Abstract
BackgroundThis 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.MethodsPatients 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).ResultsNinety-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).ConclusionsPreoperative 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.Trial registrationISRCTN11812525, registered on 25 July 2016. Retrospectively registered.
Highlights
Preoperative chemoradiation (CRT) with fluoropyrimidine such as 5-fluorouracil (5-FU) or capecitabine was shown to be effective in terms of reducing the risk of local recurrence of rectal cancer [1, 2], and has become the standard treatment
Since each package of Enteric-coated tegafur-uracil (UFT-E) contains 500 mg of granules that corresponded to 100 mg of tegafur, the recommended dosing schedule according to body surface area (BSA) was as follows: BSA ≤ 1.37 m2: 2, 2, and 1 packages an hour after breakfast, lunch and dinner, respectively; BSA 1.38 m2 – 1.62 m2: 2, 2, and 2 packages; BSA 1.63 m2 – 1.87 m2: 3, 2, and 2 packages; and BSA ≥ 1.88 m2: 3, 3, and 2 packages
Delivery of CRT In the initial 23 (25.2%) patients who received UFT-E 400 mg/m2 7 days per week (7/week cohort), the dose intensity was 92.6% of the intended dose, and the median cumulative and daily dose during RT was 14,074 mg/m2 and Statistical analysis We postulated that the pathologic complete response (pCR) rate would be 20% or more, and the rate of no interest was less than 10%
Summary
Preoperative chemoradiation (CRT) with fluoropyrimidine such as 5-fluorouracil (5-FU) or capecitabine was shown to be effective in terms of reducing the risk of local recurrence of rectal cancer [1, 2], and has become the standard treatment. UFT 300–400 mg/m2/day plus leucovorin (LV) 25–75 mg/day for 5 days a week at 45 Gy radiation (RT) for locally advanced rectal cancer was efficacious and tolerable [4] This combination produced comparable outcomes to 5-FU in terms of toxicity profile and pathologic complete response rate in a randomized trial, the study was underpowered due to incomplete accrual [5]. Many of the studies on UFT with CRT for rectal cancer were performed in a Caucasian population; the gastrointestinal toxicity of tegafur-based drugs such as UFT and S-1 is known to be more tolerable in Asian patients compared to Caucasians [6, 7] This trend has not been fully explained by differences in pharmacokinetics or genetic polymorphisms. 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)
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