A phase I/II clinical trial of preoperative docetaxel/oxaliplatin/S-1 (DOS) combination therapy for esophagogastric junction adenocarcinoma.

Abstract

429 Background: Esophagogastric junction (EGJ) cancer is difficult to cure with surgery alone, necessitating adjuvant chemotherapy. However, administering aggressive adjuvant chemotherapy after invasive surgery is difficult. Neoadjuvant chemotherapy, on the other hand, is expected to enhance compliance, increase the rate of curative resection, and reduce recurrence. Methods: We conducted a single center Phase I/II study to evaluate the safety and efficacy of neoadjuvant chemotherapy using docetaxel, oxaliplatin, and S-1 (DOS), followed by adjuvant chemotherapy with S-1 in patients with cT3-4aN0-3M0 adenocarcinoma of the EGJ. In Phase I, we estimated the maximum tolerated dose and dose-limiting toxicity of neoadjuvant DOS therapy and determined the recommended dose (RD). In Phase II, we assessed the safety and efficacy of the RD established in Phase I. The primary endpoint was the curative resection rate, with secondary endpoints including the 3-year overall survival rate, 3-year recurrence-free survival rate, treatment completion rate, response rate to neoadjuvant chemotherapy, pathological response, and adverse events. Neoadjuvant DOS chemotherapy was administered in three 3-week cycles. The starting dose of docetaxel was 50 mg/m², with plans to escalate it to 60 mg/m². Docetaxel and oxaliplatin (100 mg/m²) were administered on day 1, while S-1 (120 mg/body) was given orally on days 1-14. Postoperative adjuvant chemotherapy consisted of S-1 (120 mg/body), administered for 4 weeks followed by a 2-week rest period, repeated for 8 cycles. Results: Based on the 6 patients enrolled in Phase I, the RD of docetaxel was determined to be 60 mg/m². A total of 40 eligible patients, including 3 from Phase I, were enrolled in the study. Two patients discontinued protocol treatment during neoadjuvant chemotherapy due to adverse events and 1 patient discontinued due to positive peritoneal cytology. The R0 resection rate was 87.5% (35/40). Surgical procedures included esophagectomy in 18 patients, total gastrectomy in 15, and proximal gastrectomy in 4. Postoperative complications of Grade III or higher, as per the Clavien-Dindo classification, occurred in 15.0% of patients, with no surgery-related deaths. The response rates to neoadjuvant chemotherapy were 12.5% for PR, 2.5% for PD, and 85.0% for non-CR/non-PD. Pathological response rates were: Grade III in 8.1%, Grade II in 35.1% and Grade I in 56.8%. During neoadjuvant chemotherapy, Grade 3 or higher adverse events were observed, including neutropenia (82.5%), nausea (5%) and diarrhea (5%). The neoadjuvant chemotherapy completion rate was 92.5%, although 59.5% of patients required dose reductions. Conclusions: Neoadjuvant DOS therapy for esophagogastric junction cancer shows promise, achieving a high R0 resection rate and substantial pathological efficacy, with acceptable levels of adverse events. Clinical trial information: UMIN000022210.