This study is a prospective randomized phase II study to evaluate the difference in tolerance between perioperative XELOX and FLOT chemotherapy.
Patients who meet the inclusion criteria be included in the study after reviewing and signing an informed consent.
Randomization will be performed in 1:1 ratio dividing patients into one of the two study groups.
Patients who will be randomized to the first (control) group will receive XELOX perioperative regimen. Patients who will be randomized to the second (study) group will receive FLOT perioperative chemotherapy regimen.
Evaluation of pathomorphological response will be performed according to Becker's criteria [15]. All patients will be involved in 5-year follow-up period.
Algorithm for patients registration and inclusion in the study
Patients are enrolled by investigating physicians. Physicians explain all the necessary points about the clinical trial to patients and familiarize patients with informed consent. Patient’s consent is confirmed with the signature. After signing the informed consent, every patient will be assigned a unique number, which will be entered into a paper CRF-form and duplicated in electronic database. The paper form and electronic database completely duplicate each other. The electronic and paper forms will be completed by the researcher as soon as the patient signs an informed consent to participate in the study. The electronic form is based on REDCap data base [16].
Randomization
The randomization process will be performed by Randomization module of REDCap software [16]. Initially we input the patient’s data into the REDCap program. After the approval for the patient to be included in the study, the randomization module will randomize patient into one of the two (FLOT arm and XELOX arm) groups. Patients will further receive 3 or 4 cycles of chemotherapy following by surgery and postoperative chemotherapy.
Inclusion criteria
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cT1b, cT2, cT3, cT4a, cT4b (except invasion of the common hepatic artery, proper hepatic artery, celiac trunk, proximal part of the splenic artery)
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cN0, cN1, cN2, cN3
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M0
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Age: 18–80
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Gender: men and women
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ECOG: 0–1
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Histological type of tumor: Papillary adenocarcinoma; tubular adenocarcinoma - highly differentiated or moderately differentiated; low-grade adenocarcinoma; mucinous adenocarcinoma; squamous cell adenocarcinoma; glandular squamous cell carcinoma.
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Degree of differentiation: G0 - G4
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Tumor localization: cardio-esophageal junction (Siwert 2, 3), cardiac stomach, gastric body, antral stomach, pyloric stomach;
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Tumor spread: esophagus, diaphragm, liver, pancreas, spleen, anterior abdominal wall, small and large intestine, distal splenic artery, spleen)
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No history of cancer in the last 5 years
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Absence of prior chemotherapy, surgery or radiation therapy for cancer
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Absence of significant comorbidity
Exclusion criteria
Statistics
According to the literature, 46% of patients who receive FLOT-4 regimen do not complete the treatment protocol. In order to increase the number of cycles that complete the entire treatment protocol from 46–62% when changing regimens to XELOX with a unilateral confidence level of 5% and a power 80%, it requires 328 patients with 10% losses. The theoretical level that patients change randomization group is 5%. This will require enrollment in each group 164 patients. Recruiting of patients is planned for three years. Further follow-up period will comprise 5 years. It is planned to include 55 − 50 patients to each group annually.
Analysis
The modified intention-to-treat analysis of the primary point is planned. It provides data analysis of only those patients who will have the tumor removed during surgery, except of those patients whose surgery will not be performed due to progression or other factors ( eg, cardiac events at the beginning of surgery). The difference in quantity of patients who tolerates chemotherapy regimen will be checked using one-sided Pearson's criteria, for values less than 5 - using Fisher's exact test. Logistic regression will be used to analyze the correlation between histopathological response rate and recurrence-free survival.
Univariate analysis for each clinical factor and its relationship to the development of the main types of complications will be used to analyze treatment-related complications. Continuous data will be analyzed using an odd t-test. The comparison of toxic profile between the two groups will be performed using the bilateral Pearson agreement criterion, with values less than 5 - Fisher's exact criterion. Multivariative analysis to determine the correlation between clinical variables and complications will be performed using a logistic regression model.
Quality of life will be analyzed using the ANOVA method for correlated data.
Disease-free survival and overall survival as a secondary endpoints, will be calculated from the date of randomization until clinical or radiological signs of recurrence or death occur, whichever occurs first. The Kaplan-Meier procedure based on the intention-to-treat position will be used for the analysis.
Pathomorphological protocol
Histological examination is performed according to the adapted pathohistological protocol of the College of American Pathologists: Gastric Cancer v4.0.0.0 2017 [17]. The pathology assessment of pCR is not blinded to treatment allocation. Marking of groups of lymph nodes is not mandatory in this trial.
Staging laparoscopy
Staging laparoscopy is a mandatory stage before randomization. It is performed to evaluate the presence of tumor invasion and peritonial carcinomatosis. During the procedure, the surgeon should take a biopsy of parietal peritoneum and great omentum to exclude distant metastases. We also obtain peritoneal washings to exclude cyt + status.
