Prostate Cancer Screening

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

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