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Laparoscopic versus open gastrectomy for gastric cancer

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the benefits and harms of laparoscopic gastrectomy or laparoscopy‐assisted gastrectomy versus open gastrectomy for people with gastric cancer.

Background

Description of the condition

Adenocarcinoma of the stomach (or stomach cancer) is the fifth most common cancer and the third most common cause of cancer‐related mortality in the world (IARC 2014). In 2012, there were about 950,000 new people diagnosed with gastric cancer and 725,000 deaths due to gastric cancer globally (IARC 2014). There is global variation in the incidence of gastric cancers with an age‐standardised annual incidence rate of 30 to 42 per 100,000 population in East Asian countries such as Japan, Mongolia, and Korea compared with an age‐standardised annual incidence rate of 1 to 5 per 100,000 population in Africa, Australia, the USA, and the UK (IARC 2014). The trend in mortality is different. For example, the age‐standardised annual mortality rate in Mongolia is 25 per 100,000 population compared with 13 per 100,000 population in Korea and Japan despite a higher age‐standardised annual incidence in Korea than Mongolia (IARC 2014). There is a decreasing trend in the overall incidence of gastric cancers possibly due to lifestyle changes such as decreased consumption of salted and preserved foods, increased consumption of fruits and vegetables, decreased smoking and reduction ofHelicobacter pylori (Cancer Research UK 2014; Jemal 2010). The treatment of gastric cancer depends upon the stage of cancer. One of the common systems for staging cancer currently is the American Joint Committee on Cancer (AJCC) gastric cancer staging system according to the AJCC 7th edition (AJCC 2010; Washington 2010). This system is based on the involvement of the different layers of the stomach by the tumour (T), nodal involvement (N), and the presence of metastases (M) (TNM classification). Early gastric cancer is cancer that is confined to the submucosa (T1) with or without nodal involvement, although this definition of early gastric cancer has been challenged since nodal status is an important prognostic factor in survival (Inoue 1991; Kim 1995). If the cancer has penetrated beyond the submucosa, it is called advanced gastric cancer. Metastatic gastric cancer corresponds to Stage IV of the AJCC gastric cancer staging system. The survival after diagnosis of gastric cancer depends upon the stage with five‐year survival ranging from 70% in Stage Ia cancer to 5% in Stage IV cancer (AJCC 2010; Washington 2010). The treatment of gastric cancer depends upon the stage of the disease. Potentially curative treatment is possible for stages I to III (JGCA 2011; Waddell 2013). Apart from T1aN0M0 stage, where endoscopic treatment may be performed, and stage IV, where palliative treatment is recommended, the remaining stages are treated by resection of the stomach (gastrectomy) (Bennett 2009; JGCA 2011; Waddell 2013).

Description of the intervention

In open gastrectomy, the surgical access to the abdominal cavity (and hence the stomach) is by upper midline incision, a bilateral subcostal incision (roof‐top or Chevron incision), or a transverse abdominal incision (Inaba 2004; Stuart 1997). In laparoscopy‐assisted gastrectomy, the surgical access to the abdominal cavity (and hence the stomach) is by a small abdominal incision (about 5 cm) and additional five or six small ports (holes) of about 0.5 cm to 1 cm each through which laparoscopic instruments can be inserted after the abdomen is distended using carbon‐dioxide pneumoperitoneum. Part of the surgery, usually the anastomosis restoring the continuity of the gastrointestinal tract, is performed outside the body (extracorporeal) (Lee 2013). In totally laparoscopic gastrectomy, the surgical access to the abdominal cavity (and hence the stomach) is only by five or six small ports of about 0.5 to 1 cm each through which laparoscopic instruments can be inserted after the abdomen is distended using carbon‐dioxide pneumoperitoneum. The entire surgery is performed laparoscopically.

