Prostate Cancer: Screening

See 2018 AUA Guideline Notes on PSA Screening

See 2017 CUA Guideline Notes on PSA Screening

Definition

• WHO Definition of Screening: identification of unrecognized disease in an apparently healthy, asymptomatic population by means of tests, examinations or other procedures that can be applied rapidly and easily to the target population
  • Screening refers to testing for disease in healthy, asymptomatic populations; whereas diagnosis is the identification of disease among individuals with signs or symptoms. The principal goal of screening is to improve overall health outcomes by identifying and treating disease at an earlier stage

Benefits of Prostate Cancer Screening

• Increases detection rates of prostate cancer
• Increases the detection of prostate cancers that are more likely to be organ-confined when compared with detection without the use of PSA.

Evidence on Prostate Cancer Screening

• Randomized controlled trials to date on prostate cancer screening (7):
  1. Stockholm
  2. Norrkoping
  3. Quebec
  4. PLCO (Prostate, Lung, Colorectal, Ovarian, 2008)
  5. ERSPC (European Randomized Study of Screening for Prostate Cancer, 2009)
  6. Goteborg (2010)
  7. CAP (2018)
• Among other design problems, the Stockholm trial screened with only one test and a high cut-off of PSA for biopsy; the Stockholm, Norrkoping and Quebec trials lacked allocation concealment; and the Quebec trial did not report according to intention to screen. As such, 3 (key as per CUA/AUA) most informative randomized trials on prostate cancer screening:
  1. PLCO – NO NET BENEFIT
  2. ERSPC – NET BENEFIT
  3. Goteborg – NET BENEFIT
  • Primary outcome is always cancer-specific mortality

PLCO

• Population: 76,685 US men aged 55-74 from 10 centers
• Randomized to annual screening (PSA annually x 6 years, DRE annually x 4 years) vs. standard care
  • Biopsy recommended If PSA >4.0 or suspicious DRE
• Primary outcome: cancer-specific mortality
• Results:
  • No difference in PC mortality (Rate ratio (RR) 0.93 (95% CI 0.81–1.08) 17-year follow-up)
  • Increased incidence of prostate cancer in screening group (RR 1.05 (95% CI 1.01–1.09) 17-year follow-up)
  • No difference in disease stage
  • No difference in metastasis (RR 0.85 (95% CI 0.67 – 1.06))
  • Higher proportion Gleason 2-6 in screening arm; higher proportion Gleason ≥ 8 in control arm
    • Gleason 2–6: RR 1.17 (95% CI 1.11–1.23)
    • Gleason 7 disease RR 1.00
    • Gleason 8–10 disease RR 0.89 (95% CI 0.80–0.99)
• Criticisms (4):
  1. High rates of contamination (77% as per 2018 AUA early detection prostate cancer guidelines)
  2. High rates of pre-screening
     • In control group at baseline, 34.3% had PSA test once within past 3 years, 9.8% had PSA tests two or more times within past 3 years; 31.9% had DRE once within past 3 years, 22.0% had DRE two or more times within past 3 years
     • After 1995, trial implemented exclusion criteria of more than one PSA test within last 3 years§
  3. High rates of lLack of adherence to diagnostic biopsies among patients with abnormal screening results in the screening arm
  4. Underpowered to detect mortality benefit
• Andriole, Gerald L., et al. "Mortality results from a randomized prostate-cancer screening trial." New England Journal of Medicine 360.13 (2009): 1310-1319.
• Pinsky, Paul F., et al. "Extended follow‐up for prostate cancer incidence and mortality among participants in the Prostate, Lung, Colorectal and Ovarian randomized cancer screening trial." BJU international 123.5 (2019): 854-860.

