Statistical controversies in clinical research: assessing pathologic complete response as a trial-level surrogate end point for early-stage breast cancer.
BACKGROUND
A trial-level surrogate end point 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 end point 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.


METHODS
The differences between individual-level surrogacy (i.e. for patients receiving a specific treatment, the surrogate end point predicts the definitive end point) and trial-level surrogacy (the results of the trial for the surrogate end point predict the results of the trial for the definitive end point) 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 nonpromising 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.
Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, USA korne@ctep.nci.nih.gov.
E L
EL
Korn
Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, USA.
M C
MC
Sachs
Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, USA.
L M
LM
McShane
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015201:Meta-Analysis as Topic; D020360:Neoadjuvant Therapy; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
D000970:Antineoplastic Agents
breast cancer; pathologic complete response; randomized clinical trial; screening trials; surrogate end point; trial-level surrogate end point