The standard gastrectomies are total gastrectomy and distal gastrectomy and are recommended in the presence of nodal involvement or T2 to T4a tumours. Distal gastrectomy can be performed when a minimum of 2 to 5 cm proximal cancer‐free margin can be achieved depending upon the depth of infiltration and the growth pattern of the cancer (JGCA 2011). Proximal gastrectomy can be performed for T1N0 proximal gastric cancers when more than half of the distal stomach can be preserved; and a pylorus‐preserving gastrectomy can be performed for T1N0 cancers of the middle third of the stomach when the distal margin of the tumour is at least 4 cm from the pylorus (JGCA 2011). The extent of lymph node excision and the method of restoration of continuity of the gastrointestinal tract are controversial (JGCA 2011; Memon 2011; Waddell 2013; Xiong 2013). Postoperative chemotherapy is recommended after gastrectomy for resectable gastric cancer (Diaz‐Nieto 2013; Waddell 2013).

How the intervention might work

For many surgical procedures, laparoscopic surgery is currently preferred over open surgery. This includes surgical procedures such as cholecystectomy (removal of gallbladder), colon cancer, and hysterectomy (Bijen 2009; Keus 2006; Reza 2006; Talseth 2014; Walsh 2009). The reason for this preference of laparoscopic surgery over open surgery is because of decreased pain, decreased blood loss, shorter hospital stay, earlier postoperative recovery, better cosmesis (physical appearance), and decreased costs (Bijen 2009; Keus 2006; Reza 2006; Talseth 2014; Walsh 2009).

Why it is important to do this review

While the smaller incision and earlier postoperative recovery appear to be potential advantages of laparoscopic gastrectomy or laparoscopy‐assisted gastrectomy, the safety of the laparoscopic approach for a procedure that has a high complication rate and cancer clearance after laparoscopic and laparoscopy‐assisted gastrectomy has to be ensured before the method can be widely recommended. There are concerns about cancer clearance since port‐site metastases (recurrence of cancer at the laparoscopic port‐site) have been reported after many cancers (Kais 2014; Palomba 2014; Song 2014). Animal research has shown that the increased intra‐abdominal pressure during laparoscopy (pneumoperitoneum) may drive the malignant cells into ports resulting in seeding of the port site and port‐site metastases (Hopkins 1999). Another reason is that the malignant cells may be adherent to the laparoscopic instruments that are introduced and removed through the ports resulting in seeding of the port site and port‐site metastases (Hopkins 1999). Another issue is the adequacy of cancer clearance in terms of resection margins and the extent of lymph nodes removed with laparoscopy. Therefore, oncological safety (cancer clearance) is an important issue with laparoscopic and laparoscopic‐assisted gastrectomy. There is no Cochrane review on this topic.

Objectives

To assess the benefits and harms of laparoscopic gastrectomy or laparoscopy‐assisted gastrectomy versus open gastrectomy for people with gastric cancer.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs). We will include studies reported as full text, studies published as abstract only, and unpublished data.

Types of participants

We will include adults undergoing gastrectomy for gastric adenocarcinoma. We will include trials in which separate outcome data for people undergoing gastrectomy for gastric adenocarcinoma are available even if some of the participants underwent gastrectomy for other causes including lymphomas.

Types of interventions

We will include trials comparing laparoscopic gastrectomy or laparoscopy‐assisted gastrectomy with open gastrectomy provided that the only difference between the randomised groups is the use of laparoscopic (or laparoscopy‐assisted) or open method of access to the stomach. We will exclude trials comparing totally laparoscopic gastrectomy with laparoscopy‐assisted gastrectomy or different methods of open or laparoscopic gastrectomy.

Types of outcome measures

Primary outcomes

  1. Mortality.

    1. Short‐term mortality (in‐hospital mortality or mortality within three months).

    2. Long‐term mortality.

  2. Serious adverse events (within three months). We will accept the following definitions of serious adverse events.

    1. Clavien‐Dindo classification (Clavien 2009; Dindo 2004): Grade III or more.

    2. International Conference on Harmonisation ‐ Good Clinical Practice guideline (ICH‐GCP; ICH‐GCP 1996): we will define serious adverse events as any untoward medical occurrence that results in death, is life threatening, requires hospitalisation or prolongation of existing hospitalisation, and results in persistent or significant disability/incapacity.

