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Adult patients with an esophageal cancer can potentially be compromised with postoperative leaks or fistulae if patients’ nutritional status is in a vulnerable stage. Currently in Australia, there is a growing need for clinicians to know whether use of immune-enhancing formulas (IEFs) containing Arg, omega-3, and RNA are a cost-effective approach compared with isonitrogenous-isocaloric formulas to reduce postoperative infectious complications in esophagectomy patients. Since IEFs may carry higher costs, this has led to inconsistencies in practice among clinicians and hospitals.
Our aim is to compile and present the most up-to-date nutrition evidence available regarding the provision of IEFs containing Arg, omega-3, and RNA to help clinicians develop an evidence-based nutrition care plan; identify available evidence of whether an esophagectomy patient should receive IEF; determine the cost-effectiveness and safety of such nutrition; and determine appropriate administration quantity and timing (pre-, peri-, or postesophagectomy).
This review will include RCTs involving the use of IEFs enriched with Arg, omega-3 polyunsaturated fatty acids, and RNA in the pre-, peri-, or postoperative period (for at least 5-7 days) given orally or via enteral feeding tube, in adult cancer patients undergoing esophageal resection. Lower gastrointestinal, gastric, or head cancer surgery with parenteral nutrition or non-IEF or use of isolated immunonutrient (Arg vs omega-3 vs RNA) will be excluded. Primary outcome comprises postoperative infectious complications. Secondary outcomes (pre/postoperatively) consist of cost-effectiveness, length of stay, survival/mortality, quality of life, nutritional status, percentage of weight loss, and biochemical changes. The risk of bias will be independently assessed by the reviewers, using a domain-based evaluation tool. Blinding will be assessed for subjective and objective outcome measures. Publication bias will be visually assessed by funnel plots. A meta-analysis will be generated by the Review Manager 5.3 software and represented in forest plots.
The first results are expected in 2018. Outlining the protocol will ensure transparency for the completed review.
This protocol for a systematic review and meta-analysis will enable a comprehensive appraisal of the literature to help determine whether overall institutional savings are associated with this approach. Findings will form a knowledge base relevant to stakeholders across the health system and researchers who are involved in decision making on evidence-based nutrition care plan pathways for patients undergoing esophagectomy, as well as the use of IEF, timing, and administration quantity.
PROSPERO Registration Number: CRD42017056908; http://www.crd.york.ac.uk/PROSPERO/ display_record.asp? ID=CRD42017056908 (Archived by WebCite at http://www.webcitation.org/6rLyeqaD6)
Adult patients with an esophageal cancer or intractable strictures often require resection of the esophagus with complex anastomoses that can potentially be compromised with postoperative leaks or fistulae if patients’ nutritional status is in a vulnerable stage [
Although it is challenging to define and measure nutritional status in oncology, cancer-associated malnutrition seems to affect this population even in those overweight or well-nourished patients with a recent diagnosis [
Currently in Australia, there is a growing need for clinicians to know whether the use of immune-enhancing formulas (IEFs) containing arginine (Arg), omega-3, and ribonucleic acid (RNA) is a cost-effective approach compared with isonitrogenous- isocaloric formula to reduce postoperative infectious complications (POIC) in esophagectomy patients [
Thus, this systematic review will enable a comprehensive appraisal of the literature to assist in determining whether overall institutional savings are associated with this approach. This review also seeks to compile and present the most up-to-date available evidence on the provision of IEFs containing Arg, omega-3, and RNA, to help clinicians develop an evidence-based nutrition care plan. Furthermore, we aim to identify available evidence of whether an esophagectomy patient would be the ideal case to receive IN, and a cost-benefit analysis to determine appropriate administration quantity and timing (pre-, peri-, or postesophagectomy).
We aim to address the following research questions. In cancer patients undergoing esophageal resection and requiring postoperative nutritional support: (1) Is there sufficient quality evidence on perioperative IEF enriched with omega-3, Arg, and RNA to recommend it as routine practice among clinicians?, (2) Do IEFs enriched with omega-3, Arg, and RNA confer additional clinical benefits such as reducing the risk of POIC and improving patients’ health care outcomes compared to standard enteral nutrition?, and (3) Are IEFs enriched with omega-3, Arg, and RNA a cost-effective strategy to be considered by clinicians?
