Induction FLOT Chemotherapy Prior to Neoadjuvant Chemoradiotherapy in the Treatment of Lower Esophageal and Proximal Gastric Adenocarcinoma: A Phase II, Single-Arm Clinical Trial.

GOAL: Selecting the most effective treatment strategy for patients with distal esophageal and proximal gastric adenocarcinoma remains a clinical challenge. Although existing evidence supports the use of adjuvant therapies, the optimal sequencing of these treatments is still debated. Given that distant metastasis is the most common cause of death in this patient population, early initiation of systemic therapy may theoretically improve survival. This study aimed to evaluate the effectiveness of using the FLOT chemotherapy regimen as induction therapy before neoadjuvant chemoradiotherapy in treating distal esophageal and proximal gastric cancer. METHODS: In this single-arm, phase II clinical trial, patients with resectable, locally advanced adenocarcinoma of the distal esophagus and proximal stomach (T1-T4b, N0-N3, M0) who presented at two teaching hospitals affiliated with Mashhad University of Medical Sciences (Imam Reza and Omid Hospitals, Mashhad, Iran) were screened for eligibility. Eligible patients received two cycles of induction FLOT chemotherapy. This was followed by neoadjuvant chemoradiotherapy consisting of weekly paclitaxel and carboplatin, with a total radiotherapy dose of 45-50.4 Gy delivered in 1.8-2 Gy/fraction. Surgery was performed 4-6 weeks after completion of chemoradiotherapy. The primary endpoint was pathological tumor response. RESULTS: Among the 57 enrolled patients, 40 (70.2%) underwent surgical resection and pathological evaluation (mean age: 56.5 ± 8.9 years, range: 24-64). Based on abdominal CT and/or endoscopic ultrasound (EUS), most tumors were staged as T3 (23 patients, 40.4%) and N1 (26 patients, 45.6%). Induction FLOT was administered to all patients, with 51 patients (89.5%) completing both cycles. Additionally, the majority received more than four weekly cycles of concurrent chemoradiotherapy (42 patients, 73.6%). Pathological examination of surgical specimens revealed a complete pathological response (pCR) in 11 patients (27.5%), partial response in 10 (25%), minimal response in 12 (30%), and poor response in 7 (17.5%). The neoadjuvant regimen was generally well tolerated, with most patients experiencing either no side effects or only Grade 1 hematologic or gastrointestinal toxicity. CONCLUSION: Induction FLOT chemotherapy followed by neoadjuvant chemoradiotherapy appears to be a safe and well-tolerated treatment strategy for patients with distal esophageal and proximal gastric adenocarcinoma, yielding complete pathological response in approximately one-third of surgically treated and pathologically evaluable patients. TRIAL REGISTRATION: IRCT20210706051800N1 on 20,220,919.