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 [1,2]. Additionally, pulmonary complications, especially pneumonia, are a major component of morbidity after an esophagectomy [3].

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 [4]. Up to 85% of patients develop cancer-associated malnutrition, in which individual susceptibility depends on several factors such as the type, grade, and stage of cancer as well as the side effects of treatment modalities [5,6]. These factors may have a negative impact causing systemic anorexia combined with altered absorption of nutrients, unintentional weight loss, and depletion of lean body mass [4]. Moreover, pre-existing poor dietary habits, socioeconomic status, functional performance, nutritional impact symptoms, requirements for fasting, and inadequate nutritional therapy may affect nutritional intake as well, causing a progressive and widespread sarcopenia [6]. Because of this nutritional depletion, the risk of morbidity and mortality increases as well as the length of hospitalization and health care costs [7].

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 [8]. Since these IEFs may carry higher costs, selective and cautious use with patients has led to inconsistencies among practitioners or hospitals, possibly because of insufficient targeted evidence-based guidelines advocating or supporting enteral immunonutrition (IN) in esophageal resection patients [9].

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) [10]. As well, the manuscript will be submitted for publishing in a peer-reviewed journal or the findings presented at a relevant conference.

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 (Textbox 1).

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.

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 (Multimedia Appendix 1), which can be adjusted for other databases. Where appropriate, subject strategies will be combined with adaptations of the highly sensitive search strategy for identifying RCTs as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [14]. Additionally, during the searching process, consideration will be given to the different terminology used and the spelling of keywords as they may influence the identification of relevant studies.

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 .

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 (Multimedia Appendix 4). Also, numbers needed to treat for benefit or harm could be calculated as needed. Continuous data will be presented as mean, mean difference, or standardized mean difference with 95% CI, as applicable, excluding the nutritional status outcome measure, as it is represented exclusively as dichotomous variable. If a specific study does not report standard deviations, these will be calculated from the standard error and the sample size or the 95% CI. Finally, a P value of <.05 for both continuous and dichotomous variables will be considered statistically significant (Multimedia Appendix 4).

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 (Multimedia Appendix 5). Hence, clinical heterogeneity will be reported using subgroup (pre-, peri-, and postoperative subgroups using IEF; well-nourished vs malnourished patients’ subgroups). Sensitivity analysis might also be calculated by restricting the analysis to trials classified as having an overall low risk of bias, which will help determine whether excluding studies at high risk of bias affects the results of the meta-analysis [13,15,16].

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 [2]. Hence, values of 25%, 50%, or 75% will denote low, moderate, or high levels of heterogeneity respectively [2].

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 [14]. Thus, the meta-analysis will characterize the effect of the dichotomous and continuous outcomes.

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 Grading of Recommendations Assessment, Development and Evaluation working group methodology. Therefore, the quality of evidence will be assessed across 5 domains: risk of bias, consistency, directness, precision, and publication bias. Additional domains may be considered where appropriate. High-quality evidence will be adjudicated when further research might be very unlikely to change the reviewer’s confidence in the estimate of effect; moderate quality if further research is likely to have a significant impact on the confidence and may change the estimate; low quality if further research is needed and is very likely to have an important impact and likely to change the estimate; and very low quality if there is considerable uncertainty about the estimate of effect.

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 [17]. Research has shown that IEFs enriched with a combination of Arg, omega-3 fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), RNA, and antioxidants [18], can act pharmacologically on the immune system and potentially improve the patient’s immune response [9]. Furthermore, providing patients with peri-operative IEF has shown to favorably modulate the inflammatory, metabolic, and immune response after upper GI surgery [19,20]. These effects generated on the immune system modulated through specific nutrients are called immunonutrition.

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 [21]. Since this IEF offers the combination of immunonutrients in one product, it has been implemented in a wide range of surgical and trauma patients [22] to significantly reduce POICs by 39%-61%, LOS by 2 days [23], antibiotic use, and health-related costs [18]. Several studies have shown positive outcomes among GI surgical patients, where anastomotic leaks were 46% less prevalent when these IEFs were part of the pre-operative nutrition care plan [3,18,21,23,24]. Additionally, it has been found that LOS and POIC in malnourished (upper and lower) GI cancer patients significantly decreased when a “5-7-day peri-operative approach” was implemented with IEF over SEF [18,25,26]. Thus, nutrition support of surgical patients with malnutrition should not only include the adequate quantity but also the nutrient quality, type, and prescription timeframe to support the patient’s recovery, postoperative outcomes, and reduce health care costs [20,27-29]. In terms of health care cost-benefit analysis, the implementation of IN in surgical patients resulted in savings of US $3300 per patient based on the reduction of POIC rates [22] and reported savings of up to US $6000 per patient, based on the shortening of LOS [16], showing that enteral IEFs are a beneficial and cost-effective intervention.

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 [7,16,21,30]. However, the effect of a particular combination of immunonutrients (Arg, omega-3, and RNA) and its overall effect on postesophagectomy outcomes have not been systematically reviewed. Hence, there is a lack of sufficient, recent clinical evidence supporting the use of IEFs in esophagectomy patients. Evaluation of the studies identified in this review has merit because the review will aim to provide the most up-to-date evidence-based nutrition statements regarding pre-, peri-, and postoperative enteral IN effects on postesophagectomy outcomes.