Assessing the Measure of a New Drug: Is Survival the Only Thing That Matters?

Clinical research to improve breast cancer treatment has produced multiple, meaningful advances in the last decade. New antiestrogen and chemotherapeutic agents—novel therapies directed towards HER2—such as trastuzumab and lapatinib, and antiangiogenic agents, such as bevacizumab, have all been added to the clinician’s armamentarium to treat metastatic disease. 1 Several of these advances have now demonstrated efficacy in the adjuvant setting, which raises the important question: What exactly has improved as these agents have been introduced into the metastatic setting? Given the current limited possibility of cure for these patients, there are two clinically important goals of treatment: make the patient live longer and delay or relieve symptoms. The first of these end points, codified as overall survival (OS), is simple to measure, unambiguous, and of unquestionable clinical relevance. However, symptom relief and palliation (or quality of life), despite recent progress, is notoriously difficult to measure. 2 Ideally, a newly introduced antineoplastic agent will demonstrate a significant and clinically meaningful prolongation of overall survival in the setting of a randomized controlled trial. However, the use of overall survival as the primary end point for a clinical trial has several major drawbacks. First, because mortality occurs after a relatively long time for most patients, statistically significant differences in OS require large numbers of patients and several years to reliably detect. For example, in a recently reported trial in which women with metastatic breast cancer were randomly assigned to receive either bevacizumab or no bevacizumab, in addition to first-line paclitaxel, the median survival for the trial population was not reached until nearly 8 years after the trial was opened, a full 2 years after initial results (based on an end point of progression-free survival [PFS]) were made public. 3 Second, for many new agents, patients assigned to the control arm are either allowed to cross over to the investigational agent or to receive the investigational agent off-study on disease progression. This strategy dilutes effects of an agent on OS, since patients in both arms will receive the new agent at some point. Although a prohibition of such cross-over is scientifically appealing, ethical considerations often preclude it, particularly if outcomes on earlier end points are found to be promising or the drug is approved in later line settings. Finally, for addition of a new agent, a prolongation of OS may be more difficult to detect now than in the past due to the beneficial effects of the many other antineoplastic therapies now available for breast cancer. 1