Monday, March 17, 2014

PSA Screening for Men in their 40's: Message from the Brady

PSA screening for prostate cancer has been one of the most controversial issues in medicine, medical literature and the lay press over the past few years.  Arguably the most controversial aspects of the recent AUA (American Urological Association) Guideline on "Early Detection of Prostate Cancer" is

Guideline Statement 2:  The Panel does not recommend routine screening in men between ages 40 to 54 years at average risk. (Recommendation; Evidence Strength Grade C).

Here we review review the data regarding PSA screening in men aged 40-54.  Drs. H. Ballentine Carter, Bruce Trock, and Ashley E. Ross provide their expert interpretation of these data and comment on the AUA Guidelines.

Data Regarding PSA Screening in Men Aged 40-55

  • There are no randomized, controlled studies (Level 1 Evidence) of PSA screening of men in their 40's.
  • Baseline testing at 40-years of age can identify men at increased risk of developing prostate cancer.[1]   
    • 44% of prostate cancer deaths occur in men age 45-55 years with a PSA in the top 10th percentile.[2]
    • In the Malmo study, a single baseline PSA level in 21,277 men (age 27-52 between 1974-1984) was correlated to metastatic disease and prostate-cancer death over 25 year follow-up.[2]
    • In over 4,500 men followed for 20 years at Duke Medical Center, 0.6% of men with a PSA <4ng/mL died of prostate cancer whereas 5.9% of men with a PSA >4ng/mL died of prostate cancer.[3]
  • 98% of all prostate cancer deaths occur after age 54, 91% after age 70 years.
  • PSA Velocity (PSAV) from age 40-55 can identify men at high-risk for aggressive prostate cancer.
    • If PSAV exceeds 0.4ng/mL/year in two or more consecutive years, men had a 50% increased risk of aggressive prostate cancer.[4]
    • In a screening study, a PSAV "risk count" (the number of times PSAV exceeded 0.4ng/mL/year) >2 corresponded to a five-fold risk of Gleason 8-10 disease.[5]
    • PSAV is associated with prostate-cancer specific mortality after surgery.[6,7]
  • Randomized trials and epidemiological evidence indicate that early diagnosis and treatment of aggressive prostate cancer improves prostate cancer survival.[8-10]
  • Younger men are more likely than older men to have low-grade cancer with a longer lead time.[11]

Professional Organization in Favor of Baseline PSA Screening of Men in their 40's

Professional Organizations Against or Not in Favor of Routine Baseline PSA Screening of Men in their 40's

Expert Commentary:

H. Ballentine Carter

H. Ballentine Carter, MD
Professor of Urology and Oncology
Director, Division of Adult Urology
Chair, AUA Early Detection of Prostate Cancer Panel

"Screening for prostate cancer using prostate specific antigen (PSA) is a form of prevention among asymptomatic men. PSA based screening has been shown to reduce prostate cancer deaths among men age 55-69 years, but not among men outside this age range that were part of a randomized screening trial. The American Urological Association panel that developed a Prostate Cancer Detection Guideline concluded that as a routine, screening was not recommended in average risk, asymptomatic men age 40-54 years. To do so would be to assume that benefits would outweigh harms and there is no data to support this assumption. The Malmo study demonstrates that to detect 70% of those cancers that become lethal would require PSA testing of half of the men below age 50 years. There is no evidence that this would reduce prostate cancer mortality, but plenty of evidence to suggest that over diagnosis and over treatment would occur with the associated side effects of treatment. Younger men are more likely, when compared to older men, to harbor the low-grade cancers for which treatment has been shown to provide the least benefit, and would live with any side effects of treatment for a longer period."
"There is no evidence that this would reduce prostate cancer mortality, but plenty of evidence to suggest that over diagnosis and over treatment would occur with the associated side effects of treatment."

Bruce J. Trock
Bruce J. Trock, Ph.D.
Professor of Urology, Epidemiology, Oncology, Environmental Health
Director, Division of Epidemiology

"Routine screening in men aged 40-54:  is the glass half-full or just twice as big as it needs to be?

Lets start by considering a few things that, hopefully, are beyond dispute:

1.  Men with PSA above the median at a baseline screen below age 55 have increased lifetime risk of prostate cancer and prostate cancer mortality compared to men with PSA below the median.
2.  PSA screening explains a portion of the decrease in U.S. prostate cancer mortality since the early 1990’s.
3.  PSA screening leads to over-diagnosis and over-treatment.

