2.1 Setting
This is a single-center RCT at the Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Germany. It was initiated in February 2019 and recruitment is expected to last for 3 years. The study protocol was accepted by the independent Ethics Committee of the University of Heidelberg (registration number S-317/2017) before start of the study The trial was registered at DRKS under registration number DRKS00016773 on February 18th, 2019 (20). No Secondary Identifying Numbers such as a Universal Trial Number have been assigned. Recommendations of the SPIRIT (Standard protocol items: Recommendations for Interventional Trials) checklist (Additional file 1) were followed (21).
2.2 Patient recruitment
Recruitment exclusively takes place at the Department of General, Visceral, and Transplantation Surgery at University Hospital of Heidelberg in Germany. Possible participants will be screened for eligibility. To be eligible for the study, participants must be 18 years or older with a resectable primary malignancy in the distal esophagus including adenocarcinoma of the esophagogastric junction type 1 and 2 with curative intention and no apparent metastases. Participants with tumor localizations above the azygos vein, emergency situations such as major bleeding or perforation as well as metastasis or infiltration into adjacent tissue are excluded.
All eligible participants will be informed about either operation technique, as well as their potential benefits and side effects. Written informed consent will be obtained. Only patients who sign the informed consent form will be included. Reasons for exclusion from the MIVATE trial will be documented and explained in the screening form. Thereafter, patients will be randomized to the intervention arm (MIE with linear stapled anastomosis) or the control arm (OE with circular stapled anastomosis). For the duration of the treatment until discharge no concomitant interventions besides the in-house standards and study-related interventions are allowed.
2.3 Outcome measures
During the MIVATE trial (Figure 1), participants will be monitored before surgery, intraoperatively, on postoperative days (POD) 1-7 and on the day of discharge. Follow-up will be conducted on POD 30, as well as 3 months, 12 months, 36 months and 60 months postoperatively. During follow-up, patients will always complete a professionally administered questionnaire. Demographic and baseline clinical data, intraoperative findings and postoperative results will be recorded. To enhance participant retention and to avoid loss to follow-up, patients will be called during the follow-up period to remind them of scheduled visits and to arrange appointments. When a patient is not able to participate in a follow-up visit in person, questionnaires will be administered by telephone interview. Informed consent will be obtained and trial data will be collected by trained assessors by using CRFs and established questionnaires,
Table 1 | Trial visits.
Activity & Documentation
|
Visit 1
(screening)
|
Visit 2
(surgery)
|
Visit 3-9
(POD 1-7)
|
Visit 10
(discharge)
|
1. Follow-Up
(POD 30)
|
2. Follow-Up
(POD 90)
|
3.-5. Follow-Up
(POM 12, 36, 60)
|
inclusion & exclusion criteria and informed consent
|
x
|
|
|
|
|
|
|
biometric data (*1)
|
x
|
|
|
|
|
|
|
medical history & preoperative assessment (*2)
|
x
|
|
|
|
|
|
|
oncological baseline data (*3)
|
x
|
|
|
|
|
|
|
pain with VAS & analgetic management
|
x
|
x
|
x
|
|
|
|
|
ASA, ECOG, Revised Cardiac Risk Index, lung function
|
x
|
|
|
|
|
|
|
body weight
|
x
|
|
|
|
x
|
x
|
x
|
randomisation
|
x
|
|
|
|
|
|
|
surgery
|
|
x
|
|
|
|
|
|
surgical & anaesthetic documentation (*4)
|
|
x
|
|
|
|
|
|
documentation of complications:
|
|
|
|
|
|
|
|
|
Clavien-Dindo for CCI within 30 POD
|
|
|
x
|
x
|
x
|
|
|
Clavien Dindo for CCI within 90 POD
|
|
|
x
|
x
|
x
|
x
|
|
further complications (*5)
|
|
|
x
|
x
|
x
|
x
|
x
|
scores
|
|
|
|
|
|
|
|
|
QoR-15
|
x
|
|
x (on POD 7)
|
x
|
x
|
x
|
x
|
SF-36
|
x
|
|
|
x
|
x
|
x
|
x
|
EORTC QLQ-C30 and EORTC QLQ-OES18
|
x
|
|
|
x
|
x
|
x
|
x
|
perioperative course
|
|
|
|
|
|
|
|
|
length of (single-lung-) ventilation & extubation
|
|
x
|
|
|
|
|
|
epidural catheter management
|
|
x
|
x
|
|
|
|
|
hemodynamic medication
|
|
x
|
|
|
|
|
|
fluid management
|
|
x
|
|
|
|
|
|
blood gas analysis
|
|
x
|
|
|
|
|
|
blood count & CRP
|
x
|
|
x (selectively)
|
|
|
|
|
catheters (peridural, urine, central venous)
|
|
x
|
|
|
|
|
|
postoperative course
|
|
|
|
|
|
|
|
|
adherence to fast track protocol
|
|
x
|
x
|
|
|
|
|
gastric tube & drainage management
|
|
x
|
x
|
|
|
|
|
mobilisation
|
|
|
x
|
|
|
|
|
vegetative functions (passing stool)
|
|
|
x
|
|
