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: 100
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

Paper source

Read full text (PMC)

Embed this Rigor badge

Αlpha¹ Rigor Review — 3★ (Adequate), 0 critical, 2 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.”

Links back to this Rigor Record.

Αlpha¹ Editorial

This rigor review was examined and confirmed by Αlpha¹ Editorial · August 15, 2026

Αlpha¹ Rigor Review

Rigor Reviewed

3 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Problems surfaced4 types

Numerical inconsistencies1

Values 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

Overstated conclusions3

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.

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed
Conclusions only partially backed by the presented evidenceAssessed

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 is a well-conducted, rigorously reported phase 3 randomised controlled trial. The methodology is sound across all eight dimensions, with clear randomisation, blinding, sample size justification, ethics approval, data/code availability, and transparent reporting. The only issues are minor copyedit-level inconsistencies in reported percentages that do not undermine the statistical conclusions.

Both reviewers classified the study as interventional, and this was adopted. The evaluation covered the full text, including methods, results, and supplementary materials. Non-applicable criteria (e.g., animal housing, cell line authentication) were excluded. The statistics verification recomputed only 4 tests (those with test statistics/df or effect estimates with CIs); the remaining analyses were not machine-verified and should not be assumed correct beyond what was checked.

4 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.

Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.

Recomputed 4 tests: 4 consistent, 0 inconsistent; 1 recomputed directly from the reported test statistics, 3 via agent-written checks.

2 integrity concerns flagged (0 high).

Reporting

Eight Dimensions8 pass

The paper cites prior studies on hand-foot syndrome prevention (pyridoxine, celecoxib, urea cream) and notes their limitations (ineffectiveness, safety concerns, uncertainty). It also cites mechanistic evidence linking small fibre neuropathy to hand-foot syndrome and methylcobalamin's neuroprotective effects, forming a logical hypothesis. The limitations of prior research are addressed by designing a randomised, double-blind, placebo-controlled trial.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The introduction establishes a clear clinical need and a plausible mechanistic rationale for methylcobalamin, citing prior work and acknowledging limitations of existing preventive strategies.

Evidence

direct quote[Introduction, paragraph 2]

“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”