Surrogate endpoint validation: statistical elegance versus clinical relevance

Em, Green; Yothers, Greg; Sargent, Daniel J.

doi:10.1177/0962280207081863

Cited by 28 publications

(28 citation statements)

References 9 publications

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“…Multiple statistical methods converging to the same conclusion (as in this study) lend strength to the conclusions presented. [47] Third, the statistical methods included adjusted P-values; conclusions were drawn following adjustment, permitting cautious interpretation. [40, 41] Finally, imaging was recognized as the gold standard; AFP correlative analyses were based on imaging as the reference standard.…”

Section: Discussionmentioning

confidence: 99%

Alpha-fetoprotein response correlates with EASL response and survival in solitary hepatocellular carcinoma treated with transarterial therapies: A subgroup analysis

Memon

Kulik

Lewandowski

et al. 2012

Journal of Hepatology

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Background and Aims Alpha-fetoprotein (AFP) is a universally recognized tumor marker in hepatocellular carcinoma (HCC). Its utility in assessing response to treatment remains controversial. We sought to study the: a) correlation between AFP response and imaging response, and b) ability of AFP, EASL and WHO response to predict survival outcomes in patients with solitary HCC. Methods 629 HCC patients were treated with transarterial locoregional therapies over an 11-year period. To eliminate confounding factors, we included patients with single tumors, baseline AFP≥200 ng/mL, and no extrahepatic disease; this identified our study cohort of 51 patients. AFP response was defined as >50% decrease from baseline; this was correlated to EASL and WHO response criteria by Kappa agreement, Pearson correlation and receiver operating curves. Survival analyses were performed by Landmark, risk-of-death and Mantel-Byar methodologies. None of the patients received sorafenib. Results Three months post-treatment, AFP and EASL response correlated well (Kappa: 0.83; Pearson: 0.84); the sensitivity, specificity, positive and negative predictive values of AFP in predicting EASL response at 3 months were 96.6%, 85.7%, 92.3% and 93.3% respectively. Correlation with WHO response was low. From the 3-month landmark, WHO, EASL and AFP responders survived longer than nonresponders (P=0.006, 0.0001 and <0.0001 respectively). The risk of death was lower for EASL and AFP responders by both risk-of-death and Mantel-Byar methodologies (P<0.05). Conclusion Response by AFP and EASL are predictors of survival outcome in patients with solitary HCC. AFP correlates with imaging response assessment by EASL guidelines. Achieving AFP response should be one of the therapeutic intents of locoregional therapies.

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Section: Discussionmentioning

confidence: 99%

Alpha-fetoprotein response correlates with EASL response and survival in solitary hepatocellular carcinoma treated with transarterial therapies: A subgroup analysis

Memon

Kulik

Lewandowski

et al. 2012

Journal of Hepatology

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“…This explains the central role played by meta-analyses, which allows for reliable combining of different trials. [28][29][30][31] In the validation of surrogates, meta-analyses take advantage of some heterogeneity across trials. 28 The accompanying articles also provide strong arguments to consider PFS as a surrogate endpoint for OS in ACC.…”

Section: Resultsmentioning

confidence: 99%

Surrogate endpoints for overall survival in advanced colorectal cancer: a clinician's perspective

