Intensive chemotherapy versus standard chemotherapy among patients with high risk, operable, triple negative breast cancer based on integrated mRNA-lncRNA signature (BCTOP-T-A01): randomised, multicentre, phase 3 trial.
He M, Jiang YZ, Gong Y, Fan L, Liu XY, Liu Y, Tang LC, Mo M, Hou YF, Di GH, Liu GY, Yu KD, Wu J, Yan X, Zeng XH, Fu DY, Song CG, Zhuang ZG, Wu KJ, Wang J, Wang ZH, Shao ZM
- DOI
- 10.1136/bmj-2024-079603
- Record issued
- 2026-08-16
- Engine
- 7.39.0
- Exported
- 2026-09-20
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/88b0b4e8-6f9b-41a4-80f6-4bf6ee9c9b91 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×3−1.5★
- ReportingEthical approvals partially met−0.25★
- ReportingData & code availability partially met−0.25★
This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.
This is a well-conducted phase 3 randomized trial with rigorous design, clear reporting of methods and results, and appropriate statistical analysis. The main weaknesses are a vague ethics statement (no named committee or protocol number) and a vague data availability statement, both of which are fixable reporting gaps. Minor copyedit issues and a small internal inconsistency in Table 2 warrant attention.
Both reviewers classified the study as interventional, which is adopted. The evaluation covered the full text, with verification components checking citations (34 references, none retracted or missing), statistics (6 tests recomputed consistently), reproducibility (4 links live), and preregistration (ClinicalTrials.gov). The integrity check flagged a minor arithmetic inconsistency in Table 2 (sum of distant metastasis subtypes exceeds total).
Numerical inconsistencies
1 finding · worst lowValues that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.
- Internal contradictions in the reported numbersAssessed
Recomputed 6 tests: 6 consistent, 0 inconsistent; 4 recomputed directly from the reported test statistics, 2 via agent-written checks.
- CONSISTENTreported p = .030 · recomputed p = .031Recomputed hazard ratio 0.51 (95% CI 0.28–0.95), reported p=0.03
“hazard ratio 0.51, 95% confidence interval (CI) 0.28 to 0.95; P=0.03”
Taken as given: 0.28–0.95 is a two-sided 95% confidence interval for the hazard ratio of 0.51, not a range, an IQR, or a different interval level; the hazard ratio is a RATIO measure, so the interval is symmetric on the log scale; p=0.03 is the p for THIS estimate, not for another comparison in the same sentenceMethod: back the two-tailed p out of the log-scale CI width and compare it against the printed pHow we recomputed it: pCI(0.51, 0.28, 0.95, 1) - CONSISTENTreported p = .040 · recomputed p = .047Recomputed hazard ratio 0.50 (95% CI 0.25–0.98), reported p=0.04
“hazard ratio 0.50, 95% CI 0.25 to 0.98; P=0.04”
Taken as given: 0.25–0.98 is a two-sided 95% confidence interval for the hazard ratio of 0.50, not a range, an IQR, or a different interval level; the hazard ratio is a RATIO measure, so the interval is symmetric on the log scale; p=0.04 is the p for THIS estimate, not for another comparison in the same sentenceMethod: back the two-tailed p out of the log-scale CI width and compare it against the printed pHow we recomputed it: pCI(0.5, 0.25, 0.98, 1) - CONSISTENTreported p = .270 · recomputed p = .272Recomputed hazard ratio 0.58 (95% CI 0.22–1.54), reported p=0.27
“hazard ratio 0.58, 95% CI 0.22 to 1.54; P=0.27”
Taken as given: 0.22–1.54 is a two-sided 95% confidence interval for the hazard ratio of 0.58, not a range, an IQR, or a different interval level; the hazard ratio is a RATIO measure, so the interval is symmetric on the log scale; p=0.27 is the p for THIS estimate, not for another comparison in the same sentenceMethod: back the two-tailed p out of the log-scale CI width and compare it against the printed pHow we recomputed it: pCI(0.58, 0.22, 1.54, 1) - CONSISTENTreported p = .040 · recomputed p = .043Recomputed hazard ratio 0.57 (95% CI 0.33–0.98), reported p=0.04
