Survival Endpoints in Randomized Clinical Trials in Sarcoma Patients: Meta-analyses for the Assessment of the Impact Various Definitions on Trials' Results and of Surrogate Properties for OS

Background: In randomized phase III cancer clinical trials, the validated and most objectively defined evaluation criterion is overall survival (OS). Therapeutic progress, which in certain contexts has significantly reduced overall mortality, the development of new types of cytostatic treatments (as opposed to cytotoxic treatments), the current context of strategic trials and the multiplication of lines of treatment have resulted in the necessity of creating new evaluation criteria measuring treatment efficacy sooner and more precisely: for example, progression-free survival in second line treatment, duration of local control, and time until treatment failure. These types of surrogate endpoints are commonly used in phase II trials but are increasingly being used to replace overall survival in phase III trials. Their development is strongly influenced by the necessity of reducing clinical trial duration, cost and number of patients.

However while these survival endpoints are frequently used, they are often poorly defined and when they are, the definition can vary between trials. The lack of standardized definitions constitutes a clear limitation to their use as primary endpoints. Furthermore, this variability of definitions can have an important impact on trials' results by affecting power and estimation.

The ongoing DATECAN-1 project is aimed at providing guidelines for the definitions of survival endpoints in cancer trials (2009-2011 grant from the French League Against Cancer). Standardized recommendations will be available for survival endpoints commonly used for various cancer sites including pancreas, sarcomas and GIST (gastro-intestinal stromal tumors), breast, stomach.

Objectives: Following these guidelines, one can wonder how sensitive are these definitions? Or similarly, how do survival endpoints' definitions impact the conclusions of clinical trials? The objective of the DATECAN-2 study is to assess the impact of survival endpoints' definitions, as defined by the consensus guidelines, on trials' results and conclusions. The second objective is to study the surrogate properties for OS of these survival endpoints.

Methods: The evaluation of the impact of the variability of the definitions of survival endpoints on the results of clinical trials will be evaluated using individual data from datasets collected in the context of published (academic) clinical trials, as well as simulated datasets.