A nested case-control prospective study with 10 years of follow-up reported that a single elevated PSA higher than 4.0 ng/mL predicted subsequent cancer with a sensitivity of 71% for the first 5 years and a specificity of 91% for the first 10 years of follow-up. The cancers diagnosed were characterized by stage and grade to be clinically important. Forty-two percent were extracapsular at diagnosis. Experience with repeat PSA screening suggests that tumors detected on follow-up examinations are of lower clinical stage and grade. Although a cutoff value of 4.0 ng/mL is frequently used to prompt prostate biopsy, screening studies have demonstrated that lowering the PSA cutoff will substantially increase the number of cancers detected, particularly in African Americans. In one study of the impact of race on PSA and tumor volume, these two variables were higher among African American men after adjustment for age, stage, pathologic stage, Gleason score, and volume of benign disease. Furthermore, lower cutoff PSA values are associated with a high proportion of negative biopsies (false-positives). An initial PSA lower than 2.5 ng/mL is associated with a very low risk of cancer detection within a 4-year follow-up.[36,40]
Probably the largest PSA/DRE early diagnosis experience comes from the Prostate Cancer Awareness Week program conducted at numerous sites around the United States. A report from that program indicates that of 116,073 participating men, if a 4.0 ng/mL PSA cutoff value was used, 22,014 men had an abnormal PSA, DRE, or both.
Various methods to improve the performance of PSA in early cancer detection have been developed (see below). The proportion of men who have abnormal PSA test results that revert to normal after 1 year is high (65%–83%, depending on the method). This is likely because of a substantial biological or other variability in PSA levels in individual men. Several variables can affect PSA levels in men. Besides normal biological fluctuations that appear to occur,[41,42] pharmaceuticals such as finasteride (which reduces PSA by approximately 50%) and over-the-counter agents such as PC-SPES (an herbal agent that appears to have estrogenic effects) can affect PSA levels.[43,44] Some authors have suggested that ejaculation and DRE can also affect PSA levels, but subsequent examination of these variables have found that they do not have a clinically important effect on PSA. In any case, given this high variability, an elevated PSA should be confirmed by repeat testing before more invasive diagnostic tests are performed.
The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) is a multicenter, randomized two-armed trial designed to evaluate the effect of screening for prostate, lung, colorectal, and ovarian cancers on disease-specific mortality. From 1993 through 2001, 76,693 men at ten U.S. study centers were randomly assigned to receive annual screening (38,343 subjects) or usual care as the control (38,350 subjects). Men in the screening group were offered annual PSA testing for 6 years and DRE for 4 years. The subjects and health care providers received the results and decided on the type of follow-up evaluation. Usual care sometimes included screening, as some organizations have recommended.
In the screening group, rates of compliance were 85% for PSA testing and 86% for DRE. Self-reported rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing and ranged from 41% to 46% for DRE. Results from the first four rounds of screening are shown in the Summary of First Four Prostate, Lung, Colorectal, and Ovarian Screening Rounds table.