“hazard ratio 0.57, 95% CI 0.33 to 0.98; P=0.04”
Taken as given: 0.33–0.98 is a two-sided 95% confidence interval for the hazard ratio of 0.57, not a range, an IQR, or a different interval level; the hazard ratio is a RATIO measure, so the interval is symmetric on the log scale; p=0.04 is the p for THIS estimate, not for another comparison in the same sentenceMethod: back the two-tailed p out of the log-scale CI width and compare it against the printed pHow we recomputed it: pCI(0.57, 0.33, 0.98, 1) - CONSISTENTreported p = .007 · recomputed p = .009Reviewers 1, 2Arm C vs Arm B recurrence-free survival HR 0.42, 95% CI 0.22-0.81, P=0.007
“recurrence-free survival (three year recurrence-free survival 94.5% v 83.2%; 0.42, 0.22 to 0.81; P=0.007)”
Taken as given: The hazard ratio is 0.42 with 95% CI 0.22 to 0.81.; The CI is two-sided at 95%.; The p-value is two-sided from the log-rank test.Method: Recomputed two-sided p-value from the hazard ratio and its 95% CI using the normal approximation for the log hazard ratio.How we recomputed it: pCI(0.42, 0.22, 0.81, 1) - CONSISTENTreported p = .002 · recomputed p = .011Reviewers 1, 2Arm C vs Arm B overall survival HR 0.14, 95% CI 0.03-0.61, P=0.002
“overall survival (three year overall survival 100% v 91.3%; 0.14, 0.03 to 0.61; P=0.002)”
Taken as given: The hazard ratio is 0.14 with 95% CI 0.03 to 0.61.; The CI is two-sided at 95%.; The p-value is two-sided from the log-rank test.Method: Recomputed two-sided p-value from the hazard ratio and its 95% CI using the normal approximation for the log hazard ratio.How we recomputed it: pCI(0.14, 0.03, 0.61, 1)
- lowinternal contradictionThe abstract states 'Among the 504 enrolled patients, 498 received study treatment' and later 'Approximately 99% (498/504) of patients received at least one cycle of assigned chemotherapy'. This is consistent, but the safety population is 498, which is consistent.
“Among the 504 enrolled patients, 498 received study treatment.”
AbstractFind in source - lowinternal contradictionIn Table 2, the sum of distant metastasis subtypes (lung, liver, bone, brain, other) for arm A is 6+1+5+2+2=16, but the total distant metastasis is reported as 10. This is a clear arithmetic inconsistency.
“Distant metastasis: | 10 | 20 | 7 | | Lung | 6 | 7 | 4 | | Liver | 1 | 7 | 1 | | Bone | 5 | 8 | 2 | | Brain | 2 | 3 | 1 | | Other | 2 | 1 | 2 |”
Table 2Find in source - lowinternal contradictionThe abstract reports 504 enrolled patients, but the sample size calculation states 503 participants required. This is a minor discrepancy likely due to rounding or an extra patient.
Among the 504 enrolled patients, 498 received study treatment. ... totalling 503 participants required.
Statistical analysisreviewer’s wording
Overstated conclusions
1 finding · worst lowConclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.
- Conclusions only partially backed by the presented evidenceAssessed
8 major claims checked against the paper's own evidence: 1 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewer 1The multigene signature is more effective than traditional clinicopathological factors in predicting outcomes.The paper reports AUC analyses showing the signature outperformed traditional factors, but these are exploratory and not fully detailed in the main text.Evidence: Analysis of areas under the receiver operating characteristic curves indicated that the integrated signature was more effective than the traditional clinicopathological factors (supplementary figure B).
“Analysis of areas under the receiver operating characteristic curves indicated that the integrated signature was more effective than the traditional clinicopathological factors, including TNM stage, tumour grade, Ki-67, and age in predicting disease-free survival, recurrence-free survival, and overall survival at three years (supplementary figure B).”
