JNCI Journal of the National Cancer Institute JANUARY 06, 2012

Prostate Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: Mortality Results after 13 Years of Follow-up

Gerald L. Andriole, E. David Crawford, Robert L. Grubb, et al.

Bottom Line

After 13 years of follow-up in the PLCO trial, organized annual screening with PSA testing and digital rectal examination did not reduce prostate cancer mortality compared to opportunistic screening in usual care, despite significantly increasing the incidence of prostate cancer diagnoses.

Key Findings

1. At 13 years, cumulative incidence rates for prostate cancer were 108.4 per 10,000 person-years in the intervention arm (4,250 cases) compared to 97.1 per 10,000 person-years in the control arm (3,815 cases), representing a 12% relative increase in the screening group (RR = 1.12, 95% CI = 1.07 to 1.17).

2. Cumulative prostate cancer mortality rates at 13 years were 3.7 deaths per 10,000 person-years in the intervention arm versus 3.4 deaths per 10,000 person-years in the control arm.

3. There was no statistically significant difference in prostate cancer mortality between the organized screening and control arms (RR = 1.09, 95% CI = 0.87 to 1.36).

4. No statistically significant interactions regarding prostate cancer mortality were observed between the trial arm and age (P = 0.81), pretrial PSA testing (P = 0.52), or baseline comorbidity (P = 0.68).

Study Design

Design

RCT

Open-Label

Sample

76,685

Patients

Duration

13 yr

Median

Setting

10 US screening centers

Population Men aged 55-74 years without a prior history of prostate cancer

Intervention Organized screening consisting of annual serum PSA testing for 6 years and annual digital rectal examination (DRE) for 4 years

Comparator Usual care (control), which sometimes included opportunistic screening

Outcome Prostate cancer mortality and incident prostate cancers through 13 years of follow-up (or through December 31, 2009)

Study Limitations

• High rate of 'contamination' in the control group, as a large proportion of men in the usual care arm received opportunistic PSA testing, potentially masking a true screening benefit.

• Follow-up of 13 years may still be insufficient to capture the full, long-term mortality benefit of screening for a slow-progressing disease like prostate cancer.

• Approximately 92% of study participants were followed to 10 years, but only 57% were followed to 13 years at the time of this analysis.

• The trial heavily represents a US population with widespread, off-protocol access to PSA testing, limiting its generalizability to unscreened populations globally.

Clinical Significance

The 13-year PLCO results robustly demonstrated that routine, organized annual PSA screening offers no mortality benefit over opportunistic usual care in the United States. By showing an increase in prostate cancer diagnoses (overdiagnosis) without a concomitant drop in disease-specific deaths, this paper provided pivotal evidence that led to the 2012 USPSTF recommendation against routine population-based PSA screening, profoundly changing modern urological and primary care practices toward shared decision-making.

Historical Context

The PLCO trial was launched in the early 1990s to rigorously test whether organized screening reduced cancer-specific mortality. Initial 7-to-10-year results published in 2009 showed no prostate cancer mortality benefit. This 13-year follow-up, published in 2012, reaffirmed the absence of a survival advantage, contrasting with the concurrent European ERSPC trial (which showed a modest mortality reduction but high overdiagnosis in a population with less opportunistic screening). Together, these trials sparked intense global debate over the value and harms of PSA screening.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What are the physiological roles of prostate-specific antigen (PSA), and how do factors other than prostate cancer contribute to false-positive screening results?

Key Response

PSA is a glycoprotein enzyme (kallikrein-3) produced by the prostate gland to liquefy semen. Its levels can be elevated by benign prostatic hyperplasia (BPH), prostatitis, recent ejaculation, or urinary tract instrumentation. Understanding this is crucial because it explains the low specificity of PSA for cancer, leading to the high rates of false positives and potential overdiagnosis seen in trials like PLCO.

Resident

How should the PLCO finding that organized PSA screening did not reduce prostate cancer mortality but significantly increased cancer incidence alter your approach to shared decision-making with a healthy 60-year-old male?

Key Response

Residents must grasp that PSA screening increases the diagnosis of clinically insignificant cancers (overdiagnosis) without a clear, robust survival benefit in a heavily screened population. Counseling must explicitly weigh the risks of downstream complications, such as incontinence and impotence from biopsies and definitive treatments, against an uncertain mortality benefit.

