Final Results in 'Definitive' Prostate Cancer Trial

Message for Urologists

Nick Mulcahy

October 31, 2012

BOSTON, Massachusetts — Two treatments are better than 1 for men with locally advanced prostate cancer, according to the final results of a landmark cooperative-group trial.

Radiation therapy plus androgen-deprivation therapy (ADT) improved survival in these men, said senior investigator Padraig Warde, MBChB, from the Princess Margaret Hospital in Toronto, Ontario, Canada. He reported the results here at the American Society for Radiation Oncology 54th Annual Meeting.

Compared with ADT alone, the combination significantly improved overall survival by 30% and significantly reduced the risk of dying from the disease by 54%.

Of the 603 men randomized to the combination, 205 have died, as have 260 of the 602 men randomized to ADT alone. Median follow-up was 8.0 years.

The combination caused only a minimal increase in late treatment toxicity, Dr. Warde reported. For late gastrointestinal toxicity (above grade 2 proctitis), the combination had a small detrimental effect, compared with ADT alone (1.0% vs 0.3%).

"This is the definitive trial in patients who are suitable for radical treatment," Dr. Warde told Medscape Medical News, referring to men with locally advanced disease who are in good health and have a "reasonable life expectancy."

This is practice-changing. Dr. Padraig Warde

"This is practice-changing," he added. The change that is needed is a shift away from treating locally advanced disease with ADT alone, he added.

Dr. Warde hopes the message reaches urologists. They are the "gatekeepers" of prostate cancer treatment and the primary prescribers of ADT alone for locally advanced disease, he said. There is a mistaken belief among urologists that locally advanced disease is not curable, he added.

In his presentation, Dr. Warde quoted an anonymous urologist's wrongheaded justification for prescribing ADT by itself: "These men all have metastatic disease; adding radiotherapy to hormones is unnecessary and unkind."

An estimated 15% to 25% of all newly diagnosed prostate cancer is locally advanced, and therefore high risk, said Dr. Warde. Currently, a "huge" percentage of these cases in the United States — up to 45% — continue to be treated with ADT alone, he added.

ADT is easy to prescribe, which partially explains its widespread use in this setting, said Jeff Michalski, MD, from the Siteman Cancer Center and Washington University School of Medicine in St. Louis, Missouri, who was not involved with the study. "With ADT, there's an initial favorable response, but there is also an inevitable progression and decline in quality of life," he told Medscape Medical News.

Now data show that you compromise survival. Dr. Jeff Michalski

"Now data show that you compromise survival, too," with ADT alone, said Dr. Michalski.

Dr. Warde noted that his team's results are supported by a Scandinavian study, in which combination therapy provided better survival than ADT alone (Lancet. 2009;373:301-308).

Benefit May Be Underestimated

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

The patients 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 consisted of 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.

The combination of radiation therapy plus ADT significantly improved overall survival (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.57 to 0.85; P = .0003) and disease-specific survival (HR, 0.46, 95% CI, 0.34 to 0.61; P <.0001), compared with ADT alone.

In the study, 199 patients (43%) died of disease and/or treatment (134 receiving ADT alone and 65 receiving the combination).

The results of this study are "exciting," but they might "underestimate" the effect of combination therapy, he added.

Radiation oncologists now use 76 to 80 Gy to the prostate, Dr. Warde pointed out. "We now have the technology to do better," he said.

Not all men with locally advanced disease should receive radiation, Dr. Warde noted. The general rule is that the combination of radiation and hormone therapy should be used in men with a life expectancy of 5 to 10 years. In older men with fewer years of life remaining and in men with considerable comorbidities, especially cardiovascular comorbidities, radiation should be avoided, he said.

Very Important Results

The interim results of this study were presented by Dr. Warde at the 2010 annual meeting of the American Society of Clinical Oncology, and were reported at that time by Medscape Medical News.

At that meeting, an expert placed the study in the context of earlier research.

Previous studies have established the value of combining hormone therapy and radiation therapy, said Timothy Gilligan, MD, from the Cleveland Clinic in Ohio. "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 explained.

However, Dr. Gilligan said it was unclear whether it was the hormone therapy or the radiation therapy that was responsible for the improved survival in the previous studies.

This study provides clarity, he added. It "shows that radiation therapy makes a difference," he said.

The study was supported the National Cancer Institute, the Medical Research Council in the United Kingdom, and the National Cancer Research Network in the United Kingdom. Dr. Warde, Dr. Michalski, and Dr. Gilligan have disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 54th Annual Meeting: Abstract 8. Presented October 28, 2012.