ResultsFind in source - supportedReviewers 1, 2The multigene signature can tailor adjuvant chemotherapy for patients with operable triple negative breast cancer.The trial demonstrates that high-risk patients identified by the signature benefit from intensive chemotherapy, and low-risk patients have excellent outcomes, supporting the claim.Evidence: Primary endpoint disease-free survival HR 0.51 (95% CI 0.28-0.95, P=0.03) favoring intensive chemotherapy in high-risk patients; low-risk patients had 3-year DFS 90.1%.
“The multigene signature showed potential for tailoring adjuvant chemotherapy for patients with operable triple negative breast cancer.”
ConclusionFind in source - supportedReviewer 1Intensive chemotherapy significantly improved disease-free survival compared with standard chemotherapy in high-risk patients.The primary endpoint analysis shows a statistically significant improvement in disease-free survival with intensive chemotherapy.Evidence: HR 0.51, 95% CI 0.28-0.95, P=0.03 for disease-free survival.
“The three year disease-free survival rate was 90.9% for patients in arm A and 80.6% for patients in arm B (hazard ratio 0.51, 95% confidence interval (CI) 0.28 to 0.95; P=0.03).”
AbstractFind in source - supportedReviewer 1The prognostic value of the multigene signature was prospectively validated.Low-risk patients had significantly better survival outcomes than high-risk patients receiving the same standard chemotherapy, validating the signature's prognostic value.Evidence: Arm C vs Arm B: DFS HR 0.57 (95% CI 0.33-0.98, P=0.04), RFS HR 0.42 (95% CI 0.22-0.81, P=0.007), OS HR 0.14 (95% CI 0.03-0.61, P=0.002).
“Patients classified as being at low risk had significantly higher rates of disease-free survival (hazard ratio 0.57, 95% CI 0.33 to 0.98; P=0.04), recurrence-free survival (0.42, 0.22 to 0.81; P=0.007), and overall survival (0.14, 0.03 to 0.61; P=0.002) than did patients at high risk receiving the same standard chemotherapy”
ResultsFind in source - supportedReviewer 1The intensive regimen has manageable toxicity.Although grade 3-4 adverse events were higher in the intensive arm, no treatment-related deaths occurred and discontinuation rates were low, supporting manageability.Evidence: Grade 3-4 AEs 64% vs 51% (P=0.01), but no treatment-related deaths; discontinuation due to toxicity 5% vs 3%.
“No treatment related deaths occurred in the study.”
ResultsFind in source - supportedReviewer 2Intensive regimens incorporating gemcitabine and cisplatin into anthracycline/taxane based therapy significantly improved disease-free survival with manageable toxicity.The primary endpoint analysis showed a significant improvement in disease-free survival (HR 0.51, P=0.03) and toxicity was manageable with no treatment-related deaths.Evidence: Primary endpoint: three-year disease-free survival 90.9% vs 80.6%, HR 0.51, 95% CI 0.28-0.95, P=0.03. Safety: no treatment-related deaths, manageable toxicity.
“Intensive regimens incorporating gemcitabine and cisplatin into anthracycline/taxane based therapy significantly improved disease-free survival with manageable toxicity.”
ConclusionFind in source - supportedReviewer 2The intensive chemotherapy regimen significantly improved disease-free survival compared with standard chemotherapy in patients identified as being at high risk.The primary endpoint analysis directly supports this claim with a statistically significant hazard ratio.Evidence: Primary endpoint: HR 0.51, 95% CI 0.28-0.95, P=0.03.
The intensive chemotherapy regimen significantly improved disease-free survival compared with standard chemotherapy in patients identified as being at high risk.