|
|
|
wound healing / infection
|
|
|
x
|
|
|
|
|
diet
|
|
x
|
x
|
x
|
|
|
|
length of hospital stay & discharge
|
|
|
|
x
|
|
|
|
oncological & specific long-term
|
|
|
|
|
|
|
|
|
histopathological data (*6)
|
|
|
|
x
|
|
|
|
GI symptoms (*7)
|
|
|
|
|
x
|
x
|
x
|
adjuvant therapy
|
|
|
|
|
x
|
x
|
x
|
disease free survival
|
|
|
|
|
x
|
x
|
x
|
local recurrence
|
|
|
|
|
x
|
x
|
x
|
progession free survival
|
|
|
|
|
x
|
x
|
x
|
overall survival
|
|
|
|
|
x
|
x
|
x
|
(*1) including age, body height & sex
(*2) including medication & previous surgical intervention
(*3) including first diagnosis, cTNM status, location relative to Z-line & neoadjuvant chemo- or radiotherapy
(*4) including surgeons, experience, procedure, operation time, anastomosis, complications, conversion and drainages
(*5) including anastomotic leak, conduit necrosis, chyle leak & vocal cord injury according to ECCG and surgical site infection according to CDC
(*6) including entity, pTNM, grading and resection status, number of lymph nodes retrieved, number of tumor positive lymph nodes
(*7) including dysphagia & reflux
|
ASA American Society of Anesthesiologists classification, CCI Comprehensive Complication Index coding complications & related interventions according to the Dindo-Clavien classification, CDC Center for Disease Control & Prevention, CRP C-reactive protein, ECCG Esophagectomy Complications Consensus Group, ECOG Eastern Cooperative Oncology Group score, EORTC QLQ-C30 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, EORTC QLQ-OES18 Computerized adaptive test European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Esophageal Cancer, POD postoperative day, POM postoperative month, QoR-15 Quality of Recovery 15, SF-36 Short-Form 36, VAS visual analog scale of pain. The primary endpoint is displayed in gray.
2.3.1 Primary endpoint
The primary endpoint will be postoperative morbidity assessed as the comprehensive complication index (CCI) within 30 days after index operation (22), which enables to compare the severity of postoperative complications (23).
Postoperative morbidity is defined as any deviation from the normal postoperative course according to the Dindo-Clavien classification (24). Specifically, it includes anastomotic insufficiency or loss of anastomotic integrity verified by either CT scan with detection of contrast agent externally from the anastomosis within the abdominal or thoracic cavity, endoscopy or the detection of methylene blue in the drainage after oral application. Also, it includes pneumonia with radiological verification of pneumonic infiltrates and a minimum of 3 of 4 possible symptoms including a body core temperature above 37.5°C, purulent expectoration, leucocyte count above 12 000 or below 4 500 /ml or increased C-reactive protein (CRP) levels. Postoperative complications also include pancreatic fistula, which is defined by the International Study Group for Pancreatic Surgery (ISGPS) as the “drain output of any measurable volume of fluid with an amylase level >3 times the upper limit of institutional normal serum amylase activity, associated with a clinically relevant development/condition related directly to the postoperative pancreatic fistula”. The former grade A fistula is now called a “biochemical leak”, as it has no clinical relevance. Fistula grades B and C are defined more precisely. Grade B requires drains that are either left in place >3 weeks or repositioned. Grade C requires reoperation or leads to single or multiple organ failure (25, 26). Recommendations for reporting of complications after esophagectomy will be obeyed in order to improve comparability with future trials (27). Other aspects are postoperative bleeding with a hemoglobin relevant decrease beyond 3 g/dl or the necessity for transfusion of erythrocyte concentrates due to bleeding into the abdominal or thoracic cavity. Wound healing disorders with special wound treatment, abscess and lymphatic fistula caused by damage to the lymphatic system with leakage of chyle fluid into the cavities (defined as a milky-colored fluid from a drain, drain site, or wound on or after POD 3, with a triglyceride content ≥110 mg/dL respectively ≥1.2 mmol/L) also accounts for postoperative morbidity (28, 29). Further aspects are tracheal injuries with fistula between esophagus and trachea and loss of tracheal integrity as well as radiologically confirmed deep leg vein thrombosis and pulmonary embolism. Acute kidney failure in direct context to surgery defined as a doubling of plasma creatinine levels or necessity for hemodialysis as well as stroke and myocardial infarction are further criteria included in postoperative morbidity.
