Phase I/II pharmacokinetic and pharmacogenomic study of UGT1A1 polymorphism in elderly patients with advanced non-small cell lung cancer treated with irinotecan.
This phase II study investigated the recommended dose (RD) of irinotecan (CPT-11) by dose escalation in elderly (>or=70 years) chemotherapy-naive Japanese patients with advanced non-small cell lung cancer. UGT1A1*28 and *6 polymorphisms and pharmacokinetics were also investigated. Thirty-seven patients received the RD, 100 mg/m(2) of intravenous CPT-11, on days 1 and 8 of each 3-week cycle in phase II. The overall response rate was 8.1%. The median survival time was 441 days, and time to progression was 132 days. A significant correlation was observed between the incidence of grade 3/4 neutropenia and area under the time-concentration curve (AUC) values of SN-38. A reduction in AUC ratios (AUC(SN-38G)/AUC(SN-38)) and a rise in incidence of grade 3/4 neutropenia were observed with increase in polymorphism. The regimen was well tolerated and provided good disease control and promising survival effects. An analysis of the influence of UGT1A1*28 and *6 polymorphisms provides useful information for the prediction of CPT-11-related hematological toxicity.
Yamamoto
N
N
Thoracic Oncology Division, Shizuoka Cancer Center, Sunto-gun, Japan. n.yamamoto@scchr.jp
Takahashi
T
T
Kunikane
H
H
Masuda
N
N
Eguchi
K
K
Shibuya
M
M
Takeda
Y
Y
Isobe
H
H
Ogura
T
T
Yokoyama
A
A
Watanabe
K
K
D000368:Aged; D000369:Aged, 80 and over; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009503:Neutropenia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000187:drug effects / Q000235:genetics*; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme