Heterogeneity of nutrition care procedures in nutrition guidelines for cancer patients

Clinical Nutrition xxx (xxxx) xxx

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Review

Heterogeneity of nutrition care procedures in nutrition guidelines for cancer patients Xiao-Hu Zhao a, Ting Yang a, b, 1, Xu-Dong Ma a, b, 1, Yu-Xing Qi a, b, Yue-Ying Lin a, b, Xiong-Zhi Chen a, b, ***, 2, Yong-Qing Duan a, b, **, 2, Da-Li Sun a, b, *, 2 a b

Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China Yunnan Research Center for Surgical Clinical Nutrition, Kunming, 650101, Yunnan, China

a r t i c l e i n f o

s u m m a r y

Article history: Received 20 March 2019 Accepted 22 August 2019

Objectives: The aim of this study was to systematically assess the nutrition care procedures in nutrition guidelines for cancer patients and identify gaps limiting evidence-based practise. Methods: A systematic search of databases and websites was conducted to identify nutrition guidelines for cancer patients. The quality of the eligible guidelines was evaluated by using the Appraisal of Guidelines for Research and Evaluation (AGREE II). The Measurement Scale of Rate of Agreement (MSRA) was used to assess the scientific agreement of formulated recommendations for nutrition care procedures in the guidelines (2017e2019), and evidence supporting these recommendations was extracted and analysed. Results: Seventeen nutrition guidelines for cancer patients were identified. Only European Society for Clinical Nutrition and Metabolism (ESPEN) and Australian guidelines have a total quality score of more than 60%, which is worthy of clinical recommendation. Twelve guidelines (2017e2019) were included to further analyse the heterogeneity and causes of nutrition care procedures, and we found that the content and tools of nutrition screening and assessment, the application of immune nutrients, and the selection of nutritional support pathways were heterogeneous. The main reasons for the heterogeneity of nutrition care procedures were insufficient attention to nutrition risk screening, differences in recommendations for nutrition assessment, immune nutrients and nutritional support, unreasonable citation of screening and assessment evidence, preference of developers, and lack of evidence of high-quality research on energy and nitrogen demand. In addition, the fairness and propensity of the guidelines for the selection of evidence for different cancer patients are also potential reasons for the heterogeneity of nutritional care procedures. Conclusions: The quality of the nutrition guidelines for cancer patients was highly variable. The nutrition care procedures were heterogeneous among the different guidelines in the last 3 years. Specific improvement of the factors leading to the heterogeneity of nutrition care procedures will be a reasonable and effective way for developers to upgrade the nutrition care procedures in the guidelines for cancer patients. © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Keywords: Cancer Malnutrition Guidelines Nutrition care procedures Quality

1. Background * Corresponding author. Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China. ** Corresponding author. Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China. *** Corresponding author. Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China. E-mail addresses: [email protected] (X.-Z. Chen), [email protected] (Y.-Q. Duan), [email protected] (D.-L. Sun). 1 Authors contributed equally to this work. 2 Fax: þ0871 6535 1281.

The International Agency for Research on Cancer (IARC) reported the latest global cancer data: the cancer burden increased to 18.1 million new cancer cases and 9.6 million cancer deaths in 2018, and the IARC predicts that population growth and ageing will further increase the cancer burden [1]. Malnutrition is relatively common in cancer patients, with weight loss rates ranging from 15% to 40% among different types of cancer, and the overall incidence of malnutrition in cancer patients

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Please cite this article as: Zhao X-H et al., Heterogeneity of nutrition care procedures in nutrition guidelines for cancer patients, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.08.022

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Abbreviations ESPEN ASPEN CSPEN SFNEP CSONSC CRNG CSNO CNSCNG GST PTChO CCAW GRADE NCCN EGRRS OCEBM NHMRC SCCM USPSTF HNC

European Society for Clinical Nutrition and Metabolism American Society for Parenteral and Enteral Nutrition Chinese Society for Parenteral and Enteral Nutrition French Speaking Society of Clinical Nutrition and Metabolism Chinese Society for Oncological Nutrition and Supportive Care Cancer Radiotherapy Nutrition Group China Society for Nutritional Oncology Chinese Nutrition Society for Cancer Nutrition working Group Gastroenterological society of Taiwan Polish Society of Surgical Oncology Cancer Council Australia Wiki platform Grading of Recommendations Assessment Development and Evaluation National Comprehensive Cancer Network EAL Guideline Recommendation Rating System Oxford Centre for Evidence-based Medicine-Levels of Evidence National Health and Medical Research Council Society of Critical Care Medicine US Agency for Healthcare Research and Quality Service Grading System Head and neck cancer

can be as high as 39% [2]. Indeed, the incidence of malnutrition is associated with cancer type, location, stage, and treatment [3]. Malnutrition in cancer patients increases the complications of infection, prolongs the hospital stay, shortens the patient survival time and reduces the quality of life of the patients [4]. Nutritional support has been indicated to improve these adverse clinical outcomes [5e7]. However, in clinical practise, because of the complexity of nutrition screening, assessment and intervention, it is a great challenge for professionals to master standardized nutritional care procedures. As a result, a large number of local, national and international organizations of experts in the relevant fields have developed various nutritional support guidelines for cancer patients [8e24]. The ideal guideline for cancer nutrition is based on high-quality evidence that can help clinicians and policy makers decide how to better evaluate and treat malnutrition. However, the users of clinical guidelines are confused by the vague descriptions of screening and assessment concepts and tools, controversial recommendations and different sources of evidence in these guidelines [8e24]. Therefore, we aimed to determine the methodological quality of the current nutrition guidelines for cancer patients, reveal heterogeneity in the recommended steps for nutrition care procedures and discuss the potential reasons for this heterogeneity. 2. Methods 2.1. Study design This study was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [25]. We used the AGREE II instrument to conduct a

U.K. U.S. UG ICC SD AGREE II

The United Kingdom The United States Ungraded Intra-class correlation coefficient Standard deviation The Appraisal of Guidelines for Research and Evaluation II NRS 2002 Nutritional risk screening 2002 MUST The malnutrition universal screening tool MST Malnutrition screening tool MSRA Measurement scale of rate of agreement MNA-SF Mini nutritional assessment short form PG-SGA Patient-generated subjective global assessment SGA Subjective global assessment MNA Malnutrition universal screening tools u-3 PUFA u-3 polyunsaturated fatty acid NGT Nasogastric tube NIT Nasointestinal tube PEG Percutaneous endoscopic gastrostomy PEJ Percutaneous endoscopic jejunostomy SG Surgical gastrostomy SJ Surgical jejunostomy HPN Home parenteral nutrition DC Dietary counselling EN Enteral nutrition PN Parenteral nutrition ONS Oral nutrition supplements

