Efficacy and safety of oral Chinese medicine on cancer-related fatigue for lung cancer patients after chemotherapy: Protocol for systematic review and meta-analysis.

INTRODUCTION: Lung cancer has the highest mortality rate of about 18.0% among malignant tumors worldwide, and chemotherapy is the main treatment. 80% of patients receiving chemotherapy suffers from cancer-related fatigue, which is the most severe symptom, with a large effect on quality of life as well as prognosis. Oral Chinese medicine, a kind of complementary and alternative medicine, has been proved to benefit lung cancer patients. However, no studies have reviewed whether it can reduce fatigue in lung cancer patients after chemotherapy, which is the purpose of our study.
METHODS: Two reviewers will systematically and independently retrieve papers, select studies for inclusion, extract data, and assess risk of bias. The following nine databases will be searched: China National Knowledge Infrastructure, Wan Fang database, Chinese Scientific Journals Database, Chinese biomedical literature service system, PubMed, Web of Science, OVID, Scopus, and EMBASE from inception to February, 2022. Included studies will only be randomized controlled trials. Primary outcome is cancer-related fatigue. Secondary outcomes are quality of life, immunologic function, and the incidence of adverse events. We will use RoB 2 tool to assess the risk of bias and RevMan to analyze data. Risk ratios will be calculated for dichotomous data and mean differences for continuous data. Random-effect model will be used to integrate statistical effects. Meta-regression, subgroup and sensitivity analyses will be carried out. We will evaluate the strength and overall quality of evidence with four levels: very low, low, moderate, and high.
RESULTS: The review of current evidence of oral Chinese medicine on cancer-related fatigue for lung cancer patients after chemotherapy will be narratively summarized and quantitatively analyzed.
CONCLUSION: The definitive conclusion will help physicians to determine whether oral Chinese medicine is an effective treatment for reducing fatigue in lung cancer patients after chemotherapy in clinical settings. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021292576.

Introduction

Lung cancer (LC) has the highest mortality rate among malignant tumors worldwide and seriously harms public health. According to the latest global research, new cases and mortality due to LC reached 2.2 million and 1.79 million in 2020, accounting for 11.4% and 18.0% of the total number of new cases and deaths due to cancer, respectively [1, 2]. While LC is clinically treated via numerous therapeutic modalities, chemotherapy remains the cornerstone of treatment, and is widely used in neoadjuvant, adjuvant, and metastatic clinical settings, particularly for those with negative gene mutations or less expression of PD-1/L1 [3, 4]. Chemotherapy is associated with multiple adverse effects. Among them, fatigue, also known as cancer-related fatigue (CRF), is perceived as the most severe and distressing symptom, with a large effect on physical and emotional health, cognitive function, social relations, and quality of life (QOL) [5, 6]. CRF can last for several months to years, even more than ten years in 25% of cancer survivors [7]. Reports have shown that the prevalence of CRF in patients with LC is as high as 96%, and the incidence in patients receiving chemotherapy is 80%, contributing to the discontinuation of cancer treatment and poor prognosis [8, 9]. The mechanisms leading to CRF are complicated and largely unknown, but some possibilities have been proposed, such as the dysfunction of skeletal muscle, and the dysregulation of inflammatory cytokines [10]. Studies have revealed platinum-based chemotherapeutic drugs may result in CRF by increasing IL-8 levels [11]. Some evidence suggests the recommendation of physical activities and psychological therapies as a supportive strategy for reducing CRF [12, 13]. However, in addition to the nonpharmacologic interventions mentioned above, there is little evidence regarding medication for CRF treatment, which limits the treatment options in clinical settings. Complementary and alternative medicine has experienced increased popularity owing to its ever-increasing integrative role in the treatment of diseases. Substantial evidence indicates that the treatment, such as Chinese herbal medicine, yoga, tai chi, and acupuncture, can significantly alleviate CRF [14-16]. Among these, Chinese herbal medicine is considered an important therapeutic strategy that has been proved to improve QOL and survival time in LC patients [17, 18]. Meta-analyses have assessed the effects of traditional Chinese medicine (TCM) injection and Chinese herbal medicine on CRF [19, 20]; however, the results regarding the efficacy of oral Chinese medicine (OCM) on fatigue in patients with LC after chemotherapy were unclear. Unfortunately, no studies have reviewed this. Hence, there is a strong need for the accumulation of current evidence. The purpose of this article is to determine the efficacy and safety of OCM and whether CRF patients with LC benefit from it after chemotherapy. Our study will assist in determining effective interventions based on evidence-based medicine, by building effective, safe and individualized therapeutic strategies.

