ORLANDO, FL-Patients with prostate-specific antigen recurrence after radiation therapy live just as long if they are given intermittent breaks from androgen-suppression therapy than if they stay on continual anti-hormone therapy, researchers reported here at the Genitourinary Cancers Symposium.
In a Phase III study of nearly 1,400 men, the median overall survival time was 9.1 years for those treated with continuous anti-hormone therapy, compared with 8.8 years for men randomized to intermittent androgen suppression, said Laurence Klotz, MD, Chief of Urology at Sunnybrook Health Sciences Centre and Professor of Surgery at the University of Toronto.
Citing a hazard of 1.02 and p value of 0.009, Dr. Klotz said the findings achieved statistical significance for noninferiority and answer the question of whether periodic breaks in treatment affect survival.
"In men with PSA recurrence after radical radiotherapy, intermittent androgen suppression is not inferior to continuous androgen deprivation with respect to overall survival. Based on this study, which is really, a pivotal, definitive trial of this question, IAS [intermittent androgen suppression] should be the standard of care for most patients with PSA recurrence after radiation therapy," he told the audience.
Introduced in 1986
Dr. Klotz first described the use of intermittent androgen-suppression treatment in a group of 20 patients in 1986 (Cancer 1986;58:2546-2550). Since then, 17 Phase II and nine Phase III studies have shown favorable results, he said, explaining that none, however, answered the question of whether the increasingly popular treatment affected survival.
The new study involved men without metastatic disease who had a rising serum PSA level of greater than 3 ng/ml and a serum testosterone level of more than 5 nmol/L one year after undergoing radiation therapy, with or without radical prostatectomy.
Patients were recruited between January 1999 and October 2010. PSA and testosterone levels were monitored every two months.
A total of 696 patients were randomized to continuous treatment with an anti-androgen and a luteinizing hormone-releasing hormone (LHRH) analog until castrate resistance occurred. Another 690 patients received an anti-androgen and LHRH treatment for eight months, and then were taken off medication if PSA levels became normal.
If PSA levels rose to more than 10 ng/ml, patients were given another eight-month cycle of androgen suppression therapy. They stayed on intermittent therapy until castrate-resistant prostate cancer emerged.
Patients were switched from intermittent therapy to continuous therapy if their PSA levels were still greater than 10 ng/ml within two months of stopping anti-androgen therapy.
Castrate-resistant disease was defined as evidence of testosterone and three successive increases in PSA measured at least one month apart and/or new evidence of disease. "It could only be met when a patient was on treatment," Dr. Klotz said.
Adverse Events Similar
Over a median follow-up period of 6.8 years, 268 men in the intermittent therapy arm and 256 men in the continuous treatment arm died.
The median time to castration resistance was 10 years in the continuous group and 9.8 years in the intermittent treatment group. A stratified log-rank analysis "showed this favored the intermittent arm, but it may be because the study design was biased toward the intermittent arm as patients off treatment had to go back on treatment before they met the definition for castration resistance," he said.
The fact that the median time to castration resistance was greater than the median overall survival time indicates that men in the study were dying from diseases other than prostate cancer, Dr. Klotz said.
About 15% of the patients in the continuous-treatment group died of prostate cancer versus 18% of those on intermittent therapy, a nonsignificant difference.
Adverse events were similar between the intermittent androgen suppression and continuous androgen deprivation arms, including erectile dysfunction (86% vs 88%), libido (79% both groups), urine frequency/urgency (61% vs 57%), fatigue (59% both groups), myocardial ischemia/infarction (10% vs 11%), and osteoporotic fracture (4% vs 3%).
Patients in the intermittent androgen suppression arm were significantly less likely to have hot flashes: 90% vs 93% of patients on continuous therapy.
Dr. Klotz said that quality-of-life findings will be reported at a future meeting.
Cost Savings
One of the surprising findings of the study was that patients in the intermittent therapy group were on medication only 27% of the time, on average, with a median of 15.4 months on therapy and 37.6 months off, he said. Most of the Phase II studies suggested the on-treatment time would be closer to 50%, he said.
"This is actually quite reassuring and I think important data that, at least in this scenario, patients tend to stay off treatment for a much longer period of time," Dr. Klotz said.
"This is a win-win situation. Not only do we have a therapy that appears to be better tolerated for the patient, but it saves money."
Asked if the findings would change clinical practice, Dr. Klotz said, "Practice already has changed [with more physicians offering intermittent therapy] to some degree. But there was always this lingering question about survival. This is the best data we will ever have."
Compliance an Issue
Session Co-chair A. Oliver Sartor, MD, Medical Director of the Tulane Cancer Center and the C.E. and Bernadine Laborde Professor of Cancer Research at Tulane University, told OT that he has been using IAS for more than a decade.
"There have been a number of smaller studies showing equivalence in outcomes, but this is the largest to date. This is an important study that unequivocally demonstrates that overall survival will be the same with the intermittent and continuous approaches, and it will be the trial I cite going forward," he said.
One possible area of concern, though, is compliance. "The patient has to be compliant not only with treatment, but with monitoring," Dr. Sartor said, adding that he typically does blood work every two to three months when patients are off treatment.
"The savings in regard to cost of these medications could be enormous," Dr. Sartor added. "It is simple: Less frequent treatment and less medication translate to less money spent."
Meeting Cosponsors
The Genitourinary Cancers Symposium is cosponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.