Fellow

The PLCO trial showed no mortality benefit, whereas the European Randomized Study of Screening for Prostate Cancer (ERSPC) demonstrated a relative risk reduction in prostate cancer mortality. How do differences in control group contamination and pre-trial screening between these cohorts explain these conflicting results?

Key Response

The PLCO control group had a high rate of opportunistic PSA screening (contamination over 70%), essentially comparing organized versus opportunistic screening. Furthermore, nearly half of PLCO participants had pre-trial PSA tests, removing prevalent cancers. ERSPC had much lower contamination, reflecting a truer 'screening versus no screening' comparison, which underscores the importance of baseline trial methodology in evidence interpretation.

Attending

Given the PLCO trial's demonstration of massive overdiagnosis without mortality benefit, how should clinical practice evolve to mitigate overtreatment while still capturing lethal prostate cancer phenotypes?

Key Response

This finding mandates a paradigm shift away from reflex treatment and toward active surveillance for low-risk disease (e.g., Gleason grade group 1). It also highlights the need for secondary risk-stratification tools, such as multiparametric MRI, PSA density, and genomic classifiers, to refine biopsy decisions and focus aggressive therapy only on those with biologically significant disease.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

How does the high rate of control group contamination in the PLCO trial mathematically attenuate the hazard ratio for prostate cancer mortality in an intent-to-treat analysis, and what alternative causal inference models could estimate the true efficacy of screening?

Key Response

In an intent-to-treat framework, massive control group contamination biases the hazard ratio heavily towards the null hypothesis. Methodologists might utilize instrumental variable (IV) analysis or complier average causal effect (CACE) models to adjust for actual screening exposure, thereby recovering an estimate of the true biological efficacy of the screening intervention rather than just the programmatic assignment.

Journal Editor

As a peer reviewer, how would you critique the authors' conclusion that screening 'does not reduce prostate cancer mortality' in light of the severe statistical underpowering caused by pre-trial and out-of-protocol PSA testing?

Key Response

A critical reviewer would flag that the combination of weeding out prevalent cancers before randomization and massive in-trial screening of the control arm severely dilutes the study's power. The editorial concern is whether the definitive phrasing of the conclusion is justified, or if the results merely indicate that the trial was ultimately inconclusive due to fatal methodological compromises in the usual care arm.

Guideline Committee

Based on the PLCO 13-year data indicating significant harms from overdiagnosis and contrasting ERSPC data showing modest benefit, how should the USPSTF grade the recommendation for routine PSA screening in men aged 55 to 69?

Key Response

The PLCO trial heavily influenced the USPSTF's temporary 'D' rating in 2012, which was later revised to a 'C' recommendation (individualized decision-making) for men 55-69 in 2018. Guidelines must balance the modest mortality benefit seen in ERSPC against the PLCO's clear evidence of systemic harms (overdiagnosis and overtreatment), thereby mandating shared decision-making over blanket population-based screening mandates.

Clinical Landscape

Noteworthy Related Trials

2009

ERSPC Trial

n = 162,243 · NEJM

Tested

PSA-based screening

Population

Men aged 55 to 69 years

Comparator

No screening

Endpoint

Prostate cancer-specific mortality

Key result: PSA screening reduced prostate cancer mortality by 20 percent but was associated with a high risk of overdiagnosis.

2012

PIVOT Trial

n = 731 · NEJM

Tested

Radical prostatectomy

Population

Men with localized prostate cancer

Comparator

Observation

Endpoint

All-cause mortality

Key result: Among men with localized prostate cancer, radical prostatectomy did not significantly reduce all-cause or prostate-cancer-specific mortality compared with observation.

2016

ProtecT Trial

n = 1,643 · NEJM

Tested

Active monitoring, radical prostatectomy, or radiotherapy

Population

Men with localized prostate cancer detected by PSA screening

Comparator

Head-to-head comparison of three management strategies

Endpoint

Prostate-cancer-specific mortality at 10 years

Key result: Prostate-cancer-specific mortality was very low and did not differ significantly among active monitoring, surgery, or radiotherapy at 10 years.

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