Methods

Study registration

This protocol has been registered on PROSPERO with the number CRD42021292576 (https://www.crd.york.ac.uk/prospero/). It will adhere to the Cochrane Handbook [21] and the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocols (PRISMA-P) guidelines (S1 Table) [22].

Eligibility criteria

Types of studies

Included studies in this review will only be randomized controlled trials, irrespective of language, publication year, and publication status. Quasi-randomized trials, cases reports, and cross-sectional studies will be excluded.

Types of participants

CRF participants, who were diagnosed with LC and received chemotherapy treatment will be included, regardless of pathological type and stage. Patients diagnosed with other types of cancer will be excluded. Studies without stating diagnostic criteria of CRF will be excluded, but there will be no limits on specific diagnostic approaches.

Types of interventions

Included studies used OCM as experimental interventions, compared against any control interventions of the followings: placebo, no treatment, conventional treatment, or usual care. There will be no restriction on the types of OCM, such as single Chinese medicine, Chinese patent medicine or Chinese herbal decoction based on syndrome differentiation. If studies used OCM combination with other treatments as experimental interventions, the other treatments in the experimental group should be the same as the control group. Studies involving topical Chinese medicine or TCM injection will be excluded.

Types of outcomes

CRF is the primary outcome, which can be measured by the following scales: the Brief Fatigue Inventory (BFI), the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), the Multidimensional Fatigue Symptom Inventory (MFSI), the Piper Fatigue Scale (PFS), or other validated scales (S2 Table) [23]. Secondary outcomes: (a) QOL, measured by any validated scale, for example, the Functional Assessment of Cancer Therapy-General/Lung (FACT-G/L) [24], or the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30/Lung Cancer 43 (EORTC QLQ-C30/LC43) [25]; (b) immunologic function, measured by serum T lymphocyte subsets, such as the ratio of CD4+/CD8+T lymphocytes; (c) the incidence of adverse events, such as liver injury, kidney injury, nausea, vomiting, and constipation, among others. There will be no limits on timing of outcome assessment.

Search strategy for the identification of studies

Two reviewers (RZ and TTL) will systematically and independently search studies published in the following nine databases: China National Knowledge Infrastructure (CNKI), Wan Fang database, Chinese biomedical literature service system (SinoMed), Chinese Scientific Journals Database (VIP), PubMed, Web of Science, OVID, Scopus, and EMBASE from inception to February, 2022. There will be no limitation based on language. We will additionally search ongoing trials and unpublished trials in the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), and the ClinicalTrials.gov. We will manually search all references of included studies and grey literatures through the OpenGrey database to ensure that no pertinent studies will be omitted. We will use the following MeSH terms and keywords: fatigue, cancer related fatigue, CRF, chemotherapy-induced fatigue, chemotherapy-related fatigue, lung neoplasm, lung cancer, pulmonary neoplasm, pulmonary cancer, traditional Chinese medicine, Chinese medicine, Chinese herbal drugs, herbal medicine, herb, randomized controlled trial, controlled clinical trial, randomized, drug therapy, and placebo. The complete search strategy for PubMed is shown in Table 1 and other strategies can be found in S1 File. Any inconsistencies will be solved by discussion and consensus with a third reviewer (LXL).

Table 1

Search strategy for PubMed.