European Randomized study of Screening for Prostate Cancer (ERSPC)

• Population: 162,243 males aged 55-69 (almost twice the size of PLCO) from 8 European countries; collection of trials conducted, some differences between individual trials
• Randomized to screening every 4 years (PSA in most centres; some centres offered DRE) vs. standard care
• Primary outcome: prostate cancer-specific mortality
• Results (2019 results):
  • PC mortality: RR 0.80 (0.72–0.89)
    • Number needed to invite (NNI) to screening to prevent one prostate cancer death: 570
    • Number needed to diagnose (NND) to prevent one prostate cancer death: 18
    • Estimated that annual screening of men in the ERSPC aged 55 to 69 years would result in a 28% reduction in prostate cancer deaths (37% in those actually screened). The estimated number needed to screen to prevent one prostate cancer death was 98, and the number of cancers needed to be detected was 5
  • Incidence: RR 1.41 (1.36–1.45)
• Lower rate (≈20-25%) of contamination
• Schröder, Fritz H., et al. "Screening and prostate-cancer mortality in a randomized European study." New England Journal of Medicine 360.13 (2009): 1320-1328.
• Hugosson, Jonas, et al. "A 16-yr Follow-up of the European Randomized study of Screening for Prostate Cancer." European urology 76.1 (2019): 43-51.
• Subgoup analysis
  • Population: 7,052 males aged 70-74 at their last screening visit after a maximum of 3 consecutive screening rounds and who had completed screening without a PCa diagnosis.
  • Primary outcome: cumulative incidence of prostate cancer-specific mortality by the age of 85
  • Results
    • 324 males diagnosed with prostate cancer, after a median time period between last screening visit and diagnosis of 7 years
    • 107 males found to have metastasis
    • 81 males died of disease
    • Cumulative incidence of prostate cancer-specific survival by the age of 85 was 0.54%
      • Cumulative incidence higher in patients with higher PSA or no previous biopsy
  • de Vos, Ivo I., et al. "Prostate Cancer Mortality Among Elderly Men After Discontinuing Organised Screening: Long-term Results from the European Randomized Study of Screening for Prostate Cancer Rotterdam." European Urology 85.1 (2024): 74-81.

Goteburg

• Population: 20,000 men aged 50-64 from Sweden
  • Was included in ERSPC but was independently designed, initiated and reported separately from ERSPC. 60% of participants were included in ERSPC.
• Randomized screening every 2 years (PSA) vs. control
  • Men with PSA at or above threshold (3.4 ng/ml between 1995 and 1998, 2.9 ng/ml between 1999 and 2004, and 2.5 ng/ml after 2004 (lower than others)) were invited for clinical follow-up with DRE, transrectal ultrasound and laterally directed sextant biopsies
  • Only 3% screening of controls; 93% complied with a biopsy recommendation
• Primary outcome: prostate cancer-specific mortality
• Results:
  • PC mortality: RR 0.65 (95% CI 0.49–0.87) 18-year follow-up
    • NNI: 231
    • NND: 10
  • Incidence: RR 1.51 (1.39–1.64)
  • 41% fewer advanced cases at diagnosis in the screening arm
• Hugosson, Jonas, et al. "Mortality results from the Göteborg randomised population-based prostate-cancer screening trial." The lancet oncology 11.8 (2010): 725-732.
• Hugosson, Jonas, et al. "Eighteen-year follow-up of the Göteborg Randomized Population-based Prostate Cancer Screening Trial: effect of sociodemographic variables on participation, prostate cancer incidence and mortality." Scandinavian journal of urology 52.1 (2018): 27-37.

There was contamination in the control arms for both ERSPC and Gotteburg trials but significantly lower than PLCO.

CAP

• Population: 415,357 men aged 50-69 years from 573 primary care practices across the United Kingdom
• Randomized to an invitation to attend a PSA testing clinic and receive a single PSA test vs standard (unscreened) practice
  • Males diagnosed with cancer were then offered inclusion in the ProtecT (Prostate Testing for Cancer and Treatment) trial, in which they were randomized to monitoring, surgery or radiation, regardless of risk stratum.
• Primary outcome: prostate cancer-specific mortality
• Results
  • PC mortality:
    • Median follow-up 10 years: RR 0.93 (0.67 to 1.29)
    • Median follow-up 15 years: RR 0.92 (0.85 to 0.99)
      • Absolute risk difference 0.09% (0.69% intervention vs. 0.78% control)
  • Overall survival:
    • Median follow-up 15 years: RR 0.97 (0.94 to 1.01)
  • Detection of low-risk prostate cancer cases increased
• Criticisms:
  • High nonadherence rate with the intervention
  • Modest contamination in the controls
  • Inadequate follow-up to truly assess mortality
• Martin, Richard M., et al. "Effect of a low-intensity PSA-based screening intervention on prostate cancer mortality: the CAP randomized clinical trial." Jama 319.9 (2018): 883-895.
• Martin, Richard M., et al. "Prostate-specific antigen screening and 15-year prostate cancer mortality: a secondary analysis of the CAP randomized clinical trial." JAMA (2024).

