Prophylactic surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC CO2) versus standard surgery for gastric carcinoma at high risk of peritoneal carcinomatosis: short and long-term outcomes (GOETH STUDY)—a collaborative randomized controlled trial by ACOI, FONDAZIONE AIOM, SIC, SICE, and SICO

Hypothesis

In patients with gastric cancer at high risk of peritoneal carcinomatosis (PC), primary radical tumour resection with D2 lymphadenectomy, combined with a more aggressive surgical approach and prophylactic HIPEC, should reduce peritoneal recurrence.

Primary objective

The primary objective of the study is to compare the efficacy of prophylactic surgery with HIPEC CO2 versus standard surgery in terms of disease-free survival (DFS) in patients with gastric carcinoma (GC) at high risk of developing peritoneal carcinomatosis.

Secondary objectives

To compare the experimental treatment (prophylactic surgery plus mitomycin- and cisplatin-based HIPEC CO2) versus standard treatment on local recurrence-free survival (LRFS) and OS

To assess the safety (treatment-related morbidity and mortality) of this experimental approach

To assess the number of patients performing the adjuvant treatment

Study design

This is a phase III, randomized, multicentre, superiority trial in patients with gastric carcinoma, at high risk of peritoneal carcinomatosis. Patients may have had neoadjuvant chemotherapy according to clinical practice, or direct surgery. If, after diagnostic exams, patients are eligible for the trial and resection of the tumour is total during surgery, patients will be randomly assigned (1:1 ratio) not more than 24 h before surgery to prophylactic surgery plus HIPEC CO2 (arm A) or to standard surgery (arm B). The primary objective is to compare the efficacy of prophylactic surgery (radical gastric, appendectomy, resection of the round ligament of the liver, and bilateral adnexectomy) plus HIPEC CO2 versus standard surgery in terms of DFS. The secondary objective is to compare the safety profile and tolerability of prophylactic surgery plus HIPEC CO2 versus standard surgery.

Participants

The target population comprises patients with gastric carcinoma, at high risk of peritoneal carcinomatosis. The inclusion and exclusion criteria are reported below.

Inclusion criteria 1.

Patients with histologically documented gastric carcinoma (diffuse/intestinal histotype) eligible for R0 with (a) presurgical stage T3-T4 N0-N + primary tumour (TNM 8th), (b) urgent presentation: perforation without purulent generalized peritonitis, and (c) positive cytology of peritoneal fluid (if previously obtained)

2.

Age ≥ 18 years and ≤ 75 years

3.

Written informed consent

Exclusion criteria 1.

Gastroesophageal junction (GEJ) cancer

2.

Distant metastatic disease (even if limited and completely resected)

3.

Peritoneal carcinomatosis

4.

History of tumour diagnosed in the 3 years before entering the study, except for topical and healed pathologies that do not need further treatment (e.g. non-melanoma skin carcinomas, superficial bladder carcinomas, or in situ carcinoma of the breast or cervix)

5.

Psychological, family, or social conditions which may negatively affect the treatment and follow-up protocol

6.

Poor general condition (ECOG > 2)

7.

Impaired cardiac function (history of congestive heart failure or FE < 40%). Clinically significant cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrolment), unstable angina, congestive heart failure (New York Heart Association Classification Class > II), or serious uncontrolled cardiac arrhythmia requiring medication

8.

Impaired renal function (creatinine > 1.5 upper limit of normal or creatinine clearance < 60 mL/min)

9.

Impaired hepatic function (AST, ALT > 2.5 upper limit of normal, bilirubin > 1.5 upper limit of normal)

10.

Impaired haematopoietic function (leucocytes < 4000/mm3, neutrophils < 1500/mm3, platelets < 100,000/mm.3)

11.

Impaired pulmonary function (presence of COPD or other pulmonary restrictive conditions with FEV1 < 50% or DLCO < 40% of normal age value)

12.

History or presence of other disease, metabolic dysfunction, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of HIPEC or chemotherapy or patient at high risk from treatment complications

13.

Pregnancy

14.

Krukenberg tumour

15.

Refusal to join the study

Randomization

Patients will be randomized no more than 24 h before surgery if total resection of the tumour is intended, and a stratification procedure based on centre and neoadjuvant chemotherapy will be used. Patients will be randomized in a 1:1 ratio. The randomization lists were prepared by the study statistician using the SAS system (version 9.4).

