Pain and Opioid Consumption After Laparoscopic Versus Open Gastrectomy for Gastric Cancer: A Secondary Analysis of a Multicenter Randomized Clinical Trial (LOGICA-Trial)

Background Laparoscopic gastrectomy could reduce pain and opioid consumption, compared to open gastrectomy. However, it is difficult to judge the clinical relevance of this reduction, since these outcomes are reported in few randomized trials and in limited detail. Methods This secondary analysis of a multicenter randomized trial compared laparoscopic versus open gastrectomy for resectable gastric adenocarcinoma (cT1-4aN0-3bM0). Postoperative pain was analyzed by opioid consumption in oral morphine equivalents (OME, mg/day) at postoperative day (POD) 1–5, WHO analgesic steps, and Numeric Rating Scales (NRS, 0–10) at POD 1–10 and discharge. Regression and mixed model analyses were performed, with and without correction for epidural analgesia. Results Between 2015 and 2018, 115 patients in the laparoscopic group and 110 in the open group underwent surgery. Some 16 patients (14%) in the laparoscopic group and 73 patients (66%) in the open group received epidural analgesia. At POD 1–3, mean opioid consumption was 131, 118, and 53 mg OME lower in the laparoscopic group, compared to the open group, respectively (all p < 0.001). After correcting for epidural analgesia, these differences remained significant at POD 1–2 (47 mg OME, p = 0.002 and 69 mg OME, p < 0.001, respectively). At discharge, 27% of patients in the laparoscopic group and 43% patients in the open group used oral opioids (p = 0.006). Mean highest daily pain scores were between 2 and 4 at all PODs, < 2 at discharge, and did not relevantly differ between treatment arms. Conclusion In this multicenter randomized trial, postoperative pain was comparable between laparoscopic and open gastrectomy. After laparoscopic gastrectomy, this was generally achieved without epidural analgesia and with fewer opioids. Trial Registration NCT02248519. Supplementary Information The online version contains supplementary material available at 10.1007/s11605-023-05728-3.


SUMMARY
Rationale: Gastric cancer is a life-threatening disease with an incidence of 2.000 in the Netherlands.Surgical resection is the cornerstone of curative treatment.In the Netherlands this procedure is mainly performed by open surgery, whereas our recent meta-analysis of cohort studies showed that laparoscopic gastrectomy is associated with reduced intraoperative blood loss, reduced postoperative complications and shorter hospital stay.
These benefits were at the cost of longer operative time.However, thus far all studies were performed in an Asian population containing a large percentage of T1-2 tumors.There is no RCT in a Western population with locally advanced gastric cancer.In the Netherlands experience with laparoscopic gastrectomy has increased in the last years, with now more than 5 centers performing this type of operation on a routine basis.We have trained this Laparoscopic gastrectomy was demonstrated to be safe in our own series of 30 patients treated in the UMC Utrecht as well as in our recent meta-analysis of the literature.

Gastric cancer treatment
Gastric cancer is the fourth most prevalent malignancy worldwide (1).In the Netherlands approximately 2.000 patients are newly diagnosed every year (2).Half of these patients are eligible for surgery.The 5-year survival rate is 45% after curative resection (3).Perioperative chemotherapy is now the standard of care as it has shown to increases 5-year survival with another 10% (4).

OBJECTIVES
The aim of this study is to prospectively compare laparoscopic versus open gastrectomy in patients with gastric cancer by means of a randomized controlled trial.
Primary outcome measure: • Postoperative hospital stay Secondary outcome measures: • Cost-effectiveness • Oncologic outcome • Postoperative morbidity and mortality • Quality of Life • Readmissions

Design
The study design is a non-blinded multicenter prospectively randomized controlled trial.
Analysis will take place on an intention-to-treat basis.
The participating patients are randomized for one of the 2 treatment arms.The experimental arm consists of the laparoscopic approach, whereas the control arm is the comparison to the conventional surgery, consisting of the open approach (figure 2).