The CCI will be reported with mean and standard deviation.
2.3.2 Secondary endpoints
Secondary endpoints can be separated into short-term endpoints and long-term endpoints. Short-term endpoints include operation time, length of hospital stay, duration of stay on intensive or intermediate care unit (ICU), postoperative recovery assessed with QoL-15, postoperative pain assessed with the visual analog scale (VAS), the necessity for vasopressor agents for circulatory support, length of single-lung ventilation, number of days with invasive ventilation, fluid management, postoperative demand for analgesic drugs and levels of acute-phase proteins in the serum. The successful adherence to an already established fast-track protocol with several sub-categories will also be a secondary endpoint (Additional Table 1 & 2) (3, 30). Short-term oncological endpoints are number of removed lymph nodes and rate of R0-resections.
Long-term endpoints are QoL and oncological outcomes such as disease-free-survival, rate of local recurrence and overall-survival. QoL will be assessed with different questionnaires. SF-36 and CAT EORTC QLQ-C30 measure general aspects of health with scores ranging from 0 to 100 and with higher scores representing better well-being. CAT EORTC QLQ-OES18 assesses several aspects of esophageal function, ranging from 0 to 100 with lower scores indicating better function (31).
Extended details of the secondary endpoints can be found in Table 1. Several other scoring systems from other institutions have been included in the design of the MIVATE trail such as the surgical site infection classification according to the CDC (Center for Disease Control & Prevention) (https://www.cdc.gov/hai/ssi/ssi.html) (32), the ASEPSIS score for wound infection (33) and the standardization of data collection for complications associated with esophagectomy from the Esophagectomy Complications Consensus Group (ECCG) (27).
2.4 Standardized therapy and trial interventions
OE, hybrid esophagectomy and totally MIE with circular stapled anastomosis are established in single high-volume centers and described to have similar oncological outcomes (14, 34, 35). In the present study, the singularizing aspect is the linear side-to-side stapled anastomosis derived from bariatric surgery where it is established as a technique with excellent risk-benefit ratio and low anastomotic stricture rate compared to circular stapled and hand-sewn anastomosis (34, 35).
In the present study, for both interventions intubation is done with a double lumen tube and patients receive antibiotic prophylaxis perioperatively with Ampicillin-Sulbactam (3 g single-shot) or other in case of allergies. Surgery starts with the abdominal part.
In case of open surgery, the patient is placed in „Crawford“-position. After median laparotomy, the surgeon performs inspection of the abdominal cavity to ensure the absence of metastases and peritoneal carcinomatosis. Subsequently, the bursa omentalis is opened through incision of the gastrocolic ligament. After dissection of the Aa. gastricae breves with preservation of gastroepiploic arcade, preparation is performed up to the splenic hilus and to the left crus. The gastric conduit is formed through the application of linear staplers (Endo-GIA stapler with Tri-Staple Technology® from Medtronic®, Dublin, Ireland) alongside the lesser curvature and the separation of the distal esophagus. Additional sutures secure the integrity of the staple line. Lymphadenectomy (LAD) is following alongside the splenic artery (station 11) and around the coeliac trunk and the common hepatic artery (station 8-9). Cholecystectomy is usually performed. LAD is continued in transhiatal direction towards both crura of the diaphragm into the lower mediastinum. During this process, both pleurae are opened and partly resected. Ventral border for LAD is the pericardium, while dorsal resection is limited by the aorta. The gastric conduit is placed transhiatally for later transposition and the abdomen is preliminary closed.
For the thoracic part, the right lung is vented and a right-lateral thoracotomy is performed. The azygos vein is separated and LAD is performed following the very same. The thoracic duct is clipped and separated and LAD is performed down the aorta. Infratracheal lymph nodes are resected and the esophagus is proximally transected with a linear stapler. The specimen is retrieved and sent for pathohistological assessment. Frozen sections are usually obtained from the proximal resection line.
