Cancer symptom clusters in adult patients undergoing chemotherapy: A systematic review and meta-analysis protocol.

BACKGROUND: In oncology, the prevalence of symptoms is preferentially analyzed in isolation instead of being considered in clusters. However, clinical practice shows that symptoms rarely occur separately but rather form clusters that share common underlying mechanisms in terms of intensity and severity, creating a synergistic effect among them, which can even help predict the development of future symptoms.
OBJECTIVE: To identify and gather evidence on the prevalence, composition, severity, and predictors of cancer symptom clusters in adult cancer patients undergoing chemotherapy.
METHODS: This systematic review and meta-analysis protocol was developed in compliance with PRISMA-P. Observational and experimental study designs will be included. MEDLINE/PubMed, Cochrane Library, Embase, CINAHL, PsycINFO, Web of Science, Scopus, LILACS, clinical trials.gov-NIH, the British Library, Google Scholar, and preprints [medRXiv] will be searched with no restrictions on idioms, dates, or settings. Two investigators will independently select the studies, perform data extraction, and critically appraise the risk of bias of the included studies. Heterogeneity among the studies will be assessed using the I2 statistic. If meta-analysis was feasible, a random-effect model analysis will be carried out. For data analysis, the pooled effect will be estimated considering 95% confidence interval and α = 5%. In addition, the certainty of evidence will be rated based on Cochrane methods in accordance with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). DISCUSSION: To the best of our knowledge, this systematic review and meta-analysis will be the first to identify and critically assess evidence regarding the prevalence, composition, severity, and predictors of cancer symptom clusters in adult cancer patients undergoing chemotherapy. We intend to provide health professionals with subsidies to reflect on a better understanding of symptom clusters in adult cancer patients, with the aim of contributing to the development of evidence-based therapeutic interventions and success in clinical practice. PROSPERO REGISTRATION NUMBER: CRD42021248406.

Introduction

Tumor progression and antineoplastic therapy can result in the manifestation of numerous symptoms during and after treatment, including cancer-related fatigue (CRF), sleep disturbances, pain, cognitive dysfunction, and anxiety [1, 2]. These symptoms reduce an individual’s functional status, negatively impact quality of life, and may occur alone or together, constituting clusters of symptoms [1-4]. A cluster of symptoms was initially identified in experiments with mice subjected to the induction of infectious conditions (via administration of bacterial products such as LPS11) and administration of pro-inflammatory cytokines (interleukin [IL]-1β, IL-6, tumor necrosis factor [TNF]-α) [5], exhibiting a phenomenon called sickness behavior [6, 7].

The term sickness behavior refers to a set of behavioral changes that progress with diverse infectious and inflammatory processes, for instance, the apparent loss of interest in daily activities, such as searching for food, social interaction, and sex [6]. Studies in animals and humans have shown that cytokine infusion (either systemic or central) also induces sickness behavior [8]. Similarly, in cancer patients, a phenomenon of sickness behavior is expressed, such as cancer pain, CRF, cognitive and sleep disorders, depressed mood, anxiety and depression associated with high levels of pro-inflammatory cytokines expression, including IL-1β, IL-6, IL-8, TNF-α, IL-12p70, and interferon-gamma (IFN-γ) [5-8].

There is growing consistency that common biological mechanisms may underlie the interaction between the nervous, endocrine, and immune systems, which orchestrate a set of responses capable of inducing behavioral and physiological changes in cancer patients [5-11]. In particular, studies addressing sickness behavior as well as cancer symptom clusters in cancer patients support the hypothesis that pro-inflammatory cytokines are related to the biological mechanisms underlying the emergence of these clusters [1, 5, 7, 10, 12, 13]. Evidence suggests a strong association between depression, anxiety, cachexia, and high levels of cytokines expression (IL-1β, IL-6, IL-10, TNF-α, INF-γ, and fractalkine [CX3X]) in cancer patients [14].