What this study addsreviewer’s wording - supportedReviewer 2The prognostic value of the multigene signature was prospectively validated, with better survival outcomes in patients at low risk than in those at high risk receiving the same standard therapy.The comparison of arm C (low risk) versus arm B (high risk) on the same regimen showed significantly better outcomes, supporting the claim.Evidence: Arm C vs arm B: disease-free survival HR 0.57 (P=0.04), recurrence-free survival HR 0.42 (P=0.007), overall survival HR 0.14 (P=0.002).
The prognostic value of the multigene signature was prospectively validated, with better survival outcomes in patients at low risk than in those at high risk receiving the same standard therapy.
What this study addsreviewer’s wording
Efficacy claim is anchored to an adequate endpoint and a meaningful effect.
- ADEQUATESurrogate endpointThe primary endpoint is disease-free survival, a hard clinical outcome. The trial also reports recurrence-free survival and overall survival. Although the trial uses a multigene signature for risk stratification, the efficacy claim is based on clinical outcomes, not a surrogate biomarker.
“The primary endpoint was disease-free survival in the intention-to-treat analysis for arm A versus arm B.”
- ADEQUATEEffect sizeThe effect size is reported as a hazard ratio of 0.51 for disease-free survival, with a 10.3 percentage point absolute improvement in 3-year disease-free survival (90.9% vs 80.6%). This is a clinically meaningful improvement in a hard outcome, and the result is statistically significant (P=0.03).
“The three year disease-free survival rate was 90.9% for patients in arm A and 80.6% for patients in arm B (hazard ratio 0.51, 95% confidence interval (CI) 0.28 to 0.95; P=0.03).”
Data authenticity concerns
None foundAn adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.
Checked — nothing surfaced.
Reporting gaps
2 findings · worst mediumRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
- Data/code availability incompleteAssessed
- Ethics/consent reporting incompleteAssessed
The introduction cites prior research on multigene signatures (Oncotype DX, Mammaprint, HER2DX) and notes the lack of triple negative breast cancer-specific signatures validated prospectively. It also references the authors' previous development of the integrated mRNA-lncRNA signature and preliminary data suggesting high-risk patients derive less benefit from taxane-based chemotherapy. The hypothesis logically follows from this evidence, linking the signature to the addition of gemcitabine and cisplatin. Limitations of prior research are acknowledged (e.g., 'signatures specific to triple negative breast cancer are scarce and lack validation in prospective clinical trials').
“Given the strong pre-clinical evidence for a synergistic effect of cisplatin with gemcitabine, and the high objective response rate observed with this doublet as first line treatment in a phase 3 trial of metastatic triple negative breast cancer, we hypothesised that patients with high risk, early stage triple negative breast cancer identified using the multigene signature would benefit from the addition of gemcitabine and cisplatin to the standard anthracycline/taxane based regimen in the adjuvant setting.”
“Nevertheless, signatures specific to triple negative breast cancer are scarce and lack validation in prospective clinical trials.”
“Advances in high throughput technologies have led to the development of multigene signatures, including Oncotype DX, Mammaprint, and HER2DX, for predicting prognosis and guiding adjuvant therapy.”
“Given the strong pre-clinical evidence for a synergistic effect of cisplatin with gemcitabine, and the high objective response rate observed with this doublet as first line treatment in a phase 3 trial of metastatic triple negative breast cancer, we hypothesised that patients with high risk, early stage triple negative breast cancer identified using the multigene signature would benefit from the addition of gemcitabine and cisplatin to the standard anthracycline/taxane based regimen in the adjuvant setting.”
“Nevertheless, signatures specific to triple negative breast cancer are scarce and lack validation in prospective clinical trials.”
Randomization was computer-generated with block size four, and allocation was concealed via fax. The study was open label but outcome assessors, data collectors, and analysts were blinded. A sample size calculation was provided for the original and updated primary endpoints. Inclusion/exclusion criteria were detailed in the protocol. The primary endpoint was amended after enrolment, which is a limitation but was justified and pre-specified in an amended statistical analysis plan.
“Randomisation was generated centrally with a block size of four. This process was carried out with a computer generated random allocation sequence prepared by an independent statistician.”
