The Controversy Surrounding Prostate Specific Antigen Biology Essay

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Prostate cancer is one of the most common cancers diagnosed in Canadian men. It accounts for an estimated 27 of all newly diagnosed cancer cases in men and 10 of all male cancer deaths in Canada <1>. Given the magnitude of these statistics, early PCa detection is essential to allow for early treatment and to reduce morbidity and mortality from this disease <3>. While clinical evidence is conflicting, it has shown prostate-specific antigen (PSA) testing in combination with a digital rectal exam (DRE) increases detection of early-stage treatable cancers and reduces mortality in men experiencing PCa symptoms <1,4>. However, it has not shown that population-wide PSA screening provides the same benefits in asymptomatic men <4>. As a result, whether or not routine PSA testing should be performed in all men over the age of 50, regardless of their symptomatic profile, remains a topic of much clinical controversy and debate <2>. Therefore, this document aims to review the clinical role and evidence surrounding PSA testing and provide an up-to-date outline of current national clinical practice recommendations for PSA testing in Canada.

The PSA Test:

A PSA test is commonly used in clinical practice to detect PSA in a patient's blood and screen for PCa <1,2,3,5>. Prostate-specific antigen is a glycoprotein produced primarily by epithelial cells of the prostate gland and is normally present in the blood of all men at low concentrations <1,2,3>. Baseline levels of PSA do vary among males and tend to naturally increase with age <1,2,3,5>. A variety of conditions are also known to elevate PSA levels including PCa, benign prostatic hypertrophy (BPH), prostatitis, urinary tract infections, recent ejaculation, prostatic biopsy and undergoing a vigorous DRE <1,2,3,4,5>. Conversely, certain medications such as finasteride and dutasteride are known to artificially lower a man's PSA level <5>. In clinical practice, a PSA threshold of 4 ng/mL is routinely used to differentiate normal baseline PSA levels from pathological elevations and is associated with a 20% sensitivity of detecting PCa <3,4,5>. While there is little evidence that BPH or prostatitis directly cause PCa, a direct relationship between PSA and incidence of PCa has been shown to exist (i.e. the higher the PSA level, the great the risk of PCa) <1,2,3>. However, this relationship is not true for all PCa cases as some men with PCa will experience "normal" PSA levels <1,4>. As such, PSA testing alone or in combination with a DRE is not sufficient for a diagnosis of PCa and further investigation/testing is needed to confirm a diagnosis if PCa is suspected for any reason <1,3,4>.

The Clinical Controversy:

The usefulness of PSA blood testing for PCa screening is highly controversial <2,4>. The controversy largely stems from a lack of high quality evidence that is conflicting <4>. While PSA testing in combination with the DRE has been shown to increase early detection and reduce mortality in symptomatic men with PCa, evidence in asymptomatic men is lacking <4>. At the same time, treatment of PCa (many of which are slow growing, non-life threatening, non-aggressive and unlikely to metastasize) can result in secondary morbidities such as infection, impotence and incontinence leading to a diminished quality of life for patients <2,4>. As a result, much debate also surrounds whether the benefits of PSA screening, early detection and treatment of PCa outweigh the potential health risks and costs involved <4>.

Controversy surrounding the utility of PSA screening for PCa is also drawn from the fact that an elevated PSA level is not sufficient for a definitive diagnosis of PCa <1,5>. Several reasons have been cited for this. While evidence has demonstrated a direct relationship between elevated PSA levels and the incidence of PCa exists, it has also shown this relationship does not hold true for all cases of PCa as some cancers occur in the absence of an elevated PSA <2,3,5>. Similarly, evidence has also shown PSA levels may increase in the absence of PCa due to other causes including aging and a variety of benign conditions (outlined previously) <1,2,3,5>. In light of these findings, it is evident PSA testing can yield false-positive or false-negative test results for patients <1,2>. In clinical practice, PSA testing is actually known to be associated with a high incidence of false-positive tests contributing to healthy men enduring unnecessary and invasive medical procedures, financial burdens, secondary morbidities and emotional distress in the absence of PCa <1,2>. In fact, it is estimated that only 25 to 35% of men who undergo biopsy due to an elevated PSA level actually have PCa <2>. Likewise concerning is the incidence of false-negatives and the fact that an estimated 10 to 20% of early prostate cancers are not detected with PSA screening <1>.

