-->PONE-D-25-52742-->-->Harms of massage in persons with cancer or receiving treatment for cancer: a systematic review and meta-analysis-->-->PLOS One

Dear Dr. Kjerulf,

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PLOS One

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Additional Editor Comments:

Specific Comments to the Authors

**Statistical software specification **(Section 13d, Synthesis methods)

While the random-effects model (DerSimonian and Laird method) and the measure of statistical heterogeneity (I² statistic) are appropriately described, the name of the statistical software package used for meta-analysis (e.g., R with metafor package, RevMan, Stata) is not specified. Please add this information to enhance methodological transparency and reproducibility.

**Numerical reporting of primary meta-analysis results **(Section 20b)

The overall result of the meta-analysis (Risk Ratio and 95% Confidence Interval) is currently referenced only to Figure 2. For clarity and accessibility, please explicitly report the numerical values of the pooled RR, 95% CI, and I² statistic for the primary analysis within the main text of the Results section.

**Statistical reporting of subgroup analyses **(Section 20c)

Subgroup analyses are presented qualitatively. If formal statistical tests for subgroup differences were conducted, please report the corresponding p-values for interaction or the I² statistic between subgroups to allow readers to assess whether observed differences across subgroups are statistically meaningful.

**Operational definition of "deep massage" **(Methods/Eligibility criteria)

The manuscript excludes studies assessing "deep massage," yet an operational definition of this term is not provided. Please clarify how "deep massage" was defined for the purposes of study eligibility: Was it based on applied pressure (e.g., in Newtons), depth of tissue penetration, therapist description, or another criterion? This clarification is essential for interpreting the scope and generalizability of the findings.

Sensitivity analysis based on adverse event reporting quality:

Given the notably low median score for adverse event reporting quality (1.5 out of 16 items), we recommend conducting an additional sensitivity analysis: repeat the meta-analysis including only studies with an adverse event reporting score ≥5. This would help assess the robustness of the pooled estimates to the quality of harms reporting in the primary studies.

**Summary table of key outcomes **(Results)

To improve readability and clinical utility, we suggest adding a concise summary table in the Results section. For each primary outcome (e.g., overall adverse events, serious adverse events, local adverse events), the table should include: number of contributing studies, total participants, pooled effect estimate (RR, 95% CI), measure of heterogeneity (I²), and GRADE certainty of evidence.

**Discussion of generalizability to specific populations **(Discussion)

Please add a brief paragraph in the Discussion addressing the generalizability of findings to specific patient subgroups, such as pediatric populations, older adults, or patients with extensive bone metastases. Given the restrictive inclusion criteria of many primary studies (e.g., exclusion of patients with thrombocytopenia, open wounds, or severe symptoms), this discussion would help clinicians appropriately contextualize the results.

Formatting and language corrections:

Table 4 clarity: In the "Last follow-up" column of Table 4, time points such as "Immediately PI" are ambiguous. Please specify the unit of time (e.g., "Immediately post-intervention (within 24 hours)" or "Immediately post-intervention (same day)") to improve interpretability.

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Reviewers' comments:

Reviewer's Responses to Questions

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Reviewer #1: Yes

Reviewer #2: Yes

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-->2. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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-->5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: Thank you very much for giving me the opportunity to review this interesting manuscript. The paper is well-written and methodologically sound. You will find my comments below, which may help you to further improve the paper.

Methods

Inclusion criteria - Interventions and comparators

Line 102: Please specify the types of massage that were eligible for inclusion, as ‘other types of massage’ is mentioned here without further explanation. In one study manual lymph drainage was included as a type of massage; however, lymph drainage seems to differ from conventional massage in several ways. Please provide more information on the types of massage eligible for inclusion.

Please add the outcomes of interest to this section. Please provide more information on the types of adverse outcomes addressed.

Critical appraisal – the use of the PEDro scale should be justified more clearly as some of the items do not represent a bias in clinical trials. Please comment on why the Cochrane RoB Tool 1 or 2 was not used?

Analysis

In your analysis, all types of cancer were included in one analysis. Is there evidence that there are no differences in the risk of adverse events according to the type of cancer?