Centre registration
Any hospital that performs more than 30 gastrectomies for gastric cancer annually are able to be joined to the clinical trial. Primary investigators should guarantee following all staging, treatment, morphological assessment and follow-up pipelines according to current protocol. Local ethical committee approval is needed.
Perioperative chemotherapy
This trial includes FLOT and XELOX chemotherapy regimen. FLOT regimen includes docetaxel 50 mg/m2 on day 1, oxaliplatin 85 mg/m2 on day 1, leucovorin 200 mg/m2 on day 1 and continuous infusion of fluorouracil 2600 mg/m2 on day 1 and 2; cycle each 14 day. XELOX regimen includes oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 2 times per day on days 1–14; cycle each 21 day. Patients receive 4 preoperative cycles and 4 postoperative cycles within each of the regimen.
Preoperative care
Patients with comorbidities are treated according to national or local guidelines before starting treatment. It is required for patients to visit an appropriate consultant prior to the beginning of chemotherapy and surgery. Before preoperative chemotherapy patients are obliged to have histologically confirmed gastric cancer, CT chest, abdomen and pelvis with intravenous contrast and gastroscopy.
Surgery
Surgery is performed under general anaesthesia with spinal or epidural analgesia supplement. Date of surgery, time of start and end of surgery, blood loss, blood transfusions and approach are registered. In case of conversion, reason of conversion is noted: “tactical” conversion is performed after laparoscopic revision in case of new data, complicating laparoscopic procedure (adhesions, tumour size etc.), “reactive” conversion is a change in approach because of intraoperative
events (bleeding, perforation etc.). Intraoperative findings, main steps and type of surgery are registered in operative notes and in electronic CRF (eCRF). In case of multivisceral resections the extent and details of other organ resections are documented.
Quality control of surgery
Before and after the specimen are removed taking photos of the operating field will be mandatory The following stages are fixed:
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a stomach with a tumor before the beginning of mobilization of a stomach;
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operating field after stomach removal and lymph nodes dissection;
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removed stomach in longitudinal section; removed lymph nodes.
Postoperative care
Postoperative treatment is given according to local guidelines. Main parameters of postoperative period are registered in patient’s eCRF: admission and discharge
dates (if the discharge is postponed for social reasons - date, when patient was medically fit for discharge is documented), day of abdominal drainage withdrawal, start of fluids, patients movement activity, blood transfusions. Surgical complications are registered according to Clavien–Dindo classification. Treatment of complications is given according to local guidelines. Data on beginning, duration and treatment for complications is documented in patients eCRF (CRF).
Follow-up
Postoperative follow-up includes investigations (CT chest and abdomen, upper GI endoscopy) in 4, 8 and 12 month, than 2 times on 2nd year after surgery, afterwards annually during the follow-up period. Complications, adjuvant treatment and recurrence are registered during follow-up period. Recurrence is registered when local recurrence or distant metastases are found during investigation (upper GI endoscopy, CT, MRI); Quality of life will be assessed with validated questionnaires EORTC QLQ-C30 and EORTC QLQ-C25. Patients rejecting surgery after randomization or patients receiving different to randomization group treatment will be analysed in primary randomization groups. For patients rejecting treatment and follow-up continuation of data collection without treatment is offered.
Efficacy and safety
Postoperative period data will be assessed based on morbidity and mortality rates. Safety analysis will be performed each year and finally after all the patients will be enrolled. Surgery risks and preferable approach is under the surgeon’s responsibility. Adverse event is understood as any unwanted medical deviation in any kind of treatment and not necessarily associated with such treatment. In current study, adverse event is any unfavorable or unwanted deviation including laboratory tests or conditions not necessarily associated with the chemotherapy or surgery. Adverse event is any change from preoperative state of a patient, including exacerbation of comorbidities.
Adverse events classification is performed in accordance with CTCAE ver. 5.0 terminology for chemotherapy adverse effects [18]. Any treatment or observation in case of adverse event is prescribed by attending doctor, who is responsible for it.
Follow-up
Schedule of necessary investigations and follow-up visits is established according to clinical guidelines. Date deviation can probably happen. However, it has to be written in eCRF. Data on completed visits is transferred to eCRF in 5 working days. Quality of life is assessed via questionnaires after surgery, on day 30, 3-month visit, 1, 3 and 5-year visits.
To minimize number of patients lost during follow-up, patients are able to provide results of their routine follow-up investigations and get a consult of their physicians, which will facilitate patients’ adherence to follow-up.
Russian full-scale invasion
We suspended recruitment of patients into the study on February 24, on a day when a Russian full-scale aggression began. Main reasons for such decision were:
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inability of precision selection of the patients that may be included in the study;
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stochastic interruption in performing of diagnostic procedures, such as endoscopy, computed tomography and staging laparoscopy;
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lack of medications, especially chemotherapeutic agents;
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inability to follow timeframes and recommendations (time gap between cycles and lab tests may be longer).
Recruitment process will be continued if investigators are able to provide all patients needs per protocol.