ArticleClinical cancer research : an official journal of the American Association for Cancer Research2024
Proportional Hazards Violations in Phase III Cancer Clinical Trials: A Potential Source of Trial Misinterpretation.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
10 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Overall survival in oncology phase III trials: an individual patient level meta-analysis (OPTIMA).The oncologist · 2026Pooled it
- Visual extraction of individual patient data from published kaplan-meier survival plots using a web-based application offering different reconstruction methods (V-Exploder).BMC medical research methodology · 2026Article
- Sequential versus upfront oxaliplatin-based therapy in metastatic colorectal cancer: long-term outcomes of a randomized phase 3 trial.Communications medicine · 2026Article
- A literature review and reflection on clinical trials: current challenges, future directions, and potential strategies to overcome practical barriers.AME clinical trials review · 2026Article
- Comment on "survival of patients with 2014 FIGO stage IIIC high-grade serous ovarian cancer treated with platinum-based adjuvant chemotherapy".Turkish journal of medical sciences · 2026Article
- Reproducibility of statistically significant phase III oncology trials: An In Silico meta-epidemiological analysis.European journal of cancer (Oxford, England : 1990) · 2025Article
- Survival-inferred fragility of statistical significance in phase III oncology trials.NPJ precision oncology · 2025Article
- Flexible quantitative bias analysis for unmeasured confounding in subject-level indirect treatment comparisons with proportional hazards violation.BMC medical research methodology · 2025Article
- Impact of surrogates for insulin resistance on mortality and life expectancy in primary care: a nationwide cross-sectional study with registry linkage (LIPIDOGRAM2015).The Lancet regional health. Europe · 2025Article
- Increasing Power in Phase III Oncology Trials With Multivariable Regression: An Empirical Assessment of 535 Primary End Point Analyses.JCO clinical cancer informatics · 2024Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
19 authors.
Funding
Abstract
purposeSurvival analyses of novel agents with long-term responders often exhibit differential hazard rates over time. Such proportional hazards violations (PHV) may reduce the power of the log-rank test and lead to misinterpretation of trial results. We aimed to characterize the incidence and study attributes associated with PHVs in phase III oncology trials and assess the utility of restricted mean survival time and maximum combination test as additional analyses. EXPERIMENTAL
designClinicaltrials.gov and PubMed were searched to identify two-arm, randomized, phase III superiority-design cancer trials with time-to-event primary endpoints and published results through 2020. Patient-level data were reconstructed from published Kaplan-Meier curves. PHVs were assessed using Schoenfeld residuals.
resultsThree hundred fifty-seven Kaplan-Meier comparisons across 341 trials were analyzed, encompassing 292,831 enrolled patients. PHVs were identified in 85/357 [23.8%; 95% confidence interval (CI), 19.7%, 28.5%] comparisons. In multivariable analysis, non-overall survival endpoints [OR, 2.16 (95% CI, 1.21, 3.87); P = 0.009] were associated with higher odds of PHVs, and immunotherapy comparisons [OR 1.94 (95% CI, 0.98, 3.86); P = 0.058] were weakly suggestive of higher odds of PHVs. Few trials with PHVs (25/85, 29.4%) prespecified a statistical plan to account for PHVs. Fourteen trials with PHVs exhibited discordant statistical signals with restricted mean survival time or maximum combination test, of which 10 (71%) reported negative results.
conclusionsPHVs are common across therapy types, and attempts to account for PHVs in statistical design are lacking despite the potential for results exhibiting nonproportional hazards to be misinterpreted.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.