Total Neoadjuvant Chemotherapy in Locally Advanced Gastric and Gastroesophageal Junction Cancer

Study Overview
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Brief Summary
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The main goal of this study is to investigate the histopathological regression rate in patients with locally advanced gastric and gastroesophageal adenocarcinoma without previous treatment who will be prospectively randomized into two groups to undergo one of two chemotherapy regimens, followed by surgery: 8 cycles of Total Neoadjuvant ChemoTherapy (TNT) with 5-Fluorouracil (5-FU), Leucovorin, Oxaliplatin and Docetaxel (FLOT) followed by surgery. 4 cycles of Neoadjuvant FLOT chemotherapy scheme preoperatively and 4 adjuvant FLOT cycles postoperatively.

Detailed Description
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758 participants with resectable locally advanced gastric and gastroesophageal (Siewert 2, 3) adenocarcinoma (T3-4b, N1-3, M0) with no history of previous treatment 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 who will be randomized to the first (control) group will receive 8 cycles of perioperative FLOT chemotherapy scheme: 4 cycles before surgical treatment and 4 cycles after surgical intervention. Patients who will be randomized to the second (study) group will receive 8 cycles of FLOT total neoadjuvant chemotherapy, followed by surgery. Primary endpoint of the study is pathomorphological tumor response rate. 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.

Official Title
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Total Neoadjuvant Chemotherapy With 5-fluoruracil, Leucovorin, Oxaliplatin and Docetaxel in Locally Advanced Gastric and Gastroesophageal Junction Cancer (OCTASUR): Randomized, Single Center, Open Label Trial, Phase 2/3

Conditions
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Gastric Cancer, Stomach Cancer, GastroEsophageal Cancer, Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma, Advanced Gastric Adenocarcinoma, Gastric Neoplasm, Stomach Neoplasm, Gastrointestinal Cancer, Advanced Gastroesophageal Junction Adenocarcinoma, Advanced Gastric Carcinoma

Intervention / Treatment
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* Drug: Docetaxel
* Drug: Oxaliplatin
* Drug: Leucovorin
* Drug: Fluorouracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Tumor spread: сT3, сT4a, сТ4b (except of invasion of the common hepatic artery, celiac trunk, proximal part of the splenic artery, aorta, head of the pancreas); сN1, сN2, сN3; сM0; Performance status by Eastern Cooperative Oncology Group (ECOG): 0 - 1; Histological type of tumor: 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; No history of cancer in the past 5 years; Absence of previous chemotherapeutic, surgical or radiation treatment for oncological disease; No concomitant severe comorbidity; Patient willing to participate. Exclusion Criteria: M1 (distant metastases); ECOG 2 - 4; Age over 80 and under 18; Concomitant severe comorbidity; Refusal of the patient to participate in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Perioperative 4+4 FLOT cycles<br>4 cycles of neoadjuvant FLOT chemotherapy scheme, followed by surgery and 4 cycles of adjuvant FLOT chemotherapy scheme. | Drug: Docetaxel<br>* 50mg/m2, d1, i.v., every 2 weeks<br>Drug: Oxaliplatin<br>* 85 mg/m², d1, i.v., every 2 weeks<br>Drug: Leucovorin<br>* 200 mg/m², d1, i.v., every 2 weeks<br>Drug: Fluorouracil<br>* 2600 mg/m²d1 i.v. every 2 weeks<br>|
| Experimental: Total Neoadjuvant ChemoTherapy (TNT) 8 FLOT cycles<br>8 cycles of total neoadjuvant FLOT chemotherapy scheme, followed by surgery. | Drug: Docetaxel<br>* 50mg/m2, d1, i.v., every 2 weeks<br>Drug: Oxaliplatin<br>* 85 mg/m², d1, i.v., every 2 weeks<br>Drug: Leucovorin<br>* 200 mg/m², d1, i.v., every 2 weeks<br>Drug: Fluorouracil<br>* 2600 mg/m²d1 i.v. every 2 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histopathological tumor response rate (Becker regression criteria). | To determine the pathohistological regression rate after 8 FLOT cycles in total neoadjuvant regimen compared to 4 FLOT cycles in neoadjuvant regimen. | 14 days after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Surgical complications rate. | To determine postoperative surgical complications rate and profile after the different chemotherapy regimens, according to Clavien-Dindo classification. | 30 days after surgery. | 
| Chemotherapy toxicity rate and profile. | To determine chemotherapeutic toxicity profile, according to Common Terminology Criteria for Adverse Events (CTCEA 5.0). | At the end of each FLOT cycle (each cycle is 14 days), up to 14 days after the last cycle. | 
| Quality of patients' life, according to the European Organisation for Research and Treatment of Cancer core quality of life questionnaire (EORTC QLQ-30, QLQ-OG25). | To determine quality of life during the chemotherapy in both groups, after the surgery and 2 years follow-up after the completion of treatment, using EORTC QLQ-30, QLQ-OG25 questionnaires. | 24 months. | 
| Disease-free survival. | To determine the efficacy of total neoadjuvant FLOT regimen compared to perioperative FLOT regimen. | 1 year after the last intervention. | 
| Median overall survival. | To determine the efficacy of TNT FLOT regimen compared to perioperative FLOT regimen by assessment of overall survival. | 5 years follow-up after the last intervention. | 
| Correlation between the pathohistological response and overall and disease-free survival. | To determine the correlation between the pathohistological response and overall and disease-free survival. | 14 days after surgery. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Total neoadjuvant chemotherapy, FLOT, Fluoruracil, Gastrectomy, Perioperative chemotherapy, Docetaxel, Leucovorin