Treatment regimen

Patients assigned to arm A will receive prophylactic surgery and HIPEC CO2 with cisplatin and mitomycin in addition to primary tumour resection. Patients randomized to standard surgery (arm B) will be operated to clinical practice, without HIPEC CO2.

During surgery, surgeons will assess the presence of peritoneal carcinomatosis, and if it is found, patients randomized to arm A will not receive HIPEC and will be operated to surgery according to clinical practice.

Surgery

Diagnostic laparoscopy is suggested. Before surgical resection, peritoneal washing will be done for a definitive cytological examination. Both the laparotomic and laparoscopic surgical approaches are allowed according to clinical practice. In the experimental arm, the prophylactic surgery will include radical gastrectomy with D2 lymphadenectomy and omentectomy, resection of the round ligament of the liver, bilateral adnexectomy, and appendectomy. For women of child-bearing age, bilateral adnexectomy should be discussed. In the comparator arm, radical standard surgery will be done (radical gastrectomy with D2 lymphadenectomy). For both arms, if necessary, multivisceral resection could be done to achieve R0.

Hyperthermic intraperitoneal chemotherapy (HIPEC) procedure

In experimental arm A, patients will undergo HIPEC. We will use a closed-abdomen HIPEC technique with CO2 agitation, using a specific CE-marked device with multi-perforated catheters, two placed in the upper abdomen for the chemotherapy infusion and the other two in the lower abdomen for fluid aspiration and CO2 infusion. Chemotherapy with the perfusion solution at 42 °C and CO2 flowed into the abdominal cavity; turbulent flow was created to improve drug distribution. HIPEC may be done after laparoscopic or laparotomic primary tumour resection without interference with the standard surgical techniques.

The HIPEC CO2 regimen will be as reported below: mitomycin 15 mg/mq and cisplatin 75 mg/mq both in physiologic solution 0.9%.

The recommended temperature for HIPEC treatment is 42 °C for 60 min of perfusion.

Sodium thiosulfate will be administered to prevent nephrotoxicity induced by cisplatin as follows: sodium thiosulfate 9 g/mq bolus and then sodium thiosulfate 1.2 g/mq/h with continuous infusion for 6 h. Adequate preoperative and postoperative iv hydration is necessary.

Perioperative and adjuvant chemotherapy

Clinically staged T3-4 N0-1 M0 patients should be considered for a perioperative approach.

Neoadjuvant treatment consists of 3 months of chemotherapy followed, after surgery, by another 3 months of chemotherapy according to the same regimen used preoperatively. One can choose between epirubicin, cisplatin, fluorouracil/capecitabine (ECF/ECX) or oxaliplatin, capecitabine (XELOX) or oxaliplatin, fluorouracil/leucovorin (FOLFOX-4) or fluorouracil, leucovorin, oxaliplatin, docetaxel (FLOT). For patients who receive FLOT before surgery, chemotherapy could be changed after surgery in case of toxicity or because of a medical decision. Patients not receiving neoadjuvant chemotherapy will be given chemotherapy for 6 months in the adjuvant setting (consider ECF/ECX or FOLFOX/XELOX regimen). Adjuvant treatment should start within 8–12 weeks from surgery.

Disease assessment

Before randomization, complete blood count (CBC), blood chemistry (glucose, sodium, potassium, chloride, blood urea nitrogen (BUN), creatinine, alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGT), aspartate transaminase (AST), total and direct bilirubin, albumin, and total protein), coagulation tests (prothrombin time (PT), activated partial thromboplastin time (aPTT), INR), tumour markers (CEA, CA 19.9), B-HCG test, and electrocardiogram test will be scheduled according to clinical practice. No biological material will be collected and stored. Thoraco-abdominal computed tomography is mandatory before surgery and evaluation with endoscopic ultrasound (EUS) is suggested. Moreover, information about patients’ anamnesis and primary tumour characteristics will be collected.

A computed tomography scan (CT scan) should be done 6 weeks after surgery and adjuvant treatment should start within 8 weeks from surgery. Histological examination after surgery is required in order to confirm clinical and radiological findings before surgery according to TNM.