comprehensive evaluation of the methodological quality of the guidelines for nutritional support for cancer patients and to evaluate the rigour and transparency of the nutritional care procedures. 2.2. Data sources and literature selection process A systematic search was performed to retrieve relevant guidelines regarding nutrition for cancer patients. Relevant guidelines published between January 1, 2009 and January 1, 2019 were identified by searching electronic databases, namely, PubMed, Web of Science, Wiley Online Library, CNKI and WanFang Data. Considering that all guidelines might not be available in the abovementioned databases, Google, Baidu, ASPEN (www. nutritioncare.org), ESPEN (www.espen.org), FELANPE (www. felanpeweb.org) and PENSA (www.pensa-online.org) were also searched. A broad range of literature was gathered to retrieve all malnutrition-related guidelines, irrespective of disease. The search used a broad strategy that combined the following terms: “nutrition/enteral nutrition/parenteral nutrition/enteral feeding/oral feeding/artificial nutrition” or “cancer/tumour/carcinoma” and “consensus/guideline”. The guideline selection was based on title or abstract, and when there was disagreement or doubt about the eligibility of a specific guideline, the complete guideline was retrieved and discussed in a consensus meeting. The second reviewer had the casting vote to resolve doubt about the eligibility of a guideline. We developed a series of inclusion criteria to select the guidelines: (1) the target group included cancer patients; (2) the guidelines focused on nutrition support; (3) the full text was available online or in a book; (4) the guidelines were written in English or Chinese; and (5) the latest version was available if the guideline had updated versions.

Please cite this article as: Zhao X-H et al., Heterogeneity of nutrition care procedures in nutrition guidelines for cancer patients, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.08.022

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Guidelines were excluded according to the following criteria: (1) duplicate guidelines, (2) editorials about guidelines, (3) short summaries of guidelines, (4) outdated guideline versions, and (5) narrative reviews. 2.3. Quality appraisal of the guidelines The guidelines were reviewed based on the latest English version of the AGREE II instrument (2017 version) (http://www. agreetrust.org/) [26], which is a validated assessment instrument designed to provide a framework for the evaluation and monitoring of clinical guidelines that can be used to measure and quantify guideline quality. The AGREE II instrument consists of 23 items in the following 6 domains: Domain 1. Scope and Purpose is concerned with the overall aim of the guideline, the specific health questions, and the target population (items 1e3). Domain 2. Stakeholder Involvement focuses on the extent to which the guideline was developed by the appropriate stakeholders and represents the views of its intended users (items 4e6). Domain 3. Rigour of Development relates to the process used to gather and synthesize the evidence, the methods to formulate the recommendations, and to update them (items 7e14). Domain 4. Clarity of Presentation deals with the language, structure, and format of the guideline (items 15e17). Domain 5. Applicability pertains to the likely barriers and facilitators to implementation, strategies to improve uptake, and resource implications of applying the guideline (items 18e21). Domain 6. Editorial Independence is concerned with the formulation of recommendations not being unduly biased with competing interests (items 22e23). Each domain was rated individually by four reviewers (D.L.S, X.H.Z, Y.Y.L and Y.X.Q). Among the 4 reviewers, D.L.S, T.Y, Y.Y.L and Y.X.Q hold degrees in clinical nutrition and have extensive experience evaluating clinical nutrition guidelines. The aforementioned reviewers were trained to use the AGREE II instrument by using the AGREE online tutorials and were blinded to the ratings of the other reviewers. Each item of the AGREE II instrument focused on one key independent aspect of guideline quality. Each item is rated on a 7-point scale: 1 ¼ strongly disagree to 7 ¼ strongly agree. A score of 1 was given when little or no relevant information was presented. Scores from 2 to 6 were given when the statements did not fully meet the criteria or considered only one item in the criteria, and the scores increased as the criteria were more closely met or when greater consideration was provided. A score of 7 was given when the statement met all criteria or fully considered their standards. All items with a score difference of more than 2 or 3 between reviewers were discussed further. Finally, one reviewer summed all of the scores of the individual items to calculate each domain score using the following formula: (obtained score  minimum possible score)/(maximum possible score e minimum possible score)  100%. The overall assessment also included whether the guideline was recommended for clinical application [27]. After the assessment of 23 items and the comprehensive judgement by reviewers, the evaluated guidelines were divided into three categories according to AGREE II score, namely, recommended, recommended with some modifications, or not recommended. The AGREE II manual does not provide guidance regarding how to interpret scores. To promote consistency with extant studies that have used the AGREE II instrument [28] and given the recommendations of the level of evidence among all included guidelines, we adopted the following method [28]: guidelines receiving a standardized score of >60% were recommended, guidelines receiving an overall assessment of 30%e60% were recommended with modifications, and guidelines with an overall assessment of <30% were not recommended.

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2.4. Assessment of the heterogeneity of nutritional care procedures Considering that nutritional knowledge in oncology has been greatly updated over a 10-year period, the heterogeneity of evidence and recommendations is evident. Therefore, to analyse the heterogeneity of nutritional care procedures, we extracted recommendations and evidence about nutritional care procedures from the nutrition guidelines for cancer patients in the past three years, including the purposes, components, tools for nutritional risk screening and nutritional assessment, energy intake, protein/nitrogen intake, the nutritional support pathway and the immuneenhancing supplements. Similarities and differences in the scientific content of formulated recommendations for nutritional care procedures from the nutrition guidelines for cancer patients. The rate of agreement between guidelines was scored in each module by the use of the Measurement Scale of Rate of Agreement (MSRA) [29]: 0%e20%: Radically different 20%e40%: Numerous major differences 40%e60%: Some major differences 60%e80%: Only minor differences 80%e100%: Essentially identical Referring to the key recommendations for nutritional care procedures in the guidelines (the standardized score of quality of guidelines >60%), extracting recommendations and evaluating agreement, further extraction and analysis of the highest level of evidence to support these recommendations (MSRA >60%) was carried out [29]. The evidence was reclassified by using the Oxford Centre for Evidence-Based Medicine (OCEBM) grading system. Detailed information about the evidence classification method is presented in Table S1. 2.5. Statistical analysis We used a descriptive statistical analysis method to calculate the standardized scores for each domain, which were expressed as a percentage, and we also listed the median scores and the range of each domain. In addition, the number of recommendations and the distribution of the levels of evidence were also expressed as percentages, and we adopted a two-way ANOVA to calculate the intra-class correlation coefficients (ICCs) to examine the agreement among the scores from the four evaluators. An ICC between 0.01 and 0.20 was deemed a minor agreement, 0.21 to 0.40 was fair, 0.41 to 0.60 was moderate, 0.61 to 0.80 was substantial, and 0.81 to 1.00 was very good [30]. A value of P < 0.05 was considered statistically significant. Statistical analyses were conducted using SPSS version 17.0 (SPSS Inc., Chicago, USA). 3. Results 3.1. Guideline characteristics According to the retrieval strategy and keywords, we searched electronic databases and websites and consulted references. A total of 273 records were obtained. Ultimately, seventeen guidelines were included for evaluation [8e24] (Fig. 1). Table 1 presents the detailed information of all of the included guidelines. Ten guidelines were developed by the local or international professional medical associations [8e13,19,22e24], and seven were developed by individuals [14e18,20,21]. Developers of all guidelines included nutritional specialists. Of the seventeen guidelines included, fourteen adopted different grading systems [8e12,15,16,18e20,22e24], two did not have any evidence rating system [13,17] and one had an unclear system [14] (Table 1).

