Abstract
BackgroundThe objective of this phase I study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of preoperative chemoradiotherapy (CRT) with S-1 plus oxaliplatin in patients with locally advanced rectal cancer.MethodsPatients received radiotherapy in a total dose of 50.4 Gy in 28 fractions. Concurrent chemotherapy consisted of a fixed oral dose of S-1 (80 mg/m2/day) on days 1–5, 8–12, 22–27, and 29–33, plus escalated doses of oxaliplatin as an intravenous infusion on days 1, 8, 22, and 29. Oxaliplatin was initially given in a dose of 40 mg/m2/week to three patients. The dose was then increased in a stepwise fashion to 50 mg/m2/week and the highest dose level of 60 mg/m2/week until the MTD was attained.ResultsThirteen patients were enrolled, and 12 received CRT. Dose-limiting toxicity (DLT) occurred in two of six patients (persistent grade 2 neutropenia, delaying oxaliplatin treatment by more than 3 days) at dose level 3; there were no grade 3 or 4 adverse events defined as DLT. The RD was 60 mg/m2/week of oxaliplatin on days 1, 8, 22, and 29. Twelve patients underwent histologically confirmed R0 resections, and two out of six patients (33%) given dose level 3 had pathological complete responses.ConclusionsThe RD for further studies is 80 mg/m2 of S-1 5 days per week plus 60 mg/m2 of oxaliplatin on days 1, 8, 22, and 29 and concurrent radiotherapy. Although our results are preliminary, this new regimen for neoadjuvant chemoradiotherapy is considered safe and active.Trial registrationThis trial was registered with Clinicaltrials.gov (identifier: NCT01227239).
Highlights
The objective of this phase I study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of preoperative chemoradiotherapy (CRT) with S-1 plus oxaliplatin in patients with locally advanced rectal cancer
Hartley et al demonstrated that the incidence of pathological complete response (pCR) after CRT for rectal cancer depends on the mode of delivery of 5-FU, the use of a two-drug regimen, and the dose of radiotherapy [16]
Choi et al reported that 13% of patients who received irinotecan and S-1 combined with radiotherapy had grade 3 diarrhea [20]. These results suggest that oxaliplatin plus S-1 is better tolerated than irinotecan plus S-1
Summary
The objective of this phase I study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of preoperative chemoradiotherapy (CRT) with S-1 plus oxaliplatin in patients with locally advanced rectal cancer. CRT with continuous infusion of 5-fluorouracil (5-FU) has been recommended in addition to surgery to lower the risk of local recurrence as compared with surgical resection alone in patients with locally advanced rectal cancer. Ishihara et al Radiation Oncology (2015) 10:24 effective and less toxic than bolus injections. Oral fluoropyrimidine preparations, such as uracil and tegafur (UFT) or capecitabine, have been substituted for 5-FU in several clinical trials of preoperative CRT and have demonstrated equivalent efficacy and less toxicity than intravenous 5-FU. Sadahiro et al found that concurrent CRT with S-1 was an effective and well-tolerated regimen for locally advanced rectal cancer [8]
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