Long-term Toxicity Surprise With ADT for Prostate Cancer

Nick Mulcahy

January 06, 2016

In a surprising study result, the use of intermittent androgen-deprivation therapy (ADT) for prostate cancer is not associated with fewer long-term adverse events than continuous ADT.

The outcome was unexpected because it was hypothesized that the intermittent schedule, which gives patients a break from the treatment, would be less harmful.

ADT is a cornerstone of locally advanced and metastatic prostate cancer treatment, but is associated with an array of adverse events, including sexual dysfunction, bone demineralization, cardiovascular disease, metabolic complications, cognitive changes, and diminished quality of life.

In this study of men with metastatic disease — the first to look at long-term health issues — the stunner is that, for one category of complications — ischemic and thrombotic events — there was a significantly increased incidence with intermittent ADT.

We were all surprised.

"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," said lead author Dawn Hershman, MD, from the Columbia University Medical Center in New York City, in an email to Medscape Medical News.

The finding comes from an exploratory analysis of data from the landmark 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 was overall survival, and the trial failed to demonstrate noninferiority of intermittent ADT compared with continuous ADT, as reported by Medscape Medical News at the 2012 Annual Meeting of the American Society of Clinical Oncology.

For their study, Dr Hershman and her colleagues linked 636 men enrolled in the S9346 trial who had no private insurance with their ongoing Medicare claims to investigate differences in long-term adverse events.

Adverse events were grouped 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 10-year cumulative incidence of ischemic and thrombotic events differed significantly; it was 24% in the continuous group and 33% in the intermittent group (hazard ratio, 0.69; = .02).

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," summarized Dr Hershman.

The most common long-term events were hypercholesterolemia (31%) and osteoporosis (19%).

Dr Hershman also observed that all of the patients in the study had received ADT prior to randomization. "Therefore, the benefits of intermittent ADT on chronic complications may be limited," she said, explaining the unexpected results.

The study was published online December 23 in JAMA Oncology.

In an accompanying editorial, a pair of Canadian experts say that the study findings are weakened by "methodological limitations."

"Neither the primary SWOG study nor the current one was powered adequately to examine differences in occurrence of toxic effects between the two strategies," write Saroj Niraula, MBBS, MD, from the University of Manitoba in Winnipeg, and Ian F. Tannock, MD, PhD, from the University of Toronto.

Thus, the study does not prove the statistical superiority of continuous ADT in terms of thromboembolic and ischemic events, they say. However, the pair scknowledge that, given the direction of this trend, "it is highly unlikely that a larger RCT would find [the events] to be reduced with intermittent ADT."

Only Applies to One Type of ADT

Both the editorialists and the study authors speculate as to why there were more ischemic and thrombotic events with intermittent ADT. The authors call the result "counterintuitive."

Among other thoughts, the editorialists say this: "Multiple insults to the coagulation system with decrease and increase in testosterone levels during intermittent ADT might therefore be responsible for the observations in the study."

The authors touch 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)."

The authors also report that results from a phase 2 study showed that patients 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).

The authors conclude that intermittent ADT is something that clinicians should be "cautious" about using in elderly men with metastatic prostate cancer.

The facts that the strategy was not proven to be noninferior in terms of survival and does not appear to reduce long-term adverse events are two strikes against the on–off strategy, they suggest. Finally, the authors say that more study is needed in this area.

But the editorialists provide a slightly different summary, which accents the positive.

"Any advantage of intermittent ADT is likely to be limited to possible improvements in QOL particularly during the off-treatment period; convenience of therapy; and savings in cost," they write.

When the overall survival data were reported in 2012, one of the study's researchers cautioned that the results only apply to men who are treated in a manner similar to the study protocol.

"We cannot draw any conclusions about the myriad other androgen-deprivation regimens," Celestia Higano, MD, from the Seattle Cancer Care Alliance and the University of Washington, told Medscape Medical News at that time about the study, which is a collaboration of the SWOG, the Eastern Cooperative Oncology Group, the European Organization for Research and Treatment of Cancer, and the National Cancer Institute of Canada.

The study design called for all men to undergo a 7-month induction course of "combined" ADT (subcutaneous goserelin once a month and oral bicalutamide once daily for eight courses).

Men whose prostate-specific antigen (PSA) levels decreased to 4 ng/mL or below after months 6 and 7 of induction treatment, and who had a stable or declining trend, were deemed to be hormone sensitive and randomly assigned to either intermittent or continuous ADT for the duration of the trial. Men on intermittent therapy had their treatment initially discontinued and were monitored with PSA tests monthly; they resumed ADT if their values exceeded prespecified levels.

Dr Hershman and one of her coauthors are recipients of grants related to the study from the National Cancer Institute. Dr Niraula and Dr Tannock had no disclosures.

JAMA Oncol. Published online December 23, 2015. Abstract, Editorial


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