NO.	Search Terms
#1	fatigue [MeSH Terms]
#2	cancer related fatigue
#3	CRF
#4	Fatigue syndrome, chronic [MeSH Terms]
#5	chemotherapy-induced fatigue
#6	chemotherapy-related fatigue
#7	#1-#6/OR
#8	Lung Neoplasms [MeSH Terms]
#9	Lung Neoplasm
#10	Neoplasms, Lung
#11	Neoplasm, Lung
#12	Pulmonary Neoplasms
#13	Pulmonary Neoplasm
#14	Neoplasms, Pulmonary
#15	Neoplasm, Pulmonary
#16	Lung Cancer
#17	Lung Cancers
#18	Cancer, Lung
#19	Cancers, Lung
#20	Cancer of Lung
#21	Cancer of the Lung
#22	Pulmonary Cancer
#23	Pulmonary Cancers
#24	Cancer, Pulmonary
#25	Cancers, Pulmonary
#26	Small Cell Lung Carcinoma [MeSH Terms]
#27	Carcinoma, Non-Small-Cell Lung [MeSH Terms]
#28	#8-#27/OR]
#29	Medicine, Chinese traditional [MeSH Terms]
#30	Traditional Medicine, Chinese
#31	Traditional Chinese Medicine
#32	Traditional Chinese Medicines
#33	Chinese Traditional Medicine
#34	Chinese medicines
#35	Chinese medicine
#36	Chinese Medicine, Traditional
#37	Drugs, Chinese Herbal
#38	Herb
#39	Herbs
#40	Herbal Medicine [MeSH Terms]
#41	Herbal Medicines
#42	Medicine, Herbal
#43	Chinese Herbal Drugs
#44	Herbal Drugs, Chinese
#45	#29-#44/OR
#46	groups [Title/Abstract]
#47	trial [Title/Abstract]
#48	controlled clinical trial [Publication Type]
#49	randomized controlled trial [Publication Type]
#50	randomly [Title/Abstract]
#51	randomized [Title/Abstract]
#52	placebo [Title/Abstract]
#53	drug therapy [MeSH Subheading]
#54	#46-#53/OR
#55	animals [MeSH Terms] NOT humans [MeSH Terms]
#56	#54 NOT #55
#57	#7 AND #28 AND #45 AND #56

Data collection and analysis

Selection of studies

After retrieving studies based on search strategies and removing duplicates, two reviewers (RZ and TTL) will independently screen the titles and abstracts for the first inclusion and the full texts for the final inclusion. EndnoteX9 will be utilized to screen the titles and abstracts. Studies that are clearly inconsistent with the inclusion criteria will be rejected, and the reasons for any excluding one will be recorded. Any inconsistency will be consulted and solved by a third investigator (LXL). The research flowchart recommended by the PRISMA statement is shown in Fig 1.

Fig 1

PRISMA flowchart of studies selection.

Data extraction and management

Essential data will be extracted into an excel spreadsheet independently by two reviewers (YW and RZ) from included studies. When they can’t reach a consensus, the third reviewer (QW) should make a judgment. Required information is as follows: reference ID, author names, publication year, study design, sample size, basic information of participants (age, sex, smoking history, pathological type and stage of LC, and previous treatment), OCM intervention and comparator (randomization, allocation, blinding, types and duration of intervention, and details of OCM), follow-up period, types of outcomes measures, and other outcomes. If necessary, the authors will be contacted to acquire certain information that can not be found in the studies. The data after double-checking will be recorded to the Review Manager V.5.3 by two reviewers (YW and RZ) independently.

Assessment of risk of bias

Two reviewers (RZ and LXL) will separately assess risk of bias (low risk, high risk, or some concerns) using RoB 2 tool [26], the revised Cochrane risk-of-bias tool, including 5 aspects: randomization process (for example, whether the sequence generation is random, and the allocation is concealed), deviations from intended interventions (such as blinding), missing outcomes (for example, whether the outcome data is complete), outcome measurement (for example, whether measures are appropriate), and selection report (for example, whether the results are selective reported). Any discrepancy will be resolved by consensus with a third reviewer (PJL).