“The study was open label, and allocation was unmasked to patients and investigators. However, all outcome assessors (for example, radiologists and laboratory personnel), data collectors, and analysts were blinded to treatment assignments.”
“On the basis of a 1:1 randomisation ratio and an assumed 9% drop-out rate, 335 patients at high risk with 50 disease-free survival events would provide 80% power at a significance level of 5% for the two sided log-rank test.”
“Randomisation was generated centrally with a block size of four. This process was carried out with a computer generated random allocation sequence prepared by an independent statistician.”
“The study was open label, and allocation was unmasked to patients and investigators. However, all outcome assessors (for example, radiologists and laboratory personnel), data collectors, and analysts were blinded to treatment assignments.”
“On the basis of a 1:1 randomisation ratio and an assumed 9% drop-out rate, 335 patients at high risk with 50 disease-free survival events would provide 80% power at a significance level of 5% for the two sided log-rank test.”
The study enrolled female patients aged 18-70 years. Baseline characteristics include age, menopausal status, histological grade, tumour size, nodal status, lymphovascular invasion, Ki-67 index, and BRCA/HRR status. These are reported in Table 1. Since both pre- and postmenopausal women are included, a single-sex justification is not required. Demographics are limited to age and menopausal status; race/ethnicity is not reported, but the study is conducted in China, which may be acceptable.
“Eligible participants were women aged 18-70 years with newly diagnosed, operable, unilateral invasive triple negative breast cancer”
“Median (range) age, years | 51 (27-68) | 54 (27-69) | 53 (22-69)”
“Median (range) age, years | 51 (27-68) | 54 (27-69) | 53 (22-69)”
The ethics statement says 'This study was approved by the independent ethics committee of all participating institutions' but does not name the specific committee(s) or provide protocol numbers. Informed consent is explicitly stated: 'Written informed consent was obtained from all patients.' Regulatory compliance is mentioned via adherence to Good Clinical Practice and the Declaration of Helsinki. The lack of a named ethics body makes the irb_ethics_statement 'reported_but_inadequate'.
“This study was approved by the independent ethics committee of all participating institutions and was conducted in adherence with Good Clinical Practice and the Declaration of Helsinki.”
“Written informed consent was obtained from all patients.”
“This study was approved by the independent ethics committee of all participating institutions and was conducted in adherence with Good Clinical Practice and the Declaration of Helsinki.”
“Written informed consent was obtained from all patients.”
The investigational drugs (docetaxel, epirubicin, cyclophosphamide, gemcitabine, cisplatin) are named with doses and regimens. Reagents for RNA extraction and qPCR are identified with vendors (RNeasy Plus Mini Kit, PrimeScript RT reagent kit, SYBR Premix Ex Taq, ABI PRISM 7900HT). Statistical software (SPSS version 22.0) is identified. No antibodies, cell lines, or mycoplasma testing are applicable as this is a clinical trial.
“We used SPSS version 22.0 for statistical analyses.”
“cDNA was synthesised using the PrimeScript RT reagent kit (Takara Bio Inc, Otsu, Japan) and SYBR Premix Ex Taq kit (Takara Bio Inc, Otsu, Japan).”
“Total RNA was isolated from the samples by using the RNeasy Plus Mini Kit (Qiagen).”
“We used SPSS version 22.0 for statistical analyses.”
The paper names the statistical tests (Kaplan-Meier, log-rank, Cox models) and provides exact p-values (e.g., P=0.03) and hazard ratios with 95% CIs. Assumptions are handled by design (Cox proportional hazards). Statistical software is identified. Data presentation includes Kaplan-Meier curves and forest plots. Mathematical plausibility checks were not performed due to lack of raw data, but no obvious inconsistencies were found.
“We estimated survival outcomes by using the Kaplan-Meier method and compared them with log-rank tests. We built Cox models to control for intergroup prognostic variables and estimate hazard ratios and 95% confidence intervals (CIs).”