Despite the potential for early detection, the usefulness of PSA testing to screen for PCa is further called into question by recent research showing that up to 50% of prostate cancers detected by PSA testing may never need treatment as they are not fast growing or aggressive and have low potential progression <1>. Clinically, the detection of these types of PCa tumours is referred to as "overdiagnosis" which can increase emotional distress secondary to enduring unnecessary and invasive medical procedures and side effects including infection, impotence, incontinence and pain <1>.

PSA Testing - The Two Key Conflicting Studies:

Much of the evidence surrounding PSA testing for PCa stems from two large randomized control trials which found conflicting results in men; the U.S. Prostate, Lung, Colorectal & Ovarian Cancer (PLCO) Screening Trial and the European Randomized study of Screening for Prostate Cancer (ERSPC) <1>. Although it is not the objective of this paper to critically appraise each of these trials, the results obtained from each will be reviewed as they form the basis of the controversy surrounding routine PSA testing for PCa. Of note, the primary outcome for each trial was similar looking at the proposed mortality benefit associated with PSA testing. Furthermore, despite publishing initial findings in 2009, both studies are currently ongoing in terms of follow-up and discovery of methods to improve PSA testing alone and in combination with DRE for PCa screening.

In terms of findings, the PLCO trial was designed to determine whether routine PSA testing for PCa would reduce mortality from the disease <1,6>. It studied men who undertook regular DREs, PSA tests or both and compared them to men who did not receive testing <1,6>. Initial and subsequent follow-up results demonstrated that PSA testing did not significantly reduce mortality associated with PCa and that the rate of death from PCa was low <1,6,7,8>. Similar to the PLCO study, the ERSPC study sought to examine the effectiveness of PSA testing in PCa screening by also comparing men who undertook a DRE and PSA test to those receiving no testing <1,9>. Initial and subsequent follow-up results published directly contradicted those published by the PLCO trial and showed that PSA testing can reduce PCa mortality by 20% <1,9,10,11>. Furthermore, the ERSPC trial also went on to show that men undergoing PSA testing experienced a high rate of overdiagnosis and that 50% of the PCa detected by PSA would not have developed into health issues and thus, treatment may not have been necessary <1,9>.

Overall, these two conflicting trials suggest only a modest benefit, if any, in terms of reducing PCa mortality using routine PSA testing. They further show that the benefits of testing must be weighed against the risks of overdiagnoses and overtreatment <2,6,9>. As such, recommendations surrounding PSA testing reflect this evidence.

Clinical Practice Guidelines surrounding PSA Testing for Prostate Cancer in Canada:

Given the wide variety of PSA screening recommendations issued by various medical organizations and agencies worldwide, it is evident that PSA testing is a topic of much debate and controversy <4>. In Canada, there is a lack of clear, consistent national PSA screening guidelines and as a result, PSA screening in clinical practice largely reflects clinician preferences, men's anxiety over PCa, family histories of PCa and media influences <4>. On the basis of current evidence, although PCa screening allows the early detection of potentially lethal cancers, this comes at the expense of overdiagnosis and overtreatment. In light of this, there is consensus that patient education concerning PCa screening is paramount and that screening should be available to all men 50 years of age and older with at least a 10 year life expectancy <4>. More specifically, testing is recommended for men aged 50 plus who have a prostatic nodule found on a DRE and or are presenting with PCa symptoms <1,3,4>. If there is a higher risk of PCa, such as a family history or the male is of African ancestry, PSA screening should be offered and is recommended at an age of 40 <1,3,4,5>. Although there is still no consensus on the frequency with which PSA screening of men should take place if performed, most guidelines do agreement that population-wide PSA screening of all men is not recommended and further evidence as to the effectiveness of doing so is required <1,3,4,5>.