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Monday, May 21, 2007

PSA Screening and Early Detection - Part 3. Current Environment

[Updated December 7, 2009]

PSA Screening and Early Detection. Part 1 - Guides
PSA Screening and Early Detection. Part 2 - Key Points on PSA [previous]
PSA Screening and Early Detection. Part 3. Current Environment [current]
PSA Screening and Early Detection - Part 4. Diagnostic Testing Concepts [next]
PSA Screening and Early Detection - Part 5. More Diagnostic Testing Concepts

Typically doctor and patient organizations support annual PSA testing while government organizations regard the benefits of such testing as unproven. US physicians overwhelmingly perform PSA testing anyways but Canadian physicians only advise of its availability and order it for screening only if the patient is willing to pay for it -- Canadian provincial health insurance does not cover PSA screening. Below we discuss the guidelines of various organizations and discuss the pros and cons of PSA screening. Here we are mainly interested in PSA testing for purposes of detection of prostate cancer but mounting evidence suggests that such population screening of men in their 40's can also potentially be used to predict the risk of developing prostate cancer many years later (see [link]).

The guidelines set out by a variety of organizations are summarized in the appendix to this 2002 Ontario report and another shorter summary is in this Mayo Clinic article.

Doctor and Patient Organizations. The following organizations recommend annual testing starting at the indicated ages for the general population and high risk groups where high risk groups are blacks and those with a father, son or brother with prostate cancer. Generally, PSA testing is only recommended for those expected to live at least 10 more years due to age or co-morbidities.

  • The American Cancer Society (ACS) "The American
    Cancer Society recommends that health care providers discuss the potential
    benefits and limitations of prostate cancer early detection testing with men
    and offer the PSA blood test and the digital rectal examination annually,
    beginning at age 50, to men who are at average risk of prostate cancer and
    who have a life expectancy of at least 10 years. Those men who indicate a
    preference for testing following this discussion should be tested. Men at
    high risk of developing prostate cancer (African Americans or men with a
    close relative diagnosed with prostate cancer before age 65) should have
    this discussion with their provider beginning at age 45. Men at even higher
    risk (because they have several close relatives diagnosed with prostate
    cancer at an early age) should have this discussion with their provider at
    age 40." Also see ACS 2007 guidelines
    ACS 2009
  • The American Urological Association (AUA) Begin testing at age 50 or age 40 if at high risk.
    According to a May 8, 2007 NY Times article, or read it here, the AUA will soon release new guidelines which "will no longer rely on a single reading. Rather, they will suggest that doctors focus on changes in levels over time. They will also suggest that testing start at 40 to obtain a baseline measurement, with the test repeated at 45 and 50, after which it should be given annually until 70." There was a presentation on the 2008 AUA PSA guidelines at the 2008 AUA meeting summarized here. In March 2009 in response to two studies on PSA testing the president of the AUA, Dr. John Berry, said: "The American Urological Association has read with great interest the coverage surrounding the two studies about prostate-specific antigen (PSA) testing recently published in the New England Journal of Medicine, and is concerned about the alarm these two studies have raised with patients. The decision to screen for prostate cancer is a personal one that a man should make in conjunction with his physician or urologist. Because most cancers need to be caught in their earliest stages to achieve the best outcome for the patient, disparaging the PSA test puts men - particularly with certain risk profiles - at risk for life-threatening disease. Prior to the use of the PSA test, tumors were found mostly in advanced - and less treatable - stages, giving patients far fewer options for treatment. These studies, as well as the 2008 United States Preventive Services Task Force recommendation that men stop PSA testing after the age of 75, have potential for harm if they are not explained clearly to patients or reviewed in the context of the full debate on PSA. It is the opinion of the AUA that the PSA test is a valuable screening tool that saves lives - and men with concerns about elevated PSA scores should consult their urologists about next steps.

