Meta-analyses of randomized controlled trials show suboptimal validity of surrogate outcomes for overall survival in advanced colorectal cancer

Objectives: To quantify and compare the treatment effects on three surrogate end points, progression-free survival (PFS), time to progression (TTP), and tumor response rate (TR) vs. overall survival (OS) based on a meta-analysis of randomized controlled trials (RCTs) of drug interventions in advanced colorectal cancer (aCRC). Study Design and Setting: We systematically searched for RCTs of pharmacologic therapies in aCRC between 2003 and 2013. Trial characteristics, risk of bias, and outcomes were recorded based on a predefined form. Univariate and multivariate random-effects meta-analyses were used to estimate pooled summary treatment effects. The ratio of hazard ratios (HRs)/odds ratios (ORs) and difference in medians were used to quantify the degree of difference in treatment effects on the surrogate end points and OS. Spearman ρ, surrogate threshold effect (STE), and R2 were also estimated across predefined trial-level covariates. Results: We included 101 RCTs. In univariate and multivariate meta-analyses, we found larger treatment effects for the surrogates than for OS. Compared with OS, treatment effects were on average 13% higher when HRs were measured and 3% to 45% higher when ORs were considered; differences in median PFS/TTP were higher than on OS by an average of 0.5 month. Spearman ρ ranged from 0.39 to 0.80, mean R2 from 0.06 to 0.65, and STE was 0.8 for HRPFS, 0.64 for HRTTP, or 0.28 for ORTR. The stratified analyses revealed high variability across all strata. Conclusion: None of the end points in this study were found to achieve the level of evidence (ie, mean R2trial > 0.60) that has been set to select high or excellent correlation levels by common surrogate evaluation tools. Previous surrogacy relationships observed between PFS and TTP vs. OS in selected settings may not apply across other classes or lines of therapy

The Net Benefit of a treatment should take the correlation between benefits and harms into account

OBJECTIVE: The assessment of benefits and harms from experimental treatments often ignores the association between outcomes. Generalized pairwise comparisons (GPC) can be used to assess the Net Benefit of treatment in a randomized trial accounting for that association.STUDY DESIGN AND SETTINGS: We use GPC to analyze a fictitious trial of treatment versus control, with a binary efficacy outcome (response) and a binary toxicity outcome, as well as data from two actual randomized trials in oncology. In all cases, we compute the Net Benefit for scenarios with different orders of priority between response and toxicity, and a range of odds ratios (ORs) for the association between outcomes.RESULTS: The GPC Net Benefit was quite different from the benefit/harm computed using marginal treatment effects on response and toxicity. In the fictitious trial using response as first priority, treatment had an unfavorable Net Benefit if OR1. With OR=1, the Net Benefit was 0. Results changed drastically using toxicity as first priority.CONCLUSION: Even in a simple situation, marginal treatment effects can be misleading. In contrast, GPC assesses the Net Benefit as a function of the treatment effects on each outcome, the association between outcomes, and individual patient priorities

Massive orbital metastasis of hepatocellular carcinoma

Federal University of São Paulo Multidisciplinary Oncology Group/Department of PathologyUNIFESP, Multidisciplinary Oncology Group/Department of PathologySciEL

Treatment priorities in oncology: do we want to live longer or better?

OBJECTIVES: Despite the progress achieved in the fight against cancer over the past several years, assessing the needs, goals and preferences of patients with cancer is of the utmost importance for the delivery of health care. We sought to assess priorities regarding quantity versus quality of life among Brazilian patients, comparing them with individuals without cancer. METHODS: Using a questionnaire presenting four hypothetical cancer cases, we interviewed cancer patients, oncology health-care professionals and laypersons, most of whom had administrative functions in our hospital. RESULTS: A total of 214 individuals participated: 101 patients, 44 health-care professionals and 69 laypersons. The mean ages in the three groups were 56, 34 and 31 years old, respectively (

Use of surrogate endpoints in healthcare policy : proposal for consistent adoption of a validation framework

We propose a three step framework for the evaluation of surrogate endpoints for health policy decisions on health technologies