Prostate Cancer Screening: Clear As Mud

Prostate Cancer is Common

Prostate cancer is the 2nd most common (non-skin) cancer in men worldwide.

To screen or not to screen

For prostate cancer screening to be valuable, it must reduce disease-specific morbidity and/or mortality by detecting cancer at an early stage.

Mortality data are conflicting, but overall screening has no benefit in reducing overall mortality:

Screening increases the detection of prostate cancer, but detection at an early stage does not necessarily correlate with a clinically beneficial outcome. Furthermore, increased detection of prostate cancer subjects some patients to the risks associated with treatments that may not prolong life and that have risks of morbidity.

  • Screening may result in false-positives triggering unnecessary biopsy with complications
  • Screening may result in true-positives triggering treatment and subsequent GU complications

Shared decision-making with patients:

  • Benefits:
    • Prostate cancer is common and treatment is available
    • Prostate cancer screening may reduce the chance of dying from prostate cancer
    • Patients who choose to be screened with a PSA test are much more likely than those who decline PSA screening testing to be diagnosed with prostate cancer
    • Some people simply want to know if they have cancer
  • Risks:
    • Serial PSA levels are needed (not specific—PSA may be abnormal in the absence of prostate cancer, and it may even be normal in the presence of prostate cancer)
    • Prostate biopsy has poor sensitivity
    • Potential lead-time bias (overdiagnosis / overtreatment)
    • Post-biopsy complications can occur (e.g., infections, bleeds, LUTS)

Multiple online patient decision aids are available to facilitate shared decision-making:

Screening Guidelines are Conflicting

There is variability in the age at which expert guidelines recommend initiating a discussion about prostate cancer screening, mostly at age 50 or 55 years or, less commonly, age 45 years.

ACS:

  • The discussion about screening should take place at:
    • Age 50yo for men who are at average risk of prostate cancer and are expected to live at least 10 more years.
    • Age 45yo for men at high risk of developing prostate cancer. This includes African Americans and men who have a first-degree relative (father or brother) diagnosed with prostate cancer at an early age (younger than age 65yo.)
    • Age 40yo for men at even higher risk (those with more than one first-degree relative who had prostate cancer at an early age.)

ACP:

  • ACP recommends that clinicians inform men between the age of 50 and 69 years about the limited potential benefits and substantial harms of screening for prostate cancer…

AUA:

  • For men ages 55 to 69 years the Panel recognizes that the decision to undergo PSA screening involves weighing the benefits of reducing the rate of metastatic prostate cancer and prevention of prostate cancer death against the known potential harms associated with screening and treatment. For this reason, the Panel strongly recommends shared decision-making for men age 55 to 69 years that are considering PSA screening, and proceeding based on a man’s values and preferences. (Standard; Evidence Strength Grade B)

NCCN:

  • The 2018 NCCN Guidelines for Prostate Cancer Early Detection continue to support early detection in well-informed healthy men and to recommend be- ginning baseline screening at 45 years of age…

USPSTF:

  • For men aged 55 to 69 years, the decision to undergo periodic prostate-specific antigen (PSA)-based screening for prostate cancer should be an individual one. Before deciding whether to be screened, men should have an opportunity to discuss the potential benefits and harms of screening with their clinician and to incorporate their values and preferences in the decision. Screening offers a small potential benefit of reducing the chance of death from prostate cancer in some men. However, many men will experience potential harms of screening, including false-positive results that require additional testing and possible prostate biopsy; overdiagnosis and overtreatment; and treatment complications, such as incontinence and erectile dysfunction. In determining whether this service is appropriate in individual cases, patients and clinicians should consider the balance of benefits and harms on the basis of family history, race/ethnicity, comorbid medical conditions, patient values about the benefits and harms of screening and treatment-specific outcomes, and other health needs. Clinicians should not screen men who do not express a preference for screening. [Grade C]

Case

63yo man with remote nephrolithiasis and remote benign testicular cyst presents to establish care at our clinic. His only complaint is 6 months of stable dysuria with associated foul urine. He thinks that his father had prostate cancer, but he does not know at what age or the disease severity. Initial diagnostic testing reveals unremarkable UA and STI screening. (This case continues below in highlighted text.)

Let’s (Quickly) Talk About LUTS

Lower urinary tract symptoms (LUTS) are poorly defined but generally fall into 3 categories: storage, voiding, and post-micturition.

  • Storage symptoms: urgency, frequency, nocturia, etc.
  • Voiding: slow/intermittent stream, hesitancy, straining, etc.
  • Post-micturition: sensation of incomplete emptying, involuntary dribbling

LUTS are most often benign, and are an uncommon presentation of prostate cancer. LUTS should trigger consideration of checking PSA only if life expectancy exceeds 10 years.

Our patient’s initial PSA is normal at 1.4. Four years later (patient is now 67yo), he is seen for a well-adult exam. He now has intermittent urinary stream. Interval history: his brother was diagnosed with prostate cancer at age 60yo now s/p resection, and now he’s not sure if father’s history was actually prostate cancer or not.

What is High Risk?

What counts as high-risk family history for prostate cancer?

  1. First degree relative diagnosed at age <65yo
    a. Cancer in 3 or more affected relatives spanning 3 generations on 1 side
    b. 2 or more first- or second-degree relatives at age <55yo
  2. BRCA1 (increases risk x1.8) or BRCA2 (increases risk x4.7)
  3. Lynch syndrome

Why are black men considered high risk for prostate cancer?