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IdenƟficaƟon

4

Electronic databases searches (n=269)

Records iden fied from manual searches (n =4)

Screening

(n =273) 58 excluded -Duplicated records (n=58) 215 records screened by tle and abstract

Included

Eligibility

170 excluded -Duplicated records (n=11) -Narra ve review (n=19) -Irrelevant records (n=139) 45 records assessed by full text for eligibility

Included guidelines for quality appraisal (n = 17)

28 excluded -Not the latest version (n=6) - Mee ng summary (n=2) - Different chapters of the same guideline (n=4) -Review or others (n=16)

4 guidelines were published before 2017 The key reccomenda ons and evidence of 12 guidelines (20172019) were extracted and analyzed Fig. 1. PRISMA 2009 flow diagram.

3.2. Quality evaluation of the guidelines The results of the assessment of the methodological quality of all included guidelines using the AGREE II tool are illustrated in Table 2. The scope and purpose and clarity of presentation domains obtained relatively respectable median scores of 78.5% (range, 40.3e97.2%) and 79.4% (range, 58.3e95.8%), respectively. The stakeholder involvement and editorial independence domains obtained roughly analogous scores, which were 39.4% (range, 15.3e90.3%) and 36.7% (range, 0e100%), respectively. The median score for rigour of development was 45.5% and ranged from 13.0% to 93.2%. Unfortunately, the applicability domain achieved the lowest median score, which was 24.2% (range, 4.2%e93.8%). Finally, according to the scores, we provided an overall recommendation. The detailed overall assessment of each guideline is listed in Table 2. Remarkably, there were two guidelines with relatively perfect scores of more than 60% in every domain; these guidelines were developed by ESPEN and Australia guidelines [8,12]. There were eleven guidelines with overall assessment scores between 30 and 60% [9e11,15e19,22,23]; these guidelines fell into the recommended category but still need to be improved. There were four guidelines with overall scores of less than 30% [13,14,20,24], and these guidelines are not recommended for application. Four evaluators participated in the evaluation of the cancer nutrition guidelines. In this study, the ICCs for the AGREE II

evaluation conducted by the four evaluators were greater than 0.8, which indicated that the intra-evaluator item score agreement was high (Table 2). 3.3. Heterogeneity of the recommendations and evidence for nutrition care procedures in the nutrition guidelines for cancer patients (2017e2019) To further analyse the reasons for the heterogeneity of the recommendations for nutrition care procedures in different guidelines, referring to the key recommendations of nutrition care procedures in two high-quality guidelines [8,12], the recommendations were extracted and evidence supporting these recommendations was analysed in 12 guidelines (2017e2019) (Table 3 and Table S2). To further analyse the differences of the key recommendations among guidelines (2017e2019), MSRA was introduced [29], and ESPEN guidelines [8] were the comparison standard. The results are shown in Table 4. If the scientific agreement of formulated recommendations was 60%, then the highest evidence in support of the recommendation was extracted and reclassified by using OCEBM (Fig. 2). Recommendations and supporting evidence for nutritional risk screening are detailed in Table 3 and Table S2. Of the 12 guidelines, 10 guidelines recommending nutritional risk screening, four guidelines suggested BMI, weight loss and food intake as screening

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Table 1 Description of the guidelines included in this study. Title

Author/Organization

Short name

Subject

Target Population

Grading system

Year, Country

ESPEN guidelines on nutrition in cancer patients

ESPEN [8]

ES

Clinical oncologists and health care providers involved in supportive care of cancer patients and cancer survivors

GRADE

2017, Europe

Paper Clinical nutrition guidelines of the SFNEP: summary of recommendations for adults undergoing nonsurgical anticancer treatment Nutritional support and parenteral nutrition in cancer patients: An expert consensus report Nutrition therapy in esophageal cancerconsensus statement of the gastroenterological society of Taiwan Consensus and clinical recommendations for nutritional intervention for head and neck cancer patients undergoing chemo-radiotherapy in Taiwan Nutritional management in head and neck cancer: United Kingdom National Multidisciplinary Guidelines Expert consensus on nutrition support therapy for head and neck cancer patients receiving radiotherapy Enteral nutrition in esophageal cancer patients treated with radiotherapy: a Chinese expert consensus 2018 Guidelines on nutritional support in patients with tumor

SFNEP [19]

SF

Translating current evidence and expert opinion into recommendations for multidisciplinary teams responsible for identification, prevention, and treatment of reversible elements of malnutrition in cancer patients Management of malnutrition in adult anticancer treatment especially for palliative and elderly patients

All health professionals interested in clinical nutrition such as physicians, nurses, pharmacists, dieticians, and students

SCCM

2014, France


n Breto
n MJ et al. [17] Oco

Oc

Clinicians

None

2018, Spain

GST [11]

GS

Not specified

OCEBM

2018, China

Lin MC et al. [15]

Lin

Management of malnutrition in head and neck cancer patients undergoing chemoradiotherapy

Not specified

OCEBM

2018, China

Talwar B et al. [20]

Ta

Management of malnutrition in head and neck cancer in U.K.

Clinicians

GRADE

2016, U.K.

CRNG, CSONSC [24]

CR

Management of malnutrition in neck cancer patients receiving radiotherapy

Not specified

NCCN

2018, China

Lv JH et al. [16]

Lv

Management of malnutrition in esophageal patients receiving radiotherapy

Not specified

OCEBM

2018, China

CSPEN [22]

CSP

Not specified

GRADE

2017, China

The enteral nutrition in radiotherapeutic cancer patients

Li T et al. [14]

Li

Clinicians, radiotherapists

Unclear

2017,China

Chinese nutrition therapy guidelines for cancer patients Consensus of experts on nutrition management in patients with malignant tumor during recovery period

CSONSC [10]

CSO

2015, China

CN

Clinicians, nursing workers, dietitians, pharmacists, health policy makers Clinicians, nurses, dietitian, cancer nutrition education and health management professionals

OCEBM

CNSCNG [23]

OCEBM

2017, China

PTChO [13]

PT

Management of malnutrition in malignant tumor patients undergoing radical, palliative treatment. Management of malnutrition in malignant tumor radiotherapy patients Management of malnutrition in malignant tumor patients Management of malnutrition in convalescent malignant tumor patients who have not received radiotherapy, chemotherapy or surgical treatment and are not in hospital Management of malnutrition in patients with malignant neoplasm in Polish hospital

Not specified

None

2015, Polish

Clinical nutrition in oncology: Polish recommendations

Addressing different issues related to nutritional management of cancer patients in clinical practise Management of malnutrition in esophageal cancer patients

(continued on next page)

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Table 1 (continued ) Title

Author/Organization

Short name

Subject

Target Population

Grading system

Year, Country

ASPEN Clinical Guidelines: nutrition support therapy during adult anticancer treatment and in haematopoietic cell transplantation Evidence-based practise guidelines for the nutritional management of adult patients with head and neck cancer SEOM clinical guidelines on nutrition in cancer patients (2018) Oncology evidence-based nutrition practise guideline for adults

ASPEN [9]

AS

Management of malnutrition in haematopoietic cell transplantation and cancer patients

Healthcare professionals such as physicians, dieticians, and nurses

Sackett DL

2009, U.S.

