Prostate Cancer Screening

Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is around 11%, and the lifetime risk of dying from this condition is 2.5%. Prostate cancer is a slow-growing cancer that takes years (even decades) to develop into advanced disease, and many men remain asymptomatic and die from other medical conditions. The preferred method of screening is with prostate-specific antigen (PSA) testing. Conditions such as prostatitis and benign prostatic hyperplasia are also associated with elevated PSA levels. Thus, confirmation of the diagnosis may be pursued through prostate biopsy, which carries risks. The current recommendation is for the patient and clinician to have a discussion about the risks and benefits, and to assess the patient’s risk for prostate cancer. Factors considered in the discussion include the patient’s age, life expectancy, family history, comorbid conditions, and individual values about screening and management-associated consequences.

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Overview

Prostate cancer

  • Cancer of the prostate gland
  • Adenocarcinoma accounts for > 90% of cases.

Epidemiology

  • Worldwide:
    • 2nd most common cancer diagnosis in men
    • > 1.3 million cases diagnosed annually
  • In the United States:
    • 3rd leading cause of cancer in men
    • Approximately 192,000 cases diagnosed annually
    • Lifetime risk of a prostate cancer diagnosis is 11%.
    • Lifetime risk of dying from prostate cancer is 2.5%.
  • 5-year survival after diagnosis:
    • Localized disease or regional spread: nearly 100%
    • Distant metastatic disease: 31%

Risk factors

Inherent factors (major factors):

  • Age
    • Rare before 40 years of age
    • Peaks between 65 and 74 years of age
  • More common, and earlier onset, in African Americans
  • Family history of prostate cancer, particularly in 1st-degree relatives who were diagnosed at < 65 years of age
  • Family history of other heritable cancers
    • Breast cancer, BRCA1 and BRCA2 gene mutations
    • Melanoma
    • Colorectal cancer, Lynch syndrome
    • Ovarian cancer
    • Pancreatic cancer

Medical factors:

  • Obesity
  • 5-alpha reductase inhibitors (e.g., finasteride)
    • ↓ prostate-specific antigen (PSA) levels
    • ↑ high-grade prostate cancer risk
  • Trichomonas vaginalis infection

Social and environmental factors:

  • High-fat, low-vegetable diet
  • Cigarette smoking
  • Exposure to Agent Orange
    • Herbicide and defoliant chemical used during the Vietnam War between 1965 and 1972
    • Associated with more aggressive cancer
  • Exposure to chlordecone 
    • Insecticide used between 1973 and 2003 in the Caribbean
    • Binds estrogen receptors, which may contribute to malignancy development

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Screening Rationale

Individualized screening

  • Screening offers a small potential benefit in reducing the chance of death from prostate cancer. 
  • The potential benefit will take many years, even decades, while the harms take place soon after screening starts.
  • Prostate cancer often has a slow growth rate, in which:
    • Half of cases do not present clinically.
    • Patients frequently die from other medical conditions.
  • Each patient is encouraged to decide on the potential benefits and harms discussed based on his own values.

Benefits of screening

  • Goals:
    • Identify high-risk, localized prostate cancer that can be successfully treated 
    • Prevent prostate cancer-related morbidity and mortality, including advanced or metastatic disease
  • Benefits of PSA-based screening:
    • In men aged 55–69 years, screening may prevent 1.3 deaths from prostate cancer per 1,000 men screened over 13 years.
    • Screening may prevent 3 cases of metastatic prostate cancer per 1,000 men.
    • However, trials have not shown a reduction in all-cause mortality.

Risks of screening

  • Harms of screening: 
    • Frequent false-positive results
    • Leads to over-diagnosis (cancer diagnosed in men who otherwise would not have symptomatic cancer in their lifetime)
  • Potential harms of diagnostic biopsy:
    • Pain
    • Infection
    • Rectal bleeding
    • Urinary obstruction
    • Psychological harm
  • Potential harms of cancer management:
    • Erectile dysfunction (up to 50% of patients)
    • Urinary incontinence
    • Bowel dysfunction
    • Psychological harm 

Screening Recommendations

United States Preventive Service Task Force (USPSTF)

  • Men aged 55–69 years should: 
    • Discuss potential benefits and harms with their clinician
    • Consider age, family history, race/ethnicity, comorbid conditions, and life expectancy
    • Make an individual decision about screening
  • Men ≥ 70 years: 
    • Benefits do not outweigh the expected harms.
    • Should not be routinely screened for prostate cancer
  • Men who do not express a preference for screening should not be screened.

