Section of Hematology/Oncology, University of Chicago, Chicago, Illinois.
Department of Public Health Sciences, University of Chicago, Chicago, Illinois.
Cancer. 2019 May 15;125(10):1629-1636. doi: 10.1002/cncr.31938. Epub 2019 Jan 15.
FOLFIRINOX (5-fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) is an effective but toxic therapy for pancreatic cancer. UGT1A1 (UDP glucuronosyltransferase 1A1) eliminates the active metabolite of irinotecan. Polymorphisms reduce UGT1A1 activity, leading to toxicity. The primary objective was to determine the dose-limiting toxicity (DLT) rate in cycle 1 of modified FOLFIRINOX (mFOLFIRINOX) using genotype-guided dosing of irinotecan for the most common UGT1A1 genotypes (*1/*1, *1/*28) in advanced gastrointestinal malignancies, with expansion in pancreatic and biliary tract cancers.
5-FU (2400 mg/m over 46 hours), leucovorin (400 mg/m ), oxaliplatin (85 mg/m ), and irinotecan were given every 14 days. Irinotecan doses of 180, 135, and 90 mg/m were administered for UGT1A1 genotypes *1/*1, *1/*28, and *28/*28, respectively. Prophylactic pegfilgrastim was omitted in cycle 1 for cohort 1 (tolerability by genotype), but was given in cohort 2 (tolerability by tumor type). Doses were tolerable if the upper limit of a 2-sided 80% confidence interval for DLT rate was ≤33%.
In cohort 1, DLTs (most commonly febrile neutropenia, fatigue, diarrhea) occurred in 2/15 (13%), 3/16 (19%), and 4/10 (40%) patients with *1/*1, *1/*28, and *28/*28 genotypes, respectively. In cohort 2, 6/19 (32%) pancreatic and 4/19 (21%) biliary tract cancer patients experienced DLTs (most commonly fatigue, diarrhea, nausea/vomiting). In cohort 2, upper confidence limits of DLT rates exceeded 33%. Response rates were 38% in pancreatic and 21% in biliary tract cancers.
On the basis of our prespecified criteria, tolerability of UGT1A1 genotype-guided mFOLFIRINOX was not established in pancreatic and biliary tract cancers. However, this regimen was effective.
FOLFIRINOX（5-氟尿嘧啶[5-FU]、亚叶酸、伊立替康、奥沙利铂）是一种有效的但毒性较大的胰腺癌治疗药物。UGT1A1（UDP 葡萄糖醛酸基转移酶 1A1）可消除伊立替康的活性代谢物。多态性降低 UGT1A1 的活性，导致毒性。主要目的是确定改良 FOLFIRINOX（mFOLFIRINOX）在晚期胃肠道恶性肿瘤中应用伊立替康基于基因型指导剂量的 1 周期的剂量限制毒性（DLT）率，该研究方案在胰腺和胆道癌中进行扩展。
5-FU（46 小时内 2400mg/m2）、亚叶酸（400mg/m2）、奥沙利铂（85mg/m2）和伊立替康每 14 天给药一次。UGT1A1 基因型为*1/*1、*1/28 和28/*28 的患者，伊立替康剂量分别为 180、135 和 90mg/m2。第 1 周期中，队列 1（按基因型耐受）省略了预防性培非格司亭，而队列 2（按肿瘤类型耐受）则使用了该药物。如果 DLT 率的双侧 80%置信区间上限≤33%，则认为剂量可耐受。
在队列 1 中，最常见的 DLT（发热性中性粒细胞减少症、疲劳、腹泻）分别发生在*1/*1、*1/28 和28/*28 基因型的 15 例患者中的 2 例（13%）、16 例患者中的 3 例（19%）和 10 例患者中的 4 例（40%）。在队列 2 中，19 例胰腺和 19 例胆道癌症患者中有 6 例（32%）和 4 例（21%）出现 DLT（最常见的是疲劳、腹泻、恶心/呕吐）。在队列 2 中，DLT 率的上限置信区间超过 33%。胰腺和胆道癌症的缓解率分别为 38%和 21%。
根据我们的预设标准，在胰腺和胆道癌中，UGT1A1 基因型指导的 mFOLFIRINOX 的耐受性尚未确定。然而，该方案是有效的。
