PSA SCREENING-NO BENEFIT AT ALL?

The mortality benefit of prostate-specific antigen screening that was found in 2 major European randomized trials might actually have been the result of more men in the unscreened control group being treated with problematic androgen-deprivation therapy (ADT).

This is the controversial hypothesis put forth by 2 Australian investigators in a commentary published in the October 16 issue of the Journal of the National Cancer Institute.

Both the data and the conclusions of the trials require "reappraisal" and "more rigorous scientific scrutiny," write the Ian E. Haines, MBBS, from the Department of Medical Oncology, Monash University at Cabrini Hospital, in Malvern, Victoria, and George L. Gabor Miklos, PhD, from Secure Genetics in Newport Beach, New South Wales.

A prominent American oncologist agrees with the call for a reappraisal.

"The controversies in prostate cancer screening and treatment will only be further settled if these large trials are rigorously analyzed by an objective panel of experts with access to all the data," writes Otis Brawley, MD, chief medical officer at the American Cancer Society in Atlanta, in an accompanying editorial.

Dr. Brawley is very familiar with the findings of the European Randomized Study of Prostate Cancer (ERSPC) study and Göteborg trial, which, he points out, "suggested that screening does save lives after 11 and 14 years median follow-up, respectively." The results were reported byMedscape Medical News in 2010 and 2012.

Dr. Brawley acknowledges that, in the 2 trials, men in the control groups with high-risk localized disease were twice as likely to receive ADT as men in the screening groups (29.5% vs 14.7%). This differential, which comes from an earlier 2011 analysis and is found in the current analysis, is "concerning," he writes.

The reason for concern, says Dr. Brawley, is that ADT might increase the risk for death from cardiovascular disease and the risk for thromboembolic events in men.

But that is a big "might," he notes, because "the evidence of harms from hormonal therapies is mixed."

However, Dr. Brawley entertains the possibility that ADT is, in fact, the real reason behind the European screening findings.

"If ADT does increase the risk of cardiovascular and thrombotic events, it is an amazing treatment bias in these screening studies," he writes.

ADT Monotherapy in Locally Advanced Disease

Dr. Brawley provides a bit of background. ADT with gonadotrophin-releasing hormone analogs and oral antiandrogens was a "promising medical intervention" in the 1980s, he reports.

"Because of a bias toward newer therapies, there was early widespread uptake in Europe and the United States without full assessment of its benefits and risks," he notes.

This widespread uptake resulted in men in both the control and screening groups of the ERSPC and Göteborg trials being treated with ADT.

However, Drs. Haines and Miklos write that there were "large imbalances" in the percent of patients who received ADT in the screening and control groups of the 2 trials. Fewer men in the screening groups than in the control groups received ADT in the ERSPC (8.8% vs 19.6%) and Göteborg (7.0% vs 22.6%) trials.

There was a similar large imbalance with ADT plus radiation treatment in ERSPC (8.7% vs 19.2%).

Drs. Haines and Miklos state that "ADT as monotherapy is linked to multiple adverse events." But they further contend that the ADT itself might have led to the increase in prostate cancer deaths. In other words, ADT might have contributed to the worse overall survival (related to cardiovascular disease and other conditions) and the increase in mortality related to prostate cancer in the control groups in the 2 studies.

They cite various datasets that, in their opinion, indicate that primary ADT treatment for men with localized tumors increases prostate cancer deaths. In short, it is an inferior treatment for early prostate cancer, they suggest.

Drs. Haines and Miklos point out that ADT is not approved by the US Food and Drug Administration for locally advanced disease. "Understandably, some physicians are reluctant to use ADT other than for proven metastatic disease because it has [not] been prospectively tested as sole therapy for locally advanced disease in a randomized study," they write.

Dr. Haines, Dr. Miklos, and Dr. Brawley have disclosed no relevant financial relationships.

J Natl Cancer Inst. 2013;105: 1522-1524, 1534-1539. Editorial, Commentary