Genotype-directed, dose-finding study of irinotecan in cancer patients with UGT1A1☆28 and/or UGT1A1☆6 polymorphisms
Genotype-directed, dose-finding study of irinotecan in cancer patients with UGT1A1☆28 and/or UGT1A1☆6 polymorphisms
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DOI：
10.1111/j.1349-7006.2011.02030.x
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发表时间：
2011-10-01
期刊：
影响因子：
5.7
通讯作者：
Sakata, Yuh
中科院分区：
文献类型：
--
作者：
Satoh, Taroh;Ura, Takashi;Sakata, Yuh
伊立替康诱导的严重中性粒细胞减少症与 UGT1A1（星号）28 或 UGT1A1（星号）6 等位基因的纯合性相关。在这项研究中，我们确定了 UGT1A1 多态性患者的伊立替康最大耐受剂量 (MTD)。接受除伊立替康以外的化疗治疗转移性胃肠癌的患者被纳入研究。根据UGT1A1基因型将患者分为三组：野生型（（星）1/（星）1）；杂合子（（星）28/（星）1，（星）6/（星）1）；或纯合子（（星）28/（星）28、（星）6/（星）6、（星）28/（星）6）。伊立替康每两周给药一次，持续两个周期。野生型组接受固定剂量的伊立替康（150 mg/m(2)）作为参考。通过持续重新评估方法，杂合子和纯合子组的MTD从75 mg/m(2) 调整至150 mg/m(2)。在第 1 周期期间评估剂量限制毒性 (DLT) 和药代动力学。在 82 名入组患者中，79 名患者可评估 DLT（野生型，40 名；杂合子，20 名；纯合子，19 名）。野生型组有 1 名患者出现剂量限制性毒性，杂合子组没有出现剂量限制性毒性，纯合子组有 6 名患者（4 级中性粒细胞减少症）。在纯合子组中，MTD为150 mg/m(2)，DLT的概率为37.4%。接受 MTD 的患者中有 56.3% 因中性粒细胞减少症而延迟第二个周期。 SN-38的AUC(0-24) h在纯合子组中显着更大(P < 0.001)并且分布更广泛。 UGT1A1(star)28 或 UGT1A1(star)6 等位基因纯合的患者可以以 150 mg/m(2) 的起始剂量接受伊立替康治疗，但许多患者需要在后续周期中减少剂量或延迟治疗。 UMIN临床试验注册号：UMIN000000618。 （癌症科学 2011 年；102：1868-1873）
Irinotecan-induced severe neutropenia is associated with homozygosity for the UGT1A1(star)28 or UGT1A1(star)6 alleles. In this study, we determined the maximum-tolerated dose (MTD) of irinotecan in patients with UGT1A1 polymorphisms. Patients who had received chemotherapy other than irinotecan for metastatic gastrointestinal cancer were enrolled. Patients were divided into three groups according to UGT1A1 genotypes: wild-type ((star)1/(star)1); heterozygous ((star)28/(star)1, (star)6/(star)1); or homozygous ((star)28/(star)28, (star)6/(star)6, (star)28/(star)6). Irinotecan was given every 2 weeks for two cycles. The wild-type group received a fixed dose of irinotecan (150 mg/m(2)) to serve as a reference. The MTD was guided from 75 to 150 mg/m(2) by the continual reassessment method in the heterozygous and homozygous groups. Dose-limiting toxicity (DLT) and pharmacokinetics were evaluated during cycle 1. Of 82 patients enrolled, DLT was assessable in 79 patients (wild-type, 40; heterozygous, 20; and homozygous, 19). Dose-limiting toxicity occurred in one patient in the wild-type group, none in the heterozygous group, and six patients (grade 4 neutropenia) in the homozygous group. In the homozygous group, the MTD was 150 mg/m(2) and the probability of DLT was 37.4%. The second cycle was delayed because of neutropenia in 56.3% of the patients given the MTD. The AUC(0-24) h of SN-38 was significantly greater (P < 0.001) and more widely distributed in the homozygous group. Patients homozygous for the UGT1A1(star)28 or UGT1A1(star)6 allele can receive irinotecan in a starting dose of 150 mg/m(2), but many required dose reductions or delayed treatment in subsequent cycles. UMIN Clinical Trial Registration number: UMIN000000618. (Cancer Sci 2011; 102: 1868-1873)