Studies have shown that alterations in genes encoding pro-inflammatory cytokines (IL-1β, IL-6) and their high concentrations greatly contribute to the occurrence, intensity, and severity of various symptoms in cancer patients [15, 16]. A study conducted on 599 patients recently diagnosed with lung cancer revealed that an additive effect of the mutant alleles of IL-1β, IL-10, and TNFR2 was predictive of severe pain, depressed mood, and CRF in these patients [17].

It should be noted that oncology research preferentially focuses on the prevalence of symptoms analyzed in isolation, instead of considering them as clusters. However, clinical practice shows that symptoms rarely occur separately but rather form clusters that share common underlying mechanisms in terms of intensity and severity, creating a synergistic effect among them, and can even predict the development of future symptoms [1, 2, 4, 5, 9, 10, 12, 14].

A previous systematic review of observational studies aimed to systematically assess the composition, longitudinal stability, and consistency across methodologies of common symptom clusters and their common predictors; however, it limited the search to patients with advanced cancer, focusing especially on the various statistical methods used. In addition, the authors used a generic tool for methodological assessment rather than specific tools for observational design to assess the risk of bias in the included studies [18].

Recently, a systematic review was published with the objective of evaluating the progress in symptom cluster research in adults receiving primary or adjuvant chemotherapy since 2016 and showed that psychological, gastrointestinal, and nutritional clusters were the most commonly identified clusters. Only the psychological clusters remained relatively stable over time [19].

Our review study differs in the following aspects: we did not specified a publication date or language limit (in order to minimize publication bias). Furthermore, we explored beyond observational studies by including experimental studies, and expanded the number of databases to eight, in addition to accessing gray literature and pre-prints for Health Sciences. In addition, both previous reviews used only generic tools for methodological appraisal and assessed the report of the study more than the risk of bias (in terms of internal and external validity of the studies). We used valid and design-specific tools following the recommendations of the Cochrane Collaboration [20]. Additionally, there are no systematic reviews or meta-analyses that considers a robust assessment of the risk of bias in studies involving cancer symptom clusters with validated and design-specific tools, which justifies the potential contribution of our study to the area.

This systematic review and meta-analysis aimed to identify and gather evidence on the prevalence, composition, severity, and predictors of cancer symptom clusters in adult cancer patients undergoing chemotherapy.

Materials and methods

This systematic review and meta-analysis is in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) [21]. In addition, registration was obtained using PROSPERO/UK (registration ID: CRD42021248406).

Search strategy

Eight electronic databases will be searched, including MEDLINE/PubMed, Cochrane Library, Embase, Web of Science, CINAHL, Scopus, PsycINFO, and LILACS. In each database, all search strategies will consider records from inception up to July 31, 2022. Additional sources will be also searched, including clinicaltrials.gov-NIH, the British Library, Google Scholar, and preprints for Health Sciences [medRXiv]. This systematic review will have no restrictions on languages or the settings of the target population. Additionally, we will scrutinize the reference lists of articles to search for additional studies [22]. The PECO acronym [23], that is, P-Population = Adult patients [≥ 18 years of age] diagnosed with malignant neoplasm; E-Exposure = Chemotherapy treatment; C-Comparison = not applicable; O-Outcomes = Prevalence, composition, stability, and severity, as well as predictors of cancer symptom clusters, was used to answer our research question (what scientific evidence is available on the prevalence, composition, severity, and predictors of cancer symptom clusters in adult cancer patients undergoing chemotherapy?).

EndNote™ will be used to store, organize, and manage all retrieved studies. Study selection will be conducted by two independent reviewers (LCLJ and TF) using the Rayyan™ application. Controlled descriptors, such as MeSH terms, Emtree terms, Thesaurus, Cinahl headings, DeCS, and their synonyms will be screened. Keywords will be also identified. The Boolean operators “AND,” “OR” and “NOT” will be employed to combine the descriptors [24, 25]. The preliminary pilot search strategy combining MeSH terms, synonyms, and keywords used in MEDLINE/PubMed is detailed in Table 1.