CCAW [12]

CC

Management of malnutrition in adult patients (>18 years old) with head and neck cancer

Health professionals, clinicians

NHMRC

2018, Australia

Penas R et al. [18]

Pe

Not specified

USPSTF

2019, Spain

Thompson KL et al. [21]

Th

Management of malnutrition in cancer patients Management of nutrition for adult oncology patients in ambulatory and acute care settings

Registered dietitian nutritionists

EAL

2017, U.S.

Evidence Analysis Library (EAL).

Table 2 AGREE II domain score and ICC of the included guidelines. Guideline

Scope and purpose

Stakeholder involvement

Rigour of development

Clarity and presentation

Applicability

Editorial independence

Overall assessment

ESPEN [8] SFNEP [19]
n Breto
n MJ et al. [17] Oco GST [11] Lin MC et al. [15] Talwar B et al. [20] CRNG, CSONSC [24] Lv JH et al. [16] CSPEN [22] Li T et al. [14] CSONSC [10] CNSCNG [23] PTChO [13] ASPEN [9] CCAW [12] Penas R et al. [18] Thompson K L et al. [21] ICC (mean ± SD) Median score (range)

97.2% 73.6% 79.1% 77.8% 86.1% 55.6% 73.6% 70.8% 72.2% 68.1% 79.2% 70.8% 51.4% 79.2% 95.8% 40.3% 86.1% 0.86 ± 0.14 78.5% (40.3e97.2%)

81.9% 34.7% 41.7% 44.4% 26.4% 16.7% 20.8% 19.4% 15.3% 16.7% 48.6% 48.6% 18.1% 37.5% 90.3% 20.8% 48.6% 0.95 ± 0.03 39.4% (15.3e90.3%)

88.0% 14.6% 20.3% 42.7% 48.4% 13.0% 17.2% 43.8% 54.2% 19.8% 52.6% 38.5% 14.1% 62.5% 93.2% 27.6% 77.8% 0.95 ± 0.03 45.5% (13.0e93.2%)

90.3% 70.8% 63.9% 84.7% 69.4% 79.2% 75.0% 86.1% 76.4% 58.3% 66.7% 62.5% 66.7% 80.6% 95.8% 63.9% 80.6% 0.85 ± 0.07 79.4% (58.3e95.8%)

72.9% 4.2% 8.3% 14.6% 15.6% 21.9% 6.3% 40.6% 13.5% 5.2% 16.7% 11.5% 33.3% 9.4% 93.8% 5.2% 14.6% 0.96 ± 0.02 24.2% (4.2%e93.8%)

97.9% 77.1% 39.6% 0.0% 41.7% 0.0% 0.0% 83.3% 0.0% 2.1% 77.1% 0.0% 0.0% 0.0% 100.0% 68.8% 0.0% 1.00 ± 0.00 36.7% (0e100%)

86.1% 36.7% 35.2% 40.2% 44.0% 27.7% 27.1% 53.6% 37.4% 24.4% 51.3% 35.2% 28.9% 42.6% 94.5% 32.4% 50.0% e e

R RM RM RM RM NR NR RM RM NR RM RM NR RM R RM RM e e

R: recommended; RM: recommended with modifications; NR: not recommended.

components [8,18,22], and the agreement of screening components in 3 guidelines was 80e100% (Table 4). Eight guidelines gave clear recommendations for screening tools [8,12,14,16,18,21,22,24], and the agreement of screening tools in 4 guidelines [14,18,22,23] was 80e100%, while the agreement of screening tools in another 4 guidelines [12,16,21,24] was 60e80% (Table 4). Additionally, five guidelines cited evidence of the relationship between nutrition risk screening and outcome [8,16,21e23], five cited evidence for whether nutrition risk screening tools could detect nutritional risk or malnutrition [11,12,14,16,21], three directly recommended the application of nutrition risk screening without evidence [17,18,24]. Of the recommendations with agreement of more than 60% [8,12,14,16e18,21e24], the highest level of evidence in support of this part was 2b [8,16,21e23] (Fig. 2). Recommendations and evidence related to nutrition assessment are listed in Tables 3 and S2. Nutrition assessment was recommended in all 12 guidelines, five of which explicitly identified the content of the nutritional assessment as recommendations [8,16,17,23], and the agreement of assessment components was 80e100% in 2 guidelines [16,23] and 60e80% in 1 guideline [17]

(Table 4). In addition, eleven guidelines recommended nutritional assessment tools, and the agreement assessment tools were 80e100% in 10 guidelines [11,12,14e18,21,22,24] and 40e60% in 1 guideline [23] (Table 4). Five guidelines cited evidence of the relationship between nutrition assessment and outcome [12,14e16,22], six guidelines cited evidence of whether nutrition assessment tools could find malnutrition [11,14e17,24], four guidelines cited evidence for assessment [8,16,18,23], and five guidelines cited evidence was to compare different assessment tools [11,12,14,16,22]. Ten guidelines had more than 60% agreement in their recommendations and the highest level of evidence in support of this part was 2b (Fig. 2). Recommendations and evidence on energy intake in cancer patients are shown in Tables 3 and S2. Of the 12 guidelines, eight guidelines recommended 25e35 kcal/kg/d [8,14,16e18,22e24], and the Australia guidelines recommended a relatively wide range of energy intake, which was at least 30 kcal/kg/d for head and neck cancer patients receiving surgery, radiotherapy or chemoradiotherapy [12], and the agreement of energy was 80e100% in 8 guidelines [8,14,16e18,22e24] (Table 4). In addition, Australian

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Table 3 Recommendations for nutritional care procedures in the included guidelines (2017e2019). ES [8]

Oc [17]

GS [11]

Li [15]

CR [24]

Lv [16]

d

d

d

d

Weight loss

d

d

d

d

index of food intake

d

d

d

d

Nutrition screening components BMI

Nutrition screening tools NRS 2002

d

d

MUST

d

d

d

MST

d

d

d

MNA-SF

d

d

d

d d

Nutrition assessment components Dietary intake Body composition Physical activity

d

Nutrition symptoms Systemic inflammation

CSP [22]

Li [14]

