Once again we see what seems to be logical isn’t necessarily the way it actually works!  In a surprising study result, it was shown that the use of intermittent androgen-deprivation therapy (IADT) for prostate cancer is not associated with fewer long-term adverse events than continuous ADT!  Who would have guessed?

We all thought that intermittent ADT would be less harmful, but this hypothesis is now called into question by a recent study.

ADT comes with a guarantee of an array of adverse events, including sexual dysfunction, bone de-mineralization, cardiovascular disease, metabolic complications, cognitive changes, and a diminished quality of life. We thought that going on an intermittent schedule would minimize these events, but it isn’t necessarily true!

In this study of men with advanced metastatic prostate cancer it was shown that for one category of complications, ischemic and thrombotic events, there was an increased incidence in men on an intermittent ADT schedule. Yes, an increase, not a decrease and in a serious side effect . This is a stunning find; we might be safer having continuous ADT!

According to lead author Dawn Hershman, MD, from the Columbia University Medical Center in New York City, “We were all surprised that our analyses found an increase in the cumulative incidence of ischemic and thrombotic events in patients randomized to the intermittent ADT.”

Hershman’s finding comes from an exploratory analysis of data from the Southwest Oncology Group randomized trial, known as S9346, which compared the two schedules of ADT administration in men with metastatic prostate cancer. The primary outcome of the trial was overall survival, but the trial failed to demonstrate non-inferiority of intermittent ADT compared with continuous ADT. To translate this, intermittent and continuous ADT schedules are equal in overall survival.

Hershman’s study looked at data from 636 men enrolled in the S9346 trial using their Medicare claims to investigate differences in long-term adverse events. The researchers grouped adverse events into five categories: endocrine events, sexual dysfunction, dementia and depression, acute kidney injury, and ischemia and thrombosis.

There was no significant difference between the study groups for the first four categories. But, the great surprise was that the 10-year cumulative incidence of ischemic and thrombotic events differed significantly between the two groups with 24% in the continuous group and 33% in the intermittent group (hazard ratio, 0.69; = .02).

Hershman did say that overall, the men, who had a median age of 71 years, had a lot of health issues. “The reality is that long-term, health-related events were high in both arms.”  She also found that the most common long-term events experienced by the men were hypercholesterolemia (31%) and osteoporosis (19%).

In peer review comments to the study it was pointed out that the study findings are weakened by “methodological limitations.” According to the reviewer’s comments, Saroj Niraula, MBBS, MD, from the University of Manitoba in Winnipeg, and Ian F. Tannock, MD, PhD, from the University of Toronto, “Neither the primary SWOG study nor the current one was powered adequately to examine differences in occurrence of toxic effects between the two strategies.”

They felt that the study does not prove the statistical superiority of continuous ADT in terms of thromboembolic and ischemic events. However, the pair acknowledge that, given the direction of this trend, “it is highly unlikely that a larger cohort would find [the events] to be reduced with intermittent ADT.”

Given how counter-intuitive this finding is, we need to examine the conclusion. Both the peer reviewers and the study authors have speculated as to why there were more ischemic and thrombotic events with intermittent ADT.

Among other thoughts, the reviewers said: “Multiple insults to the coagulation system with decrease and increase in testosterone levels during IADT might therefore be responsible for the observations coming from this study.”

The study authors touched on that same idea: “Changes in the coagulation cascade have been reported with lowering of testosterone during ADT as well as with increasing estrogen (after stopping ADT).”

Hershman has also report that results from a phase 2 study showed that men treated with intermittent ADT had a higher incidence of myocardial infarction during their off-treatment period than during their on-treatment period (4.6% vs 2.8%), but the difference was not significant (Clin Genitourin Cancer. 2008;6:46-52).

Hersman has cautioned that intermittent ADT is something that clinicians should be “cautious” about using in elderly men with metastatic prostate cancer. This is, of course, a twist in what is our current thinking.

All of these findings, especially given the finding of non-inferiority in survival terms, about an intermittent schedule still doesn’t dissuade me from factoring in the very important reality, IADT does have a major positive effect on a man’s quality of life, an important factor that needs to be factored into the very personal decision each of us need to be making.

JAMA Oncol. Published online December 23, 2015.

Abstract: http://oncology.jamanetwork.com/article.aspx?articleid=2476246