UGT1A1 polymorphisms in rectal cancer associated with the efficacy and toxicity of preoperative chemoradiotherapy using irinotecan

Abstract

The purpose of the present study was to assess the efficacy and toxicity of preoperative chemoradiotherapy using irinotecan against locally advanced lower rectal cancer according to UDP‐glucuronosyltransferase 1A1 (UGT1A1) polymorphisms. Between 2009 and 2016, 46 patients with resectable rectal cancer (T3‐T4, N0‐N2, M0) received preoperative chemoradiotherapy consisting of 80 mg/m2 per day tegafur/gimeracil/oteracil (S‐1; days 1‐5, 8‐12, 22‐26, and 29‐33), 60 mg/m2 per day irinotecan (days 1, 8, 22, and 29), and 45 Gy radiation (1.8 Gy/day, 5 days per week for 5 weeks). Six to eight weeks after completing chemoradiotherapy, total mesorectal excision was carried out. Patients with UGT1A1 polymorphisms were divided into WT (n = 26), heterozygous (n = 15), and homozygous (n = 5) groups, the latter including double heterozygosities. We evaluated associations between clinical characteristics, including UGT1A1 polymorphisms, and chemoradiotherapy efficacy and toxicity. Incidence rates of grade 3+ neutropenia and diarrhea were 17.0% and 30.4%, respectively. Relative dose intensity was 89.3%. Pathological complete response rate (grade 3) was 26.1%, and the good response (grade 2/3) rate was 84.8%. UGT1A1 polymorphisms were significantly associated with neutropenia and pathological good responses, but not with diarrhea. UGT1A1 polymorphism was the only predictive factor for pathological good responses. Our results indicate that UGT1A1 polymorphism is a predictive factor to determine the clinical efficacy of preoperative chemoradiotherapy and hematological toxicity induced by chemoradiotherapy using irinotecan in locally advanced rectal cancer patients.

Management of recurrent or refractory Ewing sarcoma: A systematic review of phase�II clinical trials in the last 15�years

“…Except for monotherapy, preclinical studies have demonstrated the synergistic antiproliferative and pro-apoptotic activity of irinotecan or topotecan and aaTKIs in vitro, and the improvement of the in vivo anticancer activity on angiogenesis, endothelial and cancer cells, such as pancreatic (40) and ovarian cancer cells (41). Based on the non-overlapped adverse effects of irinotecan (42,43) and aaTKIs (44,45), these studies suggested a possible translation of this combination into the clinic. A phase I study of axitinib and irinotecan combined with 5-fluorouracil and leucovorin in patients with advanced colorectal cancer described an acceptable toxicity profile (46).…”

Adding Adjuvants to Fluoropyrimidine-based Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: An Option Worthy of Serious Consideration

“…At present, there are a limited amount of reports about UGT1A1 genotype and CPT-11 participating in nCRT of LARC patients. We only retrieved two studies in this field on the United States National Library of Medicine National Institutes of Health website, among which Kimura results [49] showed that the polymorphism of UGT1A1 affected the incidence of neutropenia. The level 3-4 neutropenia and leucopenia in heterozygote and homozygote groups were significantly higher than those in the wild-type group, but the effect on diarrhea was not found.…”

Association of UGT1A1*6,*28 or ABCC2 c.3972C>T genetic polymorphisms with irinotecan induced toxicity in Asian cancer patients: Meta-analysis

“…Following exclusion criteria, 195 articles were removed, and the rest 106 full-texts articles were assessed in depth following eligibility criteria. Finally, 42 articles were included in this meta-analysis for assessing the associations ofUGT1A1*6/*28 or ABCC2 c.3972C>T with irinotecan induced severe toxicities [12,14,21,[22][23][24][26][27][28][29][30][31]34,35,]. The complete selection process of articles following PRISMA guidelines is shown in Figure 1.…”

“…When patients inheriting both of these polymorphisms (UGT1A1*6 and UGT1A1*28), the toxicities of irinotecan may be exacerbated profoundly due to combined genetic effects as evidenced in some studies [14,[26][27][28] although the results are again inconclusive and inconsistent as found in other studies [18,[29][30][31]. In these controversial clinical situations, it is also important to noted that in addition to the UGT1A1 enzyme, irinotecan, SN-38 and SN-38G are transported out of the cell into bile by members of the ATP-binding cassette (ABC) transporter family especially ABCC2 encoded by theABCC2 gene [32,33].…”