Table 1

Preliminary pilot search strategy in MEDLLINE/PubMed.

Database	Search strategy
MEDLINE/PubMed	• Population
	#1((“Young Adult” [MeSH Terms] OR “Adult” [MeSH Terms]))
	#2 ((“Neoplasms” [MeSH Terms] OR “Neoplasia” [All Fields] OR “Neoplasias” [All Fields] OR “Neoplasm” [All Fields] OR “Tumors” [All Fields] OR “Tumor” [All Fields] OR “Cancer” [All Fields] OR “Cancers” [All Fields] OR “Malignancy” [All Fields] OR “Malignancies” [All Fields] OR “Malignant Neoplasms” [All Fields] OR “Malignant Neoplasm” [All Fields] OR “Neoplasm, Malignant” [All Fields] OR “Neoplasms, Malignant” [All Fields]))
	# 3 #1 AND #2
	• Exposure
	#4 ((“Chemotherapy” [All Fields] OR “Chemotherapy, Adjuvant” [MeSH Terms] OR “Induction Chemotherapy” [MeSH Terms] OR “Consolidation Chemotherapy” [MeSH Terms] OR “Maintenance Chemotherapy” [MeSH Terms] NOT “Radiotherapy” [MeSH Terms] NOT “Surgery” [All Fields]))
	• Outcomes
	#5((“Symptom Cluster” [All Fields] OR “Cluster, Symptom” [All Fields] OR “Clusters, Symptom” [All Fields] OR “Symptom Clusters” [All Fields] OR “Cancer Symptom Clusters” [All Fields] OR “Symptom Constellation” [All Fields] OR “Symptom Management” [All Fields]))
	#6 #3 AND #4 AND #5

Eligibility criteria

All observational and experimental study designs will be included.

Inclusion criteria: Young adults and adults of both sexes, age > 18 years, and of any ethnicity.

Exclusion criteria: Children, adolescents, pregnant women, and elderly people with cancer of both sexes. Age in this study is defined according to the MeSH term “Aged”: a person aged 65–79 years or more.

Inclusion criteria: Adult cancer patients undergoing chemotherapy treatment.

Exclusion criteria: Adult cancer patients undergoing radiotherapy or oncologic surgery.

Inclusion criteria: Prevalence, composition, severity, and predictors of cancer symptom clusters in young people and adults with cancer (> 18 years) resulting from chemotherapy treatment.

Exclusion criteria: Studies reporting the prevalence and severity of cancer symptom clusters in young people and adults who had undergone radiotherapy or oncologic surgery.

Inclusion criteria: Observational and experimental studies.

Exclusion criteria: Qualitative studies, guidelines and reviews.

Studies

The reference lists will be searched to seek additional studies. No restrictions regarding language, period of publication, or settings will be employed.

Study selection

Initially, all records scrutinized from the eight electronic databases will be imported into EndNote™. Thus, duplicate studies will be removed. Two independent researchers (LCLJ and TF) will be search and screen the records by titles and abstracts using the Rayyan™ app. Following the initial screening, the full text of the retrieved studies will be assessed for inclusion/exclusion by two independent reviewers using the Rayyan™ app. Disagreements in the selected studies will be resolved by a third reviewer (KZN). A flowchart summarizing the study selection process in line with the PRISMA 2020 statement [26] is presented in Fig 1.

Fig 1

PRISMA flowchart [26].

Data extraction and synthesis

Data extraction will be performed by two reviewers (LCLJ and TF) for each included study, based on previously published forms [22, 24, 25, 27–29]. The same two reviewers (LCLJ and TF) will independently perform the data extraction. The information to be extracted is detailed in Table 2.

Table 2

The data extraction form was based on previous publications [22, 24, 25, 27–29].