Duration
The duration of the study will be 3 years of inclusion + 5 years follow-up.

Setting
This study takes place in a hospital setting.Recruitment of patients will occur at the outpatient clinic.Participating patients will receive either laparoscopic (experimental arm) or open (conventional surgery) gastrectomy at the surgical theater.Postoperative care takes place at the surgical ward of the participating hospitals.

Quality of Life
The regular postoperative care for patients that undergo a gastrectomy for gastric cancer consists of an annual outpatient visit for the follow-up period of 5 years.This visit is used to check for signs of recurrence of disease and metastases, as well as long term complications.
In addition to this standard care quality of life questionnaires will be sent to the patients home address to check the long term effects of the surgical procedure.

Cost-effectiveness
To evaluate the cost-effectiveness of both study procedures, an important secondary study parameter, medical costs will be related to productivity and quality of life.All medical costs related to the study procedure will be collected up to five years after the operation.Quality of life will be measured as mentioned above.Furthermore, study participants will be asked to fill in the questionnaire SF-HLQ to measure the productivity after surgery (appendix 3).An expert from the UMC Utrecht Julius Center will do the final cost-effectiveness analysis.

Blood samples
Blood samples will be drawn at baseline, 6 hours postoperatively and on postoperative day 2. The aim is to monitor the CRP, leukocytes, haemoglobin and a panel of interleukines production to obtain an indication of the inflammatory response during the early postoperative course.

Biobanking
As part of a biobank side study the patients will be asked to donate body material.This will include blood samples (2x 10 ml), and tumor tissue (4x 0,5 cm³).The blood samples will be obtained during regular preoperative diagnostics and daily on the day of surgery until the fifth day after surgery.These extra blood samples will be analyzed on a broad panel of markers which may predict anastomic leakage in an early state.The tumor tissue will be obtained by the pathologist after tumor resection.After informed consent, these materials will be stored for an indefinite time in the UMC Utrecht Biobank for future studies on biomarkers and genetics to predict disease progress.

Overview of activities
In addition to the follow-up moments mentioned in the table above, one quality of life questionnaire, the productivity questionnaire and the health care use questionnaire (appendix 3) will be sent 3 months and 9 months after surgery for a complete costeffectiveness analysis.

Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all of the following criteria:

Exclusion criteria
A potential subject who meets any of the following criteria will be excluded from participation in this study:

TREATMENT OF SUBJECTS
The investigational surgery is the laparoscopic gastrectomy (distal and total).The conventional surgery treatment consists of conventional open gastrectomy (distal and total).Both techniques are described underneath.
Patients will receive a distal gastrectomy or total gastrectomy, depending on tumor location on preoperative diagnostics (Endoscopic ultrasonography [EUS], gastroscopy and CT-scan).
For tumors located in the antrum a distal gastrectomy will be performed, whereas for tumors located in the corpus, and diffuse gastric cancer, a total gastrectomy will be performed (13).
Basic summary of the surgical procedure: • Distal gastrectomy with D2 lymph node dissection (figure 3) • Total gastrectomy with D2 lymph node dissection (figure 3) Several types of reconstruction types can be performed (i.e.jejunal pouch or no pouch), according to the preference of the surgeon.Also the type of anastomosis (i.e.end-to-end, end-to-side or side-to-side) either stapled or hand sewn may be performed according to the individual surgeon's insight.Incision:

