Review PSAUpdated: Still Relevant in the New Millennium? Jay B. Shah 1 , Adam C. Reese 1 , James M. McKiernan, Mitchell C. Benson * Department of Urology, Columbia University Medical Center, 161 Fort Washington Avenue, IP-11, New York, NY 10032, USA Accepted 27 December 2004 Available online 12 January 2005 Keywords: Prostate-specific antigen; PSA; Prostate cancer; PSA screening; Verification bias; PSA velocity It is well recognized that prostate cancer is a major cause of worldwide morbidity and mortality. It has been estimated that 679,000 men worldwide were diagnosed with prostate cancer and 221,000 men died of the disease in the year 2002 alone [1]. Although prostate cancer mortality has declined slightly in recent years, the incidence of this disease has shown a marked increase in the last two decades. This increase is attributed to the widespread use of serum prostate- specific antigen (PSA) testing for the detection of prostate cancer. Since its introduction to clinical med- icine in the mid-1980s as an accurate serum marker of prostate cancer, the PSA test has replaced all previous markers and has become the backbone of prostate cancer detection. A substantial amount of clinical and basic science research over the last two decades has been dedicated to defining the precise parameters and derivatives of PSA that will optimize the sensitivity and specificity of the test. From a public health stand- point, clinical research within the last decade has also focused on determining if widespread PSA screening is beneficial (although most of this data have yet to mature). In recent years, there has been a tempering of the initial excitement over PSA and several studies have been published suggesting that the exact role of PSA in prostate cancer detection needs to be redefined. Here we review these landmark studies and discuss how they may impact the current atmosphere of PSA testing. 1. Threshold for biopsy Significant disagreement exists concerning the inter- pretation of the PSA test. A hotly debated topic in recent years has been the determination of an appro- priate PSA cutoff level to prompt prostate biopsy. In theoretical terms, the ideal cutoff point is one that can perfectly differentiate patients without prostate cancer from those with prostate cancer; a ‘‘normal’’ PSAvalue would suggest very low risk of malignancy and an ‘‘abnormal’’ value would signal high likelihood of prostate cancer (and therefore prompt a prostate biopsy). Such a cutoff point has not been identified. The traditional PSA cutoff point in the United States is 4.0 ng/ml, a level that was established in 1990 in a study conducted at a private urology practice in the United States [2]. This study reported an increased ability to detect prostate cancer when serum PSA testing, using a cutoff of 4.0 ng/ml, was used in con- junction with a digital rectal examination (DRE). Over time, the choice of 4.0 ng/ml as the optimal PSA threshold for biopsy has come under fire. Recent studies have suggested that lowering the cutoff point would increase the ability to detect prostate cancer, and increase the percentage of cancers diagnosed at an early, localized stage. There is concern that a signifi- cant percentage of patients with prostate cancer have PSA values below the traditional threshold of 4.0 ng/ ml. With a cutoff of 4.0 ng/ml, it is unlikely that these cancers would be detected at the time of screening, given the ‘‘normal’’ PSA result. Thus, the opportunity to detect these cancers at an early stage is missed, allowing the tumor to progress to a more advanced clinical stage before diagnosis. European Urology European Urology 47 (2005) 427–432 * Corresponding author. Tel. +1 212 305-5201; Fax: +1 212 305 6813. E-mail address: mcb2@columbia.edu (M.C. Benson). 1 These authors contributed equally to the writing of this manuscript. 0302-2838/$ – see front matter # 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2004.12.020