Black men are disproportionately affected by prostate cancer:

  • Highest incidence of prostate cancer in the US
  • More likely to develop prostate cancer at almost every stage of the disease continuum and in every age group
  • 2.2x higher risk of death compared to white men
  • More likely to present with prostate cancer at a younger age
  • More likely to be diagnosed with more aggressive disease and/or diagnosed at later stages, contributing to fewer treatment options and higher morbidity and mortality rates

The root cause of racial disparity in the diagnosis, treatment, and outcomes of prostate cancer is multifaceted, complex, and driven by institutional racism:

Source: Lillard et al. Cancer. 2022

Repeat PSA is now 2.2 (from 1.4). AUA LUTS score of 18. Given symptom burden, he is started on doxazosin. He returns 3 years later at age 70yo and LUTS are well controlled. But now a second brother has recently had a procedure for prostate cancer. Patient is scared and wants to be screened again. What would you do?

Effect of BPH Treatment

5-alpha reductase inhibitors (e.g., finasteride, dutasteride) prevent the intraprostatic conversion of testosterone to dihydrotestosterone, thereby reducing prostate volume and relieving urinary outflow obstruction. As such, these medications reduce PSA levels by ~50%, meaning that we should use a correction factor when checking PSA levels in these patients (add 2 to the PSA level.)

In contrast, alpha-1 antagonists (e.g., tamsulosin) have no effect on PSA levels.

Our patient’s PSA is now 3.2 (drawn at age 71yo), up from 2.2. Patient is referred to urology who performs DRE, which shows prostate measures ~45cc, characterized as symmetric, no nodules, and firm bilaterally; urology recommends annual PSA.

Digital Rectal Exam

DRE has poor sensitivity and specificity for detecting prostate cancer, and should not be performed in isolation. Most guidelines do not suggest DRE for screening, although some (ACS, AUA, NCCN), include DRE either to evaluate an elevated PSA or as an option along with PSA testing.

One year later, at 72yo, he is due for his first annual PSA per urology. He continues to endorse mild LUTS. He is still on an alpha-1 blocker. His repeat PSA has increased from 3.2 to 4.3.

Elevated PSA

Many things can cause an elevated PSA level:

  • Major causes:
    • BPH
    • Prostate cancer
    • Prostatic inflammation/infection
    • Perineal trauma
  • Other causes:
    • Urological interventions (e.g., prostate biopsy, cystoscopy, TURP)
    • Ejaculation
    • Urinary Retention

Helpful hints for testing a subsequent PSA following an elevated finding:

  • If prostatitis: defer repeat testing for 6-8 weeks
  • If acute urinary retention/urethral instrumentation: defer repeat testing for 2 weeks
  • If prostate biopsy/TURP: defer repeat testing for 6 weeks

PSA also increases with age!

Age (years)95th percentile of PSA in Healthy Men
40-492.5 ng/mL
50-593.5
60-694.5
70-796.5

When to refer to urology:

  1. PSA >4.0
  2. Increasing PSA while taking a 5-alpha reductase inhibitor
  3. Abnormal DRE including nodules, induration, and/or asymmetry

Patient returns to urology given continued rise in PSA. Urology team considers 1) rate of rise, 2) age-adjusted PSA range, and 3) exam findings, and ultimately decides to recheck PSA in 3 months.

Guidelines vary for serial PSAs:

  • PSA <0.1: repeat in 2-4 years
  • PSA >0.1: repeat in 1-2 years
  • PSA >4.5: consider repeat testing in 1 month to confirm elevation

As recommended by urology, he undergoes repeat PSA in 3 months (now 72yo), which is 4.3 and stable. LUTS remain stable. Urology recommends to repeat PSA in 6 months then STOP due to age—patient agrees to this plan. Repeat PSA is 4.8, which normal for age (now 73yo). PCP, urology, and patient all agree to stop screening. 18 months later (now 75yo), patient would like an “annual PSA” and re-evaluation with urology. Urology agrees to check “one final PSA”—it is 5.5, which is normal for age. All are in agreement to stop screening. One year later (now 76yo), patient presents to urology clinic for an obstructing stone. Their documentation suggests PSA was not indicated but “an interval PSA”, ordered with unclear indication, is 9.8, which is abnormally high for his age. What will the urologist do?

Urology’s general approach to elevated PSA:

  • Serial PSA, DRE
  • Endorectal MRI
  • Biopsy

Patient undergoes US guided prostate biopsy and is diagnosed with prostate cancer. He begins radiotherapy. His PSA downtrends on serial checks. DRE remains stable on serial examinations. No further workup or management, continues to follow with PCP and Rad-Onc annually.

Patients with prostates who don’t identify as male

The studies behind current cis-male screening guidelines do not include transgender women. Unfortunately, there are no current guidelines on screening for this population.

  • Prostate cancer is hormonally driven
  • Screen per the guidance for cis-men BUT use a lower PSA cutoff of 1 ng/mL

Take-Home Points!

  1. 55-69yo: screen with shared decision-making
  2. 45-55yo: screen if high risk (i.e., BRCA, Lynch syndrome, +family history)
  3. Consider using patient decision-making tools
  4. PSA increases with age!
  5. Refer to urology in the presence of PSA >4, rising PSA on 5-alpha reductase, and/or abnormal DRE
  6. Transgender patients with prostates should undergo routine screening with lower PSA cutoffs

Blog post based on Med-Peds Forum talk by Anu Goel, PGY2, and Maddie Ward, PGY3

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