Number Needed to Invite for Screening

• Other cancers
  • Colorectal cancer
    • FOBT: 900
    • Flexible sigmoidoscopy: 450
  • Breast cancer
    • Mammography (2016 USPSTF recommendations: grade C age 40-49; grade B age 50-74)
      • Age 39-49: 1904
      • Age 50-59: 1339
      • Age 60-69: 377
  • Prostate cancer
    • ERSPC: 570
    • Goteborg: 231
    • CAP: 1111

US Preventive Services Task Force Recommendations

• 1996
  • All men: grade I: current evidence is insufficient to assess the balance of benefits and harms
• 2002
  • All men: grade I: current evidence is insufficient to assess the balance of benefits and harms
• 2008
  • Men age <75: grade I:: current evidence is insufficient to assess the balance of benefits and harms
  • Men age ≥75: grade D: recommends against; there is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits
• 2012
  • All men: grade D: recommends against; there is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits
• 2018 (current)
  • Men aged 55-69: grade C: recommends selectively offering or providing the service to individual patients based on professional judgement and patient preferences; here is at least moderate certainty that the net benefit is small.
  • Men aged ≥70: grade D: recommends against; there is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits

When to Start Screening

AUA

• 2023 AUA Guideline Notes on PSA Screening
  • If age < 40, PSA screening is NOT recommended
  • If age > 40 and < 45
    • Offer screening if at increased risk of developing prostate cancer based on (3):
      1. Black ancestry
      2. Germline mutations (BRCA, Lynch Syndrome)
      3. "Strong" family history of prostate cancer
         1. Criteria for "strong" family history (2):[1]
            1. ≥1 brother or father OR ≥2 male relatives with one of the following (3):
               1. Diagnosed with prostate cancer at age <60 years
               2. Any of whom died of prostate cancer
               3. Any of whom had metastatic prostate cancer.
            2. Family history of other cancers with ≥2 cancers in hereditary breast and ovarian cancer syndrome or Lynch syndrome spectrum.
               • See associated cancers in Prostate Cancer: Epidemiology and Pathogenesis Chapter Notes
         2. Patients with a "strong" family history should ideally be genotyped[2]
  • If age >45-50, may begin prostate cancer screening and offer a baseline PSA test
    • Change from 2018 guidelines which recommended screening if age 55-69
      • The 2023 guidelines describe that earlier initiation of screening is supported by observational studies that have demonstrated a prognostic value of obtaining a baseline PSA in early midlife
      • The randomized trials that demonstrate a benefit for prostate cancer screening (Goteborg-1 and ERSPC) began at ages 50 and 55 years, respectively.
    • No randomized evidence showing a benefit to initiation of routine screening for prostate cancer before 45 years of age.
• Historical
  • 2018 AUA Guideline Notes on PSA Screening
    • If age < 40, PSA screening is NOT recommended
    • If age ≥ 40 and < 55
      • Consider screening if risk factors present, including:
        • African American race
        • Family history of metastatic or lethal adenocarcinomas (e.g., prostate, male and female breast cancer, ovarian, pancreatic) spanning multiple generations, affecting multiple first-degree relatives, and that developed at younger ages (age < 55)
      • Else, PSA screening is NOT recommended
      • However, neither is screening is explicitly actively discouraged in these men
    • If age ≥ 55 and ≤  69, PSA screening is recommended (after shared-decision making)

NCCN

• 2024 NCCN Guidelines[3]
  • If age < 40, PSA screening is NOT recommended
  • If age ≥ 40 and < 45
    • Consider screening if risk factors (same as AUA, see above) present
    • Else, PSA screening is NOT recommended
  • If age ≥ 45 and ≤ 75, PSA screening is recommended (after shared-decision making)