    These two studies do not clearly assert that PSA testing causes more harm than benefit. In one of the two studies, 52 percent of men in the "non-screened" arm had recent PSA tests, thus enriching the non-screened arm with men who had normal PSA levels and reducing the chance for prostate cancer death in this arm of the study. This means that more than half of the men in the non-screening arm of the study were screened, making it difficult to demonstrate a difference. In the other study, there was actually a 20 percent reduction in death from prostate cancer with a relatively short follow-up of only nine years. This is an important point. The benefit of screening may not be demonstrable until significantly longer follow up is reached for both trials. These studies therefore do not lead to the conclusion that PSA screening should be abandoned.

    Men who are concerned about these studies should talk with their urologists about their particular risk profile and whether regular PSA testing is best for them.

    The AUA is presently finalizing a new Best Practice Statement about prostate-specific antigen testing that will be unveiled during our upcoming Annual Meeting. These studies are being addressed in more detail in the Statement, but do not change the AUA's position that PSA is a valuable screening tool and should be appropriately offered to men. This document will be made available to the public in April." [link].

    Also the following statement was issued by the AUA Foundation on March 19, 2009 and is attributable to AUA Foundation Executive Director Sandra Vassos, MPA:

    The American Urological Association Foundation (AUA Foundation) is concerned that two major studies about prostate-specific antigen (PSA) testing may present conflicting information to patients about the value of this critical prostate-cancer screening test. The benefits of regular screening and early detection should not be discounted in the overall population. The decision to screen for prostate cancer with PSA and digital rectal examination should incorporate other known risk factors, including family history of prostate cancer, age, ethnicity/race, and whether or not the individual has had a previous negative prostate biopsy.

    Men should understand that studies such as these are just a part of the overall national discussion about PSA testing. An overwhelming body of evidence exists that supports the value of this test and that screening has the potential to save lives. The AUA Foundation strongly believes that the decision to screen is one that a man should make in conjunction with his physician and supports the screening recommendations of the American Urological Association. The Association is expected to release a new best practice statement about PSA testing during the group's upcoming Annual Scientific Meeting in Chicago next month. [link]

    Since the above was written the AUA Best Practices Statement has been released. A [summary] is available as well.

  • The Prostate Cancer Research Institute (PCRI) Begin testing at age 40 or age 35 if at high risk.
  • National Comprehensive Cancer Network (NCCN) guidelines recommend that physicians offer testing starting at age 45 and repeat every 5 years if PSA < 0.6 and every year otherwise. After age 50 test every year.

