ERSPC

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Schröder FH, et al. "Screening and Prostate-Cancer Mortality in a Randomized European Study". The New England Journal of Medicine. 2009. 360(13):1320-1328.
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Clinical Question

In males ages 50-74, does Prostate Specific Antigen (PSA) screening every 4 years reduce the risk of death from prostate cancer?

Bottom Line

While PSA screening every 4 years does decrease the rate of death from prostate cancer, this needs to be balanced against the number of people needing to be screened and overdiagnosis.

Major Points

The first Prostate Specific Antigen (PSA) test was released in 1986 and approved by the FDA in 1994 in conjunction with digital rectal examination to test asymptomatic men for prostate cancer.[1] Initially, many organizations recommended yearly screening for prostate cancer in men over the age of 50. The optimal screening interval or even the need for screening was unknown though, and so multiple large clinical trials including European Randomized Study of Screening for Prostate Cancer (ERSPC) and the Prostate, Lung, Colon, and Ovarian (PLCO) Cancer Screening Trial were initiated to look at the benefits vs. risks of PSA screening.

The ERSPC trial was a randomized, controlled, multicenter trial enrolling 182,000 European men between the ages of 50-74 with a predefined core age of 55-69 years old. The study opened in 1991 and data for this paper was collected through 2006. Patients were randomized to a screening group with a screening interval of 4 years or a control group. A PSA cutoff of 3.0 ng/mL was used as an indication for biopsy. Primary outcome was the rate of death from prostate cancer.

Since this was a large study done in multiple countries, there were some differences in methods between each country. First, half the countries used randomization before consent, while the other half randomized after consent. Second, Sweden (who contributed 7% of the study population) used a 2-year screening interval instead of 4 years. Third, there were variations in the PSA cutoff. Finland used a PSA of 4 ng/mL with patients who were between 3 and 4 undergoing ancillary testing. Italy was similar except using 2.5 ng/mL as a cutoff for ancillary testing.

PSA screening was associated with increased detection of prostate cancer (8.2% vs. 4.8%) with a cumulative increased incidence of 34 new diagnoses per 1000 men. This led to a statistically significant difference in prostate cancer mortality with an adjusted rate ratio of 0.80 (95% CI, 0.65-0.98; P=0.04). While significant, this translated to an absolute difference of 0.71 prostate cancer deaths per 1000 men. In order to prevent one cancer death, 1410 men would need an average of 1.7 screening visits during a 9-year period, and 48 additional subjects would need to be treated to prevent one death from prostate cancer.

Ever since its approval, PSA has been a controversial test as evidenced by the evolution of the USPSTF guidelines with both the 2002 and 2008 versions citing insufficient evidence to assess the balance of benefits and harms of screening men younger than 75.[2] While ERSPC looked at PSA screening every 4 years instead of yearly, it did provide data on harms and benefits of prostate cancer screening. Despite showing a benefit in prostate cancer mortality, the rate of overdiagnosis of likely asymptomatic prostate cancer and harm with subsequent treatment was concerning enough that along with data from the PLCO trial, this led to the 2012 USPSTF recommendation against PSA screening altogether.[3]

Guidelines

USPSTF prostate cancer screening (2012)[3]

  • Do not use prostate specific antigen-based screening for prostate cancer. (Grade D)

Design

  • Multicenter, randomized, controlled trial
  • N=182,160
    • Screening (n=82,816)
    • Control (n=99,184)
  • Setting: 7 countries (Netherlands, Belgium, Sweden, Finland, Italy, Spain, Switzerland)
  • Enrollment: 1991-2003
  • Mean follow-up: 8.8 years
  • Analysis: Intention-to-treat
  • Primary outcome: Prostate cancer mortality

Population

Inclusion Criteria

  • Males age 50-74 years

Exclusion Criteria

  • Previous diagnosis of prostate cancer
  • No exclusion based on disabling disease

Baseline Characteristics

  • Age: 61 years
  • ≥1 screening: 82%
  • Interval for screening: 2-7 years (most countries screened at 4 year intervals)
  • Positive PSA tests: 16%
    • Percent of these who underwent biopsy: 86%

Interventions

  • Participants randomized to PSA screening every 4 years or no screening
    • Exceptions:
    • Sweden - 2 years
    • Belgium - 4-7 years
  • Biopsy with PSA >3.0 ng/mL
    • Exceptions:
    • Finland - Biopsy for PSA >4.0 ng/mL, 3-3.9 ng/mL underwent DRE until 1998 and subsequently ratio of free PSA to total PSA
    • Italy - Biopsy for PSA >4.0 ng/mL, 2.5-3.9 ng/mL underwent either DRE or transrectal ultrasonography
  • Prostate cancer treatment per local policies and guidelines

Outcomes

Comparison of screened vs. control. P-Y is person-years.

Primary Outcome

Prostate cancer mortality, all and by age at randomization
0.35 vs. 0.41/1000 P-Y (RR 0.85; 95% CI 0.73-1.00; number needed to screen 1410)
50-54 yr: 0.11 vs. 0.07/1000 P-Y (RR 1.47; 95% CI 0.41-5.19)
55-59 yr: 0.19 vs. 0.25/1000 P-Y (RR 0.73; 95% CI 0.53-1.00)
60-64 yr: 0.40 vs. 0.43/1000 P-Y (RR 0.94; 95% CI 0.69-1.27)
65-69 yr: 0.58 vs. 0.79/1000 P-Y (RR 0.74; 95% CI 0.56-0.99)
70-74 yr: 1.06 vs. 0.84/1000 P-Y (RR 1.26; 95% CI 0.80-1.99)

Additional Outcomes

  • Incidence of Prostate Cancer: 8.2% vs. 4.8%
  • Positive Predictive Value of Biopsy: 24.1%

Adverse Events

  • No deaths were reported as direct complications associated with biopsy procedure.
  • Harm from prostate cancer treatment and quality of life were assessed at 2 year intervals but were not reported in this study.

Criticisms

  • The mortality benefit was evident after 7-8 years (see the Kaplan-Meier plot in Figure 2 on pg 1325) which suggests longer follow-up would lead to improved mortality benefit. This has been noted with 2013 follow-up data from the ERSPC trial which showed the NNS decreased to 781 and NNT decreased to 27.[4]
  • The European population was not as quick to adopt PSA screening as the US, and so there were fewer people that had been screened prior study participation which decreases the study results to all developed countries.
  • The choice of 4 years screening was based on prostate cancer lead time of 5 to 10 years.
  • Variations in methodology between countries.

Funding

  • Unconditional grants from Beckman Coulter who were the manufacturers of the PSA screening assay
  • Europe against Cancer
  • Each center was responsible for its own source of funding.
    • France - Major funding by URCAM (Union régionale des caisses d’assurance maladie) Languedoc Roussillon(FAQSV 2002) and Midi Pyrénées (FAQSV 2002). Other fundings by Association Française d’Urologie (AFU), CHU of Toulouse (AOL 1998-20-L, AOL 2001), Ligue départementale contre le Cancer de l’Hérault and Association pour la Recherche sur les Tumeurs Prostatiques (ARTP).

Further Reading

<references> [3] [4]