Mar 16, 2015
By Shira Klapper, Senior Writer/Editor
Among patients with prostate cancer being treated with continuous (non-intermittent) androgen deprivation therapy (ADT), those whose testosterone dipped to a nadir of less than 20 nanograms per deciliter (ng/dL) within the first year of treatment experienced improved survival and a longer time to progression, compared to men whose testosterone levels rose above 20 ng/dL. That’s according to the Journal of Clinical Oncology (JCO) study, “Nadir Testosterone within First Year of ADT Predicts for Time to Castration Resistant Progression: A Secondary Analysis of The PR-7 Intermittent Vs Continuous ADT Trial.”
The study, published online, ahead of print, March 2, looked at men with nonmetastatic prostate cancer whose PSA had returned to detectable levels after initial treatment with surgery followed by radiation, or radiation alone.
The study also found that men whose testosterone levels reached a maximum level of 50 ng/dL and above had a significantly shorter time to progression and a significantly higher risk of dying of disease, compared to men whose levels stayed under 50 ng/dL.
The conundrum posed by intermittent therapy
The study used the National Cancer of Institute of Canada Clinical Trials Group PR-7 study to gather data on 696 men who received continuous ADT. The PR-7 study’s goal was to compare these 696 men who received continuous ADT to 690 men who received intermittent ADT—in intermittent ADT, treatment is stopped after six to nine months, at which point, the patient’s testosterone and PSA are allowed to rise again until they reach a specified level, and then ADT is started again. The PR-7 study found no differences in survival between men who received continuous ADT and men who received intermittent ADT.
According to the study’s first author, Laurence Klotz, MD, PR-7’s findings—that intermittent therapy and continuous therapy are associated with similar survival—seems to contradict the current study’s findings that nadir and maximum levels of testosterone make a difference in survival.
In explaining the apparent conflict, Dr. Klotz asked, “How could this be? It seems like a conundrum. If achieving and maintaining low testosterone is beneficial for survival, then you would expect those on intermittent therapy, whose testosterone is allowed to rise, to do worse. But they don’t seem to.”
Dr. Klotz said that one possible explanation for this conundrum may be that lowering testosterone aggressively in men on intermittent therapy results in a more androgen sensitive phenotype once treatment is stopped and the cancer cells grow again. This means that patients who do not achieve lower levels of testosterone on ADT may have increased rates of progression to castration resistance, whether or not the ADT is subsequently stopped and the testosterone rises.
“So, yes, the testosterone level during the on-treatment interval is quite important. You have to drive it down low, but subsequently, you can have a period of recovery, which doesn't seem to carry any adverse consequences for long term survival,” said Dr. Klotz.
Keeping testosterone levels on the radar
According to Dr. Klotz, the current JCO study shows that in treating men with prostate cancer, “testosterone matters” and that “patients on ADT should have their testosterone levels monitored regularly within the first year of ADT,” said Dr. Klotz.
“I think that a single rise in testosterone above 20 ng/dL is not anything to be concerned about, but if the testosterone is consistently above that level, then the hormone therapy should be switched,” said Dr. Klotz. “And there are many treatment options, such as agonists, antagonists, surgical castration, and anti-androgens."
Laurence Klotz, MD, FRCSC, CM, is a Professor in the Department of Surgery at University of Toronto, the Chief of the Division of Urology at the Sunnybrook Health Sciences Centre, and the Chair of the Canadian Uro-Oncology Group, the NCIC GU Site Group, and the Global GU Oncology Group. He is also the Editor Emeritus of the Canadian Urology Association Journal.
Abstract of the original JCO article.
PDF of the original JCO article.
Klotz L, O’Callaghan C, Ding K. Nadir testosterone within first year of ADT predicts for time to castration resistant progression: a secondary analysis of the PR-7 intermittent vs continuous ADT trial. J Clin Oncol. Epub TK.
The Exclusive Coverage series on ASCO.org highlights selected research from JCO and JOP with additional perspective provided by the lead or corresponding author.
@ 2014 American Society of Clinical Oncology