Government Organizations. In contrast to the patient and doctor groups, these government groups have not made definitive recommendations or do not recommend PSA testing:
  • Center for Disease Prevention (CDC) - Position paper, Slide presentation
  • US Preventative Services Task Force (USPSTF) - Recommendation, Position Paper. Note that the task force had no urologists on it (see bottom of [this link] for the composition of the task force) and apparently just looked at randomized controlled clinical trials (RCTs) and since there are no large scale high quality RCTs they came to these conclusions not taking into account other clinical and epidemiological evidence. See the Study Selection section of [PMID: 18678846] [Full Text] where they state that they only considered RCTs for mortality but did consider non-RCTs for harms. The AHRQ government web site has a disclaimer near the bottom of [this page] that "Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services." A rebuttal by Dr. William Catalona to the task force recommendations appeared in the Washington Post [full text] on August 26, 2008 page A13 and discussed in greater detail in his [2009 Northwestern University Presentation] where he disputes the over diagnosis figures commonly cited and points out that the ESPRC trial provided level 1 evidence in favor of screening and should not be confused with the PLCO trial which was uninformative due to contamination (i.e. many men in the control group has been screened or pre-screened). Also see these articles by Catalona in the Winter 2009 issue of Quest. [article3] and [article4].
  • Australia - "The Urological Society of Australasia, The Royal Australian College of General Practitioners and the Anti-Cancer Council of Victoria do not currently endorse population based screening for prostate cancer. However, they do not actively discourage the practice of providing access to ‘screening for prostate cancer’ (utilising annual PSA and DRE) for concerned patients who are otherwise in good health and have a life expectancy of greater than 10 years. In most cases this means men in the age range 50–65 years. Screening is also recommended for men at an earlier age who have a strong positive family history of prostate cancer. Hence, while population screening is not currently endorsed, case detection is considered acceptable practice at the primary care level. What is more important than consensus agreement on the role of screening of entire populations for prostate cancer is that patients are informed at a primary care level of the options available to them in relation to PSA testing and the possible significance of the test result. Both PSA testing without the patient’s informed consent as well as the deliberate omission of PSA testing in men with a life expectancy of more than 10 years without discussing the option of testing with them, are practices that should be actively discouraged." Australian Family Physician, May, 2007
  • National Health Committee, New Zealand - Position Paper
  • National Health Service, UK - See Summary. The UK does not have a national program for PSA screening although screening is done on an opportunistic basis sometimes. See [link] for more information on prevalence of PSA testing and [PMID: 19021912] [provisional partial text] for a related study published in BMC Urology 2008. That study mentions among other points that even when PSA tests for screening is done the cutoff points used vary substantially from one doctor to another. (The UK Department of Health recommends the use of age-specific cutoffs of 3.0 for men aged 50-59, 4.0 for men 60-69 and 5.0 for men 70 and older. See [booklet] and [summary sheet].)
  • Canadian provincial health authorities. - Summary. Note that BC will not pay PSA screening tests but will pay when not "rendered for the purpose of screening" (see [link]). Ontario's government health plan, OHIP, will also not pay for PSA tests for screening but hospital labs will pay for the test from their own budgets for patients known or suspected to have cancer (see OHIP Schedule and [link]). Alberta will pay PSA tests that are "ordered by a doctor" according to this Alberta resident [link]. The province of Quebec guidelines include a decision tree.
  • Malaysia. See Clinical Practice Guidelines. The letter after each guideline refers to the strength of the evidence supporting the guideline with A being strongest and E being weakest: All males above 40 years of age with the risk factor of having a first degree relative with prostate cancer diagnosed at a young age (<60 years) may be screened. (E), PSA should be used in combination with DRE to enhance early detection. (B), The improved sensitivity and specificity of age-specific PSA ranges is at best modest and, hence, not recommended. (C), PSA velocity (0.75 ng/ml/yr) has not improved the sensitivity and specificity of the test and is probably not useful as first line assessment for prostate cancer. (C), PSA density is not recommended as there is no improvement in the sensitivity and specificity over the PSA level. (B), Free to total PSA ratio is helpful as the sensitivity and specificity for detecting prostate cancer is higher in patients with a serum PSA level of between 4 and 10 ng/ml. (B), The optimal cut-off level is still being investigated. Population screening for prostate cancer among Malaysian men is not recommended. (E), The appropriate threshold serum PSA level for case detection is 4.0 ng/ml. (B), Volunteers and/or referred patients with abnormal PSA results and/or suspicious DRE are recommended to undergo prostate biopsy. (A), PSA is useful in monitoring response to treatment. (B), PSA is useful in detection of early recurrence. (B)

The government bodies above appear to be awaiting results from the large scale PCLO (also here) and ESPRC (also here) trials.

US Private Insurers

Below we review the coverage of several major insurers based on information found on the internet. The National Prostate Cancer Coalition points out that in the US only 28 states the District of Columbia mandate insurance coverage for PSA screening (compared to 49 states mandating insurance coverage for mammograms). See the page marked 4 (the 6th page of the PDF document) here. (The NPCC also issues a report card rating each state on a number dimensions -- mortality rates, screening Rates, co-signers for early detection legislation, co-signers for Department of Defense Cancer program, co-signers for Prostate Cancer Awareness Month resolution, mandating insurance coverage, AUA urologists per capita and clinical trial sites).