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

BMI

d

d

d

d e

d

d d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

Nutrition assessment tools PG-SGA

d

SGA

d

d

d

d

MNA

d

d

d

d

d

d

d

d

Nutrition interventions Energy 25e35kcal/(kg$d)

d d

d

d

d

d

d

d

d

e d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

d

ed

d

d

d

d

d

Protein 1.0e2.0 g/(kg$d)

Immune-enhancing supplements Arginine d

d

d

d

d

d

Glutamine

u-3 PUFAs

Th [21]

d

d

Nucleotide

d

d

Pe [18]

d

d

>1.2 g/(kg$d)

CC [12]

d

Weight loss

>30 kcal/(kg$d)

CN [23]

Nutritional pathways DC ONS

d

d

d

d

d

d

d

d

d

d

d

Indicates being recommended definitely; DC indicates dietary counselling.

d

d

d

EN PN

d

d d

d

indicates being mentioned;

d

d

d

indicates being not recommended; d indicates being not mentioned.

guidelines listed recommendations about surgery and radiochemotherapy, respectively, and provided evidence to support these recommendations [12]. There are nine guidelines with more than 60% consistency [8,12,14,16e18,22e24], and the highest level of evidence in support of this part was 2b [8] (Fig. 2). Recommendations and evidence about nitrogen/protein intake in cancer patients are shown in Tables 3 and S2. Of the 12 guidelines, eight guidelines specified protein intake recommendations [8,12,16e18,22e24]; of these guidelines, seven recommended 1.0e2.0 g/kg/d protein [8,16e18,22e24], Australia guidelines also recommended a wide range of protein intake, which was at least 1.2 g/kg/d protein for head and neck cancer patients receiving

radiotherapy or chemoradiotherapy [12], and four did not have recommendations for this part [11,14,15,21]. The agreement of protein intake was 80e100% in 7 guidelines [8,14,16e18,22e24] (Table 4). There were eight guidelines with more than 60% consistency [8,12,14,16e18,22e23], and the highest level of evidence in support of this part was 2c [16] (Fig. 2). Recommendations and evidence on immune nutrition in cancer patients are shown in Tables 3 and S2. Of the 12 guidelines, although there were only two guidelines that did not provide any information about immune nutrition [23,24], other guidelines only give general recommendations [11,12,15,18,22] that immune nutrition can improve nutritional status and immune function

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Table 4 Scientific agreement of formulated recommendations for nutritional care procedures in the included guidelines (2017e2019). Types

Undifferentiated cancer

Guidelines

Oc [17] ES [8] comparison standard

Nutrition screening Components Tools Nutrition assessment Components Tools Nutrition interventions Energy Protein Immune-enhancing supplements EN PN

Head or neck cancer Li [14]

CSP [22]

Pe [18]

CN [23]

Th [21]

Esophageal cancer

CC [12]

CR [24]

Li [15]

GS [11]

Lv [16]

e 60%e80%

e 60%e80%

e e

e e

e 60%e80%

e e

80%e100% e 80%e100% 80%e100% e e 80%e100% 80%e100% 80%e100% 80%e100% 60%e80%

e e

60%e80% e e e 80%e100% e e e e e 80%e100% 80%e100% 80%e100% 80%e100% 80%e100% 40%e60% 80%e100% 80%e100% 80%e100% 80%e100% 80%e100% 80%e100%

e e e

80%e100% 80%e100% 80%e100% 80%e100% 80%e100% e 80%e100% 80%e100% e 80%e100% e 80%e100% 80%e100% 80%e100% e 80%e100% 80%e100% e 80%e100% 40e60% 40e60% 80%e100% e 80%e100% 80%e100% e 40e60%

e e 60e80%

e e

e 80%e100% 80%e100% 80%e100% 80%e100% 60%e80% 80%e100% 80%e100% 80%e100% 80%e100% 80%e100% e

80%e100% 80%e100% e e

60%e80% e

80%e100% 60%e80% 80%e100% e

80%e100% 80%e100% 60e80%

Measurement Scale of Rate of Agreement: 0%e20%: Radically different; 20%e40%: Numerous major scientific disagreements present; 40%e60%: Few major scientific disagreements present; 60%e80%: Only minor scientific disagreements present; 80%e100%: Absolute scientific agreement. In blank fields, no information is available.

Fig. 2. Distribution of the highest level of evidence to support similar recommendations (MSRA >60%) of nutrition care procedures among included guidelines (2017e2019).

[11,15], of which two guidelines indicated immune nutrition can improve clinical outcome [12,22], and one of the two guidelines [12] suggested that postoperative immune nutrition can shorten hospital stay, while the other guideline proposed that preoperative immune nutrition did not benefit patients. In addition, one guideline recommended only the use of immune nutrition [18] but did not specify the reasons, whose evidence was the guideline from ESPEN in 2017 [31]. The agreement of immune-enhancing supplements was 80e100% in 4 guidelines [12,17,18,21], 60e80% in 2 guidelines [11,16] and 40e60% in 3 guidelines [14,15,22], respectively (Table 4). With regards to glutamine supplementation, of the 12 guidelines, six listed recommendations involving glutamine [8,11,14,15,17,21]. Three of these guidelines recommended glutamine supplementation [11,14,15], whose evidence was that glutamine supplementation can improve outcome, while the other three guidelines indicated that the evidence recommending glutamine supplementation was insufficient [8,17,21]. Six guidelines with more than 60% agreement [8,11,12,16e18,21] and the highest level of evidence for glutamine supplementation was 1a [8,15,22,23] (Fig. 2).

Of the 12 guidelines, six listed recommendations on u3-PUFAs/ fish oil [8,12,14,16,18,21], all of which indicated that u3-PUFAs/fish oil can improve nutritional status and immune function. Six guidelines had more than 60% agreement [8,11,12,16,18,21] and the highest level of evidence in support of this part was 1a [8,16] (Fig. 2). Seven guidelines provided clear recommendations for parenteral nutrition [8,14,17,18,22e24], all of which indicated that parenteral nutrition should be given when the enteral nutrition was insufficient. The agreement of PN was 80e100% in 6 guidelines [8,14,17,18,22e24] (Table 4). Of these, only two guidelines cited system reviews [22,23] and more guidelines quoted the results of other guidelines [8,14,17,18,23] and reviews [8,14,23,24]. Two guidelines cited retrospective observational studies [8,18] and one guideline cited a case control study [18]. There were seven guidelines with more than 60% agreement [8,14,17,18,22e24], and the highest level of evidence in support of this part was 1a [16] (Fig. 2). Eleven guidelines provided clear recommendations about how to choose enteral nutrition pathways [8,11,12,14e16,18,21e24]. The agreement of EN was 80e100% in 7 guidelines [8,11,12,14e16,18,21e24] and 60e80% in 3 guidelines [12,15,21]