•
The incisions have to be muscle-sparing.The length of the mini-laparotomy (≤5 cm), for the laparoscopic procedure, and the length of the laporotomy for the open procedure, have to be noted on the CRF.
Surgical Quality Control A selected number of trained surgeons will perform both types of surgery.Hereby we maintain quality of the operations and minimize differences in success rates for both groups.
The participating centers have completed their learning curves (n≥20) for laparoscopic gastrectomy, since this may affect morbidity and mortality.
It is of great importance that all participating surgeons perform both the open and the laparoscopic procedure in a similar fashion.To ensure this, all selected surgeons participated in the course "One day course on minimally invasive gastrectomy", which is organized at the UMC Utrecht.The yearly course has been given at 01-11-2012 and 27-06-2013, and is also scheduled for March 2014.During the course an extensive explanation of the laparoscopic technique is combined with practical hands-on gastrectomy session on human cadavers.The surgeons are instructed by the principal investigators (RvH and JR) of this study.
To ensure consistency in techniques between the participating centers, a proctor will supervise, or systematically review the videos of 2 2 laparoscopic proceduresfrom all centers.
Total gastrectomy: The patient is positioned in supine position under general anaesthesia.The conventional open total gastrectomy is performed by means of an upper midline laparotomy.In case of the laparoscopic procedure, 5 ports are used: a camera port (10mm) , two working ports (5mm) , an assisting port (5mm) and a port (12mm) for the liver retractor.Placement of all ports is done according to the surgeons preference.The minor and greater curvatures of the stomach are dissected.The left gastric artery and vein are transected at their origin.Next, the right gastroepiploic artery and the right gastric artery are transected at their origin.The postpyloric duodenum is cleaved by means of a linear endostapler.Subsequently, the distal esophagus is dissected from the left and right crus and mobilized.At the distal esophagus 2 support sutures are placed to pull the esophagus into the abdominal cavity, after which the distal oesophagus is cleaved.Frozen section histology of the tumor resection planes is performed to assess the radicality of the resection.Optional frozen section histology can be performed for detection of local tumor invasion and metastases.The greater omentum is resected for future side-studies.Subsequently, a transverse incision is performed to take out the stomach and greater omentum (figure 1, A).A hand-sewn jejuno-jejunostomy is created.
Next, the actual esophagojejunostomy is performed.The formation of a jejunal pouch and the placement of a feeding jejunostomy should be performed according to the local hospital's policy.

Distal gastrectomy
The conventional open distal gastrectomy is performed by means of a midline laparotomy.
For laparoscopy, first a pneumoperitoneum is obtained by introducing the first trocar under direct visual control.This trocar is placed in the umbilicus.The next four trocars can be placed according to the surgeon's preference.The minor omentum is opened.Next, the greater curvature of the stomach is prepared.The gastrocolic ligament is divided at 3 cm distal to the gastroepiploic artery, after which the greater curvature is skeletonized up to the gastrosplenic ligament.The right gastroepiploic vein and artery are clipped at its origin.Next the right gastric vessels are clipped.The duodenum is divided distally at 1 cm distal to the pyloric sphincter.The proximal side of the stomach is divided at least 6cm above the tumor.Partial omentectomy is performed in the area of the antrum.The removal of the resected specimen occurs via a mini-laparotomy (max.5-6 cm), which can be located according to the surgeon's insight.The minilaparotomy must be muscle sparing as describes above.Finally, a Roux-en-Y gastrojejunostomy is performed.

Lymphadenectomy
Lymph node dissection will be performed based on the Dutch oncologic guidelines and Japanese gastric cancer treatment guidelines (13)(14)(15).For D2 lymphadenectomy no pancreato-splenectomy is performed since this is associated with high post-operative morbidity and mortality (3).Furthermore, lymph node station 10 is not dissected during total gastrectomy since it is technically difficult and associated with poor prognosis when affected (3,13).Lymph node stations 1, 3, 4d, 4sb, 5-9, 11p and 12a are dissected during distal gastrectomy.Lymph node stations 1-3, 4d, 4sa, 4sb, 5-9, 11p, 11d and 12a are dissected during total gastrectomy.All lymph node stations will be marked by the surgical team and presented to the pathologist for evaluation. Diagnostics: • Gastroesophagoscopyand biopsy for histopathologic analysis (PA).