Study number:	Level of evidence:
	Methodological appraisal tool:
STUDY CARACTERISTICS
Authors
Title
Year of publication
Country
Conflicts of interests
Sponsorship
Background
Rationale
Hypothesis
Objectives
Methods
Methodology is reported is in compliance with STROBE (observational studies) or CONSORT (clinical trials)
( ) Yes
( ) No
( ) Partially
Study design
Local:
Sample size:
Inclusion criteria (definition of exposure of interest)
Exclusion criteria
Confounding factors/Interaction factors considered
Ethical aspects
Procedure for data collection:
Instruments for data collection
Outcomes / Evaluation of outcomes(Prevalence /composition/stability/severity/ predictors of cancer symptom clusters)
Follow-up
Statistical analysis
If, cohort study	I. Number of participants in the exposed and unexposed cohort:
	II. Number of participants in each group:
	III. Comparability of exposed and unexposed cohorts
	IV. Contamination (unexposed patient being exposed):
	V. Follow-up period:
	VI. Dropouts:
If, case-control study	I. Criteria for selection of cases:
	II. Criteria for selection of controls:
	III. Comparability of groups:
	IV. Dropouts:
If, experimental or quase-experimental study	a) Trial Register:
	b) Trial arms:
	• Experimental Group:
	c) Randomization:
	d) Masking:
	e) Intervention protocol:
	f) Per-protocol and modified intention-to-treat analyses:
	• Per-protocol:
	• Intention-to-treat:
	• Dropouts:
Results
Main results
Clinical significance
Limitations of the study
Strengths of the study
Conclusions
Main conclusions
Implication for clinical practice and research or for decision-makers / stakeholders

Critical appraisal of the included studies

Initially, the level of evidence will be identified and classified according to the scale developed by the Oxford Center for Evidence-Based Medicine, which is based on the research design and classifies them as 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B, 4, and 5 [30]. The internal validity and risk of bias of randomized controlled trials will be assessed using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2) [31]. In addition, to assess nonrandomized controlled trials, the risk of bias in nonrandomized studies of interventions (ROBINS-I) will be used [32]. The Newcastle-Ottawa Scale (NOS) [33] will be used to evaluate the internal validity and risk of bias of the cohort studies. The Critical Appraisal Skills Programme (CASP) tool [34] will be employed for case-control studies. Cross-sectional studies will be assessed using the Agency for Healthcare Research and Quality (AHRQ) tool [35]. The same two reviewers (LCLJ and TF) will independently perform the critical appraisal.

Data synthesis

The study characteristics will be summarized and presented in tables. Heterogeneity among studies will be measured using the I2 statistic to estimate the percentage of variation across studies, ranging from 0% to 100% [36, 37], and its interpretation is as follows: a) I2 = 0%–40%, low heterogeneity; b) I2 = 30%–60%, moderate heterogeneity; c) I2 = 50%–90%, substantial heterogeneity; and d) I2 = 75%–100%, high heterogeneity [37, 38]. Based on the I2 statistic, we will determine whether a meta-analysis is feasible [28, 29, 39].

Moreover, subgroup analysis will be performed using a random-effect model adjusted for age, sex, cancer symptom cluster prevalence, and cancer type. For data analysis, the pooled effect estimates will be calculated considering a 95% confidence interval (CI) and alpha set at 0.05, using R statistical software v. 4.0.4 (R Foundation for Statistical Computing, Vienna, Austria). In addition, the certainty of evidence will be rated based on Cochrane methods and in accordance with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) [40]. Two reviewers (LCLJ and LBCP) will independently perform the critical appraisal of the evidence to assess the studies. Disagreements will be resolved by a third reviewer (KZN).

Ethics aspects and plans for dissemination

Ethical approval was not required for this study design. Moreover, this systematic review and meta-analysis will be conducted following the PRISMA 2020 statement [26]. Regarding plans for dissemination, we intend to disclose the results via peer-reviewed publications and presentations at international conferences.

