Protocol overview
The PREVENT (FLOT9) study is a multicenter, randomized, controlled and open-label study including patients with localized and locally advanced adenocarcinoma of the stomach and type II/III GEJ of diffuse or mixed type according to Lauren’s classification, scheduled to receive perioperative chemotherapy combined with or without intraoperative HIPEC procedure.
The scope of the trial is to evaluate the efficacy as well as the safety and tolerability of the combination of perioperative chemotherapy with an intraoperative HIPEC for resectable diffuse or mixed type gastric and GEJ (types II/III) adenocarcinoma.
Patients with localized and locally advanced diffuse or mixed type adenocarcinoma of the stomach and type II/III GEJ (i.e. ≥cT3 any N or any T N-positive) with laparoscopic exclusion of peritoneal seeding and radiological exclusion of other distant metastases will be included in this trial after a central review by medical and surgical oncologist.
All enrolled patients will have received 3–6 pre-operative cycles (de-escalation or dose modification allowed) of biweekly FLOT (Docetaxel 50 mg/m2 in 250 ml NaCl 0.9%, iv over 1 h; Oxaliplatin 85 mg/m2 in 500 ml G5%, iv over 2 h; Leucovorin 200 mg/m2 in 250 ml NaCl 0.9%, iv over 30 min; 5-FU 2600 mg/m2, iv over 24 h, q2wk) in the preoperative treatment phase. After completion of neoadjuvant FLOT- therapy followed by pre-operative tumor assessment, patients without disease progression (expected to be approximately 90% of the patients) will be included into the trial, stratified by study site, histology type of tumor (Lauren classification diffuse vs. mixed) and initial clinical stage (N- vs. N+). Pts. will be randomized 1:1 to receive either standard of care (SOC) surgery plus postoperative FLOT- regimen (Arm A- standard) or SOC- surgery combined with intraoperative cisplatin based HIPEC- procedure followed by postoperative FLOT- therapy (Arm B- experimental). Randomization will be performed electronically in the eCRF by the site staff using variance minimization, so the sequence of randomization results is not known to the investigators.
Arm A (FLOT- standard arm)
Surgery in Arm A is planned to occur 4 to 6 weeks after d1 of last FLOT cycle. Surgery is carried out in kind of standardized gastrectomy or transhiatal extended gastrectomy, both including D2- lymphadenectomy. Patients will receive 4 additional post-operative cycles (8 weeks) of FLOT (Docetaxel 50 mg/m2 in 250 ml NaCl 0.9%, iv over 1 h; Oxaliplatin 85 mg/m2 in 500 ml G5%, iv over 2 h; Leucovorin 200 mg/m2 in 250 ml NaCl 0.9%, iv over 30 min; 5-FU 2600 mg/m2, iv over 24 h, q2wk) in the post-operative treatment phase. Post-operative treatment should start 6 to 8 weeks, but at maximum 12 weeks, after surgery.
Arm B (FLOT/ HIPEC- experimental arm)
Surgery in Arm B is planned to occur 4 to 6 weeks after d1 of last FLOT- cycle. Surgery is carried out in kind of gastrectomy or transhiatal extended gastrectomy, both including D2- lymphadenectomy. Surgery will be combined with an intraoperative Hyperthermic Intraperitoneal Chemoperfusion (HIPEC).
HIPEC itself can be performed in closed or open-abdomen procedure, according to the local standards at study site. The protocols advices the prevention of nephrotoxicity during hyperthermic perfusion with cisplatin. Before hyperthermic perfusion starts, urine production should be more or equal than 1 ml/kg/hr. We recommend the usage of sodium thiosulfate, but the usage depends on the local preferences and standards. At start of hyperthermic perfusion: Sodium thiosulfate: 9 g/m2 in 200 ml distilled water, made isotone with sodium chloride, is to be given IV push over 15–20 min, concurrently at start of hyperthermic infusion of cisplatin. This is to be followed by 12 g/m2 thiosulfate IV continuous infusion over 6 h (the 12 g/m2 should be dissolved in 1 l of distilled water and infused at 167 ml/hr). After positioning of inflow catheter and drains intraabdominal cisplatin solution (75 mg/m2 in NaCl 0.9%) will be administered at a temperature of 42 °C for 90 min. Perfusion with cisplatin at a dose of 75 mg per square meter and at a flow rate of 1 l per minute will then be initiated (with 50% of the dose perfused initially, 25% at 30 min, and 25% at 60 min). The perfusion volume will be adjusted such that the entire abdomen is exposed to the perfusate. The HIPEC procedure takes 120 min in total, including the 90-min perfusion period. To prevent heat trauma to normal tissue the temperature of the silicon drain will not be increased over 42 °C. Post-surgical phase: Urine production should not be less than 1 ml/kg during hyperthermic perfusion and for 3 h following surgery.
