diphosphate glucuronosyltransferases (UGTs) gene polymorphisms are considered to be one of the predictive markers of irinotecan related toxicities. This study aims to investigate the association between UGT1A1 gene polymorphisms and irinotecan related toxicities in Chinese Han gastrointestinal cancer patients receiving FOLFIRI regimen chemotherapy. METHODS: A total of 94 gastrointestinal cancer patients with metastasis (72 colon and rectum, 20 stomach, 1 pancreas and 1 duodenum), were enrolled from 2007 to 2010 in Shanghai Ruijin Hospital. All patients received standard dosage of FOLFIRI regimen (irinotecan 180mg/m2 d1, CF 200mg/m2 d1-d2, 5-FU 400mg/m2 d1-d2, followed by continuous infusion of 5-FU 600mg/m2 for 22h d1-d2, every 2 weeks). UGT1A1 gene polymorphisms (*60 -3279T > G, *93 -3156G > A, *28 -53TA6 > TA7, *6 211G > A) were detected by direct sequencing of DNA extracted from peripheral blood. The incidence of neutropenia, diarrhea, and time to severe toxicity were recorded. The relationship between UGT1A1 gene polymorphisms and toxicities was analyzed. RESULTS: The frequencies of UGT1A1*60 (-3279 G/G), UGT1A1*93 (-3156 A/A), UGT1A1*28 (-53 7/7) and UGT1A1*6 (211 A/A) homozygote were 6.4% (6/94), 1.1% (1/94), 1.1% (1/94) and 2.1% (2/94), respectively. The incidences of grade 3/4 neutropenia and diarrhea were 53.2% (50/94) and 12.8% (12/94), respectively. Comparing those with wild type, patients with UGT1A1*28 or *93 allele had significantly high risk of grade 3/4 diarrhea (6/7, 7/7 vs. 6/6: 27.8% vs. 9.2%, OR=3.791, P=0.034; G/A, A/A vs. G/G: 29.4% vs. 9.1%, OR=4.167, P=0.023). No relationship was found between UGT1A1 allele polymorphism and grade 3/4 neutropenia. The baseline serum total bilirubin was elevated in UGT1A1*28, *93 allele carriers and *60 homozygote, but with no relationship with severe toxicities. CONCLUSION: In Chinese Han gastrointestinal cancer patients receiving standard FOLFIRI regimen, UGT1A1*28 or *93 allele carriers may have high risk of severe diarrhea.
BACKGROUND:Neutropenia and diarrhea are the common dose-limiting toxicities of irinotecan, and uridine diphosphate glucuronosyltransferases (UGTs) gene polymorphisms are considered to be one of the predictive markers of irinotecan related toxicities. This study aims to investigate the association between UGT1A1 gene polymorphisms and irinotecan related toxicities in Chinese Han gastrointestinal cancerpatients receiving FOLFIRI regimen chemotherapy. METHODS: A total of 94 gastrointestinal cancerpatients with metastasis (72 colon and rectum, 20 stomach, 1 pancreas and 1 duodenum), were enrolled from 2007 to 2010 in Shanghai Ruijin Hospital. All patients received standard dosage of FOLFIRI regimen (irinotecan 180mg/m2 d1, CF 200mg/m2 d1-d2, 5-FU 400mg/m2 d1-d2, followed by continuous infusion of 5-FU 600mg/m2 for 22h d1-d2, every 2 weeks). UGT1A1 gene polymorphisms (*60 -3279T > G, *93 -3156G > A, *28 -53TA6 > TA7, *6 211G > A) were detected by direct sequencing of DNA extracted from peripheral blood. The incidence of neutropenia, diarrhea, and time to severe toxicity were recorded. The relationship between UGT1A1 gene polymorphisms and toxicities was analyzed. RESULTS: The frequencies of UGT1A1*60 (-3279 G/G), UGT1A1*93 (-3156 A/A), UGT1A1*28 (-53 7/7) and UGT1A1*6 (211 A/A) homozygote were 6.4% (6/94), 1.1% (1/94), 1.1% (1/94) and 2.1% (2/94), respectively. The incidences of grade 3/4 neutropenia and diarrhea were 53.2% (50/94) and 12.8% (12/94), respectively. Comparing those with wild type, patients with UGT1A1*28 or *93 allele had significantly high risk of grade 3/4 diarrhea (6/7, 7/7 vs. 6/6: 27.8% vs. 9.2%, OR=3.791, P=0.034; G/A, A/A vs. G/G: 29.4% vs. 9.1%, OR=4.167, P=0.023). No relationship was found between UGT1A1 allele polymorphism and grade 3/4 neutropenia. The baseline serum total bilirubin was elevated in UGT1A1*28, *93 allele carriers and *60 homozygote, but with no relationship with severe toxicities. CONCLUSION: In Chinese Han gastrointestinal cancerpatients receiving standard FOLFIRI regimen, UGT1A1*28 or *93 allele carriers may have high risk of severe diarrhea.
Authors: Cody J Peer; Andrew K L Goey; Tristan M Sissung; Sheryl Erlich; Min-Jung Lee; Yusuke Tomita; Jane B Trepel; Richard Piekarz; Sanjeeve Balasubramaniam; Susan E Bates; William D Figg Journal: J Clin Pharmacol Date: 2015-12-04 Impact factor: 3.126
Authors: Natalie Reizine; Everett E Vokes; Ping Liu; Tien M Truong; Rita Nanda; Gini F Fleming; Daniel V T Catenacci; Alexander T Pearson; Sandeep Parsad; Keith Danahey; Xander M R van Wijk; Kiang-Teck J Yeo; Mark J Ratain; Peter H O'Donnell Journal: Ther Adv Med Oncol Date: 2020-12-17 Impact factor: 8.168