• Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N., Seattle, WA 98109-1024, USA. rgulati@fhcrc.org

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.