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Abstract
Introduction One of the topics that show differences of opinion in the scientific field of nutrition is the recommendation by clinical practice guidelines (CPGs) of an immunomodulatory diet with arginine, nucleotides and omega-3 for individuals diagnosed with cancer undergoing major surgery. The quality of the recommendations is directly related to credibility, transparency and rigour in their development, but also to the quality of the studies published and available for inclusion in the recommendation, such as systematic reviews (SRs) and randomised clinical trials. The aim of this study is to evaluate the methodological quality of the recommendation of perioperative immunomodulatory supplementation for individuals with gastrointestinal and head and neck cancer, the CPGs, and the studies that support the recommendations.
Methods and analysis We will conduct a systematic search for CPGs. Recommendations for nutritional supplementation with immunomodulatory substrates for individuals undergoing major oncological surgery will be analysed using the Appraisal of Guidelines Research and Evaluation-Recommendations Excellence tool. CPGs will be analysed using the Appraisal of Guidelines Research and Evaluation II tool. The SRs cited in the recommendations will be analysed using the A Measurement Tool to Assess Systematic Reviews II tool and additional questions regarding heterogeneity in reviews. The clinical trials cited in the SRs and in the guideline recommendations (when applicable) will be analysed according to questions regarding heterogeneity in trials. The results will be presented in tables or charts using descriptive analyses.
Ethics and dissemination The results of this study will be disseminated through relevant conferences and peer-reviewed journals.
Protocol registration number 10.17605/OSF.IO/X2GYT.
- NUTRITION & DIETETICS
- EPIDEMIOLOGY
- Protocols & guidelines
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Strengths and limitations of this study
A strength of this study is the broad systematic search in databases, repositories and websites related to the topic.
Another strength is the quality analysis using validated tools and criteria established in the literature.
The methodology can be applied to other topics in nutrition and health.
Possibility of qualification by the researcher in evaluations that presuppose a judgement, during the application of the tools that will be used to evaluate the studies.
Introduction
Research in nutrition is among the most controversial areas of science and has gained prominence in meta-research studies, a relatively new field that aims to analyse scientific questions that are not yet fully understood, aspects of the scientific method that need improvement, or those that have not been assessed with appropriate methodology.1 2
Among the nutrition topics that exhibit divergence of opinions is the recommendation of an immunomodulatory diet with arginine, nucleotides and omega-3 for individuals diagnosed with cancer undergoing major surgery.3 Despite clinical practice guidelines (CPGs) in nutrition recommending perioperative nutritional therapy with a diet containing immunomodulatory substrates (arginine, ω-3 fatty acids and nucleotides) for 5−7 days before and after the surgical procedure,4–6 it seems unclear whether the studies supporting these recommendations are robust, particularly regarding data generalisability.7 8
Reviews that have assessed this topic indicate that scientific evidence presents a high degree of uncertainty, primarily due to differences in methodological designs, the lack of definition regarding the nutritional status of the evaluated patients, the type of nutrition in the control group and the absence of blinding in the studies.3 7 8 Conversely, studies that consider these aspects do not find promising results with the supplementation of immunomodulatory substrates.9 10
The aspects presented by these studies are related to clinical heterogeneity stemming from the variability among participants, interventions and control groups, which can interfere with the potential effects of the intervention11 and should be taken into account by researchers.12 In nutrition, these and other aspects have been mentioned by the Agency for Healthcare Research and Quality (AHRQ) as specific criteria in the field of nutrition science that should be considered in the development and evaluation of systematic reviews (SRs) in nutrition.13
Currently, CPGs are used as a reference for the clinical practice of all healthcare professionals. However, their publication alone is not synonymous with absolute certainty.14 Their quality is directly related to credibility, transparency and rigour in their development, but also to the quality of the studies published and available for inclusion in the recommendation, such as SRs and randomised clinical trials (RCTs).14 15
Poorly conducted SRs and RCTs can also contribute to imprecise interpretations and estimates of evidence, and consequently, the effectiveness of treatments and reduced applicability. Therefore, it can be said that the reliability of a recommendation depends on a flow of scientific production with high methodological rigour, from the primary study to the recommendation.13 15
Therefore, to identify the direction of the duality of the issue at hand, the aim of this work is to map the CPGs and studies that substantiate recommendations for supplementation with immunomodulatory substrates in the perioperative period of tract gastrointestinal surgery—head and neck, gastric, colon and rectal to answer the following questions:
What is the methodological quality of the immunomodulatory supplementation recommendation, CPGs and the SRs that substantiate them according to the tools: Appraisal of Guidelines Research and Evaluation-Recommendations Excellence (AGREE-REX), Appraisal of Guidelines Research and Evaluation (AGREE) II and A Measurement Tool to Assess Systematic Reviews (AMSTAR) II in individuals undergoing elective oncological surgery of gastrointestinal tract—head and neck, gastric, colon and rectal?