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(Table 4). Of these guidelines, seven cited system reviews [8,11,12,15,22e24]; three cited RCTs [15,16,22]; more guidelines cited the results of other guidelines [8,14,16,18,21e24] and reviews [8,14,16,21,24]; one cited observational study [11]; and two cited case control studies [11,24]. Eight guidelines had more than 60% agreement for a dietary counselling recommendation [8,12,14,16,18,21e23], and the highest level of evidence in support of this part was 1a [8,12,16,22,23] (Fig. 2). Nine guidelines had more than 60% agreement on ONS [8,12,14,16e18,22e24], and the highest level of evidence in support of this part was 1a [8,12,22,23] (Fig. 2). Ten guidelines had more than 60% agreement on EN [8,11,12,14e16,18,22e24], and the highest level of evidence in support of this part was 1a [8,11,12,15,22] (Fig. 2). 4. Discussion

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The scores for the domains of applicability and editorial independence of the included guidelines were relatively low, with median scores of 24.2% and 36.7%, respectively (Table 2); these findings were similar to the results of previous guideline evaluation studies [28,30,35]. The low applicability score was related to the lack of consideration of facilitators and barriers to their application. In this study, only three guidelines paid enough attention to the application of the guidelines [8,12,16]. Therefore, there is still a great deal of room for improvement in the application domain. In our study, only seven guidelines defined the competing interests of the guideline development group members [8,10,12,15e17,19], and given that competing interests are a common source of bias and are frequently neglected, the guideline development committee should include a section regarding competing interests, including the developer's strict review processes and rules, to enhance the editorial independence of the guidelines.

4.1. Principal findings In this study, we conducted an overall assessment of nutritional care procedures of nutritional support guidelines for cancer patients and a methodological evaluation of nutritional support guidelines for cancer patients by using the AGREE II tool. We found that the nutritional care procedures recommended by the different guidelines varied greatly. The main reasons for the heterogeneity of nutrition care procedures were insufficient attention to nutrition risk screening, differences in recommendations for nutrition assessment, immune nutrients and nutritional support pathways, unreasonable citation of screening and assessment evidence, preferences of guideline developers for choosing evidence, lack of evidence of high quality research on energy and nitrogen demand, and so on. Additionally, the quality of evidence and the methodological heterogeneity were discrepant between the different guidelines and even between different domains of the same guidelines. 4.2. Quality evaluation of guidelines by AGREE II In addition to the need for the collaboration and contribution of different professional medical teams, considering the opinions, intentions and preferences of the stakeholders (including the patients) was also a vital component in the development of the guidelines [32]. In this study, the total median score of stakeholder involvement was 39.4%. This finding was mainly because most of the associations that developed the guidelines ignored the involvement of stakeholders and patients. Nevertheless, the guidelines from ESPEN and Australia provided us with good examples [8,12] by inviting patients to participate in the process of developing the guidelines; to some extent, this approach improves the application of the recommendations and enhances the desire of clinical practitioners to use these guidelines. Rigour is a significant component in the process of developing guidelines, and it is also an important standard to determine whether the guidelines are credible and whether they are should adopted by the users [33]. There were six guidelines in which the score for rigour of development was over 50% [8e10,12,22]; of these guidelines, two exceeded a score of 85% [8,12], while most guidelines had poor performance in terms of rigour (Table 2). The results regarding rigour were as follows: four guidelines did not describe whether a systematic method was used to retrieve evidence [14,19,20,24], seven guidelines did not clearly state the criteria used to select evidence [13e15,17,19,20,24], only three guidelines specified that the guidelines had been externally reviewed by experts prior to their publication [8,12,22], and only two guidelines clearly provided the procedures followed for the updating of the guidelines [8,12].

4.3. The heterogeneity of recommendations and evidence and the reasons for nutritional care procedures in nutrition guidelines for cancer patients According to the consensus of the ASPEN, ESPEN, and CSPEN guidelines on nutritional support, nutritional care procedures should include nutritional screening, assessment and interventions for malnourished patients [34e36]. Cancer patients are one of the populations with a high incidence of malnutrition; moreover, malnutrition seriously affects the survival time and quality of life of cancer patients. Therefore, for cancer patients, nutritional support guidelines should recommend nutritional care procedures that include nutritional screening, assessment, and intervention. 4.4. The reasons for the heterogeneity of nutrition screening and assessment recommendations and evidence (1) Insufficient attention to nutritional risk screening: ESPEN recently published the latest diagnostic criteria for malnutrition, named the Global Leadership Initiative on Malnutrition (GLIM) criteria, which clearly indicated that nutritional risk screening was the foremost step in the evaluation of nutritional status [37]. In the last three years, however, one of the guidelines did not have the content and recommendations for nutritional risk screening [15], while the other is unclear about the concept of screening and evaluation and did not give clear screening recommendations [11]. In addition, there was a lack of evidence to support nutrition risk screening, despite recommendations for nutrition risk screening. It was clear that guideline developers did not pay enough attention to nutrition risk screening. (2) Differences in the key recommendations for nutrition assessment, immune nutrients supplement and nutrition support pathways: Compared with nutritional screening, nutrition assessment was a more complex and comprehensive procedure, not just a recommendation for tools. Nutritional assessment is a comprehensive diagnosis of malnutrition, including at least three components [34e36]: ①organ function, electrolytes, acid-base balance (reference used for prescriptions); ②inflammatory factors, body composition, muscle strength, BMI; and ③recent weight loss and reduced oral intake. However, our study revealed that there were only four guidelines that recommended that the nutritional assessment include dietary intake, body composition, physical activity, nutrition-related symptoms and systemic inflammation [8,16,18,23] (Tables 3 and S2), and nine guidelines recommended nutritional assessment tools, including PG-SGA, SGA and MNA [10e12,14e16,18e20,22,24]