Preoperative policy
• Preoperative nutrition will be given to patients with >10% weight loss the last 6 months or a BMI <18kg/cm 2 , according to the 2009 European Society of Clinical Nutriorion and Metabolism (ESPEN) guidelines (16) .

Postoperative policy
To ensure fast recovery, the ERAS protocol is followed.A consensus meeting between the participating centers is organized to discuss the pre-and postoperative protocol (17).

•
Epidural analgesia will be given following open gastrectomy only.Other analgesia can be given without limitations to reach adequate pain control.

•
Urinary catheterization can be done when indicated.
• Enteral feeding via a jejunostomy catheter can be given to patients who underwent total gastrectomy, according to the local hospital's policy.No jejunostomy catheter will be placed following distal gastrectomy.

•
At postoperative day 1, patients will be encouraged to start liquid oral feeding.

•
Mobilization under supervision of a physiotherapist starts as soon the patient is stable.

•
Nasojejunal tubes for decompression will not be used (17).
However, the treating physician may implement a deviation from the protocol to avoid causing any harm or if there is a safety hazard to trial subjects without prior approval from the ethics committee.

Main study parameter/endpoint
• Postoperative hospital stay (days) The following criteria have to be met: • Adequate pain control with oral pain medication • Intoxications

Perioperative chemotherapy
Postoperative outcomes: • Operation characteristics: - • Overall survival • Disease free survival (absence of local or distant recurrence) • Patients experience: -Pain: VAS-score (see appendix 4) -Time to return to daily activity (days) -Time to return to normal nutritional regime (days) • Weight at day 5 after surgery or at discharge in case of discharge before day 5.

Randomisation, blinding and treatment allocation
After completion of preoperative chemotherapy and signing informed consent at the outpatient clinic, participants will be randomized by means of an online random number generator, stratified by centre.Randomization will be performed by the coordinating investigator and directly provided to the participating centres.The data-analyst will be blinded for the procedure.

Study procedures
Patient will undergo one of the following surgical procedures: Laparoscopic gastrectomy: n= 105 Open gastrectomy: n= 105 Additional measures:

Withdrawal of individual subjects
Subjects can leave the study at any time for any reason if they wish to do so without any consequences.The investigator can decide to withdraw a subject from the study for urgent medical reasons.Subjects not undergoing the allocated treatment (e.g.intraoperatively unresectable tumor) due to medical reasons will not be withdrawn from the study unless the subject requests to do so.Participants will be analysed in an intention-to-treat model.

Replacement of individual subjects after withdrawal
Study participants will be replaced by newly recruited and randomized subjects in case of withdrawal before surgery, in order to meet the sample size requirement.Patients who withdraw after hospital discharge will not be replaced.

Follow-up of subjects withdrawn from treatment
Patients who withdraw from the study will be followed-up until moment of withdrawal.

Inclusion of additional patients
For subjects not undergoing the allocated treatment (e.g.unresectable tumor) due to medical reasons, additional subjects will be included in the study to reach the calculated sample size (n=210).

Pre-operative Post-operative
Blood sample for biobanking and baseline Blood 6h postoperatively and on postoperative day 2.
VAS-score for pain and vital signs during hospital stay QoL assessment Groningen Frailty Indicator Score SNAQ score QoL assessment and VAS scores for pain at 6 weeks, 3, 6, 9 monhts and 1-5 year after surgery.Productivity assessment (SF-HLQ questionnaire) Health care use (questionnaire appendix 3)

Section 10 WMO event
In accordance to section 10, subsection 1, of the WMO, the investigator will inform the subjects and the reviewing accredited METC if anything occurs, on the basis of which it appears that the disadvantages of participation may be significantly greater than was foreseen in the research proposal.The study will be suspended pending further review by the accredited METC, except insofar as suspension would jeopardise the subjects' health.The investigator will take care that all subjects are kept informed.

