The main goal of this study is to investigate the proportion of participants with locally advanced gastric and gastroesophageal adenocarcinoma without previous treatment during the last 5 years who can tolerate all planned cycles of chemotherapy and radical surgical treatment who will be prospectively randomized into two groups to undergo one of two chemotherapy regimens, followed by surgery:

1. 8 cycles of Total Neoadjuvant ChemoTherapy (TNT) with 5-Fluorouracil (5-FU), Leucovorin, Oxaliplatin, and Docetaxel (FLOT) followed by surgery.
2. 4 cycles of Neoadjuvant FLOT chemotherapy scheme preoperatively and 4 adjuvant FLOT cycles postoperatively.

This is a multi-center international European prospective randomized study that aims to enroll participants with resectable locally advanced gastric and gastroesophageal (Siewert 2, 3) adenocarcinoma (≥cT3 and/or ≥cN0 and M0) with no history of previous oncological treatment during the last five years, who will be included in this study after reading and signing the informed consent. After the initial diagnostic laparoscopy, patients will be randomized into two groups in a 1:1 ratio, with allocation to one of the two study groups.

Patients randomized to the first (control) group will receive eight cycles of the perioperative FLOT chemotherapy scheme: 4 cycles before surgical treatment and four cycles after surgical intervention. Patients randomized to the second (study) group will receive eight cycles of FLOT total neoadjuvant chemotherapy, followed by surgery.

The study's primary endpoint is the proportion of patients receiving all planned chemotherapy cycles and radical surgical treatment. Secondary endpoints are perioperative morbidity and mortality (surgical and chemotherapeutic complications); disease-free survival (DFS) and 1-, 3- and 5-years overall survival (OS); quality of life during and after the treatment; correlation between the pathohistological response and chemotherapy regimen; composition and biomarkers of gut microbiota; objective tumor response.

Based on previous studies, with the current standard treatment protocol-four cycles of FLOT chemotherapy before surgery and four cycles after-only 47% of patients complete all eight cycles. In contrast, with total neoadjuvant therapy, where the entire chemotherapy regimen is administered before surgery, 71% of patients are able to complete all eight FLOT cycles.

Given these findings, it was calculated that to ensure 80% study power with a two-sided 5% significance level, each study group should include 65 participants. Considering an expected dropout rate of 15%, a total of 150 patients will be recruited. Up to 40 patients will be enrolled in Vilnius, Lithuania, with the remaining participants recruited in Kyiv, Ukraine.

Inclusion Criteria:

• Tumor spread according to TNM: ≥cT3 and/or ≥cN0 and M0 (except of invasion of the common hepatic artery, celiac trunk, proximal part of the splenic artery, aorta, head of the pancreas);
• Performance status by Eastern Cooperative Oncology Group (ECOG): 0 - 1;
• Histologically confirmed gastric adenocarcinoma or gastroesophageal junction (Siewert type 2/3) adenocarcinoma.
• Differentiation grade: G0 - G4;
• Tumor localization: cardio-esophageal junction (Siewert 2, 3), cardiac part of the stomach, body of the stomach, antral part of the stomach, pyloric part of the stomach;
• Tumor extension: esophagus, diaphragm, liver, body and tail of the pancreas, anterior abdominal wall, small and large intestine, distal part of the splenic artery, spleen;
• Patient agrees to participate in this biomedical study.

Exclusion Criteria:

• Presence of another oncological disease at a different site if less than 5 years have passed since radical treatment.
• Comorbidities or patient conditions that preclude the administration of chemotherapy.

After the initial publication every participant will receive all the data to provide further data exploration.

Data will be available after initial paper is published.