Trial Indicates No Long-term Benefit Associated With Yearly Prostate Cancer Screening

The death rate from prostate cancer in the Prostate, Lung Colorectal and Ovarian (PLCO) randomized screening trial  did not decrease after 13 years of follow-up, despite a 12 percent increase in finding prostate cancer using the prostate-specific antigen (PSA) and digital rectal examination (DRE) screenings, according to a National Cancer Institute “Special Report.”

The PLCO researchers  reported that they looked at subgroups defined by age, the presence of other illnesses and pre-trial PSA testing        to determine if a cancer mortality existed.  They first published their results in 2009, which showed no prostate cancer mortality or overall morality benefit, but critics insisted that participants needed to be followed “long enough to detect a difference in prostate cancer mortality, if one existed.”

“The natural history of prostate cancer is so long that 10 to 15 years of follow up is usually the window we look for” when determining the effectiveness of a screening intervention, said first author Gerald Andriole, M.D., who is chief urologic surgeon at the Siteman Cancer Center at Barnes-Jewish Hospital in St. Louis and the Washington University School of Medicine.

In fact, a persistent increase in the prostate cancer found in the screening arm of the trial could indicate a tendency to over diagnose disease that would not have caused symptoms or death, the NCI Bulletin article stated.

“Even if there was just a tiny mortality benefit [from prostate cancer screening], overdiagnosis wouldn’t be so bad if we didn’t hurt people. But we do hurt people by finding a lot of trivial cancers that are most often overtreated,” explained Dr. Andriole.

The trial, started in 1993, had enrolled more than 38,000 men through mid-2001 who were randomly assigned to annual screening for six years. Screening included DRE for the first four years and the PSA testing for six years, with the same number of participants assigned to usual care. In addition, more than 50 percent of the participants in the control arm underwent a screening outside the trial, which complicated the finding from that trial arm.

“Every time we screened [in the intervention arm] we got a bump of excess cases,” said Philip Prorok, M.D., a lead NCI investigator on the study. “What we can’t say for sure is whether we would have seen more of an effect on mortality had there been absolutely no screening in the control arm.”

To help reconcile differing results from a European trial that showed a benefit and the PLCO that did not, the NCI-funded Cancer Intervention and Surveillance Modeling Network (CISNET) is attempting to determine how to reconcile them through mathematical, according to Paul Pinsky, M.D., an NCI investigator on the PLCO trial and consultant to the CISNET project.

“Even though the results seem to be disparate, because one [trial] found a [statistically] significant protective effect [on prostate cancer mortality] and one didn’t, it could be because of the ways the trials were designed and carried out,” he said.

The United States Preventive Services Task Force released draft guidelines for prostate cancer screening last October, with a recommendation against routine PSA testing of men without prostate cancer symptoms. Some in the medical community believe that the guidelines should take into account the need for individual men to make informed decisions.

 “If prostate cancer constitutes a continuum of disease and its overdiagnosis and overtreatment are mainly limited to low-grade disease, then instead of completely eliminating the potential benefits of screening along with the risks, why not consider managing low-risk patients differently?” wrote Robert Volk, M.D., from the University of Texas M. D. Anderson Cancer Center and Andrew Wolf, M.D., from the University of Virginia School of Medicine in a commentary published last month in JAMA.

“There’s a lot of effort now being put into this, and not just for prostate cancer, but for a lot of other cancer types as well,” added Dr. Prorok. “If we diagnose someone with symptoms, or you find something on a screening test, can we eventually find a way to determine for which individuals the cancers are in fact aggressive and need more aggressive treatment, versus some that need less aggressive treatment or don’t need any treatment at all?”

“If we could selectively change our criteria for biopsy such that only men who are at high risk for aggressive cancer get biopsied, we might be able to substantially shift the overall risk/benefit [ratio] of screening,” said Dr. Andriole.