Results

Please add the countries of origin of the included studies to the characteristics of studies.

Table S5 should be included in the main manuscript, not the supplemental material. A description of the included studies seems essential for readers.

The results of the critical appraisal of study quality should also be included in the main manuscript (S7 and a summary of S8).

Please add the results of the meta-analysis and the GRADE rating to the description in the text (lines 278 ff.).

Reviewer #2: This study addresses a clinically important topic: massage is widely used among cancer patients, yet robust evidence on its safety is lacking. A systematic assessment of its potential harms is essential for clinical practice and patient safety. The manuscript presents a clear research question that directly addresses a key clinical concern (the safety of massage in cancer patients). The methodology is robust, including PROSPERO registration, PRISMA reporting, comprehensive multi-database searches, independent dual screening and data extraction, risk of bias assessment using the PEDro and ROBINS-I tools, and GRADE评级 for certainty of evidence. The results are presented in detail, and the systematic evaluation of the quality of adverse event reporting provides an important cautionary signal.

Recommendations for Revision:

Massage Technique Specifics: The authors have analyzed data based on massage intensity (light, moderate, deep) and type (e.g., Swedish, slow-stroke back). However, they did not explore the potential safety implications of specific manual maneuvers (e.g., swinging, friction, compression, vibration, tapping, or joint mobilization techniques commonly used in Chinese Tuina). Different maneuvers produce significantly different biomechanical effects – for example, tapping techniques may increase bleeding risk in thrombocytopenic patients, while deep kneading could be dangerous for those with bone metastases. Nevertheless, the included primary studies did not report such detailed classifications of techniques, so the authors cannot synthesize this. I suggest adding a paragraph in the Discussion (Limitations) acknowledging the lack of detail on specific techniques in the current literature and calling for future research to clearly report the types of maneuvers used and their association with adverse events. This would strengthen the manual therapy depth of the study.

Distinction Between Absolute and Relative Contraindications: In the Introduction, the authors note that clinical massage textbooks cite cancer as a contraindication. It would be helpful to explicitly distinguish between absolute and relative contraindications, as the main findings suggest that most light-to-moderate intensity massage is safe in screened patients. Furthermore, the authors do not address differences between massage systems (e.g., Chinese Tuina vs. Western massage). In China, most Tuina textbooks classify tumors as an absolute contraindication, which has severely limited clinical research on Tuina for cancer patients in China. Consequently, almost all included studies originate from Western countries, and the generalizability of the conclusions to Tuina practice in China requires caution. I recommend that the authors briefly mention this geographical and cultural difference in the Discussion to help readers understand the limitations of the evidence base.

Specific Risks for Weakened Skin: On page 10, lines 67-68, after mentioning "weakened skin from surgery and radiotherapy," please consider adding specific associated risks (e.g., infection, breakdown of radiation dermatitis).

Adverse Event Definition and Grading: The study uses the NCI CTCAE definition of adverse events. However, it is not explicitly stated whether AEs were collected according to CTCAE grades (1-5). The authors should clarify this. The results note that only one study reported on seriousness (grade 3-5), and none reported on severity grading – this should be stated more prominently.

Highlighting Key Finding on Deep Massage: In Table 2 ("Massage intensity"), three studies involving "deep" massage did not report adverse events. This is a critical piece of information that should be highlighted more prominently in the main text (it is only briefly mentioned on lines 237-239). Consider emphasizing this finding in the Results or Discussion.

Suggested New Table Column: Consider adding a column to Table 2 (or a new supplemental table) indicating whether massage was applied directly over known tumor sites. This would help distinguish the safety risks associated with local massage on cancerous tissue versus massage on distant areas.

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Reviewer #1: No

Reviewer #2: Yes: Zhitong Deng

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Harms of massage in persons with cancer or receiving treatment for cancer: a systematic review and meta-analysis

PONE-D-25-52742R1

Dear Dr. Nicolas Kjerulf,

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.

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Kind regards,

Aynollah Naderi

Academic Editor

PLOS One

Additional Editor Comments (optional):

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