American Cancer Society

  • Screening should not take place without a discussion about the harms and benefits. 
  • This discussion should occur at:
    • 50 years of age for men with an average risk of prostate cancer and life expectancy ≥ 10 years
    • 45 years of age for men with a high risk of prostate cancer (African Americans and those with a 1st-degree relative diagnosed with prostate cancer at < 65 years)
    • 40 years of age for men with a higher risk (> 1 1st-degree relative who had prostate cancer at < 65 years)

Screening Strategy: PSA

Prostate-specific antigen is currently the only recommended screening method for prostate cancer.

Background

  • A protein produced by normal and neoplastic prostate cells
  • In healthy individuals, a small proportion will enter the bloodstream.

Causes of elevated serum PSA in prostate cancer

  • An increased number of cells producing PSA, despite the fact that malignant cells generally make less PSA
  • Disruption in the normal architecture and basement membrane, allowing a higher proportion of PSA to enter the bloodstream

Interpretation of results

  • There is no perfect PSA cut-off value that avoids all false positives or all false negatives.
    • False-positive rate: approximately 70%
      • Benign causes of elevated PSA levels (contributing to false-positive rate)
        • Benign prostatic hyperplasia
        • Prostatitis 
        • Urinary retention
        • Urologic procedures (cystoscopy, transurethral resection of the prostate)
    • False-negative rate: approximately 15%
  • Positive: PSA ≥ 4 ng/mL
    • Most widely accepted standard, which tries to balance the trade-offs between sensitivity and specificity
    • Test characteristics at this cut-off level:
      • For detection of any prostate cancer: sensitivity = 21%; specificity = 91% 
      • For detection of high-grade cancer: sensitivity = 51%
    • Different cut-off levels for decision-making: age-specific reference ranges since PSA levels tend to increase with age
  • Negative: PSA < 4 ng/mL
    • Follow-up is needed
    • For patients on a 5-alpha reductase inhibitor (ARI):
      • Correction factor must be applied for accurate interpretation since ARIs lower PSA values.
      • If there is an increase in PSA level, they should be referred to urology.

Follow-up

  • Retesting should be performed every 1–2 years if the level is < 4 ng/mL.
    • Interval recommendations vary between organizations. 
    • Can be individualized based on PSA level and the patient’s risk factors
  • Consider repeat testing in 6–8 weeks if the level is between 4 and 7 ng/mL to rule out benign causes.
    • If the PSA is still elevated, or > 7 ng/mL on the initial screen, refer to urology. 
    • Further urologic workup can include:
      • Free:total (f/t) PSA ratio (f/t PSA < 10%–15% suggests cancer)
      • PSA density (ratio of PSA level to prostate volume measured on transrectal ultrasound)
      • Molecular and genomic analysis
      • Magnetic resonance imaging (MRI) of the prostate
      • Prostate biopsy

Screening Strategy: Digital Rectal Examination

  • No longer recommended for asymptomatic patients
  • Low sensitivity and specificity
  • Does not provide additional information to a PSA test

References

  1. American Cancer Society (2019). Recommendations for Prostate Cancer Early Detection. https://www.cancer.org/cancer/prostate-cancer/detection-diagnosis-staging/acs-recommendations.html
  2. United States Preventive Services Task Force (2018). Prostate Cancer: Screening. https://www.uspreventiveservicestaskforce.org/uspstf/announcements/final-recommendation-statement-screening-prostate-cancer
  3. Jahn, J., Giovannucci, E., Stampfer, M. (2015). The High Prevalence of Undiagnosed Prostate Cancer at Autopsy: Implications for Epidemiology and Treatment of Prostate Cancer in the Prostate-Specific Antigen-Era. Int J Cancer, 137(12): 2795–2802.
  4. Hoffman, R.M. (2020). Screening for prostate cancer. UpToDate. Retrieved December 20, 2020, from https://www.uptodate.com/contents/screening-for-prostate-cancer
  5. Sartor, A.O. (2020). Risk factors for prostate cancer. UpToDate. Retrieved December 20, 2020, from https://www.uptodate.com/contents/risk-factors-for-prostate-cancer
  6. Mark, J.R. (2019). Prostate cancer. MSD Manual Professional Version. https://www.msdmanuals.com/professional/genitourinary-disorders/genitourinary-cancer/prostate-cancer
  7. Tracy, C.R., Brooks, N.A., and Said, M. (2020). Prostate cancer. Medscape. https://emedicine.medscape.com/article/1967731-overview

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