Phase II study of neoadjuvant chemotherapy with fluorouracil, leucovorin, oxaliplatin and docetaxel for resectable esophageal squamous cell carcinoma.

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Background: Based on the JCOG1109 trial, neoadjuvant docetaxel, cisplatin, and fluorouracil (DCF) followed by surgery has become the standard of care for resectable locally advanced esophageal squamous cell carcinoma (ESCC). Although the combination of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) demonstrated benefits for esophageal adenocarcinoma as a perioperative therapy, its safety and efficacy for locally advanced ESCC have not been evaluated. Methods: We conducted a multicenter phase II study of neoadjuvant FLOT therapy for ESCC. Patients with cT1N1-3M0-1 or cT2-3N0-3M0-1 (only supraclavicular lymph node (SCLN) metastasis is included as M1) based on the 8th edition of the UICC TNM staging system were eligible. Neoadjuvant chemotherapy consisted of oxaliplatin (85 mg/m ² ), docetaxel (50 mg/m ² ), and l-leucovorin (200 mg/m ² ) on day 1, and continuous infusion of fluorouracil (2600 mg/m ² /day) for 24 hours. This regimen was repeated every 2 weeks with a maximum of four cycles. The prophylactic antibody and G-SCF were not used mandatory. After completion of neoadjuvant chemotherapy, esophagectomy with extended lymphadenectomy was performed. Adjuvant treatment was prohibited for all patients. The primary endpoint was the pathological response rate (pRR), defined as the Grade 2 (more than two-thirds of the tumor is necrotic or fibrotic) or 3 (no viable tumor cells), based on the Japanese Classification of Esophageal Cancer. The sample size was determined based on an expected pRR of 38%, aiming for the lower bound of the 95% confidence interval to exceed the predetermined threshold of 20%. The expected number of patients to be enrolled was 60, with enrollment to be stopped when 45 patients with negative SCLN were enrolled. Results: Fifty-four patients were enrolled between September 2020 and January 2024. Patients with cStage I/II/III/IVB were 3/16/27/8. Of 54 patients, 45 patients were M0 without SCLN metastasis. Excluding 1 patient who did not receive any treatment after enrollment, 53 patients were included in the full analysis set. During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (73.6%), and leukopenia (22.6%). Febrile neutropenia was observed in 1 patient (1.9%). Finally, 46 patients underwent surgery. No treatment-related deaths were observed and the incidence of operative morbidity was tolerable. The pRR was 43.4% (23/53) (95% CI 29.8-57.7, p=00002). This study met the primary endpoint. The radical resection rate was 83.0% (44/53). The pathological complete response rate was 13.2% (7/53). Conclusions: Neoadjuvant FLOT therapy showed a promising pathological response with acceptable toxicities. It was noteworthy that the incidence of febrile neutropenia was relatively lower with compared to neoadjuvant DCF therapy. This regimen might be a treatment option for locally advanced ESCC. Clinical trial information: jRCTs031200094.