Study endpointsEfficacy

The primary efficacy endpoint is disease-free survival. DFS is defined as the time from randomization to the date of first local relapse, distant relapse, peritoneal carcinomatosis, or death for any cause, whichever comes first. Patients alive and without relapse will be censored at their last disease evaluation.

The secondary efficacy endpoints are local recurrence-free survival (LRFS) and overall survival.

LRFS is defined as the time from randomization to the date of first local relapse, peritoneal carcinomatosis, or death for any cause, whichever comes first. OS is defined as the time from randomization to death for any cause.

Safety

The safety endpoints will be mortality 30 and 90 days from surgery, morbidity during and after surgery (graded according to the NCI-CTAE version 4.03 for AE related to chemotherapy and according to Clavien-Dindo for surgery complications) (34, 41–42), the number of post-surgery complications, the duration of surgery, the length of hospitalization, and the number of patients receiving the adjuvant chemotherapy.

Sample size

The sample size calculation considers the amount (15%) of patients with peritoneal carcinomatosis undetected by CT scan and discovered only during the surgical procedure. Since the primary endpoint will be analysed according to the ITT approach, no further loss of patients was hypothesized.

Patients will be randomized no more than 24 h before surgery if total resection of the tumour is intended, and a stratification procedure based on the centre and neoadjuvant chemotherapy will be used. Patients will be randomized in a 1:1 ratio. The randomization lists were prepared by the study statistician using the SAS system (version 9.4). Regarding the sample size, the calculation was based on the following assumption:

According to STATA Module ART (ART: Stata module to compute sample size and power for complex randomised trial designs with binary or time-to-event outcomes Abdel Babiker (a.babiker@ucl.ac.uk), Friederike Maria-Sophie Barthel (sophie@fm-sbarthel.de), Babak Choodari-Oskooei (b.choodari-oskooei@ucl.ac.uk), Patrick Royston (j.royston@ucl.ac.uk), Ella Marley-Zagar (e.marley-zagar@ucl.ac.uk), and Ian White (ian.white@ucl.ac.uk)), the number of required events is 200. Since the study is event driven, it will be stopped when this required number will be reached. In order to estimate the total sample size, we need to assume the duration of recruitment, the total study duration, and the drop-out rate.

If uniform accrual of 3 years and overall observation time of 6 years are assumed, 220 patients are required. This number has been furtherly increased to 240 to allow for a slower than expected accrual and a consequent longer accrual time, maintaining 6 years of total time. To consider also an overall dropout rate of approximately 15%, 282 patients need to be randomized.

Statistical analysis

Efficacy will be analysed on the modified intention to treat (mITT) population, including all patients randomized, without major violations of eligibility criteria and no evidence of peritoneal carcinomatosis (detected during surgery).

DFS and OS will be described with the Kaplan–Meier method. Differences between arms will be tested by the log-rank test and by univariate and multivariate Cox’s models, including stratification variables and other clinical-biological features as covariates. LRFS will be described with a cumulative incidence function and will be analysed with a Grey test to take account of the competing risks.

An interim analysis of efficacy will be done when half of the events have been observed. The conservative Haybittle-Peto boundary will be used as stopping guidance to ensure final analysis at the significance level of 0.049.

No imputation of missing data will be done.

Data collection, management, and analysis

Data will be collected using an electronic case report form (CRF). A data timing plan and data validation plan, developed by the statisticians and data managers of the coordinating centre, will be used to request data input (RID) in the electronic CRF and to check the data entered by data clarification forms (DCF). The sponsor maintains confidentiality standards by assigning a unique patient identification number to code.

Quality assurance

Each investigator will be responsible for ensuring data quality, as planned in the Data Validation Plan. Each item of information in the electronic CRF will be systematically checked for consistency, completeness, or incongruity by the Data Coordinating Center, which will issue DCFs in case of inconsistent data. Local quality control will be provided by the coordinating centre, which will be responsible for monitoring all the centres.

Monitoring the trial

During the trial, a sponsor’s representative will have regular contact with the study site, including visits to provide information and support for the investigator(s), confirm that the investigational team is adhering to the protocol, that data are being accurately and timely recorded in the eCRFs; to verify source data (comparison of the data in the eCRFs with the patient’s medical records at the hospital or practice, and other records relevant to the study) including verification of informed consent.

figure a

Authorized representatives of a regulatory authority or Ethics Committee may perform audits or inspections at the study centres, including source data verification.