This review will include randomized controlled trials (RCTs) on National Health and Medical Research Council level II intervention and use of IEFs in esophagectomy patients. The trials selected should contain IEFs (containing Arg, omega-3, and RNA) compared with standard enteral formulas (SEFs) either pre-, post-, or perioperative. Non-RCT intervention studies such as cohort studies will be excluded, since the potential risk of bias is higher. Likewise, we will exclude observational studies, abstracts, review papers, conference proceedings, and studies that are not English, Spanish, or Portuguese language.
Ethical approval is not required for the proposed systematic review and meta-analysis because the data used in this review will not involve the privacy of individual patients. Findings will be reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [
All patients 18 years or over undergoing surgical procedure for esophageal cancer will be included. Also, those included should be receiving IEF (containing a combination of Arg, omega-3, and RNA) pre-, peri-, or postoperatively for at least 5-7 days. Moreover, we will include all inpatient and outpatient/ambulatory patients in the health care facility where patients are having surgery (
The intervention will be the use of IEFs containing the immunonutrients Arg, omega-3 polyunsaturated fatty acid, and RNA provided either orally or via an enteral feeding tube. To be included, studies will have IEF given pre-, peri-, and/or postoperatively as an intervention. Co-intervention with other oral or parenteral substances will not be included. The control group should be receiving the traditional isonitrogenous-isocaloric SEF or polymeric nutritional supplements either orally or via enteral feeding tube.
The primary outcome will be POICs including wound infections or fistulae formation, bacteremia, sepsis, anastomotic leakage, abscess and pulmonary complications, especially pneumonia or bronchopneumonia within the first 2 weeks of surgery and during the whole stay in hospital [
Inclusion criteria:
Adult patients (≥18 years) undergoing an elective surgical procedure for esophageal cancer; perioperative patients
Adult patients in various stages of the disease including I, II, III, and IV
All patients (inpatient and outpatient) undergoing surgery
Receiving perioperative IEF (Impact/other similar formulation: combination of Arg, omega-3, and RNA for at least 5-7 days)
Exclusion criteria:
Lower GI cancer surgery, gastric, or head cancer surgery
Patients with cancer having parenteral nutrition or enteral feeding with non-IEF or IEF with only one isolated nutrient (Arg vs omega-3 vs RNA)
We will consider the following secondary outcomes measured pre- and/or postoperatively:
Health-related costs/cost-effectiveness/cost-benefit: defined by the authors
Health care use: length of stay (LOS) measured in number of days; readmissions to acute care, subacute care or intensive care unit; re-operations measured in number of cases
Survival/mortality: number/proportion of deaths related to treatment ˂18 months (long-term survival) [
Quality of life: health-related quality of life measures via a validated diagnostic tool such as the
Nutritional status: classified as well-nourished or malnourished and measured by validated nutrition assessment tool within 2 weeks pre-operatively
Percentage of weight loss: ˃5% weight loss in past month (1/12) and 1 week and/or 3 weeks postoperatively
Biochemical changes: as per trial authors, including C-reactive protein levels (from ≤7 days prior surgery and first 2 weeks postoperatively)
Searches for RCTs will be conducted systematically by the reviewers, with no publication year restriction. Non-English/Spanish/Portuguese studies might be excluded unless translations were provided or arranged. Also, original authors may be contacted for clarification and request of further data if trial reports seem unclear. Computerized searches will be performed for relevant published studies on the following databases from their inception until July 2017: the Cochrane Central Register of Controlled Trials (CENTRAL-The Cochrane Library), PubMed, EMBASE, CINAHL, LILACS, ClinicalTrials.gov, and the Trip (Turning Research into Practice) database. Subject strategies for databases in the search strategy will be modeled and designed for CENTRAL, CINAHL, and PubMed (
The reference lists of identified publications will be scanned for further trials, and some trial authors may be contacted if required. Additional searches with Google Scholar, Google, and Bond University Library online will be conducted to retrieve remaining systematic reviews and meta-analyses pertinent to this review, in order to scan their reference lists for additional existing trials. A search of gray literature may be performed using the and .