Assessment of publication bias

Potential publication bias will be analyzed and shown by the funnel plot if no less than ten studies can be used for meta-analysis. Egger’s test will also be used to assess publication bias, and P values below 0.05 indicate large such bias.

Measures of treatment effect

Data will be analyzed through RevMan V.5.3 software. We will calculate risk ratios (RR) and 95% confidence intervals for dichotomous variables, as well as weighted mean difference (WMD) or standard mean differences (SMD) and 95% confidence intervals for continuous data. Standard mean differences will be adopted when included studies use different measure tools.

Dealing with missing data

Two reviewers (PJL and QW) will be responsible for contacting the corresponding author through e-mails or phones to obtain the elusive or missing data. The study will be excluded if the data of which cannot be obtained. The potential influence of missing data on the analysis will be measured by a sensitivity analysis.

Assessment of heterogeneity

Statistical heterogeneity will be analyzed by Q test, significant at P-value < 0.10. The level of heterogeneity will be described by the I² statistic, and values of 0%, 25%, 50%, and 75% are considered to represent no, mild, moderate, and extreme heterogeneity, respectively. We will use random-effect model to integrate statistical effects because of anticipated heterogeneity. Potential sources of heterogeneity will be explored through meta-regression and subgroup analyses. If considerable heterogeneous exists across studies, meta-analysis should not be conducted, and a narrative report will be provided.

Subgroup analysis

If included studies are adequate, subgroup analysis will be conducted in RevMan V.5.3 based on pathological type and stage of LC, chemotherapy regimen, OCM alone or combination with other treatments, type and duration of intervention, follow-up period, and type of outcome measure.

Sensitivity analysis

We will use a sensitivity analysis to evaluate whether the pooled results are reliable. The studies with low quality will be excluded, and the pooled effect size will be analyzed again to see whether the outcomes change significantly. In addition, sensitivity analyses will be performed by using fixed-effect model and removing one study each time.

Grading the quality of evidence

We will evaluate the strength of evidence (very low, low, moderate, and high) using The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool [27], including 5 major aspects: risk of bias, publication bias, imprecision, inconsistency, and indirectness.

Ethics and dissemination

This study does not need ethical approval, since it is a protocol for systematic review. Also, no privacy data of participants will be involved, and no intervention will be performed on them. The final analysis will be disseminated through the PROSPERO website and peer-reviewed journals. Academic conferences will also share it if needed.

Patient and public involvement

This study is designed without patient and public involvement as well as performance.

Amendments

This report will involve the following major stages: search and selection of studies, extraction and management of data, and data analysis. Any changes in this original protocol for systematic review will be updated on the PROSPERO website and stated formally in the final review manuscript. If necessary, the date and reason for any changes will also be provided.

Discussion

LC remains the leading cause of cancer-related deaths worldwide and is associated with significant morbidity and mortality [1, 2]. Chemotherapy is a major treatment for LC. Reports have shown that, after chemotherapy, half of LC patients experience moderate to severe CRF, lasting for several months or longer, which seriously affects patients QOL [28]. CRF is is characterized by tiredness and many patients have difficult tolerating CRF, even more so than other symptoms such as, pain, diarrhea, decreased appetite, nausea, and vomiting. However, there are currently few drug treatments available for CRF other than some nonpharmacological interventions, such as physical activities and psychological therapies, leading to treatment limitations. Additional strategies are needed to increase CRF treatment. TCM technical committee was created in 2009 [29], showing that TCM is more widely used worldwide. OCM, an essential part of TCM, reportedly improves the overall survival of LC patients, suppresses the development of LC, reduces treatment-related adverse effects, and relieves symptoms of fatigue [30-33]. Therefore, it is important to develop evidence-based OCM strategies for CRF treatment. Given that no reviews have evaluated the efficacy and safety of OCM on CRF in patients with LC after chemotherapy, we will conduct an objective and comprehensive review of the existing evidence. We hope that this report will reach a definitive conclusion and help physicians determine whether OCM is an effective treatment for reducing CRF in LC patients after chemotherapy in clinical settings.