What are the methodological criteria considered by SRs and RCTs that substantiate recommendations regarding the heterogeneity in population, control group and intervention?
Methods and analysis
Study protocol
The recommendations of nutritional supplementation with immunomodulatory substrates for individuals undergoing major oncological surgery will be analysed using the AGREE-REX tool.16 CPGs will be analysed using the AGREE II tool.15 The SRs cited in the recommendations will be analysed using the AMSTAR II tool17 and questions presented in diagram I. The clinical trials cited in the SRs and in the guideline recommendations (when applicable) will be analysed according to questions presented in diagram II. Figure 1 presents the overall scheme of the study protocol and diagrams I and II will be presented in the following sections and correspond to figures 2 and 3.
Study protocol. AGREE, Appraisal of Guidelines Research and Evaluation; AGREE-REX, Appraisal of Guidelines Research and Evaluation-Recommendations Excellence; AMSTAR, A Measurement Tool to Assess Systematic Reviews; PISR, Perioperative Immunomodulatory Supplementation Recommendation.
Diagram I of the analysis of the heterogeneity aspects of the systematic review.
Diagram II of the analysis of the heterogeneity aspects of the clinical trial. *Food intake, use of other supplementation, use of concomitant oral or enteral diet.
Systematic search
A systematic search of the CPGs will be conducted. The research question and the CPG selection process were structured in the PICAR acronym format (online supplemental appendix 1),18 corresponding to: ‘What is the methodological quality of the recommendations for supplementation with immunomodulators for individuals undergoing major oncological surgery in the CPGs?’
Supplemental material
The searches will be conducted in three data sources: (a) bibliographic databases: MEDLINE (PubMed), EMBASE, LILACS, SCOPUS and Web of Science; (b) CPG repositories: Central Guidelines, Scottish Intercollegiate Guidelines Network, National Institute for Health and Care Excellence, AHRQ, Grading of Recommendations Assessment, Development and Evaluation (GRADEpro), Guideline International Network, Canadian Medical Association Guidelines, NZ Great Going, National Health and Medical Research Council; and (c) scientific organisations related to the topic: American Society for Clinical Oncology, European Society for Medical Oncology, Brazilian Society of Parenteral and Enteral Nutrition, American Society for parenteral and Enteral Nutrition and European society for parenteral and enteral nutrition.
For the bibliographic databases, both MeSH terms and free-text terms will be used. The search strategy will be adjusted according to the different databases, and the entire process has been reviewed by a specialised librarian from the Federal University of Santa Catarina.
For the CPG repositories and scientific organisations related to the topic, the search will be manual according to pre-established criteria (online supplemental appendix 2). The entire process will be conducted by two independent reviewers, the results will be compared, and there will be no restrictions on the publication period or language for the searches.
Eligibility
The records captured from the databases and identified on the corresponding websites will be downloaded and transferred to the Zotero reference manager for duplicate removal. The selection of CPGs records will be carried out using the online software Rayyan,19 first will be selected for titles and abstracts, and then a full-text reading will occur for evaluation according to eligibility criteria using forms created on the Google Forms platform. The entire selection process will be documented with sufficient details to complete the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart.20
Table 1 presents the inclusion criteria for CPGs in the study, according to the acronym PICAR.18 The following definition for CPG (Decision and Policy Case) has been adopted: ‘Statements that include recommendations aimed at optimizing patient care that are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options’.21
Eligibility criteria for selecting clinical practice guidelines (CPGs) according to the acronym PICAR
For major surgeries, surgical procedures performed in the following locations will be considered: head and neck, gastric, colon and rectum. The choice of these locations is due to the indication of nutritional supplementation with immunomodulators being intended for major surgeries and routinely directed at this population.22 CPGs that present recommendations for the use of supplementation for other procedures will be listed but not analysed.
The immunomodulator substrates considered in the supplementation recommendations are arginine, nucleotides and omega-3 administered together or separately.
For the exclusion criteria, only aspects related to the attributes of the CPGs will be considered:
Previous CPGs from the same guideline.
Adaptation CPGs (eg, shortened) or rapid CPGs.
CPGs focused solely on parenteral nutrition therapy.
