Effect of methylcobalamin on capecitabine induced hand-foot syndrome in patients with HER2 negative early breast cancer: multicentre, double blind, randomised, placebo controlled, phase 3 trial.

Name: Αlpha¹ Rigor Record — Effect of methylcobalamin on capecitabine induced hand-foot syndrome in patients with HER2 negative early breast cancer: multicentre, double blind, randomised, placebo controlled, phase 3 trial.
Item: Effect of methylcobalamin on capecitabine induced hand-foot syndrome in patients with HER2 negative early breast cancer: multicentre, double blind, randomised, placebo controlled, phase 3 trial.
Rating: 59
Author: Αlpha¹

Xia Y, Zhu Y, Ling L, Xu F, Yang Y, Ye J, Tan W, Chen Z, Liu Q, Wei W, Zhang J, Zhang A, Zhang L, Song E, Gong C

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Αlpha¹ Rigor Review — 3.75★ (Adequate), 0 critical, 5 high issues for “Effect of methylcobalamin on capecitabine induced hand-foot syndrome in patients with HER2 negative early breast cancer: multicentre, double blind, randomised, placebo controlled, phase 3 trial.”

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Αlpha¹ Editorial

This rigor review was examined and confirmed by Αlpha¹ Editorial · August 10, 2026

Αlpha¹ Rigor Review

Rigor Reviewed

3.75 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

ReportingBiological variables not met−0.5★
ReportingEthical approvals partially met−0.25★
ReportingKey resources partially met−0.25★
ReportingData & code availability partially met−0.25★

Model-reported confidence: moderateReviewer agreement: moderateEngine: 7.29.0Source: full text

Not verified in this report

The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run on this paper: the pass that reads its reported means did not complete. No reported mean was checked for arithmetic impossibility.

Problems surfaced5 types

Overstated conclusions1

Conclusions 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

Reporting gaps4

Required detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.

Biological variables not reportedAssessed
Data/code availability incompleteAssessed
Ethics/consent reporting incompleteAssessed
Key resources under-identified (antibodies, cell lines, RRIDs)Assessed

This Αlpha¹ Rigor Review uses AI 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 phase 3 RCT is well-designed and well-reported on most dimensions: randomisation, blinding, power analysis, statistics, and transparency are strong, and the data are openly deposited. The main weaknesses are incomplete biological-variable reporting (no weight, no explicit race/ethnicity, no sex justification), unnamed ethics committees, missing drug-source identification, and code deposited only as a supplementary appendix. No statistical errors were found in the limited machine-verification, and the copyedit flagged a numeric inconsistency in a secondary-endpoint percentage.

Three independent reviewer runs were synthesised; they converged on premise, design, statistics, and transparency but diverged on biological variables, ethics, key resources, and data/code (Reviewer 1 was more lenient, Reviewers 2/3 more stringent). The statistics verification recomputed only 3 tests/effect estimates (all consistent); the rest of the analysis is unverified. Citation check found no retracted or not-found references; data links are live.

11 major claims checked against the paper's own evidence: all adequately supported.

Efficacy claim is anchored to an adequate endpoint and a meaningful effect.

Recomputed 3 tests: 3 consistent, 0 inconsistent; 1 recomputed directly from the reported test statistics, 2 via agent-written checks.

Reporting

Eight Dimensions4 pass · 3 warn · 1 fail

The introduction cites prior studies on the incidence and impact of hand-foot syndrome, the ineffectiveness of pyridoxine, the safety concerns with celecoxib, and the uncertainty of urea-based cream. It also discusses the potential role of small fibre neuropathy and the neuroprotective effects of methylcobalamin, providing a logical rationale for the hypothesis. The limitations of prior research (e.g., safety concerns, uncertain efficacy) are explicitly acknowledged and addressed by the study design.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper clearly establishes the scientific premise by citing prior research on hand-foot syndrome, its pathophysiology, and the rationale for methylcobalamin, and addresses limitations of prior interventions.

Evidence

direct quote[Introduction, paragraphs 2-3]

“Several interventions have been investigated to prevent capecitabine associated hand-foot syndrome, including pyridoxine (vitamin B6), the cyclooxygenase 2 enzyme inhibitor celecoxib, and urea based cream. Unfortunately, pyridoxine did not significantly reduce the risk of hand-foot syndrome, and the effect of urea based cream in preventing grade 2 or 3 disease remains uncertain. Although celecoxib has been reported as effective in preventing hand-foot syndrome, its long term use is limited because of safety concerns about cardiovascular events, resulting in a relatively low grade of recommendation.”