Prostate Cancer Screening: Where Do We Stand Now?

December 9, 2009

20080311-bellevue-hospital-03Annery Garcia

Prostate cancer is the second most common cancer in western men and the second leading cause of cancer-related deaths in men in the U.S.1 In 2007 approximately 218,890 men were diagnosed with prostate cancer, and it is expected that one out of six men will receive the diagnosis in their lifetime.2 Although considered to be a slow-growing tumor, the American Cancer Society estimated that in 2008 186,330 new cases of prostate cancer would be diagnosed, and 26,000 men will die from prostate cancer.3 Several factors have been linked with the etiology of prostate cancer, including genetic, social, and environmental factors. Gene alterations on chromosome 1, chromosome 17, and the X-chromosome have been found.3 In addition, those with a positive family history, and African American men are at increased risk of prostate cancer. A diet high in fat has also been found to increase the risk of prostate cancer.3 Currently, the U.S. Preventive Services Task Force finds the evidence insufficient to recommend for or against prostate cancer screening in men younger than 75 years old.4 It recommends against prostate cancer screening in men 75 years or older.4

Screening for prostate cancer includes a digital rectal exam (DRE) and measuring blood levels of prostate-specific antigen (PSA). PSA is a protease produced in the prostate which is believed to liquefy seminal fluid.5 In general, prostate cancer screening both through PSA and DRE are inexpensive, safe tests. The rationale behind using PSA as a screening tool is that prostate cancer causes PSA to be released in the blood; the tumor does not, however, produce PSA.5 Although there is evidence that prostate cancer risk varies with the levels of PSA circulating in the blood,5 it is important to consider that there are other causes for a rise in blood PSA levels, including benign prostatic hyperplasia and prostatitis.5 PSA levels also vary with age, making it even more difficult to compare PSA studies.5  Much of the controversy with PSA testing not only has to do with the threshold level that should be set, but additionally, the accuracy of PSA testing is difficult to determine because not everyone who gets a PSA test goes on to biopsy.5 One study, the Prostate Cancer Prevention Trial, which required all participants to have a biopsy, demonstrated that a PSA level greater than 4 ng/ml had a sensitivity of 24 percent and a specificity of 93 percent.5  With a specificity of 93 percent a PSA threshold of 4 ng/ml has a high chance of correctly identifying those who do not have the disease,; however, a sensitivity of 24 percent implies that the test does poorly at correctly identifying those who do have the disease. A randomized control trial performed in Canada in 1999 proposed that the PSA threshold should be 3.0 ng/ml for the sake of increasing the sensitivity of the test.1 Using a lower PSA threshold will increase the sensitivity at the expense of specificity. Even with the current threshold of 4.0 ng/ml the proportion of cancers that are detected and will become clinically apparent is not known.4,5

Screening a patient with a PSA test comes with many consequences. The patient can be subjected to biopsies for life “just to make sure” everything is okay. Prostate biopsies are generally safe, but infections have been reported in 1 to 7 percent and hematuria in 2 to 4 percent of cases.6 However, “biopsy detection rates vary according to the number of biopsies performed during a single procedure: the more biopsies performed the more cancer cases detected”.In addition, the accuracy of the PSA test is still not exactly determined.4  “A retrospective study found the sensitivity of a PSA level of 4.0 ug/L or higher to be about 91 percent for detecting aggressive cases of prostate cancer that developed within 2 years of screening. The sensitivity was about 56 percent for detecting non-aggressive cases within the same period.”4  A 2003 meta-analysis pooling data from 13 articles reported the pooled sensitivity, specificity, and positive predictive value for PSA to be 72.1%, 93.2% and 25.1%, respectively.7

Before the advent of prostate cancer screening with PSA, patients with localized prostate cancer experienced symptoms of urinary retention, back or leg pain, urinary frequency, hematuria, decreased urinary stream, and urinary urgency. Patients with metastatic disease experienced weight loss, loss of appetite, bone pain, lower extremity pain and edema, as well as uremic symptoms.3 The use of PSA resulted in identification of patients with earlier-stage, organ- localized disease.3 PSA screening has led to an overall increase in the incidence of prostate cancer, but its effect on the mortality of prostate cancer still remains unanswered.6

Two randomized control trials have recently been published describing mortality data for prostate cancer screening using PSA. One of the studies, The European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 20 percent mortality reduction.8 In this study men between the ages of 55 and 69 years were randomly assigned to a group that was offered PSA screening at an average of once every four years or to a control group, with a total of 9 years of follow-up.  A PSA level greater than 3.0 ng/ml was considered an indication for biopsy.8 The ERSPC was a multicenter trial which included data from study centers in Finland, Sweden, Italy, Netherlands, Belgium, Switzerland, and Spain. Recruitment and randomization actually differed among the countries.8 In addition, cause of death was declared by a committee who, although not aware of study group assignments, was aware of treatments, which could have potentially created a bias toward screening.9 The ERSPC concluded that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated in order to prevent one death from prostate cancer.8