Patients will receive 4 additional post-operative cycles (8 weeks) of FLOT in the post-operative treatment phase. Post-operative treatment should start 6 to 8 weeks, but at maximum 12 weeks, after surgery.
In both arms, tumor assessments (CT or MRI) are performed before randomization prior to surgery, and then every 3 months (radiological tumor assessment) thereafter until progression/relapse, death, or end of follow-up. A change from CT into MRI in the follow up period is possible at any time. Also during tumor assessment visits and additionally after surgery blood (EDTA-plasma, serum and whole blood for genomic DNA isolation (ccfDNA)) is collected for later translational research projects.
During treatment, clinical visits (blood cell counts, detection of toxicity) occur prior to every treatment dose. Safety of FLOT/ HIPEC will be monitored continuously by careful monitoring of all adverse events (AEs) and serious adverse events (SAEs) reported.
The phase III design starts with a safety run-in phase. Eight weeks after 20 patients had curatively intended resection in Arm B, an interim safety analysis is performed that shows feasibility, safety, and tolerability of Arm B planned. It is not planned to discontinue recruitment for the interim safety analysis (see Fig. 1).
Measures of outcomes and assessments
Primary outcome
The primary efficacy objective of the study is to compare progression/disease-free survival (PFS/DFS), defined as first occurrence of progression or recurrence, as determined by the investigator using RECIST 1.1 criteria. The duration of PFS/DFS will be determined by measuring time interval from randomization until disease progression or disease recurrence after surgery or death of any cause.
Secondary outcomes
Secondary efficacy objectives are overall survival (OS, defined as the time from randomization to death from any cause), rates of peritoneal relapse at 2 and 3 years in both arms, PFS/DFS rates at 2, 3 and 5 years, OS rates at 3 and 5 years, OS and PFS/DFS (medians and rates) according to subgroups, Quality of life (QoL) – EORTC QLQ C30 and EORTC QLQ STO22 questionnaires, post-operative morbidity/mortality at day 30 after surgery acc. Clavien–Dindo classification, post-operative pain according to Visual analog scale and the safety of perioperative FLOT + HIPEC.
Main inclusion criteria
Histologically confirmed, medically operable, resectable diffuse or mixed type adenocarcinoma of the gastroesophageal junction (AEG II-III) or the stomach (uT3, uT4a, any N category, M0), or any T N+ M0 patient is eligible. No prior chemotherapy except 3–6 cycles of FLOT chemotherapy and no prior tumor resection.
Main exclusion criteria
Medical inoperability. Inability to understand the study and/or comply with the protocol procedures. Pre-existing peritoneal seeding.
Criteria of primary unresectability, e.g.: radiologically documented evidence of major blood vessel invasion or invasion of adjacent organs (T4b). Patient with involved retroperitoneal (e.g. para-aortal, paracaval or interaortocaval lymph nodes) or mesenterial lymph nodes (distant metastases).
Treatments
Control(s)/comparator(s)
FLOT consists of: Docetaxel 50 mg/m2, iv over 2 h, d1; Oxaliplatin 85 mg/m2 in 500 ml G5%, iv over 2 h, d1; Leucovorin 200 mg/m2 in 250 ml NaCl 0.9%, iv over 1 h, d1; 5-FU 2600 mg/m2, iv over 24 h, d1 (= 1 cycle); Start of next cycle on day 15 (every 2 weeks) [7].
Dose, mode, and scheme of intervention
In both arms, patients will undergo surgery 4 to 6 weeks after the 3-6th cycle of FLOT.