  • Cigna. CIGNA HealthCare covers annual prostate-specific antigen (PSA) testing for prostate cancer screening for men in high risk categories (black, relatives with PC, previous borderline PSA test) and those over 50 years old whose life expectancy is at least 10 years. CIGNA HealthCare covers percent free PSA (%fPSA) or free-to-total PSA ratio (fPSA/tPSA) testing and complexed PSA (cPSA) testing when medically necessary for deciding on the need for prostate biopsy in men with a normal or equivocal digital rectal examination (DRE) and elevated tPSA of 4-10 ng/mL. CIGNA HealthCare does not cover %fPSA (or fPSA/tPSA) testing or cPSA testing as screening tests for asymptomatic men in the general population because it is considered experimental, investigational or unproven. [link].
  • Aetna Covers PSA screening starting at 40. Earlier for those in high risk groups. See [link]

Although the government organizations did find evidence that "PSA screening can detect early-stage prostate cancer" they found "mixed and inconclusive evidence that early detection improves health outcomes. Screening is associated with important harms, including frequent false-positive results and unnecessary anxiety, biopsies, and potential complications of treatment of some cancers that may never have affected a patient's health. The USPSTF concludes that evidence is insufficient to determine whether the benefits outweigh the harms for a screened population." See USPSTF, NCI, UK NHS and the links in the list above for more on their concerns.

Pros and Cons of Screening. The pros and cons of PSA testing are discussed on pages 8 and 9 of William Ware, 2005. A debate on the screening between Dr. Catalona (pro) and Dr. Talcott (con) was featured at the 2006 AUA conference and is discussed Medscape (login required but free). An even more recent viewpoint article is this April 2008 article also in Medscape by Catalona. Another debate is presented in the June 2007 Canadian Family Physician (see [link] with Yves Fradet presenting the Yes case (in favor of PSA screening) and Michel Labrecque, France Légaré and Michel Cauchon presenting the No case.

The main argument against screening is that there is insufficient evidence of benefit combined with significant harms done to unnecesarily treated patients due to the inaccuracy of PSA testing. The reductions in prostate cancer mortality found in heavily screened Seattle were no different than found in lightly screened Connecticut. This study only focused on men over 65. (See [Full Text] [PMID: 15698354] as well as a more recent 15 year follow [PMID: 18795372].) Where reductions in mortality have been seen they may have been due to the introduction of hormone therapy around the same time [BJU Intl 2003], due to statins intended to address cardiovascular disease which may have an anti-cancer effect [PMID: 17179482] [PMID: 1601477], to the increased number of prostate biopsy cores now employed (see [link]), to the Will Rogers effect (see [link]) or to other causes and not necesarily due to the screening. Even if cancer can be detected earlier that is of no benefit if the consequent treatment is no more effective than if it had been caught later.

Results that appear to support screening are also said to suffer from lead-time and length-time bias (requires sign-in but sign-in is free) also described in this 1997 Annals of Internal Medicine paper where bias is illustrated in a set of three diagrams: [1] [2] [3]. A good description of lead-time bias by Dr. Barry Kramer of NIH (papers) appeared in Tara Parker-Hope's August 8, 2008 New York Times column
someone diagnosed with lung cancer at the age of 65 may die at 67 and be remembered as a two-year survivor. If the same man had been diagnosed at 57 through screening and died at the age of 67, he would be known as a 10-year survivor. That sounds a lot better, but the reality is that diagnosis and treatment didn’t prolong his life. He died at 67 either way.
(That column also presents a number of other arguments relating to the downside of screening.)

Proponents of screening say that since PSA screening became widespread most detected cancers are at an earlier stage than in the pre-PSA era and mortality has decreased [Full Text] [PMID: 1107461]. Screening was performed in Tyrol Austria but not the rest of the country and Tyrol experienced greater reductions in mortality than the rest of the country. Furthermore, Tyrol nearly eliminated advanced prostate cancer altogether. [PMID: 18321314] (Science Daily summary) In particular, see this summary by Roehrborn. (An argument against screening is that Tyrol also had a higher rate of prostatectomies and that, rather than screening, could be the explanation.) Also in favor of screening is that the studies that are "against screening should be considered inadequate upon closer scrutiny since they were conducted in a patient cohort that was too old, the follow-up period was too short, and inappropriate endpoints were set." [PMID: 18560799]. Recent results (see next section) tend to support screening.

