Clinical outcomes: to be a surrogate or not to be ...?

David Cameron

doi:10.1186/bcr1824

Abstract

Clinical trials remain the bedrock of the introduction of new therapies for patients with cancer. Over the past 30 years there have been enormous improvements in outcomes for patients with breast cancer, based largely (but not exclusively) on the widespread implementation of the results of randomized trials. Widespread use of screening mammography, breast conservation, adjuvant hormonal therapy, adjuvant chemotherapy and, most recently, adjuvant trastuzumab have all been based on the results of well designed clinical trials. All of these interventions have been shown to either improve survival or, in the case of breast conservation, maintain survival despite less radical surgery. For most women with early breast cancer, it is the avoidance of the death sentence they feel hangs over them when they are first diagnosed with cancer, that is the most important reason why they undergo these treatments. Clinical research in breast cancer remains as active as ever, with newer interventions being tested in ever larger and/or more complex trial designs. Many studies may not be designed to test questions about overall survival, with recent studies also addressing tolerability, issues of limited resources and, increasingly, means to target treatments to the subgroups of patients who really benefit from the specific therapy. The goal of studies that aim to optimize treatment may not be the same for the researcher and the patient. However, most would agree that it would be ideal if we could reduce the diagnosis of breast cancer to one that had the same implications as being diagnosed with a 'touch of blood pressure', namely the concept that although a few patients may still suffer unwanted consequences of the diagnosis, for the vast majority the implication is the necessity to undergo relatively nontoxic treatment that effectively prevents recurrence. To this end, many trials are now designed to address different primary end-points from the traditional one, still much beloved of the US Food and Drug Administration, of overall survival (OS).

Highlights

Clinical trials remain the bedrock of the introduction of new therapies for patients with cancer
Use of disease-free survival (DFS) as the first end-point, because it has consistently been validated as predating improvements in overall survival (OS), is perfectly acceptable, as long as studies with novel interventions continue to collect the follow-up data to demonstrate that this linkage applies to newer biological interventions just as it does for conventional treatments
For many studies there is a good clinical justification for using other end-points that meet the needs of the patient population being studied; end-points such as time to disease progression (TTP), response rate, and clinical benefit rate are not just to be seen as surrogates but as the most appropriate end-point for that trial

Summary

Introduction

Clinical trials remain the bedrock of the introduction of new therapies for patients with cancer. Most would agree that it would be ideal if we could reduce the diagnosis of breast cancer to one that had the same implications as being diagnosed with a ‘touch of blood pressure’, namely the concept that a few patients may still suffer unwanted consequences of the diagnosis, for the vast majority the implication is the necessity to undergo relatively nontoxic treatment that effectively prevents recurrence To this end, many trials are designed to address different primary end-points from the traditional one, still much beloved of the US Food and Drug Administration, of overall survival (OS). PHASE 1 To identify dose for Phase II Myelotoxicity surrogate for cytotoxicity ALL patients contribute Cohorts of 3 (or more) patients with increasing doses until 2/6 have dose-limiting toxicity (defines MTD)

Tumour biological changes surrogate for efficacy

Conventional drug development model

Presurgery systemic therapy

Findings

Conclusion