Phase 1 Trial of Total Neoadjuvant Therapy With Short-Course Chemoradiotherapy Followed by Chemotherapy for Patients With Potentially Resectable Gastric Cancer.

Purpose: The purpose of this phase 1 trial was to evaluate the safety and toxicity of preoperative short-course chemoradiotherapy (CRT) as part of total neoadjuvant therapy (TNT) for patients with potentially resectable gastric or gastroesophageal adenocarcinoma.

Methods and materials: Patients were enrolled between March 2021 and December 2022 and received CRT (30 Gy radiation in 10 fractions with concurrent capecitabine or 5-fluorouracil), then received systemic therapy for 2 months, and then underwent surgery. The primary endpoint was CRT safety; secondary endpoints were pathologic complete response, perioperative complications, and overall survival (OS).

Results: Of the 24 patients enrolled in the trial, 10 (42%) had bleeding, 3 (13%) had gastric outlet obstruction, and 2 (8%) had cirrhosis. Twelve patients (50%) had clinical nodal involvement. Twenty patients (83%) had poorly differentiated tumors, and 13 (54%) had signet ring cell histology. All patients completed CRT. CRT treatment-related toxic effects included grade 3 lymphopenia in 7 patients (29%), grade 4 lymphopenia in 1 (4%), and grade 3 anemia in 1 (4%). After CRT, 22 patients (92%) received chemotherapy, 1 patient (4%) with a microsatellite instability-high tumor received immunotherapy, and 1 patient (4%) underwent resection without systemic therapy. All patients underwent attempted resection, and gastrectomy was performed in 20 (83%). The R0 resection rate was 95%. Two patients had pathologic complete response, and an additional 5 had ≤1% viable tumor. Three patients had surgical complications [grade 1 in 1 patient (4%), grade 3b in 1 (4%), and grade 4a in 1 (4%)]; no patients died within 90 days. The median follow-up time was 28 months, and median OS was not reached. The 1- and 3-year OS rates were 96% and 85%, respectively.

Conclusion: Short-course CRT may be safely used as part of planned TNT for patients with potentially resectable gastric or gastroesophageal adenocarcinoma. The promising rates of treatment completion, pathologic response, and OS support further research of TNT for gastric cancer.