“Disease-free survival was significantly higher among patients receiving intensive chemotherapy than in those receiving standard therapy (hazard ratio 0.51, 95% CI 0.28 to 0.95; P=0.03).”
“The three year disease-free survival rate was 90.9% for patients in arm A and 80.6% for patients in arm B (hazard ratio 0.51, 95% confidence interval (CI) 0.28 to 0.95; P=0.03).”
“We estimated survival outcomes by using the Kaplan-Meier method and compared them with log-rank tests. We built Cox models to control for intergroup prognostic variables and estimate hazard ratios and 95% confidence intervals (CIs).”
“hazard ratio 0.51, 95% confidence interval (CI) 0.28 to 0.95; P=0.03”
“hazard ratio 0.51, 95% confidence interval (CI) 0.28 to 0.95”
The data availability statement says 'Requests for individual de-identified participant data that underlie the results reported in this article will be considered. Qualified researchers should submit a proposal to the corresponding author outlining the reasons for requesting the data.' This is vague as it does not specify a data access committee, platform, or timeframe. Since the data are patient-level and identifiable, repository deposit and accession numbers are not applicable. No custom code was used, so code sharing is not applicable.
“Requests for individual de-identified participant data that underlie the results reported in this article will be considered. Qualified researchers should submit a proposal to the corresponding author outlining the reasons for requesting the data.”
“No custom code was used for data analysis in this study.”
“Requests for individual de-identified participant data that underlie the results reported in this article will be considered. Qualified researchers should submit a proposal to the corresponding author outlining the reasons for requesting the data.”
The trial is registered (NCT02641847). The methods are detailed enough for replication. The paper discusses limitations extensively, including the primary endpoint amendment, open-label design, and generalizability to other ethnic groups. Funding sources and competing interests are declared. The conclusions are appropriately cautious, noting the need for long-term follow-up. A reporting guideline (CONSORT) is not explicitly mentioned, but the paper follows a structured format typical of clinical trials.
“This study has several limitations. Firstly, the primary endpoint was amended after completion of enrolment.”
“Funding: This work was supported by grants from the National Key Research and Development Project of China (2020YFA0112304), the National Natural Science Foundation of China (91959207, 92159301, 82103369), the Science and Technology Commission of Shanghai Municipality (22Y11912800), the Shanghai Key Laboratory of Breast Cancer (12DZ2260100), and the SHDC Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals (SHDC12021103).”
“Trial registration ClinicalTrials.gov NCT02641847 (https://clinicaltrials.gov/ct2/show/NCT02641847)”
“This study has several limitations. Firstly, the primary endpoint was amended after completion of enrolment.”
Registered (3 IDs: ClinicalTrials.gov). No reporting guideline cited.
Broken references and links
None foundReferences checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.
Checked — nothing surfaced.
Checked 34 references by DOI: 32 verified — 2 no DOI (shown, not verified).
- NO DOISynergistic interaction between cisplatin and gemcitabine in vitroNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIGuidelines for breast cancer diagnosis and treatment by China Anti-cancer Association (2024 edition)No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
4 data/code links checked; 4 live.
- datahttps://clinicaltrials.gov/ct2/show/NCT02641847LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://www.ncbi.nlm.nih.gov/nuccore/AK124454LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://clinicaltrials.gov/ct2/show/NCT02488967LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://clinicaltrials.gov/ct2/show/NCT04296175LIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
5 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 5 minor suggestions below.
5 copyedit issues flagged: mostly consistency, typo, clarity.
- MINORtypoAbstract, Results“The incidence of grade 3-4 treatment related adverse events were 64% (105/163), 51% (86/169), and 54% (90/166) for arms A, B, and C, respectively.”→ Change 'were' to 'was' to agree with 'incidence'.Subject-verb agreement error.
- MINORconsistencyMethods, Procedures“In both arms B and C, chemotherapy consisted of four cycles of epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 on day 1 every three weeks, followed by four cycles of docetaxel 100 mg/m2 on day 1 every three weeks).”→ Remove the extra closing parenthesis after 'weeks'.Extra parenthesis.