Frequency of Screening/Discontinuing Screening

AUA

• 2023 AUA Guideline Notes on PSA Screening
  • Offer regular prostate cancer screening every 2 to 4 years to people aged 50 to 69 years.
  • May personalize the re-screening interval, or decide to discontinue screening, following SDM, based on
    • Prostate cancer risk
      • If at increased risk of developing prostate cancer, based on Black ancestry, germline mutations, or strong family history, consider screening more frequently
    • PSA
      • If age 45-70 and
        • PSA 1-3 ng/mL, re-screening interval can be 1-4 years
        • PSA < 1 ng/mL, re-screening interval can be prolonged
      • If age 60 and PSA < 1 ng/mL (age-specific median), reasonable to significantly lengthen the re-screening interval or discontinue screening, based on SDM, provided there are no other risk factors, such as strong family history of prostate cancer
      • The Panel notes most studies regarding baseline PSA have been conducted in populations of primarily White patients.
        • The Southern Community Cohort Study (100% Black patients) showed that PSA levels in midlife were similar to those among White controls in prior studies and were strongly associated with risk of aggressive prostate cancer.
    • Age
      • If age age ≥75 and PSA is < 3 ng/mL, may discontinue or substantially lengthen the re-screening interval for patients.
    • Life expectancy
      • In select patients who are very healthy with an estimated life expectancy of at ≥10 years, ongoing screening every 2-4 years is reasonable
      • For patients with < 10 year estimated life expectancy, screening is not likely to provide a benefit in terms of disease-specific or overall mortality.
        • Based on current Social Security Administration (SSA) data, American men older than 77 years of age have less than a 10-year life expectancy.
      • Risk calculators have been developed to estimate a patient’s life expectancy
        • For the purpose of estimating life expectancy, the use of these tools is likely more reliable than individual clinician judgment.
        • Life expectancy risk calculators
          • US Social Security Administration
          • Memorial Sloan Ketettering Cancer Center Male Life Expectancy Survey
          • Cambridge Prognostic Groups
    • General health
    • Patient preference
• Historical
  • 2018 AUA Guideline Notes on PSA Screening
    • Frequency
      • Every 2 years or more
        • Intervals for rescreening can be individualized by a baseline PSA level
    • Discontinuing
      • If life expectancy <10-15 years OR age > 70
        • Select males age > 70 who are in excellent health may benefit from PSA screening

NCCN

• 2024 NCCN Guidelines[4]
  • Frequency
    • If average risk
      • PSA <1 ng/mL, repeat testing every 2 to 4 years
      • PSA 1-3 ng/mL, repeat testing every 1 to 2 years
        • Use clinical judgement
          • Younger individual on the higher end of PSA (eg, a 45-year-old with PSA 0.9 ng/mL) might be screened in 2 years, whereas an older individual with a lower PSA might be screened in 4 years
    • If high risk
      • PSA ≤ 3 ng/mL, repeat testing every 1 to 2 years
    • If age >75 and undergoing screening
      • If PSA < 4 ng/mL, normal DRE, and no other indications for biopsy: repeat testing every 1-2 years, but only in very healthy individuals
      • If PSA >4 ng/ml OR very abnormal DRE, consider biopsy (+/- pre-biopsy MRI)
  • Discontinuing
    • If life expectancy < 10 years OR age > 75
      • Continuing screening beyond age 75 years should be performed only with caution in very healthy patients with little to no comorbidity

Questions

1. Describe the 3 key trials in prostate cancer screening?
2. List 3 limitations in interpreting the findings of the PLCO trial
3. What was the primary outcome in the PLCO, ERSPC, and Goteborg trials?

Answers

1. Describe the 3 key trials in prostate cancer screening?
   1. PLCO
   2. ERSPC
   3. Goteborg
2. List 3 limitations in interpreting the findings of the PLCO trial
3. What was the primary outcome in the PLCO, ERSPC, and Goteborg trials?
   1. Cancer-specific mortality

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 111
• Wei, John T., et al. "Early detection of prostate cancer: AUA/SUO guideline part I: prostate cancer screening." Journal of Urology 210.1 (2023): 46-53.
• Wei, John T., et al. "Early detection of prostate cancer: AUA/SUO guideline part II: considerations for a prostate biopsy." Journal of Urology 210.1 (2023): 54-63.