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(Table 3). Notably, regarding the nutritional assessment, the guideline developers had substantial differences in the selection of nutritional assessment components and tools, which resulted in a lack of uniform criteria for nutritional assessment among the guidelines. Recently, ESPEN convened experts from ASPEN, ESPEN, FELANPE and PENSA to establish the GLIM criteria, which included five main aspects: body weight loss, BMI, reduced muscle mass, nutrition intake and disease burden [37]. Currently, only Japanese scholars have validated the GLIM criteria and determined the reference value of BMI that was suitable for Asians [38]. In the future, we look forward to more clinical studies to validate the feasibility and reasonableness of the GLIM diagnostic criteria. Because cancer patients often have low immune function, it was the original intention to replenish immune supplements to improve the immune status of cancer patients and then improve the clinical outcome. Although most of the evidence cited in the immune supplements recommendation was from systematic reviews or RCTs and the level of evidence was relatively high, the heterogeneity of recommendation and evidence was still obvious. Most of the guidelines provided clear recommendations for the application of immune supplements, but the focus of the recommendations was different. Some guidelines generally recommend immune nutrition [11,12,15,18,22], and some guidelines identified recommendations related to specific immune nutrients (such as glutamine and u 3- PUFAs/fish oil), which included two guidelines of enteral nutrition support in cancer patients [14,16]. At present, most of the evidence in support of recommended immune nutrients was intestinal supplementation, with only a few guidelines quoting evidence of intravenous supplementation of immune nutrients [8], while evidence of the effect of adequate intravenous glutamine and fish oil supplementation on the clinical outcomes of cancer patients has not been cited [39e42]. The guidelines varied widely on the recommendation of glutamine supplementation, some of which consider glutamine supplementation to have insufficient evidence [8,17,21], while others suggested that glutamine supplementation can improve clinical outcomes [11,14,15]. The recommendations of all guidelines on how to choose nutritional support for cancer patients tend to be the same. It was suggested that parenteral nutrition should be supplemented when the enteral nutrition supply was insufficient, and in terms of enteral nutrition, oral enteral nutrition was the first choice, followed by a non-invasive tube (NIT/NGT) and then an invasive tube (PEG/PEJ). The heterogeneity and causes for the recommendations of the guidelines were mainly due to the different pathways of enteral nutrition, including ONS, NIT/NGT, PEG/PEJ, and SG/SJ. The recommendations of different guidelines had a different emphasis, and the evidence cited was also different, such as the recommendation of one guideline that PEG and NG were similar in improving nutritional status and clinical outcome, and the evidence cited was a systematic review, an RCT and a case-control study [15]. The recommendations in the ESPEN guidelines indicated that if the oral diet was insufficient, oral nutrition supplements or nutrition counselling were recommended, and if insufficient, enteral nutrition supplements are recommended, whose evidence included a systematic review, an RCT, two guidelines and four reviews [8]. (3) Unreasonable citation of evidence for nutritional risk screening and assessment: The main criterion of validity for any screening tool, or diagnostic method, is that treatment will improve outcome among those found positive [43]. According to this criterion, the purpose of nutrition risk screening is to identify people whose clinical outcomes can be improved by nutritional support. Therefore, most

guideline recommendations, citing the evidence of the use of nutritional risk screening tools to identify nutritional risks or malnutrition [11,12,14,16,21] and recommendations that directly quote other guidelines [17,18,24], were unreasonable. More rather, we do not know the level of evidence for specific references when developers cited other guidelines. Additionally, one guideline [12] for a nutritional risk screening tool was inappropriate because three of the involved RCTs were studied on the effect of intervention on nutritional status and adopted PG-SGA, which was a nutrition assessment tool rather than nutritional risk screening tool, to screen nutritional risk. Additionally, the aim of this study was not to validate whether nutrition support can improve the clinical outcome of patients who were positive via nutritional screening. For nutrition assessment, one guideline [22] recommended ‘nutritional assessment methods for cancer patients, including body weight, SGA, PG-SGA, MNA, and so on’, whose developer citied a system review [44]. However, the result of this review suggested that the current nutritional assessment was ‘none of these assessment methods (including SGA, PG-SGA, MNA) has acceptable content validity when compared against a construct based on ESPEN and ASPEN definitions of malnutrition’. This result clearly did not support the use of these evaluation tools in cancer patients. Another guideline [17] included recommendations for evaluation content and tools, quoting the ESPEN guideline [8] and the ASPEN guideline [9], neither of which used an assessment tool as the main recommendation, and the ASPEN guideline has the problem of unclear screening and evaluation concepts and tools, so the reference was unreasonable. (4) Preferences of guideline developers for choosing evidence: As the developers of the guidelines, it is necessary to search systematically, select high-quality evidence fairly and give reasonable recommendations. In the Australian guideline [12], regarding the recommendations of nutritional risk screening, the developer only citied the evidence of the MST tool and did not cite the evidence from the NRS 2002 tools [45,46] and the Prognostic Nutritional Index (PNI) [47], which also determined that other tools did not have the opportunity to appear in the recommendations of this guideline. In the guidelines of Thompson et al. [21], although the evidence including MUST, MST, NRS 2002, and NRS 2002 was not recommended, the main recommendations suggest that the purpose of guideline development screening is to screen for malnutrition risk rather than nutritional risk. For nutritional assessment, most of the guidelines recommend PG-SGA, so most of the evidence cited studies were closely related to PG-SGA, while there was a lack of evidence from other assessment tools [11,12,14,16,21]. (5) Lack of high quality research evidence for energy and nitrogen requirements: The consideration of energy and nitrogen was the main content in the development of nutrition intervention programmes. Most of the guidelines gave clear recommendations on energy and nitrogen intake, of which the energy was 25e35 kcal/kg/d, the nitrogen/protein was 1.0e2.0 g/kg/d, and only the Australian guideline gave the lower limits of energy and nitrogen, but no upper limit [12]. The reason for this result was a lack of high enough quality research to consider the energy and nitrogen intake and clinical outcome of cancer patients; therefore, most guidelines only took into account the basic metabolic situation of the human body, or refer to other guidelines or expert advice to form recommendations [8,14,17,18,22e24]. Although a few

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guidelines had some research support [8,12,16,22], most of the levels of cited evidence were low. In addition, some guidelines did not pay attention to the intake of energy and nitrogen and lacked clear recommendations for energy [11,15,21] and nitrogen [11,14,15,21], which was obviously not conducive to the use of the guidelines users. Only the ESPEN guideline about energy intake recommendations [8] had support evidence from RCTs [48], which involved 24 pancreatic cancer patients with cachexia. The authors only compared the effects of oral nutritional supplementation with or without n-3 fatty acids on body activity and quality of life; however, in terms of energy comparison, the baseline value was compared with the predicted value of healthy adults, and the viewpoint of increased energy demand in patients with pancreatic cancer with cachexia was obtained. Therefore, this evidence cannot be classified as a RCT. (6) Other reasons for the heterogeneity of nutrition care procedures in nutrition guidelines for cancer patients are as follows: The differences in the target population of the guidelines: Of the 12 guidelines, seven [8,14,17,18,21e23] did not specifically distinguish between specific cancer groups, three were for patients with head and neck cancer [12,15,24], two were for oesophageal cancer [11,16], two were for patients with head and neck cancer who experienced radiotherapy and chemotherapy [15,24], one was for radiotherapy patients [14], one was for patients with convalescent cancer [23], and two were for enteral nutrition in cancer patients [14,16]. Although we did not find significant differences in subgroup analysis of different cancer guidelines (Table 4 and Fig. S1), the available research evidence was different for different cancer populations and would also affect the intensity of the recommendations. Characteristics of Guidelines for Different Regions: Of the 12 guidelines, seven were from Asia [11,14e16,22e24], four were from Europe [8,17,18,21] and one was from Australia [12]. When we analysed the highest-grade supporting evidence for the main recommendation, it seems that the region has no influence on the citation of the main evidence (Fig. S2). However, some factors should be considered: the level of understanding of nutrition care procedures among local developers was different; when the developers in different areas quoted the evidence, they tended to choose the research evidence from local area or the developers themselves, which also reduced the fairness of evidence citation to a certain extent; and the recommendations supported by the local research evidence were more suitable for the local population. Our findings provide some references for the development of cancer nutrition guidelines in the future. (1) The existing guidelines should be stringently re-scrutinized for eligibility in terms of quality standards before their implementation to make the clinical use of these guidelines more normative. (2) The guideline developers should be familiar with guideline development standards such as the AGREE II instrument. (3) The guideline development process should give ample consideration to the input of stakeholders (including patients). (4) An objective retrieval system and a comprehensive assessment of the level of evidence, in addition to the annotation of the evidence, should be made clear in the guidelines, and a periodic update mechanism for the evidence included in the guidelines should be established. (5) The guidelines should be externally reviewed by experts prior to their publication. (6) More attention should be paid to the differences in the recommendations among different countries; convincing evidence should be utilized, and consensus conferences should be held for the development of recommendations. (7) The guideline

