OVERALL ABSTRACT WINNER (CLINICAL OUTCOMES)

Abstract

Background: Irinotecan (CPT-11) has demonstrated its potent efficacy in treating various malignancies, including advanced gastrointestinal cancers as a single agent, or in combination with chemotherapeutic and targeted agents. Yet, various degrees of dose-limiting toxicities, including diarrhea and neutropenia, were observed in some patients. It was reported that the incidence of such irinotecan-related adverse events was associated with polymorphism of the uridine diphosphate glucuronosyltransferases (UGTs) gene, and demonstrated an obvious ethnic diversity. Detection of these polymorphisms may guide the clinical decision for irinotecan dosage and the chemotherapeutic partner for individualized regimens. The aim of this study is to observe the frequency and severity of various adverse events in Han patients with advanced gastrointestinal cancer who were treated with irinotecan-based therapy. Simultaneously, the relationship between severe adverse events and the UGT1A1 gene promoter polymorphism (UGT1A1*28) was investigated. Methods: Sixty-six patients (42 men and 24 women; median age, 58 years; range, 30 –7 6 years) with advanced gastrointestinal carcinoma receiving irinotecan-based chemotherapy were enrolled. The inclusive criteria were: (1) pathologically/cytologically confirmed adenocarcinoma of the gastrointestinal tract, (2) expected survival time over 3 months, (3) no severe concomitant diseases of any vital organs, (4) no jaundice and digestive tract obstruction, (5) no acute infection. The adverse events during the course of chemotherapy, the pretreatment serum bilirubin level, as well as the time to grade 3 –4 toxicities were recorded. Genomic DNA was extracted from the peripheral blood to detect the polymorphism of UGT1A1*28 (TATA box thymine-adenine TA repeats). The relationship between the severity of adverse events and the UGT1A1*28 polymorphism, pretreatment bilirubin level, as well as the time to severe toxicity was investigated. Results: Of 66 enrolled patients, 55 patients (83.3%) were identified with the thymine-adenine (TA)6/(TA)6 genotype, and 11 patients (16.7%) were identified with the thymine-adenine (TA)6/(TA)7 genotype; no (TA)7/(TA)7 genotype was found. Twenty-six of the (TA)6/(TA)6 and 5 of the (TA)6/(TA)7 patients (47.3% vs 45.5%, P ¼ 1.000) developed grade 3 – 4 neutropenia, while 5 and 4 patients (9.1% vs 36.4%, P ¼ .036) experienced grade 3 – 4 diarrhea. The occurrence of grade 3 –4 diarrhea, but not neutropenia, was closely related with the (TA)6/(TA)7 genotype in the UGT1A1 promoter region in patients receiving irinotecanbased chemotherapy. The median time to severe toxicity of these 2 groups were 9 weeks (6 cycles) and 3 weeks (2 cycles), respectively (P ¼ .186). The pretreatment serum bilirubin levels in these 2 groups were (15.1+ 1.1) mmol/L and (20.8+ 5.1) mmol/L, respectively, which were not significantly associated with the occurrence of grade 3 – 4 diarrhea and neutropenia (P ¼ .09). Conclusion: The frequency of the UGT1A1*28 gene polymorphism in Han patients is 16.7%, which is lower than that reported in Western populations. The marked increase in grade 3 –4 diarrhea is related with the (TA)6/ (TA)7 genotype of UGT1A1 in patients receiving irinotecanbased chemotherapy. Detection of this gene polymorphism might help to select optional dosage and chemo-partner of irinotecan-based regimen in treating GI cancer patients in China.