The formation of an end-to-side esophagogastrostomy starts with the transection of the esophagus at the resection line and the insertion of the circular stapler anvil with the size chosen depending on the anatomic situation. The size of the anvil is usually 25 or 28 mm (preferably) in diameter and as large as possible in order to prevent strictures. The anvil is positioned and fixed with a purse-string suture. The gastric conduit is now moved towards the anastomotic site in the thoracic cavity and incised distally in order to insert the circular stapler shaft. After the stapling process for the creation of the end-to-side anastomosis, the inserting incision on the ventral side of gastric conduit is closed with another linear stapler. A toluidine blue test is performed to check for anastomotic integrity. Finally, a Robinson drainage (16 Chr) is used as a target drainage and placed in front of the anastomosis followed by bilateral Bülau drains (24 Ch). The thoracotomy is closed with sutures and an EasyFlow-Drainage can be placed intraabdominally close to the upper pancreatic margin upon preference of the surgeon. The laparotomy is then finally closed with sutures.
The technique of MIE used within this study has recently been shown in detail elsewhere (36). The patient is first placed in “French”-position. After left paramedian skin incision and the insertion of a 12 mm optical trocar, a pneumoperitoneum is established with a pressure of 15 mmHg. After insertion of further trocars (2 x 5mm, 2 x 12mm) as well as a subxiphoidal Nathanson liver retractor, surgery continues as described above. Single button sutures are used on the crossing sites of the linear stapler lines as opposed to the continuous sutures covering the whole linear stapler lines in the open approach and facilitate manipulation of the gastric conduit. Placement of an abdominal drain is optional. For the thoracic part, the patient is placed in left lateral decubitus position. After insertion of a 12 mm optical trocar below the right scapula, a pneumothorax is established with a pressure of 8 mmHg and further working trocars (3 x 12mm) are placed under permanent visual control. Further surgical steps are identical to the open approach. The specimen is then put into an 800 ml-retrieval bag and evacuated via a 4 cm incision along the 11th intercostal space.
The formation of a side-to-side esophagogastrostomy starts with the incision of the esophageal stump in the middle of the linear stapler line under continuous counterpressure through a 42-French-esophageal-tube. The gastric conduit is positioned atraumatically by exclusively moving it via the vicryl sutures. It is now incised 5 cm away from the oral stapling margin and a 45 mm linear tristapler is inserted into both incisions entering only 3 cm into both luminae at the same time. The incomplete insertion of the stapler leaves a length of 2 cm between distal staple line and anastomosis. After the stapling process, the remaining aperture is closed with a two-layer continuous suture with Stratafix® (Ethicon Endo-Surgery®, Cincinnati, Ohio, USA). Thoracic drains are inserted as in the open approach.
For standardization purposes surgeons performing this type of surgery for following trials must have surpassed the learning curve which is described to last until at least 50 esophagectomies with the specific technique (37, 38). This is clearly relevant in order to reduce surgeon-related influences as it could be shown by Nimptsch in 2018 that the mortality rate after esophageal surgery was lower in centers with high case numbers compared to those with very low case numbers with an OR[CI] of 0.50 ([0.42; 0.60]). Among patients who had complications the in-hospital mortality[CI] was 12.3% [11.1; 13.7] in hospitals with very high case numbers compared to 20.0% [18.5; 21.6] in hospitals with very low case numbers, indicating that the quality of treatment for patients undergoing esophageal resection could be improved if more patients were treated in hospitals with high case numbers (2). Therefore, an expertise-based design was chosen for the MIVATE trial and only the single most experienced surgeon of the center for the respective technique is performing trial surgeries.
2.5 Modification of the protocol
The current protocol version from March 2020 is the protocol the trial was initiated with (protocol version 1.0). In case of protocol amendments, these will be submitted to the ethics committee for approval and no further recruitments will take place until the modifications are accepted.
2.6 Assessment of safety and termination criteria
All adverse events will be documented and analyzed because complications form the study’s primary endpoint in the form of the CCI. Participants will be excluded from the study if they withdraw their consent to participate in the trial. A participant may withdraw consent at any time without explanation and without affecting further medical care. The principal investigator may terminate the trial at any time in consultation with the key research associates and the biostatistician. Possible reasons for termination include high morbidity or mortality rates and any indication of potential health hazards caused by either the study treatment or external factors. In case of intraoperative complications in the minimally invasive group, there might be the need to convert to open surgery. In the case of intraoperatively identifying advanced and irresectable disease, there will be a change to palliative treatment strategies. There are no other criteria for modifying or discontinuing treatment.
