Genotype-driven phase I study of weekly irinotecan in combination with capecitabine-based neoadjuvant chemoradiation for locally advanced rectal cancer.

PURPOSE:We aimed to identify the maximum tolerated dose (MTD) of weekly irinotecan in combination with capecitabine-based neoadjuvant chemoradiation according to the UGT1A1∗28 genotype in patients with locally advanced rectal cancer. PATIENTS AND METHODS:Patients with clinical stage T3-4, N0-2 who were eligible for preoperative chemoradiotherapy were screened for the UGT1A1∗28 genotype. Twenty-six patients with either the ∗1∗1 or ∗1∗28 genotype were eligible for dose escalation of irinotecan, and patients with a ∗28∗28 genotype were excluded. The starting dose of weekly irinotecan was 50 mg/m2 for the two genotype groups, whereas the dose of capecitabine was fixed at 625 mg/m2. Intensity-modulated radiation therapy (IMRT) was applied to the whole pelvis (total dose of 50 Gy in 25 fractions). RESULTS:The dose of weekly irinotecan was escalated to 95 mg/m2 in patients with the ∗1∗1 genotype and to 80 mg/m2 in those with the ∗1∗28 genotype. Dose-limiting toxicities (DLTs) were observed in 2/2 ∗1∗1 patients at 95 mg/m2 and 2/3 ∗1∗28 patients at 80 mg/m2. No DLT cases were observed among the three ∗1∗1 patients at 80 mg/m2, and one DLT case was observed among the six patients with ∗1∗28 at 65 mg/m2. Hence, 80 mg/m2 and 65 mg/m2 were the MTDs for the two groups. The most common grade 3 to 4 toxicities were neutropenia and diarrhea. CONCLUSION:A higher dose of weekly irinotecan in combination with capecitabine-based CRT is feasible under the guidance of the UGT1A1∗28 genotype. Further clinical trials at these dose levels are warranted.