The impact of PLCO control arm contamination on perceived PSA screening efficacy

Abstract

Purpose: To quantify the extent to which a clinically significant prostate cancer mortality reduction due to screening could have been masked by control arm screening (contamination) in the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial.

Methods: We used three independently developed models of prostate cancer natural history to conduct a virtual PLCO trial. Simulated participants underwent pre-trial screening based on population patterns. The intervention arm followed observed compliance during the trial then resumed population screening. A contaminated control arm followed observed contamination during the trial then resumed population screening, while an uncontaminated control arm discontinued screening upon entry. We assumed a clinically significant screening benefit, applied population treatments and survival patterns, and calculated mortality rate ratios relative to the contaminated and uncontaminated control arms.

Results: The virtual trial reproduced observed incidence, including stage and grade distributions, and control arm mortality after 10 years of complete follow-up. Under the assumed screening benefit, the three models found that contamination increased the mortality rate ratio from 0.68-0.77 to 0.86-0.91, increased the chance of excess mortality in the intervention arm from 0-4 % to 15-28 %, and decreased the power of the trial to detect a mortality difference from 40-70 % to 9-25 %.

Conclusions: Our computer simulation models indicate that contamination substantially limited the ability of the PLCO to identify a clinically significant screening benefit. While the trial shows annual screening does not reduce mortality relative to population screening, contamination prevents concluding whether screening reduces mortality relative to no screening.

Conflict of interest statement

CONFLICT OF INTEREST

HJK received partial funding from Beckman Coulter to evaluate cost-effectiveness of the prostate health index. All other authors declare that they have no conflict of interest.

Figures

Fig 1. Percent of men in each arm of the virtual PLCO trial receiving PSA tests per year

All simulated participants undergo pre-trial screening (solid black line before virtual trial period) based on our model of PSA testing patterns in the general US population applied to the virtual PLCO cohort. The intervention arm follows annual screening subject to observed compliance for the virtual trial period (dark gray line) then resumes population screening (solid black line after virtual trial period). The contaminated control arm follows a higher intensity of screening (solid medium gray line) than in the general population (dashed black line) for the virtual trial period then resumes population screening. The uncontaminated control arm discontinues screening upon entry into the trial (solid slight gray line).

Fig 2. Observed and model-projected cumulative prostate cancer incidence in each arm of the virtual PLCO trial

The figure illustrates cumulative number of prostate cancer diagnoses in the intervention arm (black), contaminated control arm (dark gray), and uncontaminated control arm (light gray) observed in the trial (solid lines) and projected by the models (dashed lines).

Fig 3. Observed and model-projected cumulative prostate cancer mortality in each arm of the virtual PLCO trial

The figure illustrates cumulative number of prostate cancer deaths in the intervention arm (black), contaminated control arm (dark gray), and uncontaminated control arm (light gray) observed in the trial (solid lines) and projected by the models (dashed lines). Model projections assume a stage-shift benefit for screening and a protective benefit of curative treatment. Results are presented separately for unadjusted (top panels) and adjusted (bottom panels) baseline prostate cancer survival to account for lower-than-expected observed mortality.

Fig 4. Observed and model-projected mortality rate ratios relative to contaminated and uncontaminated control arms

The figure illustrates ratios of mortality rates of the intervention arm relative to the contaminated and uncontaminated control arms and corresponding 95% confidence intervals observed in the trial (dashed gray horizontal lines) and projected by the models (solid black vertical lines) after 10 years of complete follow-up. The model projections represent a sorted random sample of 20 mortality rate ratios and 95% confidence intervals are based on assumed Poisson distributions for the number of deaths.