The results of the searches will be combined as indicated in
Data such as study design and setting, number of participants, outcome measure, and timing of IN initiation, route feeding, and total duration of IN will be autonomously extracted and organized on a matrix table (
The risk of bias in the eligible studies will be independently assessed by the reviewers. Any disagreements will be resolved through discussion with an external arbitrator if required. Risk of bias assessment will be performed using the domain-based evaluation tool described by the
Every RCT will be appraised according to the quality of 6 domains: (1) random sequence generation and allocation concealment (selection bias), (2) blinding of participants and personnel (performance bias), (3) blinding of outcome assessment (detection bias), (4) incomplete outcome data (attrition bias), (5) selective reporting (reporting bias), and (6) any other potential concerns to validity [
Based on study reports, preliminary information will be collected in matrix tables to inform the risk of bias assessments (
A low risk of bias RCT will be considered if all or the majority of domains were gauged as adequate. RCTs will be considered as having a high risk of bias when one or more of the assessed domains within that trial were unclear or inadequate (unless original authors answer queries otherwise). The “risk of bias or internal validity” will be reported as part of the “characteristics and outcomes of identified studies” matrix (
Categorical data will be presented as risk ratio and risk difference or odds ratio including their 95% confidence intervals (CI), which will be calculated/extracted for the analysis of most of the outcome measures apart from health care use (ie, LOS) and biochemical/immunological changes that are exclusively represented as continuous variables (
Heterogeneity must be considered from both a clinical and statistical perspective. On one hand, clinical expertise will be used to decide whether it would be meaningful to combine the studies based on the potential sources of heterogeneity for each outcome measure. The potential sources where the RCTs may not show the exact same result could depend on factors such as the patients’ demographics (eg, age: adult vs elderly), nutritional status baseline, type of surgery (invasive or less invasive), different doses and timing of pre- versus peri- versus postoperative IEF, definition of the outcome measures, as well as the timing for measuring those outcomes (
On the other hand, statistical heterogeneity, which quantifies the variation due to heterogeneity and not due to chance across the RCTs, will be also checked through the statistical calculation of an I2 test [
After that process, if the degree of clinical and statistical heterogeneity of studies are not excessive, a quantitative summary measures (meta-analysis) will be generated by the Review Manager (RevMan) 5.3 software and represented in forest plots [
Where statistical pooling is not possible, the findings will be presented in narrative form or a table to describe the outcomes, different tools used to assess the outcomes listed for this review, or continuous data that can be pooled for meta-analysis.
The quality of evidence for all outcomes will be judged using the
The first results are expected in 2018. Outlining the protocol will ensure transparency for the completed review.
Given the nature of esophageal cancer and the significant potential for nutritional deficiencies prior to resection as compared with other gastrointestinal (GI) pathologies, it seems appropriate that there should be a specific focus on the role of perioperative nutritional supplementation [
IEFs enriched with a combination of immunonutrients (Arg, omega-3, and RNA) are well known to Australian clinicians. However, IN is not consistently used with cancer patients undergoing esophageal resection as standard practice [
To date, there have been several systematic reviews and meta-analyses of RCTs undertaken to determine the effectiveness of IN in elective upper and lower GI surgical practice [
Search terms and results of the search strategy.
Characteristics of studies including immunonutrition for esophagectomy.
Characteristics of RCTs included in meta-analysis of immune-enhancing formula versus standard enteral formula.
Outcome measures analysis table.
Table of the planned statistical analysis for the meta-analysis.
arginine
confidence intervals
gastrointestinal
immune-enhancing formula
immunonutrition
length of stay
postoperative infectious complication
randomized controlled trial
ribonucleic acid
standard enteral formula
None declared.