preSponge RCT Protocol (preliminary version)
Preemptive endoluminal negative pressure therapy at the anastomotic site in minimally invasive transthoracic esophagectomy – An international multicenter randomized controlled trial
Anastomotic leakage after esophagectomy occurs in 10 – 30% of patients undergoing total minimally invasive transthoracic esophagectomy (ttMIE) and is highly associated with a significantly prolonged postoperative hospital stay as well as with a fatal outcome. Endoluminal negative pressure therapy of anastomotic leaks has a high success rate of 85-90% and represents the current gold standard of care for this condition. Negative pressure therapy has various effects on the wound site (e.g. reduction of wound secretion and edema, improving microcirculation, inducing granulation tissue) and may prevent formation of anastomotic leaks if applied in a preemptive setting during esophagectomy upon completion of esophago-gastrostomy.
The aim of the preSponge RCT will be to assess the potential protective effects of preemptiveendoscopic negative pressure therapy (ENP) on postoperative morbidity in high-risk patients undergoing ttMIE, as reflected by the total postoperative length of stay up to 90 days of follow up.
This international multicenter preSponge RCT will consist of two parts. In both parts, patients will be randomized into either conventional ttMIE or ttMIE with intraoperative preemptive endoscopic negative pressure therapy (ENP). First, a feasibility trial will be conducted in the 40 enrolled patients from all participating centers in order to assess feasibility and safety. If the results are encouraging, according to the external data monitoring committee, we will proceed with the completion of the formal RCT.
Feasibility and Safety phase
Feasibility will be assessed by recording the numbers of eligible patients of the whole targeted population, the recruitment rates, the refusal rates for participation, the retention and follow-up rates as the participants move through the feasibility phase, and the adherence rates to study procedures, intervention attendance, and engagement.
Safety will be assessed with any event of sponge-displacement, dislocation or intolerability will be recorded up to 90 days postoperatively. Morbidity will be assessed by the Clavien-Dindo Classification of postoperative complications as well as with the novel Comprehensive Complication Index (CCI). During the 90-day follow up, the anastomotic stricture rate, as a possible adverse event of the ENP therapy, will be also recorded. Finally, the 90-day hospital readmission rate and mortality will be also recorded.
The preSponge RCT pilot study is designed to provide us with estimates of the probable effect of ENP on the reduction of the postoperative length of stay, enabling us to calculate an adequately powered sample size for our formal preSponge RCT.
Formal preSponge RCT
The primary outcome measure will be the total length of postoperative hospital stay up to 90 days of follow up. Secondary outcome measures include complications, length of intensive care unit stay, hospital readmission rates, anastomotic stricture rate, mortality rates and patient satisfaction until 90 days after surgery.
- Adult patients with resectable esophageal cancer (adenocarcinoma or squamous cell carcinoma) with high operative riskscheduled for ttMIE (robotic-assisted or laparoscopic and thoracoscopic) will be included.
- Eligible high-risk patients must have at least oneof the following comorbidities:
- ASA score >2
- Diabetes (insulin dependent or HbA1c ≥ 6.5%)
- Chronic pulmonary disease (FEV1/FVC ratio <70%)
- Heart failure (LVEF <55%)
- Preexisting cardiac arrhythmia (pacemaker or paroxysmal supraventricular tachyarrhythmia)
- Chronic kidney disease stage 4-5 (GFR < 30ml/min/1.73 m2)
- Chronic liver disease with treated portal hypertension (porto-caval pressure gradient >5-≤10mmHg, including patients after TIPS)
- Previous radiation or radio-chemotherapy >50 Gy (salvage esophagectomy
- Alternatively, eligible high-risk patients must have at least twoof the following comorbidities:
- Arteriosclerosis score ≥ 2 according to van Rossum et al.(aorta and coeliac axis)
- Malnutrition (BMI ≤ 18.5 kg/m2)
- Obesity (BMI ≥ 35 kg/m2)
- Heart failure with preserved ejection fraction (LVEF >55%)
- Active or former smoking
- Age > 65 years
- WHO/Zubrodt score > 1
- Chronic kidney disease stage 2-3 (GFR 30-89 ml/min/1.73 m2)
- Chronic liver disease without portal hypertension (porto-caval pressure gradient ≤5mmHg)
- Patients unable to follow the study procedures
- Patients under 18 years of age
- Patients scheduled for esophagectomy for benign disease
- Patients scheduled for open, hybrid or transhiatal esophagectomy
- Chronic liver disease with portal hypertension (porto-caval pressure gradient >10mmHg)
- Distant organ metastasis (cM+)
- Planned additional major organ resection (pancreas, liver, lung)
Study Product / Intervention
Endoscopic negative pressure therapy (ENP) will be performed immediately upon completion of the esophago-gastrostomy intraoperatively, but no later than 12 hours after the start of the surgical intervention. The sponge is positioned under gastroscopic guidance via an overtube at the level of the esophago-gastrostomy. All procedures will be videotaped and saved for further assessment. ENP will be maintained for 5 (4-6) days and will be monitored with clinical parameters (suction rate, leak rate, routine laboratory values, repeated routine chest x-rays, dislocation). Discontinuation of ENP therapy requires endoscopic removal of the Eso-SPONGE®. During sponge removal, the anastomosis will be checked for patency and documented with a standard protocol including video and pictures.
For ENP, an Eso-SPONGE® size 1 (overtube inner diameter: 13mm, outer diameter 17mm) or size 2 (overtube inner diameter: 15mm, outer diameter 19mm) system will be inserted. Eso-SPONGE® consists of an open-pored polyurethane foam fitted to a gastric tube. Secretions are then continuously evacuated using a suction pump generating a negative pressure of 75 mmHg.
For the feasibility study, we are aiming at including 40 consecutive patients in total from all centers (approximately 10-20 cases from 4-6 centers). For the formal preSponge RCT, additional patients will be needed according to the sample size calculation generated from data from the feasibility and safety study.
Sponsor / Principal-Investigator
Prof. Dr. med. Christian A. Gutschow
Department of Surgery
University Hospital Zurich
Raemistrasse 100, 8091 Zürich, Switzerland
Dr. Dimitri A. Raptis, MD, MSc, PhD
Department of Surgery
Royal Free Hospital
Pond Street, NW3 2QG, London, United Kingdom