Adverse events (AEs)
Adverse events are defined as any undesirable experience occurring to a subject during the study, whether or not considered related to allocated surgery.All adverse events of a modified Clavien-Dindo classification grade 2 and higher and reported spontaneously by the subject or observed by the investigator or his staff, will be recorded starting from the day of surgery until the start of adjuvant therapy or up to 3 months after surgery.Events occurring outside of this period are not expected to be related to the study intervention, but more likely to (neo)adjuvant treatment or disease progression.

Serious adverse events (SAEs)
A serious adverse event is any untoward medical occurrence or effect that at any dose: results in death; is life threatening (at the time of the event); -requires hospitalisation or prolongation of existing inpatients' hospitalisation; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; -Any other important medical event that may not result in death, be life threatening, or require hospitalization, may be considered a serious adverse experience when, based upon appropriate medical judgement, the event may jeopardize the subject or may require an intervention to prevent one of the outcomes listed above.The SAE's that will be reported during this study are SAE's occurring starting from the day of surgery until the start of adjuvant therapy or up to 3 months after surgery.
Events occurring outside of this period are not expected to be related to the study intervention, but more likely to (neo)adjuvant treatment or disease progression.
The local coordinating investigator per centre is responsible for reporting the SAEs to the sponsor.The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited METC that approved the protocol, within 3 months after the sponsor has first knowledge of the serious adverse reactions by means of a periodical overview SAEs that result in death should be reported expedited.The expedited reporting will occur not later than 7 days after the responsible investigator has first knowledge of the adverse reaction.This is for a preliminary report with another 8 days for completion of the report.

Annual safety report
Not applicable.

Follow-up of adverse events
All AEs will be followed until they have abated, or until a stable situation has been reached.Depending on the event, follow up may require additional tests or medical procedures as indicated, and/or referral to the general physician or a medical specialist.SAEs need to be reported till end of study within the Netherlands, as defined in the protocol

Data Safety Monitoring Board (DSMB)
The stop-criteria are: • <70% complete resection without tumor residual in the proximal or distal surgical resection plane (R0) in one or both arms, • >50% less than 10 lymph node harvested in one or both arms.A data safety monitoring board will be assigned to evaluate the outcomes at 105 patients.
A DSMB is established to perform ongoing safety surveillance and to perform interim analyses on the safety data.This committee is an independent committee, which is composed of (names will be determined at a later stage).
None of the members have a conflict of interest with the sponsor of the study.
Criteria on which the DSMB may decide to terminate the trial prematurely: • Clear evidence of benefit of laparoscopic gastrectomy • Clear evidence of harm of laparoscopic gastrectomy • External evidence, such as other trials or published data, not available during the start of this trial.
The advice(s) of the DSMB will only be sent to the sponsor of the study.Should the sponsor decide not to fully implement the advice of the DSMB, the sponsor will send the advice to the reviewing METC, including a note to substantiate why (part of) the advice of the DSMB will not be followed.

STATISTICAL ANALYSIS
Subjects will be analysed by means of an intention-to-treat model.

Primary study parameter
The primary outcome measure is postoperative hospital stay.This variable is expected to have a non-Gaussian distribution and will therefore be analysed by means of a Mann-Whitney-U test in univariate analysis.

Secondary study parameters
Binary variables will be displayed in cross-tabulations.The Person χ 2 will be used for analysis between groups.
Variables with a non-Gaussian distribution and will be analysed by means of a Mann-Whitney-U test in univariate analysis.
Statistical significance is defined as P<0.05.

Other study parameters
Binary variables will be displayed in cross-tabulations.The Person χ 2 will be used for analysis between groups.
Variables with a non-Gaussian distribution and will be analysed by means of a Mann-Whitney-U test in univariate analysis.
Statistical significance is defined as P<0.05.

