ASCO 2010-USE RADIATION WITH ADT IN LOCALLY ADVANCED PROSTATE CANCER

June 8, 2010 (Chicago, Illinois) — In men diagnosed with high-risk locally advanced prostate cancer, radiation therapy should be added to continuous androgen-deprivation therapy (ADT) as part of standard treatment.

The recommendation comes from a cooperative study involving 1205 men, said lead author Padraig Warde, MBChB, from the University of Toronto's Princess Margaret Hospital in Ontario.

At 7 years, 74% of the 603 men who received ADT plus external-beam radiation were still alive, compared with 66% of the 602 men who received ADT alone.

The combination therapy also reduced the risk of dying from prostate cancer by 43%, compared with ADT alone.

The results should guide clinical practice, and challenge the "dogma" that ADT alone is the treatment of choice for locally advanced prostate cancer, said Dr. Warde at a press conference here at the American Society of Clinical Oncology 2010 Annual Meeting.

"This study firmly cements radiation as part of the foundation of the treatment of high-risk prostate cancer," said Jennifer Obel, MD, from the Northshore University Health System in Evanston, Illinois. Dr. Obel moderated the press conference.

The new findings are at odds with what many clinicians believe and practice, said Dr. Warde.

About 15% to 25% of all newly diagnosed prostate cancer is locally advanced and therefore high risk, he noted.

"In the past, many clinicians thought that these patients were incurable and should be treated with androgen-deprivation therapy alone," Dr. Warde explained.

"Up to 45% of these high-risk patients are treated with androgen-deprivation therapy alone," said Dr. Warde, citing information from the Cancer of the Prostate Research Endeavor (CaPSURE) treatment database in the United States. "We feel that a substantial portion of these patients would benefit from radiation therapy."

Dr. Warde also cited a survey of Canadian urologists and radiation oncologists. The survey, performed in the mid-1990s, indicated that "more than 60% felt that radiation therapy was not an established treatment for these patients with locally advanced disease."

However, a number of prostate cancer experts from academic centers told Medscape Oncology that radiation therapy plus ADT (also known as hormone therapy) has been their standard of care for some time.

"It's what we are already doing," said Oliver Sartor, MD, from the Tulane Cancer Center in New Orleans, Louisiana.

"I trained from 1999 to 2001 and this [combination therapy] is what we were doing then," said Timothy Gilligan, MD, from the Cleveland Clinic in Ohio.

Dr. Gilligan explained that earlier studies established the value of combining hormone therapy and radiation therapy.

"Multiple randomized controlled trials have shown that men with high-risk locally advanced prostate cancer live longer if they receive hormone therapy at the same time as radiation therapy," he said.

However, Dr. Gilligan said the study designs raised a question: Is it the hormone therapy that is responsible for the improved survival?

"This study shows that radiation therapy makes a difference — it provides very important data," he said, adding that there is still no clinical trial that proves that radiation therapy alone improves survival. Hormone therapy, however, provides "an unquestioned survival benefit in locally advanced disease," said Dr. Warde.

At the press conference, Dr. Warde said that his study results are also supported by a study from Scandinavia, in which combination therapy provided better survival than ADT alone (Lancet. 2009;373:301-308).

Exceptions to the RT + HT Rule

All of the men in the study had T3/T4 disease or T2 prostate adenocarcinoma with a prostate-specific antigen (PSA) level above 40 μg/L, or T2 prostate adenocarcinoma with a PSA level above 20 μg/L and a Gleason score of 8 or higher.

They were randomized, from 1995 to 2005, to lifelong ADT (bilateral orchiectomy or luteinizing hormone-releasing hormone agonist) with or without radiation therapy.

The radiation therapy was 65 to 69 Gy to the prostate, with or without radiation to seminal vesicles. If needed, 45 Gy was delivered to the pelvic nodes. "It was the standard dose at the time," said Dr. Warde.

"Today, we would use 74 to 78 Gy and 45 to 50 Gy to the nodes," he added, explaining that the study probably "underestimates the value of radiation therapy" because radiation technology and doses were less potent at the start of the study.

In addition to the improved overall survival with the combination therapy, there was better diseases-specific survival. In the ADT-only group, 26% of the men died from their prostate cancer, compared with 10% of the ADT-plus-radiation group.

Serious toxicities (≥grade 3) were similar in both groups. There were no data on cardiovascular disease, which is an adverse effect of concern with ADT, as reported by Medscape Oncology. Dr. Warde acknowledged that patients ask about cardiotoxicity. "You must balance the benefits and risks of treatment," he said, adding that locally advanced prostate cancer is life-threatening.

There were no serious long-term adverse effects from radiation therapy, said Dr. Warde.

Not all men with locally advanced disease should receive radiation, Dr. Warde noted. The general rule is that in men with a life expectancy of 5 to 10 years, use both hormone therapy and radiation. However, in older men with few years of life remaining and in men with considerable comorbidities, especially those cardiovascular in nature, radiation should be avoided.

Dr. Obel and Dr. Gilligan have disclosed no relevant financial relationships. Dr. Sartor reports being a consultant or advisor to, and receiving honoraria and research funding from, Sanofi-Aventis

American Society of Clinical Oncology (ASCO) 2010 Annual Meeting: Abstract CRA4504. Presented June 6, 2010.