A Phase II Study of Clinical Outcomes of 3-Week Cycles of Irinotecan and S-1 in Patients with Previously Untreated Metastatic Colorectal Cancer: Influence of the <b><i>UGT1A1</i></b> and <b><i>CYP2A6</i></b> Polymorphisms on Clinical Activity

Abstract

<b><i>Objectives:</i></b> We investigated the efficacy and safety of the combination of irinotecan (CPT-11) and S-1 (IRIS regimen) as a first-line treatment in patients with metastatic colorectal cancer. We also evaluated the association between <i>UGT1A1</i> and <i>CYP2A6</i> polymorphisms and clinical phenotypes. <b><i>Methods:</i></b> The patients received CPT-11 (225 mg/m<sup>2</sup>) on day 1 and S-1 (80 mg/m<sup>2</sup>) on days 1–14 every 3 weeks. The association of the <i>UGT1A1 (</i>*<i>6</i> and *<i>28)</i> and <i>CYP2A6</i><i>(</i>*<i>4, </i>*<i>7, </i>*<i>9</i>, and *<i>10)</i> polymorphisms with toxicities and efficacy were analyzed. <b><i>Results:</i></b> Thirty patients were treated. The overall response rate was 66.7% (95% CI 48.7–84.6). The median time to progression was 7.6 months (95% CI 5.8–9.5). The most common grade 3/4 hematologic and non-hematologic toxicity were neutropenia (53.4%) and diarrhea (16.7%), respectively. The allele frequencies of <i>UGT1A1</i>*<i>6</i> and *<i>28 </i>were 15.5 and 10.3%, respectively. The frequencies of <i>CYP2A6</i>*<i>4</i>, *<i>7</i>, *<i>9, </i>and *<i>10</i> were 15.5, 8.6, 29.3, and 3.5%, respectively. Stratification of patients according to the number of <i>UGT1A1</i>*<i>28</i> and *<i>6</i> alleles showed a significant correlation between the number of defective alleles and the incidence of grade 3/4 neutropenia. <b><i>Conclusions: </i></b>Our results indicate that IRIS is a promising first-line regimen in patients with metastatic colorectal cancer. Severe neutropenia may be associated with interindividual variations in <i>UGT1A1</i> polymorphisms.