CPGs in a language other than Portuguese, English, French and German (three languages are spoken by at least one of the authors of this study).
Subsequently, the SRs cited in the perioperative immunomodulatory supplementation recommendation will be retrieved and, finally, the RCTs cited by the SRs of the perioperative immunomodulatory supplementation recommendation (if applicable) will be retrieved.
Data extraction
The entire data extraction process will be carried out by two independent reviewers using forms specifically constructed for data collection in this research. The forms will be created on the Google Forms platform. Before commencing the extraction, the reviewers will be calibrated through a pilot test with 3–4 studies for SRs and RCTs, and with one study for CPGs.
For the characterisation of CPGs, the following data will be collected: title, year, authors, organisation, version of guideline (original or update), country, scope (national or international), target population, language, consensus methods (formal or informal), recommendation (timing and dosage), characteristics of the target population for the recommendation (tumour location, nutritional status, etc), recommendation level, types of studies included in the recommendation, funding source and participation of researchers in the field of nutrition.
Subsequently, for the characterisation of the SRs, the following data will be extracted: title, year, authors, country, protocol registration of the review, types of included studies, review question, eligibility criteria for population, intervention and control groups, bias risk and quality assessment method, funding sources, and presence of researchers in the field of nutrition. The following definition for SRs has been adopted: articles that explicitly stated methods to identify studies (ie, a search strategy), explicitly stated methods of study selection (eg, eligibility criteria and selection process) and explicitly described methods of synthesis (or other types of summary).20
Finally, for the characterisation of the RCTs cited by the SRs the following primary study characterisation data: title, year, authors, country, study registration, design, setting (hospital, outpatient or both), study objective, population of interest, eligibility criteria (inclusion and exclusion), randomisation type, allocation concealment, level of blinding (participants, assessors and researchers), intervention details (dose, time, timing and administration route), control group details (dose, time, timing and administration route), evaluated outcomes and assessment timing, outcome assessment method. Additionally, the following data will be collected: nutritional status assessment, method of nutritional status assessment, assessment of dietary intake in the evaluated groups, disease staging.
Quality assessment of the recommendation and CPGs
The recommendations will be analysed using the AGREE-REX tool,16 which assesses the credibility and applicability of CPGs recommendations. It consists of three domains with nine items: clinical applicability (domain 1), values and preferences (domain 2) and implementability (domain 3), along with one item for the overall assessment of quality. This is important to ensure that the guideline recommendations are clinically reliable and implementable. The evaluation will be conducted independently by three reviewers using forms developed on the Google Forms platform exclusively for this research. The results will be compared, and any discrepancies will be resolved by a fourth reviewer.
The CPGs will be analysed using the AGREE II tool,15 which critically assesses the methodological rigour and reports the quality of the guidelines. AGREE II consists of six domains with 23 items: scope and purpose (3 items), stakeholder involvement (3 items), rigour of development (8 items), clarity of presentation (3 items), applicability (4 items) and editorial independence (2 items), along with 1 item for the overall assessment of the quality of the DPCs and whether they are recommended for use. The evaluation will be conducted independently by three reviewers using the ‘My AGREE Plus’ platform. The results will be compared, and any discrepancies will be resolved by a fourth reviewer.
Each item in the AGREE-REX and AGREE II tools will be assessed and rated on a 1 to 7-point Likert scale, where 1 (strongly disagree) and 7 (strongly agree). The score for each domain will be calculated by summing all the scores of the individual items within the domain and then scaling the total as a percentage of the maximum possible score for that domain. This will be done using the formula (obtained score−minimum possible score)/(maximum possible score−minimum possible score)×100%. The minimum and maximum scores will be calculated by multiplying one (strongly disagree) or seven (strongly agree) by the number of items in the domain and the number of assessors, respectively. The standardised percentage for each domain ranges from 0% to 100%. The domain scores will be useful for comparing guidelines and providing recommendations on whether a guideline should be recommended or not.
Quality assessment of the SRs
AMSTAR II tool
The SRs with or without meta-analysis cited in the CPGs recommendations will be analysed using the AMSTAR II tool.17 This tool assesses the methods used in a review through 16 criteria, including 7 critical items (registered protocol before the start of the review, adequacy of literature search, justification for excluding individual studies, risk of bias in individual studies included in the review, adequacy of meta-analytical methods, consideration of bias risk in interpreting review results, assessment of the presence and likely impact of publication bias). The critical items will be analysed taking into account the specificities of the topic. The possible response options for applying the tool include: yes, no and partially yes. At the end of the tool application, an overall classification of the SR will be made as follows:
High: no or one non-critical item: the review provides an accurate and comprehensive summary of the results of available studies addressing the question of interest.