    3. Individual complications that can clearly be classified as Grade III or more with Clavien‐Dindo classification (Clavien 2009; Dindo 2004), or as a serious adverse event with ICH‐GCP classification.

  3. Health‐related quality of life (using any validated scale).

    1. Short‐term (four weeks to three months).

    2. Medium‐term (more than three months to one year).

Secondary outcomes

  1. Recurrence (local recurrence, surgical wound recurrence (also called port‐site metastases in the laparoscopic group) or distal metastases).

    1. Short‐term recurrence (within six months).

    2. Long‐term recurrence.

  2. Adverse events (within three months). We will accept all adverse events reported by the study author irrespective of the severity of the adverse event.

  3. Perioperative blood transfusion requirements (during surgery or within one week after surgery) (whole blood or red cell transfusion).

    1. Proportion of people requiring blood transfusion.

    2. Quantity of blood transfusion.

  4. Measures of earlier postoperative recovery.

    1. Length of hospital stay (including the index admission for gastrectomy and any surgical complication‐related re‐admissions).

    2. Time to return to normal activity (return to pre‐operative mobility without any additional carer support).

    3. Time to return to work (in people who were employed previously).

  5. Positive resection margins (presence of macroscopic or microscopic cancer tissue at the plane of resection) at histopathological examination after surgery.

  6. Number of harvested lymph nodes during surgery.

We based the choice of the above clinical outcomes on the necessity to assess whether laparoscopic surgery results in adequate cancer clearance, is safe, and is beneficial in terms of decreased blood transfusion requirements; earlier postoperative recovery allowing earlier discharge from hospital, return to normal activity, and return to work; and improvement in health‐related quality of life. We highlight that the positive resection margins at histopathological examination after surgery and the number of harvested lymph nodes during surgery are surrogate outcomes and have included these in order to explore whether these are responsible for any differences in survival or mortality.

Studies which meet the inclusions criteria will be included irrespective of whether they report the secondary outcomes.

Search methods for identification of studies

Electronic searches

We will conduct a literature search to identify all published and unpublished RCTs. The literature search will identify potential studies in all languages. We will translate any non‐English language papers and assess them fully for potential inclusion in the review as necessary.

We will search the following electronic databases for identifying potential studies:

  1. the Cochrane Central Register of Controlled Trials (CENTRAL; to present) (Appendix 1);

  2. MEDLINE (1966 to present) (Appendix 2);

  3. EMBASE (1988 to present) (Appendix 3); and

  4. Science Citation Index (1982 to present) (Appendix 4).

We will also conduct a search of ClinicalTrials.gov (ClinicalTrials.gov; Appendix 5) and the World Health Organization ‐ International Clinical Trials Registry Platform (WHO ICTRP; www.who.int/ictrp/en/; Appendix 6).

Searching other resources

We will check reference lists of all primary studies and review articles for additional references. We will contact authors of identified trials and ask them to identify other published and unpublished studies.

We will search for errata or retractions from eligible trials on PubMed (www.ncbi.nlm.nih.gov/pubmed) and report the date this was done within the review.

Data collection and analysis

Selection of studies

Two review authors (trained research assistants or students or colleagues of K Gurusamy) will independently screen titles and abstracts for inclusion all the potential studies that we identify as a result of the search and code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will retrieve the full‐text study reports and two review authors (research assistants or students or colleagues of K Gurusamy) will independently screen the full text, identify studies for inclusion, and identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreements through discussion or, if required, we will consult third person (K Gurusamy). We will identify and exclude duplicates and collate multiple reports of the same study so that each study, rather than each report, is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table.

