Intermittent vs Continuous ADT Similar in Earlier Prostate Cancer

Zosia Chustecka

September 05, 2012

September 5, 2012 — A big question in the treatment of prostate cancer is whether to give androgen deprivation therapy (ADT) continuously, or whether there can be breaks in the treatment without detriment to the outcome.

This answer appears to depend on the specific patient population.

Results just published in the September 6 issue of the New England Journal of Medicine show that, in earlier disease, there is little difference between the 2 administration schedules. The patients in this study, the Southwest Oncology Group (SWOG) JPR 7 trial, were men with localized prostate cancer treated with radiation (either primary or salvage) who had then developed raised levels of prostate-specific antigen (PSA > 3 ng/mL) a year or more later.

The results show that overall survival was similar for continuous and intermittent ADT, although some of the quality-of-life factors favored intermittent administration. One of the study authors suggested that intermittent ADT should become a standard of care in this patient population, as it reduces side effects without reducing survival.

These findings contrast with the results reported earlier this year from a trial in men with metastatic prostate cancer (the SWOG 9346 study), which showed that continuous ADT was superior to intermittent administration in terms of overall survival. Those study authors concluded that continuous ADT should remain the standard of care in this patient population.

There are, however, many questions about ADT administration and its timing that remain unanswered, comments Oliver Sartor MD, from Tulane University School of Medicine, in New Orleans, Louisiana, in an editorial published in the New England Journal of Medicine.

"Does early ADT in asymptomatic men with rising PSA levels provide more benefit than treatment in symptomatic men with metastases?" he writes. "This question bedevils our field, and we are no closer to an answer now than we were before."

Trial in Earlier Disease

The new paper, authored by Juanita Crook, MD, from the British Columbia Cancer Agency, in Kelowna, Canada, and colleagues, reports results from a median follow-up of 6.9 years. The trial was conducted in 1386 men with rising PSA levels more than a year after receiving radiation for localized prostate cancer.

They were randomized to receive ADT continuously or intermittently (in 8-month cycles). ADT was composed of a luteinizing hormone-releasing hormone agonist (LHRHa) combined with a nonsteroidal antiandrogen. The authors note that the cost of drugs in the intermittent group was about one-third that in the continuous group, but was offset to some extent by the closer monitoring that was required.

The median overall survival was 8.8 years with intermittent therapy and 9.1 years for continuous therapy, and the statistical analysis found that intermittent therapy was not inferior to continuous therapy.

In the quality-of-life assessments, the scores for functional domains were slightly better in the intermittent groups compared with the continuous group, but not significantly so. For symptoms, however, the difference between the 2 groups was greater, and the intermittent group had significantly better scores for hot flashes (P < .001), desire for sexual activity (P < .001), and urinary symptoms (P = .006), and showed a trend toward improvement in the level of fatigue (P = .07).

"Although intermittent ADT appears to provide an overall quality-of-life benefit, as compared with continuous ADT, the difference is not as profound as one might expect," the authors comment in the paper.

However, the difference in side effects was highlighted by 1 of the study authors, the principal investigator of the United Kingdom portion of the trial. David Dearnaley, MD, professor of uro-oncology at the Institute of Cancer Research and honorary consultant at the Royal Marsden NHS Foundation Trust, said: "This large-scale trial has shown that periodically stopping men's hormone therapy can give them fewer side effects without reducing their chance of survival, and should lead to a change in clinical practice.

"Our findings have the potential to benefit thousands of men" who are treated with potentially curative radiotherapy for prostate cancer, he added in a statement.

But Is ADT Necessary?

In the editorial, however, Dr. Sartor questions whether the men taking part in this study really needed to be treated with ADT. He points out that as well as the choice between intermittent and continuous ADT, there is also the option of "none at all."

"How many patients...were unnecessarily exposed to the side-effects and expense of ADT?" he ponders.

The men participating in the trial reported by Dr. Crook and colleagues represent a "heterogeneous patient group, and only a minority of men might be expected to have clinical consequences from their rise in PSA level," he notes. "Given the slow progression of prostate cancer in many men, which of these asymptomatic patients actually benefited from ADT? This important issue is not addressed," he writes.

The trial was supported by the Canadian Cancer Society Research Institute, the US National Cancer Institute, and Hoechst Marion Roussel Canada.

Dr. Crook and Dr. Dearnaley reported no conflicts of interest, but 2 coauthors reported consultancy for several pharmaceutical companies, as detailed in the paper. Dr. Sartor reports consultancy for Tolmar.

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