- MINORclarityResults, Patients’ characteristics“Approximately 99% (498/504) of patients received at least one cycle of assigned chemotherapy (), with most completing chemotherapy treatment as specified in the protocol (91% (149/163) of patients in arm A, 93% (158/169) in arm B, and 95% (157/166) in arm C).”→ Remove the empty parentheses '()' and ensure the reference to the figure is correct.Empty parentheses likely due to missing figure reference.
- MINORconsistencyAbstract, Results“The three year disease-free survival rate was 90.9% for patients in arm A and 80.6% for patients in arm B (hazard ratio 0.51, 95% confidence interval (CI) 0.28 to 0.95; P=0.03).”→ Ensure consistent use of 'three-year' hyphenation throughout.Hyphenation of 'three year' is inconsistent.
- MINORgrammarResults, Safety“The overall incidence of grade 3 or 4 treatment related adverse events was 105 (64%) of 163 patients in the arm A, 86 (51%) of 169 patients in arm B, and 90 (54%) of 166 patients in arm C.”→ Change 'in the arm A' to 'in arm A' for consistency.Inconsistent article usage.
The published work is robust overall, but an informed reader should weigh the vague ethics and data availability statements, the primary endpoint amendment, and the minor internal inconsistency in Table 2. These do not invalidate the conclusions but warrant a correction or clarification from the authors.
- 1.HIGHethicsIn the Ethics statements section, name the specific ethics committee(s) that approved the study and include protocol approval numbers.The current statement is vague and does not meet standard reporting requirements for clinical trials.
- 2.HIGHdata codeIn the Data availability statement, specify a concrete mechanism for data access, such as a data access committee or a platform like Vivli, and include conditions and expected timeframe for response.The current 'on request' statement is vague and does not provide sufficient detail for qualified researchers to access the data.
- 3.HIGHrigorIn Table 2, correct the arithmetic inconsistency where the sum of distant metastasis subtypes (16) exceeds the reported total (10) for arm A.This internal contradiction could undermine the credibility of the reported safety data and should be resolved.
- 4.MEDIUMreportingIn the Methods or a separate section, add a statement about adherence to the CONSORT reporting guideline.Explicitly referencing the reporting guideline would strengthen transparency and demonstrate compliance with standard requirements.
- 5.MEDIUMreportingIn the Demographics section, consider reporting race/ethnicity or justify its omission, given the study's focus on Chinese patients.Reporting race/ethnicity would improve generalizability assessment, though its omission is not a fatal flaw.
- 6.MEDIUMstatisticsIn the Statistical analysis section, explicitly state that proportional hazards assumptions were checked for the Cox models, or note that standard methods were used.This would clarify the validity of the Cox model results.
- 7.MEDIUMreportingIn the Discussion, explicitly address the potential for bias due to the open-label design and how blinding of outcome assessors mitigates it.This would strengthen transparency and address a common reviewer concern.
- 8.MEDIUMreportingIn the Data availability statement, clarify whether the study protocol and statistical analysis plan are publicly accessible, as they are mentioned as supplementary material.This would improve transparency and reproducibility.
- 9.LOWcopyeditIn the Abstract, Results, change 'were' to 'was' in 'The incidence of grade 3-4 treatment related adverse events were 64%...'.Subject-verb agreement error.
- 10.LOWcopyeditIn Methods, Procedures, remove the extra closing parenthesis after 'weeks' in the sentence about arms B and C.Extra parenthesis is a typographical error.
- 11.LOWcopyeditIn Results, Patients' characteristics, remove the empty parentheses '()' and ensure the figure reference is correct.Empty parentheses likely due to missing figure reference.
- 12.LOWcopyeditIn the Abstract, Results, ensure consistent use of 'three-year' hyphenation throughout.Hyphenation of 'three year' is inconsistent.
- 13.LOWcopyeditIn Results, Safety, change 'in the arm A' to 'in arm A' for consistency.Inconsistent article usage.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.