PSA Screening for Prostate Cancer: Evidence As Interpreted by the Guidelines

Prostate-specific antigen (PSA) is an enzyme secreted by the epithelial cells of the prostate gland. PSA is produced for the ejaculate, where it liquefies semen, allows sperm to swim freely and facilitates pregnancy. PSA is present in small quantities in the blood of men with healthy prostates, but can be elevated in the presence of prostate cancer or other prostate diseases. PSA screening for prostate cancer is a hotly debated subject. Physician associations have created guidelines for prostate cancer screening which often differ, leaving patients exasperated. To understand the guidelines for PSA screening, an evaluation of the history of PSA screening and the available evidence can be instructive.

PSA HISTORY

PSA was first discovered in the 1970's and was approved in the 1980's by the FDA to monitor prostate cancer recurrence. In 1991, Catalona et al. published a seminal paper in the New England Journal of Medicine showing that PSA was a good predictor of a prostate cancer diagnosis.[1] PSA soon became a widely used screening test throughout the United States for asymptomatic men. Following this, the incidence of prostate cancer skyrocketed. The figure below from SEER data displays this rapid increase. Prior to routine PSA testing, 1 in 10 men were diagnosed with prostate cancer. After widespread PSA testing, 1 in 6 men were diagnosed with prostate cancer. Correspondingly, in the mid 90's mortality due to prostate cancer began to decline at a rate of approximately 4% per year, as seen in the graph below. This may have been due to an increase in PSA screening, however, some have suggested it is due to earlier and increasingly aggressive prostate cancer treatments beginning around the same time period.

Prostate cancer incidence and mortality before, during and after the introduction of PSA testing, 1975-2011.

PSA & EVIDENCE FROM THE SCREENING TRIALS

Eventually, a number of randomized control trials were performed to determine if screening for prostate cancer using PSA conferred a prostate cancer survival benefit. Perhaps the two best designed studies were the Prostate, Lung, Colorectal and Ovarian Screening Trial (PLCO) and the European Randomized Study of Screening for Prostate Cancer (ERSPC) which are summarized below.[2,3]

	PLCO	ERSPC
Cohort size	76,693	162,243
Age range	55-74	55-69
PSA interval	Annually for 6 years	Every 2 to 4 years
Median follow-up	~13 years	~13 years
Contamination	~77%	~20%
PCSM RR (screen v control)	1.08	0.79

In summary, PLCO is an American trial that enrolled men aged 55-74 to a screening or non-screening arm. After 10 years of follow-up there was no improvement in prostate cancer specific mortality in the screened group. However, this study has been criticized for its high level of contamination. This refers to the fact that a large percentage of men in the non-screening arm (approximately 77%) had a PSA level tested during the study. PLCO did not compare screening to non-screening; it compared routine screening to opportunistic screening, which is highly prevalent in the US.

The ERSPC is a European trial of men aged 55 to 69 randomized to a screened arm that received PSA screening every 2 to 4 years and a non-screening group. The contamination rate was much lower in the ERSPC trial as routine PSA tests are uncommon throughout Europe. The 13 year update of this study was recently published, and it shows that a man's risk of dying of prostate cancer is 21% less when screened for prostate cancer. 781 men would need to be screened and 27 cancers would need to be diagnosed to save one life from prostate cancer.[3]

While the evidence supporting a mortality benefit for prostate cancer is somewhat conflicting, evidence related to the harm of screening are not. Below is a table that summarizes some of the negative aspects of screening that have been cited in the literature.

Harm	Estimate	Source
False positive	75.9%	Proportion w PSA >3, negative bx (ERSPC)
Overdiagnosis	66% 23-42%	Screen detected, 4 year interval (ERSPC) Modelling studies (Heijnsdijk et al 2009) [4]
Post-biopsy fever	4%	Loeb et al 2012 ERSPC [5]
Post-biopsy hospitalization	1%	Loeb et al 2012 ERSPC [5]
Hematuria/hematospermia	20-50%	Post-biopsy (ERSPC)
Incontinence/ED	20-30%	All treatment types (Chou et al 2011, USPSTF meta-analysis) [6]
Death	1-5/1000	Within 1 month of surgery (Chou et al 2011, USPSTF meta-analysis) [6]

THE GUIDELINES

Based on the above information the American Urological Association (AUA), The National Comprehensive Cancer Network (NCCN) and the Unites States Preventative Services Task Force (USPSTF) have created guidelines that physicians and patients can use to make decisions about prostate cancer screening.