11

developers should be rigorously investigated for competing interests, and the guideline development process should be transparent. To improve the nutrition diagnosis and treatment procedures, it is advisable for developers to finish the following contents: (1) Attach the importance of nutrition risk screening, according to the disease screening principle [43], with a fair selection of appropriate screening tools; (2) Nutrition assessment is a comprehensive diagnosis of malnutrition, not just the choice of nutrition assessment tools, and there are at least three aspects to consider [34e36]; (3) Although the energy and nitrogen demand of cancer patients can be roughly calculated according to the basic metabolism of the human body, there is a lack of high-quality research to evaluate the influence of the difference of energy and nitrogen content on clinical outcome, and researchers are encouraged to carry out highquality research in this area; (4) Lack of evidence and recommendations of intravenous supplementation of immune nutrients (glutamine, fish oil, etc.) in cancer patients, which is expected to be supplemented when the guidelines are updated; (5) There were huge differences in some recommendations, such as some guidelines with insufficient evidence for glutamine supplementation [8,17,21], and others suggesting that glutamine supplementation could improve clinical outcomes [11,14,15]. Therefore, in further revision of the guidelines, it would be advisable to carry out a discussion of the fairness of evidence for widely varied recommendations to determine the final recommendation. 4.5. Strengths and limitations Our research has some strengths and some limitations. The strengths of this study are as follows: (1) the guideline evaluations and recommendations have increased reliability because proper weights were applied to each domain assessed in this study; and (2) we carried out a detailed analysis of the recommendations and evidence of the nutritional care procedures, which is helpful for the guideline developers to identify gaps in practise and is also helpful for users to decide which recommendation to follow. The limitations of this study are as follows: (1) in this study, we evaluated only guidelines written with English or Chinese, and guidelines published in other languages were excluded; and (2) the AGREE II instrument can focus on only the methodology of developing guidelines, and it is unable to evaluate the impact of the recommendations on the clinical outcomes of patients. 5. Conclusions The methodological evaluation of the cancer nutrition guidelines revealed significant discrepancies, especially in stakeholder involvement, rigour of development, applicability and editorial independence domains, which exhibited poor performance and showed substantial room for improvement. Nutritional care procedures in cancer nutrition guidelines (2017e2019) varied greatly. Thus, the main reasons for the heterogeneity of nutrition care procedures were insufficient attention to nutrition risk screening, differences in recommendations for nutrition assessment, immune nutrients and nutritional support, unreasonable citation of screening and assessment evidence, preference of developers, lack of evidence of high quality research on energy and nitrogen demand, and so on. It would be advisable for developers to address the above problems when updating the guidelines to improve the nutritional care procedures and facilitate the use of the guidelines. Ethics approval and consent to participate Not applicable.

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Consent for publication Not applicable. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Funding This study was supported by the National Natural Science Foundation of China (NSFC) (No. 81860098) to D.L.S and the Foundation of Research Center for Surgical Clinical Nutrition in Yunnan Province and Professor Yang Hua Research Station in YunNan Province. Author contributions X.H.Z, D.L.S, X.D.M, X.Z.C and Y.Q.D designed this study; X.H.Z, D.L.S, T.Y, Y.Y.L and Y.X.Q searched databases and collected full-text papers; X.Z.C, D.L.S and Y.Q.D extracted and analysed data; X.H.Z, T.Y, D.L.S and X.D.M wrote the manuscript. Conflict of interest The authors declare that they have no competing interests. Acknowledgements Not applicable. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.clnu.2019.08.022. References [1] World Health Organization. Latest global cancer data: Cancer burden rises to 18.1 million new cases and 9.6 million cancer deaths in 2018. 2018. Available from: https://www.iarc.fr/wp-content/uploads/2018/09/pr263_E.pdf. [2] Gyan E, Raynard B, Durand J-P, Gouy S, Movschin ML, Khemissa F, et al. Malnutrition in patients with cancer: comparison of perceptions by patients, relatives, and physicians-results of the NutriCancer 2012 study. JPEN 2018;42(1):255e60. [3] Laviano A, Gianluca DLG, Koverech A. Does nutrition support have a role in managing cancer cachexia. Curr Opin Support Palliat Care 2016;10(4):288e92. [4] Fujiya K, Kawamura T, Omae K, Makuuchi R, Irino T, Tokunaga M, et al. Impact of malnutrition after gastrectomy for gastric cancer on long-term survival. Ann Surg Oncol 2018;25:974e83. [5] Baldwin C, Spiro A, McGough C, Norman AR, Gillbanks A, Thomas K, et al. Simple nutritional intervention in patients with advanced cancers of the gastrointestinal tract, non-small cell lung cancers or mesothelioma and weight loss receiving chemotherapy: a randomised controlled trial. J Hum Nutr Diet 2011;24(5):431e40. [6] Baldwin C, Weekes CE. Dietary advice with or without oral nutritional supplements for disease-related malnutrition in adults. Cochrane Database Syst Rev 2011;7:CD002008. [7] Pan H, Cai S, Ji J, Jiang Z, Liang H, Lin F, et al. The impact of nutritional status, nutritional risk, and nutritional treatment on clinical outcome of 2248 hospitalized cancer patients: a multi-center, prospective cohort study in Chinese teaching hospitals. Nutr Cancer 2013;65(1):62e70. [8] Arends J, Bachmann P, Baracos V, Barthelemy N, Bertz H, Bozzetti F, et al. ESPEN guidelines on nutrition in cancer patients. Clin Nutr 2017;36(1):11e48. [9] August DA, Huhmann MB. ASPEN Clinical Guidelines: nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. JPEN 2009;33(5):472e500. [10] Chinese Society for Oncological Nutrition and Supportive Care. Chinese nutrition therapy guidelines for cancer patients. Beijing: People's Medical Publishing House; 2015.

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Please cite this article as: Zhao X-H et al., Heterogeneity of nutrition care procedures in nutrition guidelines for cancer patients, Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.08.022