End-points in clinical trials for liver cancer and their value in evidence based clinical decision making: an unresolved Gordian knot.

Abstract

Design and execution of clinical trials use definitions and criteria to permit a homogeneous study development avoiding heterogeneous decisions by investigators at different sites. Ideally, definitions and decision making in clinical practice should mimic those implemented in trials, but this is not the case. Target population is narrowly defined in trials and the goal of them is the evaluation of activity and toxicity, and ultimately, the demonstration of a survival benefit. In practice, treated patients may not fit into the inclusion/exclusion criteria of the trial, the evaluation of activity may also differ and the common policy to stop therapy upon progression may not be followed if progression is minor. Indeed, registration of progression may not reflect treatment failure or resistance. As known, the hardest end-point in therapeutic cancer studies is survival. Parameters such as response according to RECIST criteria, time to progression and progression free survival are not fully informative and can not be assumed as a definitive surrogate for survival. The reason for such situation is related to the varying methods of evaluating drug activity and how it impacts the tumor evolution, that ultimately dictate patient outcome. This review exposes the current discrepancies between research trials and clinical practice. Understanding the origin and limitations of such conundrum should be the first step to refining the set of criteria that define drug activity, toxicity and treatment failure leading to treatment interruption. Otherwise, evidence based clinical practice and precision oncology will be an unattainable reality.