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

Publication date: Available online 19 December 2017
Source:Radiotherapy and Oncology
Author(s): Ji Zhu, Xinxiang Li, Yunzhu Shen, Yun Guan, Weilie Gu, Peng Lian, Weiqi Sheng, Sanjun Cai, Zhen Zhang
PurposeWe 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 methodsPatients 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).ResultsThe 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.ConclusionA 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.



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