Discussion

Indeed, there is a high prevalence of cancer symptom clusters in adult cancer patients, and such unpleasant symptoms are reported daily by patients and health professionals [4, 9, 16] in clinical practice. These symptom clusters are associated with worse prognosis and decreased quality of life. Thus, its effective management is crucial in oncology. The importance of evaluating and intervening in cancer symptom clusters, not only in terms of patient survival rate but also in terms of quality of life across the treatment, is a priority and an integral part of the pillars of research in oncology and for the advancement of science in symptom management in oncology [41-45].

Conclusion

To the best of our knowledge, this systematic review will be the first to identify and critically assess evidence of the prevalence, composition, severity, and predictors of cancer symptom clusters in adult cancer patients undergoing chemotherapy. We intend to provide health professionals with subsidies to reflect on a better understanding of symptom clusters in adult cancer patients undergoing chemotherapy, with the aim of contributing to the development of evidence-based therapeutic strategies and success in clinical practice.

PRISMA checklist.

(DOCX)

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6 May 2022

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Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

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(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I appreciate the opportunity to review this article protocol. This  systematic review is important in clinical practice, especially in  the developing countries that have high mortality rates in cancer patients.There are currently no comments on the study protocol, but there is the systematic review (Skye Tian Dong, et al 2014 "Symptom Clusters in Patients With Advanced Cancer: A Systematic Review of  Observational Studies"), I hope to return to. I wish the researchers success and await such the important  systematic review. No need to chart1

Reviewer #2: The authors aim to identify and gather evidence on the prevalence, composition, severity, and predictors of cancer symptom clusters in adult cancer patients undergoing chemotherapy. However, a similar study has recently been carried out elsewhere and the results have been published: Harris CS, Kober KM, Conley YP, et alSymptom clusters in patients receiving chemotherapy: A systematic review; BMJ Supportive & Palliative Care 2022;12:10-21. Hence, this study is not warranted.

Reviewer #3: The present is a protocol aiming to capture clusters of symptoms of patients undergoing chemiotherapy. The paper is very clear regarding goal source of participants and outcomes

Some issues are needed

1) Abstract and full paper>why will search be stopped on August 2021?

2) Introduction and methods>authors spoke correctly about physical and physiological symptoms. Do they think subgroup analysis may be needed?

3) Methods: elderly patients should be defined with a clear cut off or reported according to definition of each papers

4) Methods: regarding features of the studies I’m not sure that impact factor may be so relevant (just a comments) as IF does not always relate with quality of the paper

5) Conflict of interests>please define better

6) Methods>do authors think that a subgroup analysis for kinf of cancer and for protocol of chemiptherapy may be useful?

7) Moreover, do they think that some quantitative analysis (e.g meta-regression to evaluate impact of gender, age,) on clusters may be of interest?

8) Methods: primary and secondary end points should be better defined

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Fabrizio D'Ascenzo

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17 May 2022

Vitoria,ES, May 15, 2022

Dear Dr. Senthilnathan Palaniyandi,

We would like to thank you for the opportunity to review the manuscript after the reviewers' suggestions and recommendations.

All points were addressed and/or clarified in this new version. In addition, we responded item by item to the questions raised by the reviewers in this letter.

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

6. Review Comments to the Author

Reviewer #1: I appreciate the opportunity to review this article protocol. This systematic review is important in clinical practice, especially in the developing countries that have high mortality rates in cancer patients.There are currently no comments on the study protocol, but there is the systematic review (Skye Tian Dong, et al 2014 "Symptom Clusters in Patients With Advanced Cancer: A Systematic Review of Observational Studies"), I hope to return to. I wish the researchers success and await such the important systematic review. No need to chart1

Response: Thank you so much for your comments! We have added a paragraph mentioning this review (Dong et al., 2014) in the introduction and specified how ours differs from this one as well as the current one by Harris et al., 2022. In addition, we have removed the chart 1 as per suggested. Thanks!