That was easy.

Now let’s consider the choice between engaging in some form of screening at ages 40-54 vs. beginning screening around age 55.  Who would be screened and how often if beginning at ages 40-54?  We often hear of “baseline” screening to segregate men into those with PSA below vs. above the age-specific median, with the latter being at significantly increased risk.  But what happens after baseline?

For men below age 55 most data relevant to PSA screening comes from large prospective cohorts where PSA was measured at baseline and men were followed for cancer outcomes.  Given the attention focused on the age to start screening it is surprising that there is so little data with detailed distributions of PSA by age group and associated prostate cancer outcomes from these cohorts.  Some of the most informative data come from the group that has evaluated PSA and prostate cancer outcomes in the cohort of men from the Malmo Preventive Project.  21,277 men aged 33-50 provided baseline blood samples for a study of cardiovascular disease; the samples were subsequently tested retrospectively for PSA and correlated to cancer outcomes.  Because this cohort represented 74% of the men in this age group in Malmo, the study is essentially a population study.  Active PSA screening was minimal in this population.

A case-control study nested in the Malmo cohort suggests that men with baseline PSA <1.0 ng/ml (median PSA at age 60) may require only 3 lifetime PSA tests – at age mid-to-late 40’s, early 50’s, and age 60, while those >1 ng/ml should repeat testing at intervals of 2-4 years, based on the literature.[2]  This sounds reasonable at first, after all, data from the same case-control study show that only 0.2% of men with PSA<1.0 at age 60 will die from prostate cancer by age 85.[12]

But how much is gained by beginning PSA testing in the 40’s vs. waiting until age 55?  In the same case-control study, the highest quartile of PSA in men 45-49 is >1.06 ng/ml, virtually identical to the cut-point above.  So the scheme proposed above would mean that 25% of men would undergo biennial or quadrennial screening beginning in their mid 40s, while 75% of men would not need to be screened until early 50s.  What happens if the 25% of men with PSA above the cut-point at age 45-49 wait until the early 50s to be screened?

Based on the data from the same Malmo cohort, [2] men in the upper PSA quartile at age 45-49 had a 2.7% risk of prostate cancer death within 25 years, that is by the early 70s.  If we assume that most of the men in the upper quartile at age 45-49 will also be in the upper quartile of PSA (>1.40 ng/ml) at ages 51-55*, their risk of prostate cancer death was 3.0% by the early 70s (within 20 years).  Thus, waiting to begin screening until the early 50s results in an increase in the risk of death of only 0.3% by the early 70s.  This is actually an upper limit on the increase in deaths because it is based on death rates in an unscreened population; if active screening were occurring some of the men in the upper quartile would be treated while still curable and death prevented.  It is likely that few men would progress from curable to incurable cancer by age 51-55, since the median time from baseline blood draw to cancer diagnosis was 18 years,[13] and 94% of advanced cancer cases were diagnosed after age 60.[14]  Another way to look at the deaths avoided is by analogy to number needed to treat, in this case number of men needed to evaluate at ages 45-49 to avoid one prostate cancer death that would occur if waiting until 51-55 = 100/0.3 = 333.

From this it seems clear that proposals to conduct a baseline screen in the early 40s, followed by targeted screening of those men with PSA above a cut-point will result in only a small decrease in the absolute risk of prostate cancer death, compared to beginning screening for all men in the early 50s.

Finally, we need to consider that interpretation of the guidelines depends on whether we are addressing the perspective of an individual man aged 40-54 facing the decision to screen, the physician who is talking to that man, or the public health scientist who is considering the impact of population screening for men 40-54.  From the perspective of the individual man the absolute probabilities may have little impact.  Individuals tend to think that outcomes will be either good or bad, which is closer to reality, i.e. an individual will either not die of prostate cancer (0% probability) or he will (100% probability).  So other factors may have greater weight (friends or relatives with prostate cancer, perceived harms of treatment).  In this regard the guidelines state “we are not explicitly stating that screening should be actively discouraged in this group of men.”[15]  The physician’s perspective (this is a personal view since the author is not a physician) is to balance risk of prostate cancer morbidity or death vs. harms of over diagnosis and over treatment.  So the physician tries to find common ground between the probabilistic risk information and the patient’s wishes and concerns.  This perspective is included in the guidelines:  “recommendation against routine screening in men aged 40-54 years is not a recommendation against screening per se, but a benefit to harm assessment of beginning screening before the age of 55 years vs initiating at the age of 55 years for those who wish to be screened.” [16]  Finally, the public health scientist, perhaps an epidemiologist, will focus primarily on the population probabilities of benefit vs. harm, which favor beginning screening in the early 50s, in accord with the guidelines statement:  “Routine screening in men aged 40-54 years at average risk is not recommended.”[15]"


