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Bi-daily tegafur-uracil (UFT) plus leucovorin (LV) versus capecitabine as first-line therapy in elderly patients with advanced colorectal cancer, unfit or unwilling to receive combination chemotherapy. - A randomized, open-label phase III study -

ABSTRACT: Interventions: Arm A: UFT 300 mg/m2 orally, divided in two daily doses, days 1-28 Leucovorin: 60 mg/day orally, divided in two daily doses, days 1-28, Q5 weeks, until disease progression or unacceptable toxicity Arm B: Capecitabine 2500 mg/m2 orally,divided in two daily doses, days 1-14 Q3 weeks, until disease progression or unacceptable toxicity Primary outcome(s): Comparison of progression free survival Study Design: Randomized controlled trial, Open (masking not used), Active, Parallel

DISEASE(S): Metastatic Colorectal Cancermale Or Female > 65 Years Of Agefrail Patients

PROVIDER: 15650 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Acetamide (CAS 60-35-5) is detected in common foods including milk, eggs, beef, and roasted coffee beans. Chronic rodent bioassays using high doses (≥1000 mg/kg/day) suggest acetamide is a group 2B possible human carcinogen due to the induction of liver tumors. Weight-of-evidence indicates acetamide is not genotoxic, and therefore a threshold response is expected. We used a toxicogenomics approach in Wistar rats gavaged daily for 7 and 28 days to determine the benchmark dose (BMD), and investigate its mode of action from differential gene expression. Two exposure experiements were carried out in succsession. An initial dose range finding experiment used male Wistar rats gavaged daily for 7 days at 0, 30, 100, 300 and 1000 mg/kd/day. A second experiment used both male and female Wistar rats exposed for 7 and 28 days to 0, 300,500,750,1000 and 1500 mg/kg/day. No treatment related changes in terminal body weight, clinical chemistry, or histopathology were observed at doses of 30, 100, or 300 mkd. At 1000 mkd, the dose reported to elicit carcinogenesis, liver weights decreased 1.3-fold with the presence of single cell necrosis, hepatocyte vacuolization, and increased mitotic activity consistent with a 4.2 fold increase in the cell proliferation index. Accordingly, plasma ALT and AST were increased 2.0- and 2.2-fold, respectively. RNA-Seq analysis identified 1 differentially expressed gene at 300 mkd, and 2,685 at 1000 mkd (|fold-change| ≥ 1.5 and FDR ≤ 0.05). Down-regulated genes were associated with lipid metabolism while up-regulated genes included cell signaling, immune response, and cell cycle functions. Collectively, these results revealed a no-observable adverse effect level (NOAEL) and no-observed-transcriptional effect level (NOTEL) at 300 mkd, warranting further investigation at doses between 300 and 1000 mkd to identify the benchmark dose (BMD). Functional enrichment indicates perturbation of cell cycle and lipid metabolism, though a more refined dose-response evaluation will be needed to demonstrate dose-dependent effects related to the MOA of acetamide. Funding by the Bill and Melinda Gates Foundation (OPP1142801).

Dataset Information

Bi-daily tegafur-uracil (UFT) plus leucovorin (LV) versus capecitabine as first-line therapy in elderly patients with advanced colorectal cancer, unfit or unwilling to receive combination chemotherapy. - A randomized, open-label phase III study -

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