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Quantifying the association between progression-free survival and overall survival in oncology trials using Kendall's ?.

ABSTRACT: This paper considers methods for estimating the association between progression-free and overall survival in oncology trials. Copula-based, nonparametric, and illness-death model-based methods are reviewed. In addition, the approach based on an underlying illness-death model is generalized to allow general parametric models. The performance of these methods, in terms of bias and efficiency, is investigated through simulation and also illustrated using data from a clinical trial of treatments for colon cancer. The simulations suggest that the illness-death model-based method provides good estimates of Kendall's ? across several scenarios. In some situations, copula-based methods perform well but their performance is sensitive to the choice of copula. The Clayton copula is most appropriate in scenarios, which might realistically reflect an oncology trial, but the use of copula models in practice is questionable.

SUBMITTER: Weber EM

PROVIDER: S-EPMC6585767 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Quantifying the association between progression-free survival and overall survival in oncology trials using Kendall's τ.

Weber Enya M EM Titman Andrew C AC

Statistics in medicine 20181012 5

This paper considers methods for estimating the association between progression-free and overall survival in oncology trials. Copula-based, nonparametric, and illness-death model-based methods are reviewed. In addition, the approach based on an underlying illness-death model is generalized to allow general parametric models. The performance of these methods, in terms of bias and efficiency, is investigated through simulation and also illustrated using data from a clinical trial of treatments for ...[more]

PMID: 30311243

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Project description:Introduction: With a gap in a full understanding of the mechanisms by which survival is extended for patients with cancer who are treated with novel biologic and targeted agents, there is the risk that discordant progression-free and overall survival outcomes are observed due to poor clinical trial design or biases in the interpretation of data. This study was designed to examine the role of study quality and design on the outcomes observed with biologic and targeted agents. Methods: A review of studies in clinicaltrials.gov supplemented with a literature review in OVID Medline was conducted to identify all randomized trials of a biologic/targeted agent versus a non-biologic/targeted comparator in oncology that report both median overall and progression-free survival outcomes. Details of the study, design, population, drugs, and outcomes were extracted. Study quality was evaluated using the PEDro scale. Data were summarized using SPSS 22.0.0.0. Results: A total of 192 unique studies of 206 pairwise comparisons between a biologic/targeted and comparator were identified. The average absolute magnitude of post-progression survival (difference between OS and PFS) was 9.7 months for biologic/targeted therapy and 9.8 for the comparator. A total of 64 comparisons (31.1%) showed an increase in OS and decrease in PFS, or vice versa, and 25 (12.1%) showed a magnitude of more than 4 months difference between the delta of OS and delta of PFS between the biologic/targeted and comparator arms. Average study quality was high overall (7.7/10), and was comparable for studies with directional differences (7.2/10) as well as for those with the greatest magnitude in post-progression survival (7.4/10). Conclusion: This review and analysis specifically examined small PFS benefit with large OS benefit as well as small OS benefit with large PFS benefit, including differences in direction of PFS and OS outcomes. No evidence was identified that these are the result of poor study design, but may rather be due to the mechanism of action, specific disease, and population under study. Further work is needed to understand the mechanism of action of novel biologic/targeted agents to better understand their interaction with the tumor microenvironment.

Project description:BackgroundSupratotal resection is advocated in lower-grade gliomas (LGGs) based on theoretical advantages but with limited verification of functional risk and data on oncological outcomes. We assessed the association of supratotal resection in molecularly defined LGGs with oncological outcomes.MethodsIncluded were 460 presumptive LGGs; 404 resected; 347 were LGGs, 319 isocitrate dehydrogenase (IDH)-mutated, 28 wildtype. All patients had clinical, imaging, and molecular data. Resection aimed at supratotal resection without any patient or tumor a priori selection. The association of extent of resection (EOR), categorized on volumetric fluid attenuated inversion recovery images as residual tumor volume, along with postsurgical management with progression-free survival (PFS), malignant (M)PFS, and overall survival (OS) assessed by univariate, multivariate, and propensity score analysis. The study mainly focused on IDH-mutated LGGs, the "typical LGGs."ResultsMedian follow-up was 6.8 years (interquartile range, 5-8). Out of 319 IDH-mutated LGGs, 190 (59.6%) progressed, median PFS: 4.7 years (95% CI: 4-5.3). Total and supratotal resection obtained in 39% and 35% of patients with IDH1-mutated tumors. In IDH-mutated tumors, most patients in the partial/subtotal group progressed, 82.4% in total, only 6 (5.4%) in supratotal. Median PFS was 29 months (95% CI: 25-36) in subtotal, 46 months (95% CI: 38-48) in total, while at 92 months, PFS in supratotal was 94.0%. There was no association with molecular subtypes and grade. At random forest analysis, PFS strongly associated with EOR, radiotherapy, and previous treatment. In the propensity score analysis, EOR associated with PFS (hazard ratio, 0.03; 95% CI: 0.01-0.13). MPFS occurred in 32.1% of subtotal total groups; 1 event in supratotal. EOR, grade III, previous treatment correlated to MPFS. At random forest analysis, OS associated with EOR as well.ConclusionsSupratotal resection strongly associated with PFS, MPFS, and OS in LGGs, regardless of molecular subtypes and grade, right from the beginning of clinical presentation.

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Quantifying the association between progression-free survival and overall survival in oncology trials using Kendall's ?.

Publications

Quantifying the association between progression-free survival and overall survival in oncology trials using Kendall's τ.

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