William J. Catalona

CONTEXT: The percentage of free prostate-specific antigen (PSA) in serum has been shown to enhance the specificity of PSA testing for prostate cancer detection, but earlier studies provided only preliminary cutoffs for clinical use. OBJECTIVE: To develop risk assessment guidelines and a cutoff value for defining abnormal percentage of free PSA in a population of men to whom the test would be applied. DESIGN: Prospective blinded study using the Tandem PSA and free PSA assays (Hybritech Inc, San Diego, Calif). SETTING: Seven nationwide university medical centers. PARTICIPANTS: A total of 773 men (379 with prostate cancer, 394 with benign prostatic disease) 50 to 75 years of age with a palpably benign prostate gland, PSA level of 4.0 to 10.0 ng/mL, and histologically confirmed diagnosis. MAIN OUTCOME MEASURES: A percentage of free PSA cutoff that maintained 95% sensitivity for prostate cancer detection, and probability of cancer for individual patients. RESULTS: The percentage of free PSA may be used in 2 ways: as a single cut-off (ie, perform a biopsy for all patients at or below a cutoff of 25% free PSA) or as an individual patient risk assessment (ie, base biopsy decisions on each patient's risk of cancer). The 25% free PSA cutoff detected 95% of cancers while avoiding 20% of unnecessary biopsies. The cancers associated with greater than 25% free PSA were more prevalent in older patients, and generally were less threatening in terms of tumor grade and volume. For individual patients, a lower percentage of free PSA was associated with a higher risk of cancer (range, 8%-56%). In the multivariate model used, the percentage of free PSA was an independent predictor of prostate cancer (odds ratio [OR], 3.2; 95% confidence interval [CI], 2.5-4.1; P < .001) and contributed significantly more than age (OR, 1.2; 95% CI, 0.92-1.55) or total PSA level (OR, 1.0; 95% CI, 0.92-1.11) in this cohort of subjects with total PSA values between 4.0 and 10.0 ng/mL. CONCLUSIONS: Use of the percentage of free PSA can reduce unnecessary biopsies in patients undergoing evaluation for prostate cancer, with a minimal loss in sensitivity in detecting cancer. A cutoff of 25% or less free PSA is recommended for patients with PSA values between 4.0 and 10.0 ng/mL and a palpably benign gland, regardless of patient age or prostate size. To our knowledge, this study is the largest series to date evaluating the percentage of free PSA in a population representative of patients in whom the test would be used in clinical practice.

OBJECTIVE: To determine whether prostate-specific antigen (PSA)-based screening alters the proportion of organ-confined prostate cancers detected. DESIGN: A prospective, nonrandomized, serial PSA-based screening trial (follow-up from 6 to 37 months), and a concurrent comparison group. SETTING: General community outpatient screening program based at a university center. PATIENTS: The study group consisted of 10,251 men aged 50 years and older (mean and median age, 63 years; mean and median age of patients who underwent biopsies, 66 years) who presented to a prostate cancer screening program and consented to phlebotomy. The comparison group consisted of 266 concurrently studied private patients in the same age range (mean and median age, 68 years) who were referred for prostatic ultrasonography and biopsy because of an abnormal digital rectal examination (DRE). MAIN OUTCOME MEASURE: Proportion detected with clinically or pathologically advanced prostate cancer. RESULTS: The men were divided into three groups: the comparison group, the initial PSA-based screening group, and the serial PSA-based screening group. The proportions of prostate cancers detected that were clinically or pathologically advanced were as follows: comparison group, 57% (27/47); initial PSA-based screening group, 37% (91/244); and serial PSA-based screening group, 29% (37/129). Screened patients had a lower proportion of advanced cancers than the comparison group (chi 2 [2] = 12.3; P = .002); this advantage was observed principally in patients younger than 70 years. Surgical staging revealed that the cancer was microscopically focal and well differentiated (possibly latent cancer) in 2.5% (1/40) of the nonscreened group, 2.9% (7/244) of the initially screened group, and 7.8% (10/129) of the serially screened group (generalized Fisher's Exact Test, P = .08). CONCLUSION: Screening based on PSA identifies some men with prostate cancer who have a significantly increased proportion of organ-confined tumors compared with those detected through evaluation for an abnormal DRE alone.

OBJECTIVE: To determine the detection rate of prostate cancer in a screening population of men with prostate-specific antigen (PSA) concentrations of 2.6 to 4.0 ng/mL and a benign prostate examination, to assess the clinicopathological features of the cancers detected, and to assess the usefulness of measuring the ratio of free to total PSA to reduce the number of prostatic biopsies. DESIGN: A community-based study of serial screening for prostate cancer with serum PSA measurements and prostate examinations. SETTING: University medical center. SUBJECTS: A total of 914 consecutive screening volunteers aged 50 years or older with serum PSA levels of 2.6 to 4.0 ng/mL who had a benign prostate examination and no prior screening tests suspicious for prostate cancer, 332 (36%) of whom underwent biopsy of the prostate. MAIN OUTCOME MEASURES: Cancer detection rate, clinical and pathological features of cancers detected, and specificity for cancer detection using measurements of percentage of free PSA. RESULTS: Cancer was detected in 22% (73/332) of men who underwent biopsy. All cancers detected were clinically localized, and 81% (42/52) that were surgically staged were pathologically organ confined. Ten percent of the cancers were clinically low-volume and low-grade tumors, and 17% of those surgically staged were low-volume and low-grade or moderately low-grade tumors (possibly harmless). Using a percentage of free PSA cutoff of 27% or less as a criterion for performing prostatic biopsy would have detected 90% of cancers, avoided 18% of benign biopsies, and yielded a positive predictive value of 24% in men who underwent biopsy. CONCLUSIONS: There is an appreciable rate of detectable prostate cancer in men with serum PSA levels of 2.6 to 4.0 ng/mL. The great majority of cancers detected have the features of medically important tumors. Free serum PSA measurements may reduce the number of additional biopsies required by the lower PSA cutoff.

BACKGROUND: Prostate-specific antigen (PSA) is a widely-used tumor marker to aid in the early detection of prostate cancer. PSA testing has appreciable false-positive and false-negative results, particularly in the 2.5-10.0 ng/ml range. Measurements of the percentage of nonprotein-bound (free) PSA in serum, which is lower in patients with prostate cancer, has been evaluated as a method for increasing the accuracy of PSA testing. METHODS: The literature on forms of PSA in serum, as it relates to issues of clinical utility for prostate cancer screening, was reviewed and summarized through May 1996. RESULTS: Measurements of the percentage of free PSA in serum increase the accuracy of PSA testing for prostate cancer in men whose total PSA levels are 2.5-10.0 ng/ml. Cutoffs for screening are affected by prostate volume and total PSA levels. One study also demonstrated a correlation between percentage of free PSA and pathologic features of cancer aggressiveness. CONCLUSIONS: Measurement of free PSA in serum has potential clinical utility for increasing the sensitivity and specificity of PSA screening. Insufficient data are available to establish cutoffs to be used in clinical practice. Cutoffs are affected by total PSA level and prostate volume. The prevalence rate of cancer in the screened population (age, race, previous biopsy history, etc.) will also influence screening cutoffs. Percentage of free PSA may also correlate with the potential aggressiveness of early-stage prostate cancer.