• Role for true prostate cancer screening is not proven. Absolute proof of screening is a decrease in the death rate of that cancer due to screening activity. Stage shift in prostate cancer and decrease in death rate statistics indirectly suggest a positive effect of PSA in disease detection. Prospective trials are in progress.
• The American Cancer Society, American Radiological Association, and American Urological Association recommends early detection with an annual DRE and PSA beginning at age 50 for all men with a life expectancy greater than 10 years and age 40 for men of African American race or a family history of prostate cancer. The 2004 recommendation of a consensus panel from the National Comprehensive Cancer Network recommends a baseline PSA at age 40 for all men. Those men with a serum PSA equal or greater to 0.6 ng/ml (the median PSA for that age group) should undergo yearly screening, whereas those with a value less than 0.6 ng/ml may have another interval PSA at age 45. The same rule applies at age 45. Please refer to www.nccn.org for specific guidelines for biopsy and follow-up.
• Digital Rectal Exam. More cancer is detected with the use of DRE and PSA than with either exam alone. With high penetrance of PSA use in younger patients however, abnormal DRE exams are much less common.
• PSA. In general 5-8 percent of a screening population will have an abnormal DRE. A value between 4-10 ng/ml has a 15-30% chance of being positive. Values above 10 are associated with a positive biopsy in greater than two thirds of cases. PSA has a sensitivity of 80% and a specificity of 35-50%. False positive findings are common. The optimal upper limit of normal for PSA is controversial. Recent studies suggest that using a PSA cutoff of 2.5 ng/ml for men younger than 60 years may be more appropriate. A subset analysis of data from the Prostate Cancer Prevention Trial from men with serum PSA levels less than 4.0 ng/ml (2950 men) showed a prostate cancer incidence of 15.2%, with 15% of these being of Gleason score 7 or greater. The prostate cancer prevalence was 6.6% among men with a PSA level of =0.5 ng/ml, 10.1% among those with values of 0.6 to 1.0 ng/ml, 17.0% among those with values of 1.1 to 2.0 ng/ml, 23.9% among those with values of 2.1 to 3.0 ng/ml, and 26.9% among those with values of 3.1 to 4.0 ng/ml. These data suggest that using absolute values for triggering a biopsy may not be as important as assessing PSA velocity.
• Free and complexed PSA. PSA may be found free in serum or bound to alpha -1-antichymotrypsin and alpha-2 macroglobin. Higher fraction of free PSA noted in benign disease. If percent free PSA is >25% the probability of a positive biopsy drops from 15-30 percent to 5-7%. Generally used in consideration for repeat biopsies. As a single test for screening, cPSA may improve specificity over total PSA and comparable specificity to free-to-total PSA for prostate cancer detection, and may reduce the number of unnecessary prostate biopsies in the 2.6-4.0 ng/mL tPSA range.
• Precursor PSA (pPSA). PSA is secreted from the prostate luminal epithelial cells as pPSA, an inactive proenzyme containing a 7-amino acid pro-leader peptide and 237 amino acids of mature PSA. The pro-leader peptide is removed extracellularly to produce active, mature PSA. Since no pPSA forms have been found in seminal plasma, pPSA has been identified as a serum marker with greater cancer specificity. Using 1091 retrospective serum specimens of patients with a total PSA between 2 and 4 ng/ml, Catalona and colleagues recently showed that using a cutoff of pro- to free-PSA (percent pro-PSA) of 1.8% for recommending prostate biopsy detected 90% of cancers, including 16 of 16 extracapsular tumors and 28 of 29 tumors with a pathology Gleason score of 7 or greater, while avoiding 19% of unnecessary biopsies
  • PSA velocity. Several studies suggest that if the serum PSA increases greater than 0.75 g/mL per year the potential for prostate cancer is greater. Unfortunately, since PSA variability can be as high as 23.5 percent per reading, three separate readings 6 months apart are necessary to establish a true trend. In addition, no added benefit has been demonstrated in patients with a PSA level between 4 and 10 ng/mL. A recent study by D'Amico et al published in the New England Journal of Medicine suggested that an annual PSA velocity of 2 ng/ml or greater was independently associated with prostate cancer mortality after radical prostatectomy. Potentially this may serve as a marker for identifying patients who may be considered for novel neoadjuvant strategies before undergoing surgery.
  • Age adjusted PSA. Concept of raising PSA threshold in older patients and lowering it in younger patients. Data suggests normal PSA of 2.5 may be more appropriate in men under the age of 60. Many suggest lowering value for young men and maintaining 4.0 for older patients to minimize "miss rate" in this population
• Screening bias. Length time bias consists of detecting a case at an earlier time in its history and suggesting a longer survival period from treatment, which is actually just a longer period of observation. Lead-time bias consists in part of selecting cases from a disease population with good survival traits and thus suggesting an apparent survival benefit that does not exist.
• Beneficence. Does disease detection provide a benefit, or do side effects of therapy or the anxiety of false negative tests outweigh the benefit?
• Screening costs. Can be significant, yet most estimates based on extremely high compliance rates. Elevated PSA detects clinically significant tumors and does not over detect microscopic pathological disease.

References

• Albertson PC, Hanley JA, Gleason DR, Barry MJ: Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 280:975-980, 1998.
• Catalona WJ, Bartsch G, Rittenhouse HG, Evans CL, Linton HJ, Horninger W, Klocker H, Mikolajczyk SD.Serum pro-prostate specific antigen preferentially detects aggressive prostate cancers in men with 2 to 4 ng/ml prostate specific antigen. J Urol. 2004 Jun;171(6 Pt 1):2239-44.
• D'Amico AV, Chen MH, Roehl KA, Catalona WJ. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med. 2004 Jul 8;351(2):125-35.
• Parsons JK, Brawer MK, Cheli CD, Partin AW, Djavan R.Complexed prostate specific antigen (PSA) reduces unnecessary prostate biopsies in the 2.6-4.0 ng/mL range of total PSA. BJU Int. 2004 Jul;94(1):47-50.
• Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford ED, Crowley JJ, Coltman CA Jr. Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. N Engl J Med. 2004 May 27;350(22):2239-46.

Written by Ricardo Sånchez-Ortiz, MD, a Contributing Editor with UroToday.

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