The AUA assembled a panel of experts in the field, led by Johns Hopkins professor Dr. H. Ballentine Carter. The AUA Guideline, "Early Detection of Prostate Cancer," recommend screening men aged 55-69 only after an informed decision is made by the patient following a discussion of the risks and benefits. There is no high-quality evidence showing that men under 55 do not benefit from screening, rather, there is an absence of evidence - the ERSPC and PLCO only included men over 55. For men 70 and older with less than 10-15 years life expectancy screening for prostate cancer is not recommended.  

The NCCN also assembled a group of leading urologists and created guidelines. For men interested in screening, they recommend obtaining a baseline PSA at age 45-49. This initial value has been shown to be highly predictive of prostate cancer development up to 30 years later. If the PSA is less than 1 (the median value for men in this age group), they should not be retested until age 50. If the PSA is greater than 1, PSA should be retested every 1 to 2 years. Men 50 to 70 should undergo PSA testing and can be retested every 1 to 2 years. The NCCN recommends exercising caution in testing men over 70, and suggests limiting it to men with few to no comorbidities.

The USPSTF, a panel composed of primary care physicians, also creates best practice recommendations through guidelines. Unlike the AUA and NCCN, they discourage PSA testing of all age groups, regardless of risk status. They place a relatively higher value on the results of the PLCO trial as it is an American study and is presumably more applicable to our population than a European study. In regards to the high level of contamination, they feel that there was still an increased incidence of prostate cancer in the screened group, and yet no prostate cancer mortality benefit was observed. In regards to the results of the ERSPC, the USPSTF notes that while there was an improvement in prostate cancer specific mortality, but no difference in overall mortality. It is important to note that the ERSPC authors specifically did not design the study with overall mortality as a primary endpoint. The USPSTF notes that the harms of prostate cancer screening are well known and thus outweigh an as of yet unproven benefit.

SUMMARY

Unfortunately, until more data is available the debate over prostate cancer screening will continue- leaving patients and physicians to come to their own conclusions based on individual priorities. To paraphrase Dr. Patrick Walsh, 

the studies discussed above are conducted from a population-based perspective. An urologist evaluating a patient has an individual and personal perspective. They see a patient's general health, family history, fears and wishes. For that man, the desire to avoid dying of prostate cancer often prompts PSA screening. 

With a quality study showing a decrease in prostate cancer mortality, PSA screening will likely continue until there is solid evidence that men are not being saved from prostate cancer death.


The Blog was written by Wesley Ludwig, MD. Dr. Ludwig is an urology resident at the Brady Urological Institute at Johns Hopkins.

 



REFERENCES
[1] Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuan JJ, Petros JA, Andriole GL. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med. 1991 Apr 25;324(17):1156-61. Erratum in: N Engl J Med 1991 Oct 31;325(18):1324.
[2] Andriole GL, Crawford ED, Grubb RL 3rd, Buys SS, Chia D, Church TR, Fouad MN, Isaacs C, Kvale PA, Reding DJ, Weissfeld JL, Yokochi LA, O'Brien B, Ragard LR, Clapp JD, Rathmell JM, Riley TL, Hsing AW, Izmirlian G, Pinsky PF, Kramer BS, Miller AB, Gohagan JK, Prorok PC; PLCO Project Team. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst. 2012 Jan 18;104(2):125-32. doi: 10.1093/jnci/djr500. Epub 2012 Jan 6.
[3] Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Zappa M, Nelen V, Kwiatkowski M, Lujan M, Määttänen L, Lilja H, Denis LJ, Recker F, Paez A, Bangma CH, Carlsson S, Puliti D, Villers A, Rebillard X, Hakama M, Stenman UH, Kujala P, Taari K, Aus G, Huber A, van der Kwast TH, van Schaik RH, de Koning HJ, Moss SM, Auvinen A; for the ERSPC Investigators. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet. 2014 Aug 6. pii: S0140-6736(14)60525-0. doi: 10.1016/S0140-6736(14)60525-0. [Epub ahead of print]
[4] Heijnsdijk EA, der Kinderen A, Wever EM, Draisma G, Roobol MJ, de Koning HJ. Overdetection, overtreatment and costs in prostate-specific antigen screening for prostate cancer. Br J Cancer. 2009 Dec 1;101(11):1833-8. doi: 10.1038/sj.bjc.6605422. Epub 2009 Nov 10.
[5] Loeb S, van den Heuvel S, Zhu X, Bangma CH, Schröder FH, Roobol MJ. Infectious complications and hospital admissions after prostate biopsy in a European randomized trial. Eur Urol. 2012 Jun;61(6):1110-4. doi: 10.1016/j.eururo.2011.12.058. Epub 2012 Jan 5.
[6] Chou R, Dana T, Bougatsos C, Fu R, Blazina I, Gleitsmann K, Rugge JB. Treatments for Localized Prostate Cancer: Systematic Review to Update the 2002 U.S. Preventive Services Task Force Recommendation [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Oct.