Moderate: more than one non-critical item: the review has more than one weak point but no critical flaws. It may provide an accurate summary of the results of available studies that were included in the review.
Low: one critical item with or without non-critical items: the review has a critical flaw and may not provide an accurate and comprehensive summary of available studies addressing the question of interest.
Critically low: one critical item with non-critical items: the review has more than one critical flaw and should not be considered to provide an accurate and comprehensive summary of available studies.
The assessment will be conducted independently by two reviewers using a form created in Google Forms. The results will be compared, and any discrepancies will be resolved by a third reviewer.
Aspects of heterogeneity in SRs
The SRs with or without meta-analysis will also be analysed for aspects of heterogeneity using the diagram I presented in figure 2.
Description of studies selection of SR
Population: investigation on whether the authors considered the location of the tumour, the nutritional status of the individuals and the disease staging in the selection of the studies.
Intervention: investigation on whether the authors considered the types of immunomodulators, the administration route of supplementation, the volume/quantity of supplementation, and the duration of supplementation in the selection of the studies.
Comparator: investigation on whether the authors considered any comparison group in the selection of the studies.
Description of the analyses of SR
Investigation on whether the aspects of heterogeneity in relation to population, intervention and control group mentioned above were analysed by the authors such as exclusion criteria, sensitivity analysis, subgroup analysis, meta-regression, were not considered in the analysis or presented in the Discussion.
Investigation on whether the authors have published a study protocol with a description of the analyses and any changes to the protocol. The protocol number reported in the manuscript will be considered.
Description of funding and conflict of interest in the SR
Type of funding, classified as: ‘non-profit’, ‘for-profit’, ‘mixed’, ‘no funding’ or ‘not reported’. We will classify ‘for-profit’ and ‘mixed’ types of funding as ‘food industry’ or ‘other industry’.
Conflicts of interest of study authors as disclosed in any of the study materials, classified as: ‘conflict of interest present’, when at least one author reported any conflict of interest. Present conflicts of interest will be classified as: ‘financial’ or ‘non-financial’.
Affiliation of the corresponding author, classified as: ‘industry’ or ‘non-industry’ or ‘mixed’.
The assessment will be conducted independently by two reviewers using a form created in Google Forms. The results will be compared, and any discrepancies will be resolved by a third reviewer.
Aspects of heterogeneity in clinical trials
The RCTs and non-RCTs will be analysed regarding the aspects of heterogeneity considered in the selection and analysis of the population, intervention and control group, as presented in the diagram II shown in figure 3.
Population: investigation on whether the authors considered the location of the tumour, the nutritional status of the individuals and the disease staging in the study.
Intervention: investigation on whether the authors considered the estimated nutritional requirements; confounding factors (food intake, use of other supplementation, use of concomitant oral or enteral diet) and treatment adherence analysed in the in the study.
Comparator: investigation on whether the authors considered an adequate comparator group. Inadequate comparators: intravenous fluids or crystalloids, or no intervention.12 23
Will be identified whether the authors have published a study protocol/registry with a description of the process and any changes to the protocol. The protocol number reported in the manuscript will be considered.
Data synthesis
The results will be presented in tables or charts using descriptive analyses based on the questionnaires of the tools used for the study analysis, as well as the results from the diagram application. For categorical variables, will be presented the raw numbers and proportions in each response category. For continuous variables, will be presented means, SD, medians and IQRs. The analyses will be conducted using Stata software V.14.0.
Development of the project
The project was initiated in December 2023 and is currently in phase I of analysing the CPGs, with an expected completion date in February 2025.
Patient and public involvement
None. Patients and/or the public will not be involved in the design, conduct, reporting or dissemination plans of this research.
Ethics and dissemination
Patients and/or the public will not be involved this research. The results of this study will be disseminated through relevant conferences and peer-reviewed journals.
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
X @arthurthives
Contributors LPdL: conceptualisation, methodology, writing - original draft preparation, writing - review and editing. ATM: conceptualisation, methodology, writing - review and editing. GMN: conceptualisation, methodology, writing - review and editing. EBSdMT: conceptualisation, methodology, writing - review and editing.
Funding This work is supported by the Brazilian Coordination for the Improvement of Higher Education Personnel – CAPES scholarship (process number 164700/2015-3). The funding source did not influence the content of this study.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.