Phase I/II Study of Preoperative Concurrent Chemoradiotherapy with S-1 for Locally Advanced, Resectable Rectal Adenocarcinoma

Abstract

Purpose: To assess the maximum tolerability of a combination of S-1 and preoperative radiotherapy and to evaluate the feasibility and activity in patients with locally advanced rectal cancer. Methods: Patients (n = 30) with adenocarcinoma of the middle or lower rectum were enrolled in a phase I (n = 9) and/or phase II (n = 21) trial. A total dose of 45 Gy was delivered in 25 fractions over 5 weeks, and S-1 was orally administered twice a day on days 1–14 and 22–35. Surgical resection was scheduled 4–8 weeks after the completion of chemoradiation. Results: In phase I, the recommended dose (RD) of S-1 was 80 mg/m²/day, and the maximum-tolerated dose was never reached. A total of 27 cases, including the 6 RD cases in phase I, were enrolled in phase II. In phase II, a pathological complete response (pCR) was observed in 6/27 patients (22%), pathological downstaging was observed in 21/27 patients (78%), and a tumor volume reduction of 69 ± 22% was obtained. These results were similar to the previously reported pCR rates of 16–18%, pathological downstaging rates of 49–59%, and tumor volume reduction of 68% after chemoradiotherapy with capecitabine. Grade 3 adverse events consisted of one case of leukopenia (4%), 2 cases of anemia (7%) and 3 cases of diarrhea (11%). Overall, the adverse events were very mild. Hand-foot syndrome was not observed. Conclusion: The efficacy of chemoradiotherapy with S-1 seems to be equivalent to the efficacy reported for chemoradiotherapy with capecitabine, but the adverse events were much milder, although further study is warranted.

Phase II Study of Preoperative Concurrent Chemoradiotherapy with S-1 plus Bevacizumab for Locally Advanced Resectable Rectal Adenocarcinoma

“…In recent studies comparing the outcomes of preoperative CRT with 5-FU or capecitabine in patients with LARC, the pCR rate ranged from 11 to 18% for 5-FU and from 16 to 30% for capecitabine, with no significant difference between the drugs [17,18,19,20]. In our previous study of preoperative CRT with S-1 alone, the pCR rate was 22%, consistent with the results of previous studies [5]. …”

“…We previously obtained a pCR rate of 22% (95% confidence interval 8.6-42.3) in patients who received CRT with S-1 alone [5]. In the present study, we assumed that the pCR rate would be 25%, with a minimum activity level pCR rate of 10%, an α level of 0.05 (two-sided), and a β level of 0.20.…”

“…We previously performed a phase I/II study of preoperative concurrent CRT with S-1 in patients with LARC and reported that the effectiveness of CRT with S-1 was similar to that of CRT with capecitabine. Moreover, CRT with S-1 was associated with mild adverse events, with no hand-foot syndrome [5]. …”

S-1 Monotherapy as Second- or Third-Line Chemotherapy for Unresectable and Recurrent Esophageal Squamous Cell Carcinoma

“…These findings indicate that S-1 can enhance the efficacy of conventional chemotherapy. In addition, clinical trials have reported better results for combination therapy with S-1 in head and neck cancer [16] and rectal cancer [17]. Furthermore, Fukushima et al [18 ]reported that gimeracil, a component of S-1, enhances the anticancer effects of radiation.…”

The gene expression levels of gamma-glutamyl hydrolase in tumor tissues may be a useful biomarker for proper use of S-1 and tegafur-uracil /leucovorin in preoperative chemoradiotherapy in patients with rectal cancer

“…Therefore, S-1 has a stronger antitumor effect than UFT and is commonly used without LV. We previously reported the efficacy and safety of oral UFT/LV therapy for the longterm treatment of patients with colon cancer [16] and of CRT including UFT or S-1 in patients with rectal cancer [17][18][19][20][21].…”