Recent Research Results. A trial of 220,000 men in 8 countries, The European Randomised Study of Screening for Prostate Cancer [ESRPC], is currently underway and preliminary results suggest that screen detected prostate cancer has more favourable prognostic indicators that non-screen detected prostate cancer, but as yet no mortality advantage to screening has been shown [PMID: 18774469]. "The ERSPC trial has sufficient power to detect a significant difference in prostate cancer mortality between the two arms if the true reduction in mortality by screening is 25% or more (or, if contamination remains limited to 10 % if the true effect is 20 % or more). These results can be expected between 2008 and 2010." [ESRPC]. Further discussion can be found in Goel & Rendon, Feb 2007 and also in UroToday, March 2007.

A 2008 study of US screening and urologist density to be published in Prostate Cancer Prostatic Disease [PMID: 18268527] "found that prostate cancer mortality rates correlated inversely with urologist population densities (P<0.01) and PSA screening (P<0.01) suggesting that screening and treatment reduce prostate cancer mortality."

A particularly interesting presentation by Claus G. Roehrborn (mentioned in several connections already) is given on this Medscape page. He reviews mortality statistics since the introduction of PSA screening, cutoff guidelines (ACS has lowered the cutoff from 4 to 2.5), the Tyrol study which showed reduction in mortaility and vanquishing of advanced cancer after screening in Tyrol vs. no screening the rest of Austria, early results from the PLCO trial which suggests that screening less frequently than annually may be adequate if the PSA level is less than 1.0, results from the PCPT study that show that the risk of prostate cancer and even high grade prostate cancer at low PSA values is higher than commonly thought, the 2005 Whittemore study that showed that a PSA > 0.24 in men in their early 30's was associated with an elevated risk of prostate cancer 20 to 30 years later and the risk increased as the PSA increased. He also discusses evidence in favor of using PSA density (PSA divided by the volume of the prostate) as a diagnostic. (Other discussion not related to screening includes the possibility that a retrovirus can cause prostate cancer and the preventative effect of 5AR inhibitors.)

Two mathematical modelling teams, one of the Fred Hutchinson Center and one at the University of Michigan concluded that it was plausible that 45% to 70% of the improved survival to the year 2000 could be attributed to PSA testing. [PMID: 18027095]

An April 2008 a paper from the University of Bristol [PMID: 18424233] discusses the decline in prostate cancer deaths in the US (where screening is common) vs. UK (where it is not):
The striking decline in prostate-cancer mortality in the USA compared with the UK in 1994-2004 coincided with much higher uptake of PSA screening in the USA. Explanations for the different trends in mortality include the possibility of an early effect of initial screening rounds on men with more aggressive asymptomatic disease in the USA, different approaches to treatment in the two countries, and bias
related to the misattribution of cause of death. Speculation over the role of screening will continue until evidence from randomised controlled trials is published.

Analogy to Mammograms. The pattern of lagging recommendations for testing appears to be following the path set with breast cancer in which twenty years ago breast cancer screening was questioned while today it is accepted practice. See link and for further comparison see link.

Current Practice. Based on a 2001 survey 81% of primary care physicians in the US do routine PSA testing. This may be due to a combination of their belief in the test, AUA recommendations discussed previously and the fact that US physicians who do not perform such screening risk being sued, even by older patients. UroToday, March, 2007. According to [PMID: 17372918] about 45% of men in the US within ages 40 - 84 had had at least one PSA test by the year 2000.

Technology In Part 2 of this series we discussed new tests that are being investigated and appear to be more accurate than the PSA test. Validation and use of these could materially impact the screening question by significantly reducing the number of needless biopsies.

PSA Screening and Early Detection. Part 1 - Guides
PSA Screening and Early Detection. Part 2 - Key Points on PSA [previous]
PSA Screening and Early Detection. Part 3. Current Environment [current]
PSA Screening and Early Detection - Part 4. Diagnostic Testing Concepts [next]
PSA Screening and Early Detection - Part 5. More Diagnostic Testing Concepts