Interim analysis
If the DSMB requires an interim-analysis for benefit the Peto approach will be followed meaning that the study will only be stopped for beneficial effects in case of a P<0.001.An interim analysis is performed at 105 patients.The interim-analysis is performed by the study coordinator and the epidemiologist/statistician of the DSMB together and discussed in a private meeting by only the DSMB members.If the DSMB suspects harm there will be a meeting between the DSMB, the trial research group and an independent statistician.
During this meeting there should be a discussion about any potential causal relation between gastrectomy and harm based on the current literature.The final decision is made by the DSMB and their opinion is sent to the study coordinator and principal investigator.
There will be no futility for this trial.The ethics committee will receive a direct copy of this advice.

Regulation statement
This study will be conducted according to the principles of the Declaration of Helsinki (2008) and in accordance with the Medical Research Involving Human Subjects Act (WMO).

Recruitment and consent
Patients are recruited to participate in this trial at the outpatient clinic.They are introduced to the study by a sub-investigator who will not be involved in the care and treatment of the patient but who is part of the study team and therefore can inform the patient about the study and answer the questions of the patient.The subjects will be fully informed about the study by means of a patient information letter that explains the trial.Potential participants can contact the coordinating investigator or independent physician for any questions concerning the trial.The subjects will be given a week to consider their decision.The informed consent form will be signed by both the participant and the investigator.The patient information brochure and the informed consent form are attached (appendix 5)

Objection by minors or incapacitated subjects (if applicable)
Not applicable

Benefits and risks assessment, group relatedness
All surgical techniques used in this research are known to be safe.

Compensation for injury
The sponsor/investigator obtained dispensation from the statutory obligation to provide insurance from the Medical Ethics Committee UMC Utrecht.The reason for dispensation is that if a study includes two different, but commonly used procedures, the insurance does not cover damage caused by the study.

Incentives (if applicable)
Not applicable

ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 10.1 Handling and storage of data and documents
The subjects will be coded by patient number in order to handle personal information about patients anonymously.The patient's information will solely be available to this research group by the use of SPSS guarded with a password.The coordinating investigator and the principal investigator know this password.The data will be kept for 15 years.This will be done in concordance with the Dutch Personal Data Protection Act (Wet Bescherming Persoonsgegevens, WBP)

Monitoring and Quality Assurance
The study is classified as a low risk study (verwaarloosbaar risico) and will be monitored accordingly.For details, see monitoring plan.

Amendments
Amendments are changes made to the research after a favourable opinion by the accredited METC has been given.All amendments will be notified to the METC that gave a favourable opinion.

Annual progress report
The investigator will submit a summary of the progress of the trial to the accredited METC once a year.Information will be provided on the date of inclusion of the first subject, numbers of subjects included and numbers of subjects that have completed the trial, serious adverse events/ serious adverse reactions, other problems, and amendments.

End of study report
The investigator will notify the accredited METC of the end of the study within a period of 8 weeks.The end of the study is defined as the last patient's last visit.
In case the study is ended prematurely, the investigator will notify the accredited METC within 15 days, including the reasons for the premature termination.
Within one year after the end of the study, the investigator/sponsor will submit a final study report with the results of the study, including any publications/abstracts of the study, to the accredited METC.Did you use supplemental drinks or tube feeding over the last month?
11.8 Appendix 8 Sarcopenia will be assessed on the preoperative CT scans (these scans were made as standard of care) by the study team of the Orbis Medisch Centrum in Sittard.The cross sectional skeletal muscle surface (cm 2 ) assessment of sarcopenia will be performed at the level of the third lumbar vertebra (L3) on a single slice transversal coupe on which both vertebral spines are visible.This measurements will be performed using Slice-O-Matic software.Each participating centre will use the study subject ID to pseudonymise the CTscans of their study patients and transfer the scans to the study team of the Orbis Medisch Centrum.The Orbis Medisch Centrum cannot trace the study subject ID back to individual patient identities and the patient privacy is thus protected.The transfer of the scans will be performed according to secured localized procedures of each centre.
technique to 30 surgeons visiting our Minimally Invasive Gastrectomy course in the past 2 years.Objective: To evaluate the benefits, risks and costs of laparoscopic gastrectomy as an alternative to open gastrectomy (conventional surgery) as treatment for gastric cancer in a Western population.Study Design: Multicenter prospectively randomized controlled trial.Study population: Patients (age ≥ 18) with histological proven surgically resectable (cT1-4a, N0-3b, M0) gastric cancer with European Clinical Oncology Group (ECOG) performance status 0, 1 or 2. Intervention: In total 210 patients will be randomized over 2 treatment groups; The experimental group consists of 105 patients that receive laparoscopic gastrectomy and the control consists of 105 patients that undergo conventional open gastrectomy.Main study parameters/endpoints: Primary outcome is postoperative hospital stay (days).Secondary outcomes are cost-effectiveness, oncologic outcomes, postoperative morbidity, mortality, readmissions and quality of life.Follow-up: 60 months after surgery Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Patients will undergo either laparoscopic gastrectomy (experimental arm) or the conventional open gastrectomy (conventional surgery).Tumor biopsies will be collected pre-operatively.Blood samples will be drawn at baseline, direct postoperatively and on postoperative day 2. Patients are required to fill out quality of life questionnaires (preoperatively and <5 days, 6 weeks, 6 months, and yearly up to 5 years postoperatively).