PRISMA-P 2015 checklist.

(PDF)

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Measures of CRF.

(PDF)

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Search strategies.

(PDF)

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13 Apr 2022

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Reviewer #1: In this paper, the authors tried to set up a protocol for systematic review and meta-analysis in efficacy and safety of oral Chinese medicine on cancer-related fatigue for lung cancer patients after chemotherapy. They used two parts to explain their methods, which may be useful for physicians to decide whether oral Chinese medicine can be used as an adjunctive treatment. The protocol was described in detail, but some issues may need to be explained.

1. Chinese medicine is mainly used by Chinese, so the availability of this analysis can be limited. Do the authors think it may also applicable to other countries?

2. Please correct the spelling mistakes (such as Line 68, 106), punctuations (such as Line 75, 125) and reorganization of sentences.

3. For S1 table, Item No 16 “Specify any planned assessment of meta-bias(es) (such as publication bias across studies, selective reporting within studies”, did not report on P14.

4. The Introduction is long and not so specific, the authors should rewrite this part in a better way.

Reviewer #2: Li et al. described a protocol for a meta-analysis to determine the efficacy and safety of oral Chinese medicine and whether cancer-related fatigue patients with lung cancer after chemotherapy can benefit from it.

1. The authors seem only to want to evaluate the effects only after chemotherapy treatment. Whether the team will consider those who were treated with surgical resection, immunotherapy, or targets therapy? If only chemotherapy will be included, whether ‘chemotherapy-related fatigue’ is more suitable?

2. Please cite the most recent version of Cochrane handbook.

3. Timing of outcome assessment should be clarified.

4. In the search strategies section, please use the RCT filters described in Cochrane handbook and display strategy for each database.

5. Whether oral Chinese medicine could be considered as one entity also raised concern. Clinical heterogeneity exists. I recommend the usage of random-effect model in the future study. Besides, subgroup analysis is needed for this question.

6. I recommend using RoB 2 tool for risk of bias assessment.

7. Whether there are existing meta-analyses concerning this topic. If yes, please explain the reason you are conducting this study in the introduction section

8. PRISMA flowchart should be in accordance with PRISMA 2020.

9. The English language should be edited by a native speaker.

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Reviewer #2: Yes: Zhaolun Cai

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26 May 2022

Dear Editor:

Thank you for your kind letter and for the reviewers’ comments concerning our manuscript entitled “Efficacy and safety of oral Chinese medicine on cancer-related fatigue for lung cancer patients after chemotherapy: Protocol for systematic review and meta-analysis” (ID: PONE-D-21-40607). Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied comments carefully and have revised the manuscript in accordance with your kind advice and referee’s detailed suggestions, and have carefully proof-read the manuscript to minimize typographical, grammatical, and bibliographical errors. Here below is our description on revision according to the reviewers’ comments:

Reviewer 1:

Comment 1: Chinese medicine is mainly used by Chinese, so the availability of this analysis can be limited. Do the authors think it may also applicable to other countries?

Response: Thanks for the referee’s comment. Chinese medicine, considered as a kind of complementary and alternative medicine, is widely used in Japan, Korea, Germany and other countries. It is recognized across the world that Chinese medicine plays an important role in the treatment of cancer, COVID-19, and other diseases. We believe that this analysis can provide valuable information to physicians in China as well as other countries.

Comment 2: Please correct the spelling mistakes (such as Line 68, 106), punctuations (such as Line 75, 125) and reorganization of sentences.