* This seems reasonable since the highest quartile and highest 10% of PSA at age 45-49 capture 54% and 44%, respectively, of prostate cancer deaths, while the highest quartile and highest 10% of PSA at age 51-55 capture 59% and 44%, respectively.[2]
"Thus, waiting to begin screening until the early 50s results in an increase in the risk of death of only 0.3% by the early 70s. Another way to look at the deaths avoided is by analogy to number needed to treat, in this case number of men needed to evaluate at ages 45-49 to avoid one prostate cancer death that would occur if waiting until 51-55 = 100/0.3 = 333."

Ashley E. Ross
Ashley E. Ross, MD, PhD
Assistant Professor, Departments of Urology, Oncology and Pathology

"The new AUA guidelines aim to maximize the benefits of screening while reducing harms by targeting a select population of men where the incidence of clinically significant prostate cancer is relatively high and for whom level one clinical data exists.  As pointed out, perhaps the most controversial part of the guidelines was the somewhat radical change from recommendations to begin shared decision making regarding routine screening at 40 to now beginning this at 55 for those who are not at increased risk.

The AUA identifies African Americans and those with family history of prostate cancer as being of increased risk and as men in whom individualized decision making regarding screening during the ages of 40 and 55 can be considered, but what of the men who do not meet these criteria?  As a population yes, the majority of them who will develop clinically significant prostate cancer may be identified at curable stages of disease after age 55, That said, while the practice of medicine should be evidence based we should also treat our patients as individuals and it may not be sound to only use race and family history as the determinants of risk.  The guideline authors are correct, it is hard as a urologist to separate yourself from anecdotal experiences, particularly as we are not on the front lines of PSA screening and suffer from "denominator neglect."  Not to feed into that, but in defense of my bias for not lumping all the "average risk" men together and not screening them, there are a lot of anecdotes.     For instance, I looked back at our radical prostatectomy dataset of over 20,0000 men diagnosed in the PSA screening era which contained over 5,500 men who were under 55 years old at diagnosis of which about 3,800 were of "average risk" men.  For these average risk men men 37% were diagnosed with NCCN intermediate or high risk disease and at prostatectomy over 30% had Gleason 7 or above prostate cancer and about 30% had non-organ confined disease (all characteristics of cancer very likely to harm these young men in their lifetime).  Of note, among the NCCN intermediate or high risk men, only 7.3% and 4.6% respectively had PSA of less than 3 at diagnosis.  I find it hard to not want to diagnose these men.
This brings up the concept of a baseline prostate cancer risk assessment among those of "average risk" to then guide screening.  I think that over the next several years, structured on discoveries like those of Dr. Isaacs and others of genetic influences of prostate cancer (such as HoxB13 mutations) and as we find superior molecular markers for the disease (or propensity to develop it) we will see the increased availability of "Prostate Cancer Risk Tests" and these tests might help inform us on who may need screening.  Certainly if there was a test that told a young "average risk" man that he was at as high risk or more of having significant prostate cancer as say an African American man, and we think screening in African Americans makes sense then we logically would consider screening that previously average risk man, right?  In that regard, while we wait for the better tests on the horizon would it be helpful to use PSA to determine risk?  What was brought up in our discussion is that the data on using PSA for baseline risk assessment are flawed and hazy in both pro and con directions.  In addition, after 5 years a previous baseline PSA may not be meaningful and a new baseline may be needed.  Suddenly PSA based "risk assessment" seems very much like PSA screening.  And perhaps, until a better risk assessment tool is developed that is what we should do for younger men.  PSA screening but at wide intervals (every 4-5 years) with strict thresholds for action (i.e. PSA >3 for discussion of biopsy).  The argument can be made that we don't have enough self control to do this kind of long interval screening, but I think that perspectives towards cancer screening have evolved substantially among providers and patients alike in a very short time frame and will evolve more as health care and the structure of compensation changes.  I also believe we will become more comfortable screening younger men as better screening tests are developed (even incrementally better ones)."

