Title: Association between physical activity and gynecological cancers: A meta-analysis of
prospective cohort studies
Version: 0 Date: 14 Apr 2025
Reviewer's report:
1. Introduction and Background
Lack of Mechanistic Depth: The introduction mentions that physical activity (PA) influences
systemic functions like insulin metabolism, immune response, and inflammation (Page 3), but it
does not elaborate on how these mechanisms specifically relate to gynecological cancers (GCs).
A detailed discussion of the biological pathways (e.g., hormonal regulation, oxidative stress)
linking PA to GC risk is needed to strengthen the rationale for the study. I recommend adding
a paragraph to explore these mechanisms in detail.
Insufficient Literature Contextualization: The authors state that prior research on PA and GCs
is inconsistent (Page 3), but they fail to critically review or compare previous meta-analyses
or systematic reviews (e.g., Schmid et al., 2015; Zhong et al., 2014, referenced on Page 16).
A discussion of how this study builds on or differs from prior reviews is essential to justify its
novelty. I suggest incorporating a detailed comparison with existing literature.
Unclear Scope of GCs: The introduction lists eight categories of GCs (Page 3) but focuses only
on endometrial cancer (EC), ovarian cancer (OC), and cervical cancer (CC) in the analysis. The
rationale for excluding other GC types (e.g., vulvar, vaginal) is not provided, which limits the
comprehensiveness of the study. I recommend clarifying the scope of the analysis and justifying
the focus on EC, OC, and CC.
2. Methods
Limited Search Strategy: The search terms listed (e.g., "physical activity," "exercise,"
"gynecological," "ovarian") are relatively narrow (Page 4). Broader terms such as "movement,"
"fitness," or specific cancer subtypes (e.g., "endometrioid carcinoma") could have increased
the yield of relevant studies. Additionally, the search strategy (Supplementary Table 1) is not
provided, hindering reproducibility. I recommend expanding the search terms and including the
full search strategy in the supplementary material.
Ambiguity in PA Classification: The authors define PA levels based on metabolic equivalent
tasks (METs) (<600, 600–3000, >3000 METs) for studies that did not classify PA qualitatively
(Page 5). However, the rationale for these cutoffs and their alignment with standard PA
guidelines (e.g., WHO or ACSM) is not justified. Furthermore, the classification of PA domains
(e.g., household, leisure) is mentioned but not consistently applied in the analysis. I suggest
providing a clear justification for the MET cutoffs and ensuring consistent application of PA
domains in the analysis.
Inadequate Handling of Confounders: The methods do not describe how potential confounders
(e.g., BMI, diet, smoking) were addressed in the included studies or the meta-analysis (Page 5).
Given the known impact of these factors on GC risk, their omission introduces bias. I recommend
conducting a meta-regression or subgroup analysis to explore the influence of key confounders.
Limited Subgroup Analysis: The subgroup analyses are restricted to geographic region (United
States) and menopausal status (Page 6), which do not fully address potential sources of
heterogeneity. Other factors, such as PA type (e.g., aerobic vs. resistance), duration, or baseline
BMI, could provide deeper insights. I suggest expanding the subgroup analyses to include these
variables.
Incomplete Quality Assessment Reporting: The Newcastle-Ottawa Scale (NOS) scores are
summarized (mean = 7.12, Page 7), but the manuscript does not provide a detailed breakdown
of scores across the NOS domains (selection, comparability, outcome). This limits the reader’s
ability to assess study quality comprehensively. I recommend including a table with individual
NOS scores for each study in the supplementary material.
3. Results
Insufficient Data on Cervical Cancer (CC): The analysis of CC risk is based on only one study
(Page 8), which is inadequate for a meta-analysis and precludes meaningful conclusions. The
authors should either exclude CC from the meta-analysis due to insufficient data or conduct a
narrative synthesis instead. Additionally, the decision to include CC despite limited data should
be justified.
Unexplored Heterogeneity: The meta-analyses for EC and OC show moderate to high
heterogeneity (e.g., I² = 56.5% for moderate PA and EC, I² = 58.1% for high PA and OC,
Page 7). However, the authors do not adequately explore potential sources of heterogeneity
beyond subgroup analyses by region and menopausal status. Factors such as study population
characteristics, PA measurement methods, or follow-up duration could contribute to this
variability. I recommend conducting additional subgroup analyses or meta-regressions to
investigate these factors.
4. Discussion
Limited Interpretation of OC Findings: The lack of association between PA and OC risk (Page
10) is discussed, but the authors do not explore potential reasons for this null finding in depth.
For example, differences in OC subtypes (e.g., serous vs. endometrioid), genetic factors, or PA
timing (e.g., early life vs. adulthood) could influence the results. I recommend a more thorough
discussion of these factors and their potential impact on the findings.
Inadequate Discussion of Heterogeneity: The authors acknowledge heterogeneity in their meta-
analyses (Page 10) but fail to propose specific explanations or solutions. Potential sources
such as variability in PA assessment methods, study populations, or cancer subtypes should be
explored. I suggest dedicating a paragraph to discuss these factors and their implications for the
study’s findings.
Lack of Clinical Implications: The discussion does not address the practical implications of
the findings for public health or clinical practice (Page 9). For example, what specific PA
recommendations (e.g., frequency, intensity) can be made based on the observed risk reductions
for EC and CC? I recommend adding a section on the clinical and public health implications
of the findings.
Overgeneralization of Findings: The authors state that moderate-to-high PA “considerably
lowers the risk of EC and CC” (Page 11), but the evidence for CC is based on only one study,
and the effect sizes for EC (RR = 0.89 for moderate PA, RR = 0.80 for high PA) are modest. This
language overstates the strength of the findings. I suggest revising the conclusions to reflect the
uncertainty and limitations of the data, particularly for CC.
Neglect of Confounding Factors: The discussion mentions potential confounders (e.g., diet,
lifestyle habits) (Page 10) but does not explore their specific impact on the PA-GC relationship.
For example, BMI is a known confounder for EC risk, yet its role is not analyzed in depth.
I recommend discussing how confounders might have influenced the results and suggesting
strategies for future studies to address them.
5. Conclusions
Vague Future Directions: The call for “more well-designed cohort studies” to validate the
findings (Page 11) lacks specificity. The authors should provide concrete recommendations,
such as investigating specific PA types, durations, or populations (e.g., premenopausal women,
specific OC subtypes). I recommend revising this section to include actionable suggestions for
future research.
Overemphasis on Positive Findings: The conclusions focus on the protective effects of PA on
EC and CC (Page 11) while downplaying the null findings for OC and the limitations of the
study (e.g., heterogeneity, limited CC data). A more balanced conclusion that acknowledges
these uncertainties is needed. I suggest revising the conclusions to reflect the study’s limitations
more explicitly.