Reviewer #2: The authors aim to identify and gather evidence on the prevalence, composition, severity, and predictors of cancer symptom clusters in adult cancer patients undergoing chemotherapy. However, a similar study has recently been carried out elsewhere and the results have been published: Harris CS, Kober KM, Conley YP, et alSymptom clusters in patients receiving chemotherapy: A systematic review; BMJ Supportive & Palliative Care 2022;12:10-21. Hence, this study is not warranted.

Response: We have added a paragraph mentioning this review (Dong et al., 2014) in the introduction and specified how ours differs from this one.

“Recently, a systematic review was published with the objective of evaluating the progress in symptom clusters research in adults receiving primary or adjuvant chemotherapy since 2016, and showed that psychological, gastrointestinal, and nutritional clusters were the most commonly identified clusters. Only the psychological clusters remained relatively stable over time [19].

It is stand out that our review study differs from the latter in the following aspects: we will not specify a publication date or language limit (in order to minimize publication bias). Furthermore, we will explore beyond observational studies, as we will include experimental studies and also, we will expand the number of databases to 8, besides the access gray literature and pre-prints for Health Sciences. Another difference is that both previous reviews used only generic tools for methodological appraisal and that assess the report of the study more than the risk of bias (in terms of internal validity and external validity of the studies). Here, we will use valid and design-specific tools, following the recommendations of the Cochrane Collaboration [20]. Additionally, there is still no systematic review and metanalysis taking into account a robust assessment of the risk of bias in studies involving cancer symptom clusters with validated and design-specific tools, which justifies our study for a potential contribution to the area”.

Reviewer #3: The present is a protocol aiming to capture clusters of symptoms of patients undergoing chemiotherapy. The paper is very clear regarding goal source of participants and outcomes

Response: Thank you so much!

Some issues are needed

1) Abstract and full paper>why will search be stopped on August 2021?

Response: In fact, we put August, 2021 because that was the date when we submitted the article to PLOS ONE. However, we will update the search once the protocol is accepted. We edit this in the paper. Thank you!

2) Introduction and methods>authors spoke correctly about physical and physiological symptoms. Do they think subgroup analysis may be needed?

Response: This is an important point to consider. Thank you very much! Yes, probably depending on the results we will find we will do subgroup analysis. We really appreciated this comment. I have added one paragraph on the sub-item “Data synthesis” into the methods section.

3) Methods: elderly patients should be defined with a clear cut off or reported according to definition of each papers

Response: Thanks for this comment. We have added one sentence in order to make it clearer. “Aged in this study is defined according to MeSH term “Aged”: a person 65 through 79 years of age or more”.

Aged

A person 65 through 79 years of age. For a person older than 79 years, AGED, 80 AND OVER is available.

Year introduced: 1966

4) Methods: regarding features of the studies I’m not sure that impact factor may be so relevant (just a comments) as IF does not always relate with quality of the paper

Response: Indeed, we agreed with you. So, we have removed. Thanks!

5) Conflict of interests>please define better

Response: The Committee on Publication Ethics (COPE) states in its Guidelines on Good Publication Practice (2003) that: 'Conflicts of interest arise when authors, reviewers, or editors have interests that are not fully apparent and that may influence their judgments on what is published.

6) Methods>do authors think that a subgroup analysis for kind of cancer and for protocol of chemiptherapy may be useful?

Response: This point is very interesting. Studies with cancer symptom clusters are quite heterogeneous around the target population, types of cancers included in the analyses, tumor staging and chemotherapy protocol. Thus, this stratification can be carried out depending on the evidence that we will find, especially if the meta-analysis is feasible. I have added this on “Data Synthesis”. Many Thanks!

7) Moreover, do they think that some quantitative analysis (e.g meta-regression to evaluate impact of gender, age,) on clusters may be of interest?