Data extraction and management

We will use a standard data collection form for study characteristics and outcome data that has been piloted on at least one study in the review. Two review authors (research assistants or students or colleagues of K Gurusamy) will extract study characteristics from included studies and detail them in a 'Characteristics of included studies' table. We will extract the following study characteristics:

  1. methods: study design, total duration study and run in, number of study centres and location, study setting, withdrawals, date of study;

  2. participants: number, mean age, age range, gender, tumour stage, tumour location, performance status, American Society of Anesthesiologists (ASA) status (ASA 2014), inclusion criteria, exclusion criteria;

  3. interventions: intervention, comparison, concomitant interventions;

  4. outcomes: primary and secondary outcomes specified and collected, time points reported;

  5. notes: funding for trial, notable conflicts of interest of trial authors.

Two review authors (research assistants or students or colleagues of K Gurusamy) will independently extract outcome data from included studies. If outcomes were reported multiple times for the same time point, for example, short‐term health‐related quality of life was reported at six weeks and three months, we will chose the later time point (i.e. three months) for data extraction. For time‐to‐event outcomes, we will extract data to calculate the natural logarithm of the hazard ratio (HR) and its standard error using the methods suggested by Parmar et al. (Parmar 1998).

We will included all randomised participants for medium‐term and long‐term outcomes (e.g. mortality or quality of life) and this will not be conditional upon the short‐term outcomes (e.g. being alive at three months or having a low or high quality‐of‐life index at three months).

We will note in the 'Characteristics of included studies' table if outcome data are reported in an unusable way. We will resolve disagreements by consensus or by involving a third person (K Gurusamy). One review author (K Gurusamy) will copy across the data from the data collection form into Review Manager 5 (RevMan 2012). We will double check that the data are entered correctly by comparing the study reports with how the data are presented in the systematic review.

Assessment of risk of bias in included studies

Two review authors (research assistants or students or colleagues of K Gurusamy) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving a third person (K Gurusamy). We will assess the risk of bias according to the following domains:

  1. random sequence generation;

  2. allocation concealment;

  3. blinding of participants and personnel;

  4. blinding of outcome assessment;

  5. incomplete outcome data;

  6. selective outcome reporting;

  7. other bias.

We will grade each potential source of bias as high, low, or unclear risk of bias and provide a quote from the study report together with a justification for our judgement in the 'Risk of bias' table. We will summarise the risk of bias judgements across different studies for each of the domains listed. We will consider blinding separately for different key outcomes where necessary (e.g. for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different from a participant‐reported pain scale). Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table.

When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.

Assessment of bias in conducting the systematic review

We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review.

Measures of treatment effect

We will analyse dichotomous data as risk ratio (RR) with 95% CI and continuous data as mean difference (MD) with 95% CI when the outcome is reported or converted to the same units in all the trials (e.g. hospital stay, time to return to work) or standardised mean difference (SMD) with 95% CI when different scales are used for measuring the outcome (e.g. quality of life). We will ensure that higher scores for continuous outcomes have the same meaning for the particular outcome, explain the direction to the reader, and report where the directions were reversed if this was necessary. We will calculate the rate ratio (RaR) with 95% CI for outcomes such as adverse events and serious adverse events, where it is possible for the same person to develop more than one adverse event (or serious adverse event). If the authors have calculated the RaR of adverse events (or serious adverse events) in the intervention versus control based on Poisson regression, we will obtain the RaR by the Poisson regression method in preference to RaR calculated based on the number of adverse events (or serious adverse events) during a certain period. We will calculate the HR for time‐to‐event outcomes such as long‐term mortality, long‐term recurrence, and time‐to‐first adverse event (or serious adverse event).

We will undertake meta‐analyses only where this is meaningful (i.e. if the treatments, participants, and the underlying clinical question are similar enough for pooling to make sense).

A common way that trialists indicate when they have skewed data is by reporting medians and interquartile ranges. When we encounter this, we will note that the data are skewed and consider the implication of this.

Where multiple trial arms are reported in a single trial, we will include only the relevant arms. If two comparisons (e.g. laparoscopy‐assisted gastrectomy versus open gastrectomy and totally laparoscopic gastrectomy versus open gastrectomy) must be entered into the same meta‐analysis, we will halve the control group to avoid double counting. The alternative way of including such trials with multiple arms is to pool the results of the laparoscopy‐assisted gastrectomy and totally laparoscopic gastrectomy and compare it with open gastrectomy. We will perform a sensitivity analysis to determine if the results of the two methods of dealing with multi‐arm trials lead to different conclusions.