Piedbois

Croswell

2008

Stat Methods Med Res

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Surrogate endpoints in oncology research and practice have garnered increasing attention over the past two decades. This activity has largely been driven by the promise surrogate endpoints appear to hold: the potential to get new therapies to seriously ill patients more rapidly. However, uncertainties abound. Even agreeing upon a definition of a "valid" surrogate endpoint has not been a straightforward exercise; this article begins by highlighting differences in how this term has been previously captured and applied, as well as laying out the basic criteria essential for its application in advanced colorectal cancer. Ideally, these elements include (but are not limited to) ease of measurement, rapid indication of treatment effect, and, most importantly, reliable and consistent prediction of the true impact of a treatment on the ultimate outcome of interest: overall survival. The strengths and weaknesses of current potential surrogate endpoints in advanced colorectal cancer, including performance status, carcinoembryonic antigen plasma level, overall response rate, time to progression, and disease-free survival, are each considered in turn. Finally, limitations of surrogate endpoints in the clinical setting, including challenges in extrapolation to new therapies, and the incomplete provision of information about potential adverse effects, are discussed. Work remains to be done between physicians and statisticians to bridge the gap between that which is statistically demonstrable and that which will be clinically useful.The term ;surrogate endpoint' was virtually unknown by most oncologists 15 years ago. A search in PubMed [http://www.ncbi.nlm.nih.gov] based on the words ;surrogate and cancer' shows that more than 2000 papers were published in medical journals in the last 20 years, with a dramatic increase of interest in the last five years. Interestingly, the same trend is observed when the words ;surrogate and heart' are entered into PubMed, suggesting that the issue of surrogate endpoints goes beyond the field of oncology, although the frequency of discussion varies (Figure 1; note different y-axis scales for oncology and cardiology).The goal of the present paper is to discuss the main issues surrounding surrogate endpoints from a clinician's point of view, using as an example surrogate endpoints of overall survival (OS) in advanced colorectal cancer (ACC).

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“…Others have emphasized that a surrogate endpoint could never be validated by a single method [34]; rather, a candidate endpoint should demonstrate consistently high surrogacy across a range of measures. Moreover, statistical evaluation of surrogacy should complement the intuition of clinicians, those most familiar with the disease being treated and the mechanisms of action by which the intervention being studied may affect the surrogate and clinical endpoints of interest.…”

Section: Discussionmentioning

confidence: 99%

Bayesian adjusted R² for the meta‐analytic evaluation of surrogate time‐to‐event endpoints in clinical trials

Renfro

Sargent

Carlin

2011

Statistics in Medicine

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Burzykowski et al. introduced a two-stage model to evaluate both trial and patient level surrogacy of correlated timeto-event endpoints using patient level data when multiple clinical trials are available. However, their maximum likelihood approach often suffers from numerical problems when different baseline hazards among trials and imperfect estimation of treatment effects are assumed. We propose performing the second-stage, trial-level evaluation of potential surrogates within a Bayesian framework, where we may naturally borrow information across trials while maintaining these realistic assumptions. Posterior distributions on surrogacy measures of interest may then be used to compare measures or make decisions regarding the candidacy of a specific endpoint. We perform a simulation study to investigate differences in estimation performance between traditional maximum likelihood and new Bayesian representations of common metaanalytic surrogacy measures, while assessing sensitivity to data characteristics such as number of trials, trial size, and amount of censoring. Furthermore, we present both frequentist and Bayesian trial-level surrogacy evaluations of time-torecurrence for overall survival in two meta-analyses of adjuvant therapy trials in colon cancer. Based on these results, we recommend hierarchical Bayesian methods as an attractive alternative in the multi-trial evaluation of potential surrogate endpoints.

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Surrogate endpoint validation: statistical elegance versus clinical relevance

Cited by 28 publications

References 9 publications

Alpha-fetoprotein response correlates with EASL response and survival in solitary hepatocellular carcinoma treated with transarterial therapies: A subgroup analysis

Alpha-fetoprotein response correlates with EASL response and survival in solitary hepatocellular carcinoma treated with transarterial therapies: A subgroup analysis

Surrogate endpoints for overall survival in advanced colorectal cancer: a clinician's perspective

Bayesian adjusted R² for the meta‐analytic evaluation of surrogate time‐to‐event endpoints in clinical trials

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Surrogate endpoint validation: statistical elegance versus clinical relevance

Cited by 28 publications

References 9 publications

Alpha-fetoprotein response correlates with EASL response and survival in solitary hepatocellular carcinoma treated with transarterial therapies: A subgroup analysis

Alpha-fetoprotein response correlates with EASL response and survival in solitary hepatocellular carcinoma treated with transarterial therapies: A subgroup analysis

Surrogate endpoints for overall survival in advanced colorectal cancer: a clinician's perspective

Bayesian adjusted R2 for the meta‐analytic evaluation of surrogate time‐to‐event endpoints in clinical trials

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Bayesian adjusted R² for the meta‐analytic evaluation of surrogate time‐to‐event endpoints in clinical trials