Response: Yes. I specified this in the topic “Data Syjthesis”. Thank you so much for your valuable contribuitions.

8) Methods: primary and secondary end points should be better defined

Response: We have edited this in the chart 1. Actually, our outcomes are including: “Prevalence /composition/stability/ severity/ predictors of cancer symptom clusters, as stated in the PECO acronym.

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Fabrizio D'Ascenzo

Submitted filename: Response to Reviewers .docx

Click here for additional data file.

12 Jul 2022

15 Jul 2022

Response to Reviewers

Vitória, ES, Brazil, July 15th, 2022

Minor revision

PONE-D-21-25793R1

Cancer symptom clusters in adult patients undergoing chemotherapy: a systematic review and metanalysis protocol

Dear Dr. Lopes-Júnior,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Your manuscript has been reassessed by the three reviewers from the previous round, whose reports can be found below. As you will see from the comments, the reviewers acknowledge that the manuscript has improved significantly.

Response: Dear Dr. Joseph Donlan,

Thank you for the opportunity to review the manuscript after the reviewers' suggestions and recommendations.

All points were addressed and/or clarified in this new version. In addition, we responded item by item to the questions raised by the reviewers in this letter.

While assessing your manuscript, we noticed several errors in the use of spelling, punctuation and grammar throughout the manuscript. So that your manuscript meets our publication criterion requiring that 'the article is presented in an intelligible fashion and is written in standard English.', we request that you thoroughly copyedit your manuscript to fix these errors. You may wish to use a professional scientific editing service to do this.

Response: Ok. As suggested, we have done it. So, we have paid an English proofreading to Editage (https://www.editage.com) for polishing the text and correct grammar and spelling mistakes according to the cultured language. Therefore, an extensive review of English was carried out.

We look forward to receiving your revised manuscript.

Kind regards,

Joseph Donlan

Editorial Office

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Response: We have carefully reviewed the reference list and we ensure that it is complete and correct. Also, we have no papers retracted cited in this manuscript.

Review Comments to the Author

Reviewer #1: When mentioning this review(...2014), this review was not intended in itself, but rather the intent was, the authors should clarify the strengths of their study and its difference from what preceded it, especially since the authors indicated in the study protocol that (this systematic review and comprehensive analysis will be the first to identify and evaluate Evidence about prevalence, composition, and severity ....)

I wish you success in publication a valuable study.

Response: OK. We addressed this in the introduction. Thank you so much!

Reviewer #2: Thank you for addressing the earlier comments. The manuscript needs a thorough proof reading for syntactic errors and grammars, especially in the paragraphs that have been added now to address the reviewers' comments.

Response: Thank you so much! We have paid an English proofreading to Editage (https://www.editage.com) for polishing the text and correct grammar and spelling mistakes according to the cultured language. Therefore, an extensive review of English was carried out.

Reviewer #3: all comments have been addressed.

i have no further comments, because the authors cleary detailed all the comments

Response: Thank you so much!

Reviewer #1: Yes: Rania E Moustafa

Reviewer #2: No

Reviewer #3: Yes: Fabrizio D'Ascenzo

Yours Sincerely,

The authors,

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

9 Aug 2022

Cancer symptom clusters in adult patients undergoing chemotherapy: a systematic review and metanalysis protocol

PONE-D-21-25793R2

Dear Dr. Lopes-Júnior,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

James Mockridge

Staff Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #3: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #3: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #3: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thanks for reviewing this article.

for There are no comments. Because the authors made all points clear.

Reviewer #3: All comments have been addressed. Authors should be complimented for performing such an accurate analysis

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Rania E Moustafa

Reviewer #3: Yes: Fabrizio D'Ascenzo

**********

23 Aug 2022

PONE-D-21-25793R2

Cancer symptom clusters in adult patients undergoing chemotherapy: a systematic review and meta-analysis protocol

Dear Dr. Lopes-Júnior:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr Joseph Donlan

Staff Editor

PLOS ONE