Review for 10.1186/s12876-025-04207-0 (2025)

Title: Efficacy and safety of programmed death-1 inhibitors combined with chemotherapy in
patients with advanced gastric cancer
Version: 1 Date: 11 May 2025
Reviewer's report:
The authors present a retrospective observational study evaluating the efficacy and safety of
PD-1 inhibitors (camrelizumab, sintilimab, and tislelizumab) combined with chemotherapy in
45 patients with advanced gastric cancer. The reported objective response rate (ORR) was
22.2%, with a notably high disease control rate (DCR) of 97.8%. The median progression-free
survival (PFS) was 14.6 months, and the 1- and 2-year cumulative PFS rates were 68.5% and
29.9%, respectively. Hematologic toxicities, particularly decreased hemoglobin and leukocyte
counts, were the most frequent adverse events, with grade 3 events observed in a subset
of patients. While the topic is of clinical interest and the manuscript attempts to contribute
real-world data to an evolving therapeutic area, the study is significantly limited by multiple
methodological flaws, lack of proper controls, and weaknesses in data interpretation. As it
stands, the conclusions are overstated in relation to the strength of the evidence presented, and
substantial revision is necessary.
Major Concerns
One of the key issues lies in the inappropriate inclusion of two patients with TNM stage II
disease, which contradicts the manuscript’s stated focus on advanced gastric cancer. While the
authors mention these patients were older and declined surgery, their inclusion undermines
the internal consistency of the cohort and violates standard clinical classification. This choice
introduces heterogeneity that weakens any conclusions drawn about advanced-stage disease.
Moreover, no subgroup analysis is provided to assess the impact of including early-stage
patients on the outcomes. Another serious limitation is the absence of a control group
receiving chemotherapy alone. Given the retrospective nature of the study, a comparison
with either historical data or a matched cohort would have been methodologically sound and
essential to support claims regarding treatment efficacy. As presented, the manuscript lacks any
comparative framework, rendering it impossible to distinguish whether the observed outcomes
are attributable to PD-1 inhibitors or to the underlying effects of chemotherapy.
Furthermore, the median PFS of 14.6 months reported by the authors appears unusually
favorable when compared to major trials such as ATTRACTION-4 and KEYNOTE-859.
The explanation offered—that the majority of patients had stable disease—is speculative and
unsupported by more granular time-to-event analyses, such as landmark analyses or stratification
by best overall response. Given that stable disease does not always correlate with prolonged
PFS, especially in older and comorbid populations, the authors should provide a more detailed
survival analysis that accounts for early treatment discontinuation and the substantial number of
patients who were lost to follow-up. According to the discussion, 23 of 45 patients (more than
50%) either suspended treatment, abandoned therapy, or were uncontactable. This high attrition
rate casts doubt on the robustness of the reported PFS and should be addressed explicitly in the
survival analysis and the interpretation of findings.
The manuscript also falls short in its reporting of adverse events. Although a list of hematologic
toxicities is provided, it lacks sufficient clinical context. There is no information about treatment
delays, dose reductions, or therapy discontinuations related to these toxicities. Additionally,
the data on safety are limited to hematologic labs, without addressing immune-related adverse
events, hepatic dysfunction, or gastrointestinal toxicities, which are particularly relevant for
PD-1 inhibitor therapy. The safety interpretation, therefore, remains superficial.
Lastly, statistical analysis and reporting are inadequate. For instance, multivariate analysis of
prognostic factors influencing PFS is missing, despite the availability of baseline variables such
as age, ECOG score, tumor markers, and histologic type. The use of univariate log-rank tests
without adjusting for confounders is insufficient and weakens the credibility of the conclusions.
Minor Concerns
Several aspects of the manuscript would benefit from improved clarity and rigor. The eligibility
criteria are vaguely stated, particularly the phrase “not suitable for tumor resection and received
advanced treatment actually,” which is grammatically and conceptually imprecise. The methods
section fails to clarify the retrospective data collection process, the institutional treatment
protocols used, or the rationale for choosing one PD-1 agent over another. The term “others
or unknown” used for histology classification is also vague and should be clearly defined.
Moreover, the study population is not well contextualized; for instance, there is no detailed
description of comorbidities, prior treatments, or performance status beyond a brief ECOG score
summary.
There are inconsistencies in the terminology used throughout the manuscript. The abbreviation
“PS” is used for performance status, which should be consistently referred to as “ECOG PS.”
Also, the authors interchangeably use “PD-1 inhibitors combined with chemotherapy” and
“PD-1 plus chemotherapy” without clarification, and the abbreviation “PFS” is at times repeated
unnecessarily. Several sentences are repetitive, such as the reiteration of DCR and ORR in both
the abstract and the results section, without adding new information.
The manuscript acknowledges some limitations but omits several others that are critical.
The retrospective nature of the study inherently subjects it to selection bias, which
is particularly relevant given the non-randomized, non-controlled design. The choice of
immunotherapy regimens and chemotherapeutic backbones was left to physician discretion,
introducing significant treatment heterogeneity. Furthermore, the influence of prior gastrectomy,
radiotherapy, or comorbidities such as hypertension on outcomes is not explored. The authors
also fail to mention whether any patients received subsequent lines of therapy post-progression,
which could confound the survival data. Finally, the small sample size limits the power of
subgroup analyses and makes the findings exploratory at best.
The manuscript requires substantial language editing for grammar, syntax, and clarity. Multiple
sentences are awkwardly constructed and contain grammatical errors. For example, the sentence,
“patients were older and refused to receive surgery, therefore they received…” should be
rewritten for clarity and correct use of punctuation. Phrases like “treatment was conducted
according to the patient’s own willingness” are vague and should be replaced with clearer
medical phrasing such as “treatment selection was based on physician judgment and patient
preference.” Repetition should be reduced throughout the discussion, and transitions between
sections improved for better flow.
The manuscript generally cites appropriate sources, including landmark trials such as
ATTRACTION-4 and KEYNOTE-859. However, citation formatting should be improved to
match the journal’s style guide. In-text citations should be integrated smoothly and placed in
correct order. The reference list appears mostly accurate but should be carefully cross-checked
for journal names, author order, and DOI inclusion where applicable. Some data, such as the
justification for using PD-1 inhibitors in elderly patients or real-world attrition, could benefit
from referencing recent registry studies or real-world observational trials.