Figure 1 :
Figure 1: Postoperative hospital stay was evaluated in 7 out of 8 comparative cohort studies in our meta-analysis. 16Hospital stay was shortened from 18 days after open gastrectomy to 14 days after laparoscopic gastrectomy.

Figure 2 :
Figure 2: Treatment allocation.Based on tumor location patients will undergo either distal or total gastrectomy, according to the Dutch gastric cancer guidelines.
years) who are diagnosed with gastric adenocarcinoma are eligible to participate in the study.The centres perform 20-30 gastric resections per year.A total number of 210 patients is required for inclusion, which makes the inclusion time of 3 years feasible.

Figure 4 :
Figure 4: Maximally 5 trocar ports are used.Trocar positions: trocar 1 (5mm), 2 (5mm), and 4 (5mm) are used for instrumentation used during the LTG.The camera is inserted through trocar 3 (10mm), which is the location of the minilaparotomy (A) for the removal of the stomach as well.The liver retractor is inserted through trocar 5 (12mm).

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Duration of surgery -Blood loss during operation -Conversion to alternative surgical procedure • Postoperative course: Duration of Intensive Care stay -Duration of Medium Care stay -Mechanical ventilation -Vital signs (heart rate, blood pressure, temperature)

Mobility 5 .Vision 6 .Hearing 7 .Nourishment 8 .Morbidity 9 . 1 .
be defined according to the Esophageal Complications Consensus Group.All complications will be scored according to the modified Clavien-Dindo classification and the Comprehensive Complication Index.Is the patient able to carry out these tasks single-handed without any help?(The use of help resources, such as walking stick, walking frame, wheelchair, is considered independent.)1. Shopping 2. Walking around outside (around the house or to the neighbors) 3. Dressing and undressing 4. Going to the toilet Physical Fitness What mark does the patient give himself/herself for physical fitness?(scale 0-10) Does the patient experience problems in daily life due to poor vision?Does the patient experience problems in daily life due to being hard of hearing?During the last 6 months has the patient lost a lot of weight unwillingly?(3 kg in 1 month or 6 kg in 2 months) Does the patient take 4 or more different types of medicine?Did you lose weight unintentionally?-More than 6 kg in the last 6 months -More than 3 kg in the last month Did you experience a decreased appetite over the last month?

Table 1 : Intraoperative and Postoperative Outcomes *Results presented as medians (min-max) Reasons for conversion: tumor ingrowth in surrounding structures (6x), arterial bleeding (1x), venous bleeding (1). R0 resection: proximal and distal resection margin.
This meta-analysis was predominantly based on patients from Asian studies (90%), since research on this topic is still limited in Western countries.Therefore, we analysed our own