The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening trial randomized 76,693 men between 55 to 74 years of age at ten U.S. study centers to receive annual screening with PSA and digital rectal examination (DRE) or to usual care.10 Subjects were recommended to undergo further evaluation if they had a suspicious DRE or a PSA level of more than 4.0 ng/ml.10 After a follow-up time of 7 to 10 years, the PLCO trial concluded there was no significant difference in mortality between the two groups.10 Limitations of the PLCO trial include a wide confidence interval and possible contamination of the control group.9 Both the ESRC and PLCO trials concluded that PSA screening led to overdetection and overtreatment of some patients.8,10

            The American Urologic Association (AUA) released its revised prostate cancer screening guidelines in April 2009. Two differences from its previously released report in 2000 include:

(1) the recommended age of screening has been lowered from 50 to 40 years of age, and (2) a single PSA threshold value is no longer recommended; instead the decision to biopsy should be made based on PSA, DRE, total PSA, PSA velocity, PSA density, the patient’s family history, and ethnicity.11 AUA further states that since there is now evidence from a randomized, controlled trial regarding a mortality decrease associated with PSA screening; it recommends PSA screening for well-informed men who wish to pursue early diagnosis.11

Where does prostate cancer screening stand at this point? An important point made in a recent New England Journal of Medicine editorial stated that the key question is not whether PSA screening is effective but whether it does more good than harm.9 One should consider that most men diagnosed with prostate cancer die with, as opposed to from, prostate cancer.12 In fact, the risk of dying from prostate cancer is 3 percent.12 Recent autopsy studies have shown that one-third of men greater than 50 years old had histologic evidence of prostate cancer, with up to 80 percent clinically insignificant.11 Screening for prostate cancer can potentially save a patient’s life if the patient were to develop metastatic, highly aggressive cancer. On the other hand, if this tumor was destined to remain clinically insignificant and cause no harm, then screening for it may condemn a patient to lifelong retesting, a series of invasive, risky procedures, as well as prolonged anxiety.2

 Annary Garcia is 3rd year medical student at NYU Medical Center.

Peer reviewed and commentary below by Nate Link MD, NYU Division of General Internal Medicine

This excellent comprehensive review summarizes our current knowledge about prostate cancer screening, with a focus on recent reports of two randomized trials, the true gold standard for screening effectiveness.   The American trial failed to achieve statistical significance but was probably underpowered to do so.  The European trial did show a statistically significant, albeit modest, benefit in terms of lives.   In the core age group (55-69 years), there were 53 fewer prostate cancer deaths than expected in 72,890 subjects randomized to the screening arm.   On the cost side, there were 17,543 prostate biopsies and 1,683 extra prostate cancers discovered in the screening group.

Putting this all together, the European study suggests that to prevent 1 prostate cancer death, one must conduct about 2400 PSA tests, perform 330 biopsies, and treat 32 “extra” prostate cancers (usually with prostatectomy).  By way of comparison, to prevent 1 breast cancer death, one must conduct about 2500 mammograms, perform 50 biopsies, and treat 1 additional cancer (unlike the PSA test, mammography does not identify many extra cancers).   In this light, prostate cancer screening is much less effective than breast cancer screening, already in the spotlight because of unfavorable press about the high cost to save one life.  

The bottom line?   When we screen healthy populations for cancer, we can expect modest benefits at a high cost. Whether the juice is worth the squeeze is a question that is best left to the well-informed physician and patient. 

 
References:        

1. Labrie F, Candas B, Dupont A, et al. Screening decreases prostate cancer death: first analysis of the 1988 Quebec prospective randomized control trial. Prostate. 1999;38(2): 83-91.

2. Lin K, Lipsitz R, Miller T, Janakiraman S. Benefits and harms of prostate-specific antigen screening for prostate cancer: an evidence update for the U.S. Preventive Services Task Force. Ann Intern Med. 2008;149(3):192-199.

3. Theodorescu Dan, Krupski Tracey. Prostate Cancer: Biology, Diagnosis, Pathology, Staging, and Natural History. Available at http://emedicine.medscape.com/article/458011-overview. Accessed on August 26, 2009.

4. U.S. Preventive Services Task Force. Screening for prostate cancer. U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2008;149(3):185-191.

5. Lilja H, Ulmert D, Vickers AJ. Prostate specific antigen and prostate cancer: prediction, detection, and monitoring. Nat Rev Cancer. 2008;8(4):268-278.

6. Eastham JA, Riedel E, Scardino PT, et al. Variation of serum prostate-specific antigen levels: an evaluation of year-to-year fluctuations. JAMA. 2003;289:2695-2700.

7. Mistry K, Cable G. Meta-analysis of prostate-specific antigen and digital rectal examination as screening tests for prostate carcinoma. J Am Board Fam Pract. 2003;16(2):95-101.

8. Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360(13):1320-1328.

9. Barry MJ. Screening for prostate cancer–the controversy that refuses to die. N Engl J Med. 2009;360(13):1351-1354.

10. Andriole GL, Crawford D, Grubb RL, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360:1310-1319.

11. Carrol P, Albertsen P, Greene K, et al. Prostate-specific antigen best practice statement: 2009 update. J Urol.  2009;182(5):2232-2241.

12. Harris R, Lohr K. Screening for prostate cancer: an update of the evidence.  Agency for Healthcare Research and Quality. Available at http://www.ahrq.gov/clinic/3rduspstf/prostatescr/prostatesum.htm. Accessed on August 26, 2009.

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