Statistical Controversies in Clinical Research: Assessing pathologic complete response as a trial-level surrogate endpoint for early-stage breast cancer
Cet article analyse la controverse relative à l'usage de la réponse pathologique complète comme critère de jugement de substitution dans les essais cliniques randomisés d'un traitement néoadjuvant pour les patientes atteintes d'un cancer du sein de stade précoce
Background : A trial-level surrogate endpoint for a randomized clinical trial may allow assessment of the relative benefits of the treatment to be performed at an earlier time point and potentially with a smaller sample size. However, determining whether an endpoint is a reliable trial-level surrogate based on results of previous trials is not straightforward. The question of trial-level surrogacy is easily confused with the question of individual-level surrogacy, and this confusion can lead to controversy. A recent example concerns the evaluation of pathologic complete response (pCR) as a surrogate for event-free survival (EFS) and overall survival (OS) in early-stage breast cancer.
Materials and methods : The differences between individual-level surrogacy (i.e., for patients receiving a specific treatment, the surrogate endpoint predicts the definitive endpoint) and trial-level surrogacy (the results of the trial for the surrogate endpoint predict the results of the trial for the definitive endpoint) are discussed. Trial-level data used in two previous meta-analyses evaluating pCR as a trial-level surrogate for EFS and OS were re-analyzed using methods that appropriately account for the variability in pCR rates as well as the variability in the hazard ratios for EFS and OS.
Results : There is no evidence that pCR is a trial-level surrogate for EFS or OS, nor is there evidence that pCR could be used reliably to screen out non-promising agents from further drug development.
Conclusions : At present, neoadjuvant RCTs should continue to follow patients to observe EFS and OS to assess clinical benefit, and they should be designed with sufficient sample size to reliably assess EFS. However, one cannot rule out the possibility that future meta-analyses involving more trials and in which the patient population or class of treatments is restricted could suggest the validity of pCR as a trial-level surrogate for EFS or OS in some focused settings.
Annals of Oncology , résumé, 2015