Department of Radiation Oncology, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China.
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China.
Radiother Oncol. 2018 Oct;129(1):143-148. doi: 10.1016/j.radonc.2017.11.026. Epub 2017 Dec 19.
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 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/m for the two genotype groups, whereas the dose of capecitabine was fixed at 625 mg/m. Intensity-modulated radiation therapy (IMRT) was applied to the whole pelvis (total dose of 50 Gy in 25 fractions).
The dose of weekly irinotecan was escalated to 95 mg/m in patients with the ∗1∗1 genotype and to 80 mg/m in those with the ∗1∗28 genotype. Dose-limiting toxicities (DLTs) were observed in 2/2 ∗1∗1 patients at 95 mg/m and 2/3 ∗1∗28 patients at 80 mg/m. No DLT cases were observed among the three ∗1∗1 patients at 80 mg/m, and one DLT case was observed among the six patients with ∗1∗28 at 65 mg/m. Hence, 80 mg/m and 65 mg/m were the MTDs for the two groups. The most common grade 3 to 4 toxicities were neutropenia and diarrhea.
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.
我们旨在根据 UGT1A1∗28 基因型，确定在局部晚期直肠癌患者中，每周伊立替康联合卡培他滨新辅助放化疗的最大耐受剂量（MTD）。
筛选出适合术前放化疗的临床 T3-4、N0-2 期患者，检测 UGT1A1∗28 基因型。26 例具有 ∗1∗1 或 ∗1∗28 基因型的患者有资格进行伊立替康剂量递增，而具有 ∗28∗28 基因型的患者则被排除在外。每周伊立替康的起始剂量为 50mg/m2，对于两种基因型组，卡培他滨的剂量固定为 625mg/m2。采用调强放疗（IMRT）对整个骨盆进行照射（总剂量 50Gy，共 25 次）。
在具有 ∗1∗1 基因型的患者中，每周伊立替康的剂量递增至 95mg/m2，在具有 ∗1∗28 基因型的患者中递增至 80mg/m2。在 95mg/m2 剂量下，2/2 ∗1∗1 例患者和在 80mg/m2 剂量下，2/3 ∗1∗28 例患者观察到剂量限制毒性（DLTs）。在 80mg/m2 剂量下，3 例 ∗1∗1 患者中没有观察到 DLT 病例，在 6 例 ∗1∗28 患者中，1 例观察到 65mg/m2 的 DLT 病例。因此，80mg/m2 和 65mg/m2 是两组的 MTD。最常见的 3 至 4 级毒性是中性粒细胞减少症和腹泻。
在 UGT1A1∗28 基因型的指导下，联合卡培他滨的每周更高剂量的伊立替康联合 CRT 是可行的。需要在这些剂量水平进行进一步的临床试验。
