Landmark PSA Screening Trial Results Challenged
The PLCO trial's conclusion that routine PSA testing does not affect prostate cancer mortality risk could be wrong.
Recommendations against routine PSA screening from the US Preventive Services Task Force (USPSTF) are based largely on a landmark trial showing that such screening does not decrease the risk of death from prostate cancer (PCa), but this conclusion may be invalid, according to the authors of a Letter to the Editor in The New England Journal of Medicine (2016; 374:1795-1796).
The trial in question is the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, in which 76,693 men in the United States were randomly assigned to receive either annual screening (intervention arm) or usual care. Men in the intervention arm were offered annual PSA testing for 6 years and digital rectal examinations for 4 years. Results of that study were published in NEJM in 2009.
Jonathan E. Shoag, MD, and Sameer Mittal, MD, of New York Presbyterian Hospital, and Jim C. Hu, MD, MPH, of Weill Cornell Medical College, New York, contend that the rates of PSA testing in the control arm have been misinterpreted and are substantially higher that currently recognized. As interpreted by the USPSTF, approximately 50% of controls received at least 1 PSA test during the study. Drs. Shoag, Mittal, and Hu, however, conclude that close to 90% of controls had at least 1 PSA test before or during the trial. Men in the control group, they stated, reported having had more cumulative PSA testing than those in the intervention arm.
In an interview with Renal & Urology News, Dr Hu said such excessive “contamination” makes for an unfair group-to-group comparison, making conclusions about the effect of routine PSA testing on PCa mortality unreliable.
“The study design set out to compare apples to oranges and ended up comparing apples to apples, which isn't the intent of a randomized controlled trial,” said Dr Hu, the Ronald Lynch Professor of Urologic Oncology and Professor of Urology at Weill Cornell. “I think the original study investigators didn't anticipate that PSA [testing] would be so widely used.”
Excessive contamination in the control arm, Dr Hu pointed out, could explain why the European Randomized Study of Screening for Prostate Cancer (ERSPC)—which enrolled 162,388 men—found that regular PSA testing (every 4 years in 87% of subjects and every 2 years in the remaining 13%) was associated with a significant 21% decrease in the risk of PCa mortality compared with controls. In that study, the contamination rate in the control arm was lower, he noted.
“It was a head scratcher that the outcomes of 2 randomized trials were so different,” Dr Hu commented.
In their analysis, Dr Hu and his co-authors said their clarifications about control group contamination “should be considered by policymakers and payers debating reimbursement and meaningful use of PSA testing, particularly given the mounting evidence that intermittent PSA testing decreases the costs and harms of screening while preserving the benefits of annual testing.”