2.7 Randomization and blinding
A random allocation sequence has been generated by computer through block-randomization prior to the start of the trial by an independent third party. These allocations have then been put in sequentially numbered, sealed, opaque envelopes and are opened prior to the patient’s surgery. Block sizes of 4, 6 and 8 were used in a variable order. After informed consent, patients will be enrolled by trial-trained physicians and randomized to the intervention or control group on the day before surgery. Allocation is performed by opening these envelopes containing cards displaying “Endoscopic” or “Open.
Blinding of study contributors (39): No attempt will be done to blind patients and the access sites will be covered with standard wound dressings until discharge. The blinding of the operating surgeon is not possible. The severity of pain and rescue analgesic will be evaluated by anesthesiologists otherwise not involved in the study (data collectors). All cases are reviewed regarding the primary endpoint by a neutral outcome assessor. The statistical analysis will be performed according to the outlined protocol; no additional attempts are made to blind the statistician as this will have no influence on the predefined statistical analysis of previously recorded and saved data.
2.8 Data management
All data will be collected and recorded in case report forms (CRFs) by an investigator before transfer to the data management center. Personal information about potential and enrolled participants will be collected, shared, and maintained with third-party only after pseudonymization in order to protect confidentiality. All demographic and baseline clinical data, as well as primary and secondary outcome measures, will be recorded in the CRF. To promote data quality there will be automated checks for double data entry and value ranges. To ensure patient confidentiality, the CRF for each patient will be given an anonymous allocation number. We will obtain permission to continue follow-up and data collection in the event of withdrawal from the study. The responsible investigator must review and sign all completed CRFs.
2.9 Statistical methods
2.9.1 Sample size
The sample size calculation is based on the primary endpoint “postoperative morbidity measured with the CCI until POD 30”. MIVATE is a superiority trial. The null hypothesis claims that the minimally invasive approach is not superior to open surgery in terms of CCI. The alternative hypothesis claims that the minimally invasive approach is superior to open surgery in terms of CCI within POD 30. A decrease of the CCI by 10 points between the minimally invasive and open group is considered relevant by patients and clinicians and a standard deviation of 10 is assumed based on in-house data leading to an effect size d of 1,0. There are no studies explicitly indicating the standard deviation of the CCI after esophagectomy.
Based on a t-test with a two-sided significance level of α = 0.05, a sample size of n = 34 patients (17 per group) is required in the analysis dataset in order to achieve a power of 80% (calculations performed with Prism 8.0, G*Power and SPSS). To compensate for early trial termination, drop-outs & loss-to-follow-ups further 15% of patients will be randomized leading to a total randomization & allocation size of 40 patients (20 per group). The number of patients to be screened and assessed for eligibility (n = 200; 100 per group) was calculated with an assumed 20% of exclusions due to exclusion criteria and a 75% of interfering circumstances (200 x 0,8 x 0,25 = 40; 20 per group). These interfering circumstances are due to the fact that MIVATE is an expertise-based trial which only allows the institution’s single best surgeon for each allocated technique. Consequently, both surgeons have to be available at the time of randomization which is not possible in 3 of 4 cases.
Screened & assessed for eligibility (n = 200; 100 per group)
Allocated to trial & analysed for intention-to-treat dataset (n = 40; 20 per group)
Per-protocol & as-treated dataset (n = 34; 17 per group)
There will be regular meetings by the investigators every 3 months in order to optimize recruitment and ensure sufficient enrolment.
2.9.2 Statistical analysis
Superiority of the intervention versus the control will be assessed using a two-sided t-test. The primary analysis will be based on the intention-to-treat population. If values do not display normal distribution the Mann-Whitney-U-Test will be used. A per protocol and an as treated set will be evaluated as a sensitivity analysis. Missing data for the primary outcome variable will be replaced by using imputation (40). The primary analysis will test the following hypotheses:
H0: CCIopen ≤ CCIminimally invasive
H1: CCIopen > CCIminimally invasive
CCIopen and CCIminimally invasive are the mean of the indices of both groups at different time points.
All secondary outcomes will be evaluated descriptively, and descriptive p-values are reported. All analyses will be done using SPSS, SAS & R. A detailed statistical analysis plan is developed prior to the analysis of the trial results in order to guarantee for neutrality during the analysis.
There will be no interim analysis for the primary endpoint. However, the primary endpoint will be analyzed as soon as all relevant data has been obtained. There will be interim analyses for the secondary endpoints.