Trial managementAdministrative structure

The coordinating centre is the Policlinico Universitario Agostino Gemelli IRCCS, Roma.

The sponsor is “Associazione Chirurghi Ospedalieri Italiani (ACOI)”, which has delegated the Mario Negri Institute for Pharmacological Research as the Data Coordinating Center for oversight of clinical operations, data management support, and clinical monitoring.

About 60 experimental centres are expected to participate. These centres have been selected based on the report and recommendation of the Italian National Agency for Regional Healthcare Services (AGENAS) with at least 30 surgeries for gastric disease per year. It will also be possible to include centres from other countries.

Independent data monitoring committee (IDMC)

An independent data monitoring committee (IDMC) comprising three international experts (one oncologist, one surgeon, and one statistician), not involved in the trial and with no conflict of interest with respect to the results, will monitor the progress of the trial from the ethical and scientific viewpoints. The IDMC will review the interim efficacy analysis and the safety reports in order to monitor toxicity. Based on this, the IDMC will provide recommendations to the study sponsor and the Steering Committee (SC).

Safety reporting

The collection, assessment, and presentation of safety reports will be carried out in accordance with the detailed guidance on the collection, verification, and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use (European Commission guidance on adverse reaction reporting (ENTR/CT3)).

Patients will be carefully monitored for any AE occurring during the trial conduct. Such monitoring also includes clinical laboratory tests. AEs will be assessed in terms of their seriousness, severity, and causal relation to the study treatment. Safety reporting to study investigators, ECs, and competent authorities will then follow in accordance with the results of such assessment.

Severity and seriousness will be independently assessed for each AE and recorded on the e-CRF.

Ethics approval, consent to participate, and dissemination

The trial will be conducted in accordance with the ethical principles set out in the Declaration of Helsinki and are consistent with ICH/Good Clinical Practice and regulatory requirements for participant data protection.

Prior to entering the study, patients will be given key information about the trial, verbally and in a written consent form. Patients are notified that they are free to withdraw from the trial at any time.

The use of participant data and biological samples is not intended for further ancillary studies.

The study has been approved by the Ethics Committee of the Università Cattolica, Policlinico Agostino Gemelli IRCCS (protocol IRFMN-GCC- 7813), Rome, and has been approved or is under evaluation by the Ethics Committees of all the participating centres. Any substantial amendment made to the protocol by the coordinating investigator is submitted to the local ethics committee and health authorities for approval, prior to implementation.

According to local and international regulations, the trial results are the property of the sponsor who will share them with all participating investigators. There is a commitment to post trial results in a public register 1 year after the trial is completed and to publish results, irrespective of the findings, in a peer-reviewed journal.

The sponsor maintains confidentiality standards by coding each patient enrolled in the study through assignment of a unique patient identification number.

Records and documents pertaining to the conduct of this study, including eCRFs, ICFs, and investigator site files (ISFs) must be retained by the principal investigator for at least 15 years after completion or discontinuation of the study or for the length of time required by relevant national or local health authorities, whichever is longer. After that period of time, the documents may be destroyed, participant to local regulations.

The sponsor of the study (ACOI) agrees with Istituto di Ricerche Farmacologiche Mario Negri IRCCS to take out adequate clinical insurance to cover its obligations, including but not limited to providing compensation to patients in the study suffering injury of death or loss caused by the administration of drugs or any clinical intervention or procedure in accordance with the relevant protocol and all legal requirements. All patients participating in this clinical trial will therefore be covered by a civil liability policy in accordance with the DM 14–07-2009.

Results derived from the trial are the property of the sponsor which shares them with all participating investigators and regulatory authorities. We plan to share the results with the scientific community and national gastric cancer patient associations.

Publications will be decided by the SC. Authors to be reported in the front page will be selected on the basis of the specific contribution or the number of enrolled patients and/or on the consistency, completeness, and accuracy of the data.

Standard for protocol publication

This clinical trial protocol follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. The trial is registered on clinicaltrial.gov (NCT039171730).

Patient and public involvement

Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

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