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A phase II study of preoperative chemoradiation with tegafur-uracil plus leucovorin for locally advanced rectal cancer with pharmacogenetic analysis.

ABSTRACT: This study aimed to evaluate the efficacy of a high dose of oral tegafur-uracil (400 mg/m2) plus leucovorin with preoperative chemoradiation of locally advanced rectal cancer and to explore the impact of polymorphisms of cytochrome P 2A6 (CYP2A6), uridine monophosphate synthetase (UMPS), and ATP-binding cassette B1 (ABCB1) on clinical outcome.Patients with cT3 or cT4 rectal cancer were enrolled and were given tegafur-uracil 400 mg/m2/day and leucovorin 90 mg/m2/day for 7 days a week during preoperative chemoradiation (50.4 Gy/28 fractions) in this phase II trial. Primary endpoint was pathologic complete response rate, and the secondary endpoint was to explore the association between clinical outcomes and genetic polymorphisms CYP2A6 (*4, *7, *9 and *10), UMPS G638C, and three ABCB1 genotypes (C1236T, C3435T, and G2677T).Ninety-one patients were given study treatment, and 90 underwent surgery. Pathologic complete response was noted in 10 patients (11.1%). There was no grade 4 or 5 toxicity; 20 (22.0%) experienced grade 3 toxicities, including diarrhea (10, 11.0%), abdominal pain (2, 2.2%), and anemia (2, 2.2%). Relapse-free survival and overall survival at 5 years were 88.6% and 94.2%, respectively. Patients with the UMPS 638 CC genotype experienced significantly more frequent grade 2 or 3 diarrhea (p for trend?=?0.018).Preoperative chemoradiation with tegafur-uracil 400 mg/m2/day with leucovorin was feasible, but did not meet the expected pathologic complete response rate. The UMPS 638 CC genotype might be a candidate biomarker predicting toxicity in patients receiving tegafur-uracil/leucovorin-based preoperative chemoradiation for locally advanced rectal cancer.ISRCTN11812525 , registered on 25 July 2016. Retrospectively registered.

SUBMITTER: Kim SY

PROVIDER: S-EPMC5369180 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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A phase II study of preoperative chemoradiation with tegafur-uracil plus leucovorin for locally advanced rectal cancer with pharmacogenetic analysis.

Kim Sun Young SY Baek Ji Yeon JY Oh Jae Hwan JH Park Sung Chan SC Sohn Dae Kyung DK Kim Min Ju MJ Chang Hee Jin HJ Kong Sun-Young SY Kim Dae Yong DY

Radiation oncology (London, England) 20170327 1

<h4>Background</h4>This study aimed to evaluate the efficacy of a high dose of oral tegafur-uracil (400 mg/m<sup>2</sup>) plus leucovorin with preoperative chemoradiation of locally advanced rectal cancer and to explore the impact of polymorphisms of cytochrome P 2A6 (CYP2A6), uridine monophosphate synthetase (UMPS), and ATP-binding cassette B1 (ABCB1) on clinical outcome.<h4>Methods</h4>Patients with cT3 or cT4 rectal cancer were enrolled and were given tegafur-uracil 400 mg/m<sup>2</sup>/day a ...[more]

PMID: 28347333

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Project description:Shikha VermaBackground Systemic fluoropyrimidines, both oral and intravenous, are an integral part of colorectal cancer (CRC) management. They can be administered either with curative or palliative intent. Objectives This article examines the literature to analyze the efficacy and safety of the oral fixed-dose combination of uracil and tegafur (UFT)/leucovorin (LV) compared with other fluoropyrimidine agents, with an intention to implement the findings into the current treatment algorithms for CRC. Methods An exhaustive systematic literature search was performed for prospective studies using PUBMED, Cochrane Library, and EMBASE database. Studies which met eligibility criteria were shortlisted and grouped into chemotherapy given for curative or palliative intent. Results Eight trials were shortlisted involving 4,486 patients for the analysis. There was no difference between UFT/LV and other fluoropyrimidines in the primary endpoints-disease-free survival (hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.90-.15; p = 0.81) and progression-free survival (HR 0.87; 95% CI 0.66-.66; p = 0.35) for curative and palliative intent CRC patients, respectively. In secondary analyses, there was no significant difference observed between UFT and other fluoropyrimidines in overall survival in CRC patients with curative intent (HR 1.04; 95% CI 0.88-1.23; p = 0.63) and palliative intent (HR 1.02; 95% CI 0.97-1.06; p = 0.42) . In the safety analysis, we found significantly lesser patients on UFT/LV had stomatitis/mucositis (odds ratio [OR] 0.20; 95% CI 0.05-0.85; p = 0.03), fever (OR 0.46; 95% CI 0.29-0.71; p < 0.001), infection (OR 0.42; 95% CI 0.24-0.74; p < 0.01), leukopenia (OR 0.04; 95% CI 0.00-0.95; p = 0.05), febrile neutropenia (OR 0.03; 95% CI 0.00-0.24; p = 0.001), and thrombocytopenia (OR 0.14; 95% CI 0.02-0.79; p = 0.03) compared with other fluoropyrimidines. Conclusion Oral UFT/LV is equally efficacious to other fluoropyrimidines, especially intravenous 5-fluorouracil, in the management of early as well as advanced CRC patients. Importantly, UFT/LV has a superior safety profile compared with other fluoropyrimidines in terms of both hematological and nonhematological adverse events.

Dataset Information

A phase II study of preoperative chemoradiation with tegafur-uracil plus leucovorin for locally advanced rectal cancer with pharmacogenetic analysis.

Publications

A phase II study of preoperative chemoradiation with tegafur-uracil plus leucovorin for locally advanced rectal cancer with pharmacogenetic analysis.

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