Review for 10.1186/s12876-025-03667-8 (2025)

Title: Short- and long-term outcomes of neoadjuvant chemotherapy compared with neoadjuvant
chemoradiotherapy for locally advanced rectal cancer: An updated meta-analysis
Version: 1 Date: 30 Nov 2024
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-There were "no significant differences" between the two groups regarding lymphovascular
invasion, perineural invasion, R0 resection, local recurrence, distant metastasis, overall survival,
disease-free survival, or grade 3–4 adverse events. This suggests that the two approaches may
have comparable long-term outcomes. However, it would be beneficial to clarify whether
this implies true equivalence in survival outcomes and disease control, or if the lack of
statistical significance was due to limitations or variability in the included studies. Additionally,
mentioning whether these findings were consistent across all studies or if there was any
heterogeneity in the results could enhance understanding.
-While the NAC group showed a lower rate of pathologic complete response (pCR) and tumor
regression grading (TRG), which is consistent with existing evidence that chemoradiotherapy
(CRT) often results in better downstaging, the clinical significance of these findings warrants
further discussion. For instance, how do the lower pCR and TRG rates correlate with long-
term survival or recurrence rates? Although the authors indicate no significant differences in
survival, further clarification on how pCR and TRG impact survival outcomes would strengthen
the interpretation.
-It is important to specify how much higher the sphincter-preserving rate was with NAC
compared to NACRT. Also, we should consider whether this finding is generalizable to all
patients with locally advanced rectal cancer (LARC) or if it is more applicable to specific
subgroups, such as those with low rectal tumors.
-The introduction effectively addresses the limitations of NACRT, but it could benefit from a
more in-depth discussion of the reasons behind the inconsistencies in findings among the cited
studies. Factors such as variations in chemotherapy regimens, patient demographics (including
age and co-morbidities), and differences in trial design could help explain these discrepancies,
thereby strengthening the rationale for the meta-analysis.
-The discussion on NAC is somewhat brief; additional details would enhance understanding of
why NAC is considered an attractive alternative, particularly regarding its efficacy, side effect
profile, and potential impact on surgical outcomes. This would provide a clearer justification for
its investigation alongside NACRT in the meta-analysis.
-The inclusion of Egger’s test to assess publication bias is a strong methodological approach, but
the authors should specify how they plan to handle potential publication bias in their analysis.
Will studies with small sample sizes or low-quality data be excluded? Will sensitivity analyses
be conducted to evaluate the influence of these studies?
-A more detailed explanation of the sources of heterogeneity, particularly for outcomes like pCR
and TRG, is also necessary. Exploring how different patient characteristics or chemotherapy
regimens might have contributed to the observed variability in results would be beneficial.
-Additionally, more discussion on the clinical relevance of statistically significant findings
is required, especially when there are notable differences in outcomes such as sphincter
preservation, local recurrence, or grade 3–4 adverse events.
-Exploring why prospective studies show more favorable results for NAC in terms of pCR and
TRG would strengthen the discussion. Are there differences in patient populations or treatment
protocols that account for these variances?
-Lastly, a recommendation or clarification on which patient group would benefit most from
NAC—especially regarding sphincter preservation—would be valuable. Identifying specific
subgroups of LARC patients who are more likely to benefit from the sphincter-preserving
outcomes of NAC would be helpful.
-The radiation toxicity section could also be expanded with examples of specific adverse events
that are more common with NACRT. This would provide greater context for why NAC may be
preferable for certain patients.