Prostate-Specific Antigen Levels, Prostate-Specific Antigen Kinetics, and Prostate Cancer Prognosis: A Tocsin Calling for Prospective Studies

Abstract

In 1985, a US man had an 8.7% lifetime risk of receiving a diagnosis of prostate cancer and a 2.5% risk in his life of death from the disease; these two risks today are 17% and 3%, respectively (1,2). Prostate-specific antigen (PSA) screening is largely responsible for this increase in diagnosis; its contribution to the 31% fall in mortality between 1990 and 2003 remains a subject of heated debate (2). Along with the substantial increase in detection of the disease has been a concomitant stage migration from tumors of high volume and grade to tumors of lower volume and grade — and presumably of lower biologic potential. Recognizing the substantial impact of all prostate cancer treatment options on a man’s quality of life, including sexual, urinary, and bowel function, interest in active surveillance as a management option for prostate cancer has increased substantially. Active surveillance is a management strategy that acknowledges that many tumors are slow growing and may not cause morbidity or mortality during a patient’s lifetime. Active surveillance commonly includes regular PSA tests and rectal examinations as well as periodic prostate biopsy to detect any increase in tumor volume and grade. The premise with this management is that should evidence of increased tumor volume or grade be detected, potentially curative treatment can be initiated to control the disease. This approach differs from that of Fall et al. (3), who followed patients expectantly, without attempting early intervention for cure. Although a strategy of active surveillance makes intuitive sense, in practice there are few data to guide physicians and their patients with the question of when to treat. Because we are a risk-averse society, most recommendations favor early treatment to avoid the potential loss of the “window of curability” of these tumors. Current strategies often focus on absolute PSA levels, PSA kinetics, and evidence of increase in tumor grade or volume (4). In practice, the most common reason for treatment is a “worrisome” PSA level or an increase in PSA velocity. In this context, Fall et al. show the challenges with using PSA measures to identify tumors that meet the ultimate defi nition of “biologic aggressiveness,” causing the death of the patient. It must be recognized, however, that the patients in this series were substantially different from the majority of patients with localized prostate cancer today in countries where PSA screening is highly prevalent (such as the United States): PSA levels were above 10 ng/mL in 48% of the patients in that population, and more than 60% of men had tumors that were palpable on rectal examination. At diagnosis, these were high-volume tumors, tumors more likely to exhibit stronger PSA kinetics driving more favorable PSA operating characteristics than would be expected from popula tions containing higher fractions of screen-detected cancers (5). As a result, we would expect less optimistic performance of these PSA measures in a typical US