Response: Thanks for the referee’s suggestion. We are very sorry for our incorrect spellings, punctuations and reorganization of sentences. Multiple checks have been performed, and any mistakes have been corrected in the paper. The English language of full text has been revised by an expert whose first language is English. Also, we have modified and perfected the content of our manuscript in accordance with the referee’s suggestions, especially the abstract, introduction and discussion sections.

Comment 3: For S1 table, Item No 16 “Specify any planned assessment of meta-bias(es) (such as publication bias across studies, selective reporting within studies”, did not report on P14.

Response: Thanks the referee for drawing my attention to a mistake appearing in S1 table. The page Item No 16 reported on has been corrected as “P12-13”. Assessment of risk of bias in 5 aspects (randomization process, deviations from intended interventions, missing outcomes, missing outcomes, and selection report) was reported in Line 206-216, P12-P13, and publication bias was reported in Line 217-221, P13 in our revised manuscript.

Comment 4: The Introduction is long and not so specific, the authors should rewrite this part in a better way.

Response: Thanks for the referee’s kind advice, which is very beneficial to the improvement of our article. According to the proposal, we have simplified and streamlined the Introduction (Line 60-106, P3-P5) so that it is more clearly to present the main background questions and hopefully more to the reviewer’s liking.

Special thanks to you for your good comments.

Reviewer #2:

Comment 1: The authors seem only to want to evaluate the effects only after chemotherapy treatment. Whether the team will consider those who were treated with surgical resection, immunotherapy, or targets therapy? If only chemotherapy will be included, whether ‘chemotherapy-related fatigue’ is more suitable?

Response: Thanks for the referee’s valuable suggestions. This study is focus only on lung cancer patients after chemotherapy treatment, irrespective of surgical resection, immunotherapy, or targets therapy. Cancer-related fatigue is described as a tiredness or exhaustion related to cancer or cancer treatment in NCCN guidelines and ESMO Clinical Practice Guidelines, which is also a candidate term in Emtree, while chemotherapy-related fatigue is not. Therefore, we think cancer-related fatigue is more formal and more widely used. Thanks again for your advice, which is very helpful for us.

Comment 2: Please cite the most recent version of Cochrane handbook.

Response: Thanks very much for the referee’s important suggestion. We have cited the most recent version of Cochrane handbook in Line 112, P6 in our revised manuscript.

Comment 3: Timing of outcome assessment should be clarified.

Response: Thanks for the referee’s kind advice. We will place no limitations on timing of outcome assessment (Line 151-152, P7). We will extract the duration of intervention and follow-up period from included studies (Line 200-201, P12). If possible, we will also conduct subgroup analysis for the duration of intervention and follow-up period (Line 248-249, P14). The above supplements have been added in our revised manuscript.

Comment 4: In the search strategies section, please use the RCT filters described in Cochrane handbook and display strategy for each database.

Response: Thanks for the referee’s suggestion. We have read the use of the RCT filters described in Cochrane handbook carefully and have reviewed the relevant papers. In accordance with the referee’s suggestion, we have refined the search strategy for PubMed (Table 1) and have added the search strategies for other databases in S3 File.

Comment 5: Whether oral Chinese medicine could be considered as one entity also raised concern. Clinical heterogeneity exists. I recommend the usage of random-effect model in the future study. Besides, subgroup analysis is needed for this question.

Response: Thanks for the referee’s kind advice. We believe that the future study will be useful to determine whether oral Chinese medicine can be considered as one entity and an effective treatment for cancer-related fatigue. According to the referee’s proposal, we will use random-effect model to integrate statistical effects in the future study (Line 240-241, P14). Because of anticipated heterogeneity, meta-regression and subgroup analyses will be performed to explore the sources of heterogeneity (Line 241-242, P14). Subgroup analysis for the pathological type and stage of lung cancer, the type and duration of intervention, type of outcome measure, and follow-up period will be conducted in the future study (Line 245-249, P14).

Comment 6: I recommend using RoB 2 tool for risk of bias assessment.