Surgery is carried out in kind of gastrectomy, transhiatal extended gastrectomy. In the experimental arm surgery will be combined with an intraoperative Hyperthermic IntraPEritoneal Chemoperfusion (HIPEC).
HIPEC itself can be performed in closed or open-abdomen procedure. At start of hyperthermic perfusion, Sodium thiosulfate: 9 g/m2 in 200 ml distilled water, made isotone with sodium chloride, is to be given IV push over 15–20 min, concurrently at start of hyperthermic infusion of cisplatin. This is to be followed by 12 g/m2 thiosulfate IV continuous infusion over 6 h (the 12 g/m2 should be dissolved in 1 l of distilled water and infused at 167 ml/hr). After positioning of inflow catheter and drains intraabdominal cisplatin solution (75 mg/m2 in NaCl 0.9%) will be administered at a temperature of 42 °C for 90 min. Perfusion with cisplatin at a dose of 75 mg per square meter and at a flow rate of 1 l per minute will be then initiated (with 50% of the dose perfused initially, 25% at 30 min, and 25% at 60 min). The perfusion volume will be adjusted such that the entire abdomen is exposed to the perfusate. The HIPEC procedure takes 120 min in total, including the 90-min perfusion period. For a more exact description see above under: Arm B (FLOT/ HIPEC- experimental arm).
Sample size calculation
The primary efficacy analysis will compare randomized surgical resection combined with HIPEC to randomized surgical resection only on the time to the primary efficacy endpoint using the intent-to-treat population. The hypothesis test will use the log rank test to compare the investigational arms. The study assumes a Hazard ratio of 0.65 favoring the HIPEC group. The PFS/DFS in the reference arm is set as 20.19 months (calculation on complete data from study FLOT4) for signet ring cell containing gastric cancers. Accrual time is 42 months followed by 2 years follow up period. Dropouts prior to randomization are set at 35%. Dropouts after randomization are set 5%. Type I error is 5% and one-sided Log rank test is used. Two hundred patients are to be randomized to provide a statistical power of 80%. These 200 patients will be recruited in 20 German sites with already proven experience in conducting HIPEC procedure.
Monitoring
All adverse events and severe adverse events occurring after informed consent are recorded in the patient’s electronic case report form by the responsible site staff. Adverse events will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. With this data the safety will be monitored continuously by careful monitoring of all adverse events and serious adverse events reported. A compilation of all serious adverse events is sent to lead Ethic, regulatory body and the Safety Monitoring Board (SMB). The SMB furthermore provides the sponsor with recommendations regarding study modification, continuation or termination. In this process the SMB may give advice for continuation, changes to the study protocol or termination of the study. The SMB may claim unplanned interim analyses of any variable and – beyond the aforementioned items – it may ask for any additional activity within the trial if the activity is on behalf of patients’ security.
Premature termination of the study may also be decided if unexpected severe surgical complications occur, more effective therapies become available or if patient enrollment is insufficient. Final decision is made by sponsor representative and the lead coordinating investigator.
It is understood that an outside monitor and other authorized personnel may contact and visit the investigator, and that they will be allowed direct access to source data/documents for trial-related monitoring, audits, IRB review, and regulatory inspection. Direct access is defined as permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial. All reasonable precautions within the constraints of the applicable regulatory requirements to maintain the confidentiality of patients’ identities and sponsor’s proprietary information will be exercised. In case of an audit by the sponsor/sponsor representative or an appropriate authority, the investigator will make all relevant documents available.
Ethical considerations, information giving and written informed consent
The study protocol was approved by the responsible lead ethics committee on the July 27th, 2020 under the identification number 2020–1709-fAM. The study has been registered on the ClinicalTrial.gov website under the identification number NCT04447352 and under EudraCT 2017–003832-35. The PREVENT (FLOT9) study complies with the Declaration of Helsinki rules, the principles of Good Clinical Practice guidelines and the Data Protection Act. The trial will also be carried out in compliance to local legal and regulatory requirements. For each patient to be enrolled into the study, obtaining written informed consent prior to inclusion into the study is essential.