Progression-free survival as a surrogate endpoint in advanced breast cancer

Surrogate endpoints are attractive in clinical trials when the primary endpoint is difficult to measure because of time, costs, the need to test multiple regimens, ethical considerations, or pressure from patient advocacy groups (27;41). In advanced breast cancer, prolongation of survival and symptom improvement are commonly accepted as evidence of clinical benefit and as appropriate primary endpoints (27;65). However, a validated surrogate endpoint allows for inferences about a treatment’s benefit when primary endpoint data are not available (6;7;26). One potential surrogate endpoint for overall survival (OS) in advanced breast cancer is progression-free survival (PFS), a composite endpoint defined by the United States (U.S.) Food and Drug Administration (FDA) as the time from randomization to documented progression or death from any cause (25;65). However, the association between PFS and OS has not been systematically evaluated in advanced breast cancer for anthracycline and taxane-based chemotherapy. PFS includes death as part of its composite endpoint— and, therefore, differs from other progression-based endpoints. For example, time to progression is defined by the U.S. FDA as the time from randomization until tumor progression (death is censored), and time to treatment failure is a composite endpoint defined as the time from randomization until the patient stops the trial treatment for any reason including progression, toxicity, or preference (death is censored) (25;65). The inclusion of death in PFS may be important in advanced breast cancer because tumor growth, whether or not it is documented, usually precedes death. In other words, background mortality contributes relatively little to the 2-year median survival for advanced breast cancer and death likely reflects the treatment’s ability, or lack thereof, to control disease progression (30;64;65). Therefore, censored deaths may constitute informative censoring and may impact the ability of other progression-based endpoints to predict OS. Because PFS uniquely overcomes this limitation by including death, its ability to predict OS should be evaluated separately from other progression-based endpoints. PFS has additional benefits as an endpoint because it is measured before postprogression treatments are initiated. Therefore, PFS data is not affected by postprotocol agents. Furthermore, PFS is measured earlier and has a higher event frequency compared to OS. Consequently, PFS results may be available sooner and, potentially, with smaller and less costly trials (2;22;33). However, PFS has several potential limitations that it shares with all progression-based endpoints. The need for frequent radiologic studies raises the potential for assessment bias and increases the complexity of data capture and validation (25;65). PFS may be sensitive to differences in the duration between assessments (25;47), unprotocolled assessments (25;47), variations in censoring (25;46), and the use of cytostatic agents (67). Furthermore, variability in PFS measurement may be magnified when it is used to predict OS (20;26). With multiple effective therapies available for advanced breast cancer, the link between PFS and OS may be distorted by nonprotocolled treatments given after the trial regimen (19;22;33). Although PFS has not been systematically evaluated in advanced breast cancer for anthracyclineand taxane-based chemotherapy, studies suggest that time to progression and response rate have a statistically significant association with OS (1;33). However, only 34 to 37 percent of OS variability was explained by variability in time to progression and response rate, respectively (1;33). An abstract suggested a similar result (R2 = .44) for PFS for trials comparing taxane and anthracycline chemotherapy (13). However, cross-validation was not performed for this narrowly defined set of trials. Although there is controversy about the optimal approach for validating surrogate endpoints (12;15;42), one option is to evaluate performance at the trial level (33). The primary aim of this study was to evaluate the association between the direction and magnitude of the treatment effect on PFS compared with the treatment effect on OS for anthracycline- and taxane-based chemotherapy regimens in advanced breast cancer using a trial-based, meta-analytic approach. We limited our analysis (and the generalization of our results) to anthracycline- and taxane-based chemotherapy for advanced breast cancer because the relationship between PFS and OS may differ for different anti-cancer agents and in different cancers due to underlying biologic factors, the interaction of each anti-cancer agent with each cancer, and differences in the availability of active subsequent line treatments (26).