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.
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Acknowledgments
We are grateful to Dr. Paul F. Pinsky for careful reading and helpful comments on an earlier draft. Any remaining errors are our own. This research was supported by U01CA157224-01 from the National Cancer Institute and U01CA157224 from the National Cancer Institute and the Centers for Disease Control. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, the National Institutes of Health, or the Centers for Disease Control.
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.
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Gulati, R., Tsodikov, A., Wever, E.M. et al. The impact of PLCO control arm contamination on perceived PSA screening efficacy. Cancer Causes Control 23, 827–835 (2012). https://doi.org/10.1007/s10552-012-9951-8
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DOI: https://doi.org/10.1007/s10552-012-9951-8