"For these average risk men men 37% were diagnosed with NCCN intermediate or high risk disease and at prostatectomy over 30% had Gleason 7 or above prostate cancer and about 30% had non-organ confined disease (all characteristics of cancer very likely to harm these young men in their lifetime)...  I find it hard to not want to diagnose these men."

Additional reading on the PSA Screening Controversy for Men Aged 40-55

Judd W. Moul et al.  Re: Early Detection of Prostate Cancer: AUA guideline: H. B. Carter, et al.  J Urol 2013; 190: 419–426, The Journal of Urology, Volume 190, Issue 3, September 2013, Pages 1134-1139, ISSN 0022-5347,

Catalona WJ and Carter HB.   Pro/ Con: Baseline PSA Testing for Men in Their 40s: Currently Available Evidence Strongly Supports Baseline PSA Measurements in This Age Group.  ONCOLOGY ( Feb 2014), pp 82-84.

[1] Loeb S, Carter HB, Catalona WJ, Moul JW, Schroder FH.  Baseline prostate-specific antigen testing at a young age. Eur Urol. 2012 Jan;61(1):1-7. doi: 10.1016/j.eururo.2011.07.067. Epub 2011 Aug 10.
[2] Vickers AJ, Ulmert D, Sjoberg DD, et al. Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40-55 and long term risk of metastasis: case-control study. BMJ. 2013;346:f2023. doi: 10.1136/bmj.f2023.
[3]  Tang P1, Sun L, Uhlman MA, Polascik TJ, Freedland SJ, Moul JW.  Baseline PSA as a predictor of prostate cancer-specific mortality over the past 2 decades: Duke University experience.Cancer. 2010 Oct 15;116(20):4711-7. doi: 10.1002/cncr.25447.
[4] Carter HB, Kettermann A, Ferrucci L, Landis P, Metter EJ. Prostate-specific antigen velocity risk count assessment: a new concept for detection of life-threatening prostate cancer during window of curability. Urology 2007; 70: 685–90
[5] Loeb S, Metter EJ, Kan D, Roehl KA, Catalona WJ. Prostate-specific antigen velocity (PSAV) risk count improves the specificity of screening for clinically significant prostate cancer. BJU Int. 2012 Feb;109(4):508-13; discussion 513-4. doi: 10.1111/j.1464-410X.2011.10900.x. Epub 2012 Feb 1.
[6] 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; 351: 125–35. 
[7] D'Amico AV, Renshaw AA, Sussman B, Chen MH. Pretreatment PSA velocity and risk of death from prostate cancer following external beam radiation therapy. JAMA 2005; 294: 440–7.
[8] Surveillance, Epidemiology and End Results. Fast stats. Available from: Accessed May 19, 2013. 
[9] Schröder FH, Hugosson J, Roobol MJ, et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med. 2012;366:981-90.
[10] Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol. 2010;11:725-32.
[11] Draisma G, Boer R, Otto SJ, et al. Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst. 2003;95:868-78.
[12] Vickers AJ, Cronin AM, Bjork T, et al.  Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer:  case-control study.  BMJ 2010; 341:c4521.
[13] Lilja H, Ulmert D, Bjork T, et al.  Long-term prediction of prostate cancer up to 25 years before diagnosis of prostate cancer using prostate kallikreins measured at age 44 to 50 years.  J Clin Oncol 2007; 25:431-6.
[14] Lilja H, Cronin AM, Dahlin A, et al.  Prediction of significant prostate cancer diagnosed 20 to 30 years later with single measure of prostate-specific antigen at or before age 50.  Cancer 2011; 117:1210-19.
[15] Carter HB, Albertsen PC, Barry MJ, et al.  Early dection of prostate cancer:  AUA guideline.  J Urol 2013; 190:419-426.
[16] Carter HB.  American Urological Association (AUA) guideline on prostate cancer detection:  process and rationale.  BJU Int 2013; 112:543-7.

1 comment:

  1. It all sounds theoretical and ephemeral until you've had a family member without any risk factors diagnosed at 52 with high risk prostate cancer following a random PSA screen.