Unit of analysis issues

The unit of analysis will be individual participants undergoing gastrectomy. We do not anticipate finding any cluster‐randomised trials for this comparison but if we do identify cluster‐randomised trials, we will obtain the effect estimate adjusted for the clustering effect. If this is not available, we will perform a sensitivity analysis excluding the trial from the meta‐analysis, as the variance of the effect estimate unadjusted for cluster effect is less than the actual variance that is adjusted for cluster‐effect giving inappropriately more weight to the cluster RCT in the meta‐analysis.

Dealing with missing data

We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is identified as abstract only). If we are unable to obtain the information from the investigators or study sponsors, we will impute mean from median (i.e. consider median as the mean) and standard deviation from standard error, interquartile range, or P values according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), but assess the impact of including such studies as indicated in a sensitivity analysis. If we are unable to calculate the standard deviation from standard error, interquartile range, or P values, we will impute standard deviation as the highest standard deviation in the remaining trials included in the outcome fully aware that this method of imputation will decrease the weight of the studies in the meta‐analysis of MD and shift the effect towards no effect for SMD.

Assessment of heterogeneity

We will use the I2 statistic to measure heterogeneity among the trials in each analysis. If we identify substantial heterogeneity as per Cochrane Handbook for Systematic Reviews of Interventions (greater than 50% to 60%; Higgins 2011), we will explore it by pre‐specified subgroup analysis. 

Assessment of reporting biases

We will attempt to contact study authors asking them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results using a sensitivity analysis

If we are able to pool more than 10 trials, we will create and examine a funnel plot to explore possible publication biases. We will use Egger's test to determine the statistical significance of the reporting bias (Egger 1997). We will consider a P value less than 0.05 statistically significant reporting bias.

Data synthesis

We will perform analyses using Review Manager 5 (RevMan 2012).

'Summary of findings' table

We will create a 'Summary of findings' table using all the outcomes. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence as it relates to the studies that contribute data to the meta‐analyses for the pre‐specified outcomes. We will use methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and using GRADEpro software. We will justify all decisions to downgrade or upgrade the quality of studies using footnotes and make comments to aid reader's understanding of the review where necessary. We will consider whether there is any additional outcome information that we were unable to incorporate into meta‐analyses and note this in the comments and state if it supports or contradicts the information from the meta‐analyses.

Subgroup analysis and investigation of heterogeneity

We plan to carry out the following subgroup analyses:

  1. totally laparoscopic and laparoscopy‐assisted gastrectomy;

  2. different cancer stages (early gastric cancer and advanced gastric cancer; node‐positive and node‐negative gastric cancer);

  3. different types of gastrectomy (proximal, pylorus preserving, distal, total gastrectomy);

  4. different methods of anastomoses (stapler versus hand‐sewn anastomoses);

  5. people with different anaesthetic risk (ASA I (a healthy person) or II (a person with mild systemic disease) versus ASA III or more (a person with severe systemic disease or worse).

  6. Different body mass index (BMI) (health weight (BMI 18.5 to 25) versus overweight or obese (BMI 25 or greater).

We will use all primary outcomes in subgroup analyses.

We will use the formal Chi2 test for subgroup differences to test for subgroup interactions.

Sensitivity analysis

We will perform sensitivity analysis defined a priori to assess the robustness of our conclusions. This will involve:

  1. excluding trials at unclear or high risk of bias (one of more of the risk of bias domains (other than blinding of surgeon) classified as unclear or high);

  2. excluding trials in which either mean or standard deviation, or both are imputed;

  3. excluding cluster RCTs in which the adjusted effect estimates are not reported;

  4. different methods of dealing with multi‐arm trials (see Measures of treatment effect).

Reaching conclusions

We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies for this review. We will avoid making recommendations for practice and our implications for research will give the reader a clear sense if where the focus of any future research in the area should be and what the remaining uncertainties are.