PSA Kinetics and Risk of Death From Prostate Cancer

Abstract

ADENOCARCINOMA OF THE PROSTATE IS THE MOST commonly diagnosed malignancy in men in the United States. It is estimated that, in 2005, 232 000 new cases will be diagnosed and 30 350 men will die from this disease. Even though prostate-specific antigen (PSA) screening has not been conclusively demonstrated to reduce mortality from prostate cancer, this practice has been widely adopted in the United States. As a result, more patients are being diagnosed at a younger age and with disease localized to the prostate. For these patients, radical prostatectomy (RP) and radiation therapy (RT) remain the mainstays of curative therapy. Nevertheless, prostate cancer remains primarily a disease of older men, many of whom have other serious coexisting illnesses from which they may be far more likely to die. Thus, it remains a major challenge for the clinician to identify which patients need aggressive treatment and which do not. The long natural history of localized prostate cancer makes it a particularly difficult disease in which to study the impact of any therapy. Most newly diagnosed patients with prostate cancer would live for many years without treatment, those that are treated often live more than a decade even if they are not cured by their therapy, and the majority of patients die of something other than prostate cancer whether or not they are treated. Since improved survival has traditionally been the criterion standard against which cancer treatments are measured, it may take 15 to 20 years from a study’s inception to demonstrate a survival advantage, or lack thereof, in localized prostate cancer. Contrast this situation to that of glioblastoma or pancreatic cancer, diseases which, if left untreated, have survival time measured in weeks: with these cancers, death usually follows closely on the heels of a relapse, and few patients die of competing causes. Moreover, new treatments for these malignancies can be definitively studied in one tenth of the time required for most prostate cancer trials, and improvement in survival should be the end point measured. If major advances in the treatment of prostate cancer are to occur in a more timely manner, end points other than overall survival must be identified and validated. Since the introduction of PSA screening into clinical practice, the quest to identify the best surrogate end point has been a major focus of prostate cancer research. In this issue of JAMA, 2 provocative retrospective studies involving 2 very different patient populations make major contributions toward the identification of surrogate end points. Freedland et al studied 379 patients who developed an increasing PSA level after RP, whereas D’Amico et al evaluated 358 newly diagnosed men treated with external beam RT for localized prostate cancer. The surgical group was much younger (59 vs 71 years old), was followed for a much longer period of time (10 vs 4 years), and had more adverse clinical and pathologic features. Despite these differences, the methods of data analysis revealed important similarities. First, both studies use death from prostate cancer (prostate cancer–specific mortality), rather than overall survival, as their primary end point. In theory, prostate cancer– specific mortality is an attractive end point, since death from causes other than prostate cancer are censored rather than counted as deaths. In practice, however, it can be difficult to determine exactly what an individual patient died from, especially in a retrospective analysis. Simply determining whether a patient is dead or alive is much more straightforward. The investigators in both studies adopted a reasonable solution to this conundrum, given the era in which the patients were treated. The investigators attributed death as due to prostate cancer in patients with either a documented history of hormone-refractory metastatic disease with evidence of an increasing PSA level at last follow-up (D’Amico et al) or evidence of metastatic disease with progression following hormone therapy (Freedland et al).