Assessment of proportional hazard assumption in aggregate data: a systematic review on statistical methodology in clinical trials using time-to-event endpoint
Open Access
- 13 November 2018
- journal article
- review article
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 119 (12), 1456-1463
- https://doi.org/10.1038/s41416-018-0302-8
Abstract
BACKGROUND: The evaluation of the proportional hazards (PH) assumption in survival analysis is an important issue when Hazard Ratio (HR) is chosen as summary measure. The aim is to assess the appropriateness of statistical methods based on the PH assumption in oncological trials. METHODS: We selected 58 randomised controlled trials comparing at least two pharmacological treatments with a time-to-event as primary endpoint in advanced non-small-cell lung cancer. Data from Kaplan-Meier curves were used to calculate the relative hazard at each time point and the Restricted Mean Survival Time (RMST). The PH assumption was assessed with a fixed-effect meta-regression. RESULTS: In 19% of the trials, there was evidence of non-PH. Comparison of treatments with different mechanisms of action was associated (P = 0.006) with violation of the PH assumption. In all the superiority trials where non-PH was detected, the conclusions using the RMST corresponded to that based on the Cox model, although the magnitude of the effect given by the HR was systematically greater than the one from the RMST ratio. CONCLUSION: As drugs with new mechanisms of action are being increasingly employed, particular attention should be paid on the statistical methods used to compare different types of agents.Keywords
This publication has 86 references indexed in Scilit:
- Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of randomized trials with a time-to-event outcomeBMC Medical Research Methodology, 2013
- Crizotinib versus Chemotherapy in AdvancedALK-Positive Lung CancerThe New England Journal of Medicine, 2013
- International, Randomized, Placebo-Controlled, Double-Blind Phase III Study of Motesanib Plus Carboplatin/Paclitaxel in Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer: MONET1Journal of Clinical Oncology, 2012
- Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trialThe Lancet Oncology, 2012
- Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curvesBMC Medical Research Methodology, 2012
- Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trialThe Lancet Oncology, 2010
- The Hazards of Hazard RatiosEpidemiology, 2010
- Gefitinib or Carboplatin–Paclitaxel in Pulmonary AdenocarcinomaThe New England Journal of Medicine, 2009
- Proportional hazards tests and diagnostics based on weighted residualsBiometrika, 1994
- Nonparametric Estimation from Incomplete ObservationsJournal of the American Statistical Association, 1958