Response: Thanks for the referee’s suggestion, which is very correct and helpful for our study. RoB 2 tool, the version 2 of the Cochrane tool for assessing risk of bias in randomised trial, is an authoritative tool. We have revised the assessment of risk of bias section in accordance with your recommendation (Line 206-216, P12-13).

Comment 7: Whether there are existing meta-analyses concerning this topic. If yes, please explain the reason you are conducting this study in the introduction section.

Response: Thanks for the referee’s kind advice, which is very beneficial to the improvement of our article. There are several meta-analyses related to this topic, but they are not entirely consistent with our analysis. These meta-analyses assessed the effectiveness and safety of Chinese herbal medicine and traditional Chinese medicine injection for the treatment of cancer-related fatigue, which didn’t focus only on lung cancer patients. No studies have reviewed the efficacy and safety of oral Chinese medicine on fatigue in lung cancer patients after chemotherapy. We have added the relevant content in the introduction section according to the referee’s advice (Line 95-101, P5).

Comment 8: PRISMA flowchart should be in accordance with PRISMA 2020.

Response: Thanks for the referee’s very helpful suggestion. We have updated the PRISMA flowchart in accordance with PRISMA 2020 (Fig 1). This is an omission on our part. Thanks again for the referee’s advice.

Comment 9: The English language should be edited by a native speaker.

Response: Thanks for the referee’s kind advice. The English language has been revised by an expert whose first language is English. We hope that the English language in our revised manuscript meet your expectations.

Special thanks to you for your good comments.

Other changes:

1.We have modified and checked the format of our article to ensure that out manuscript meet PLOS ONE’s style requirements.

2.We have added the data availability in the cover letter, and have provided the minimal underlying data in S3 File.

3.After consulting an expert in methodology, we have added OVID and Scopus databases to search published studies, as well as the ClinicalTrials.gov to search ongoing and unpublished trials. We have also added the OpenGrey database to search grey literatures. These changes will be updated on the PROSPERO website.

We have tried our best to improve the manuscript and have revised many grammatical or typographical errors. All the lines and pages indicated above are in the revised manuscript. All the changes will not influence the content and framework of the paper. And here we did not list all changes but marked in red/yellow in the revised manuscript.

We appreciate for the warm work of Editors and Reviewers earnestly, and hope that the correction will meet with approval.

Thank you and all the reviewers very much the comments and suggestions.

Sincerely yours,

Peijin Li

Submitted filename: Response to Reviewers.pdf

Click here for additional data file.

7 Jun 2022

Efficacy and safety of oral Chinese medicine on cancer-related fatigue for lung cancer patients after chemotherapy: Protocol for systematic review and meta-analysis

PONE-D-21-40607R1

Dear Dr. Feng,

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.

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Kind regards,

Ning Wei

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The revised version of this manuscript is acceptable.

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 #2: 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 #2: Partly

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

Reviewer #1: Yes

Reviewer #2: 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 #2: Yes

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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: Yes

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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: In this paper, the authors tried to set up a protocol for systematic review and meta-analysis in efficacy and safety of oral Chinese medicine on cancer-related fatigue for lung cancer patients after chemotherapy. They used two parts to explain their methods, which may be useful for physicians to decide whether oral Chinese medicine can be used as an adjunctive treatment. The protocol was described in detail, only few issues may need to be explained.

1. What is the differences between Chinese herbal medicine and oral Chinese medicine (OCM), they should have some overlaps and how the authors group them? If Chinese herbal medicine also included OCM, whether there are existing meta-analyses concerning this topic?

Reviewer #2: The authors revised the manuscript in accordance with the comments.

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Reviewer #1: No

Reviewer #2: Yes: Zhaolun Cai

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21 Jun 2022

PONE-D-21-40607R1

Efficacy and safety of oral Chinese medicine on cancer-related fatigue for lung cancer patients after chemotherapy: Protocol for systematic review and meta-analysis

Dear Dr. li:

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. Ning Wei

Academic Editor

PLOS ONE