November 2, 2012 — In a finding that challenges a reportedly common clinical practice, radiation therapy plus long-term androgen-deprivation therapy (ADT) improved overall survival in men with high-risk locally advanced prostate cancer, compared with ADT alone.
The benefits of this combined treatment "should be discussed with all patients with locally advanced prostate cancer," say the study authors, led by Padraig Warde, MBChB, from the University of Toronto's Princess Margaret Hospital in Ontario, Canada.
The findings from the randomized trial of 1205 men are published online November 3 in the Lancet. They were first presented at the 2010 annual meeting of the American Society of Clinical Oncology (ASCO), and were reported by Medscape Medical News at the time.
At that ASCO meeting, Dr. Warde said that "up to 45%" of patients with high-risk locally advanced prostate cancer are treated with ADT alone, citing information from the Cancer of the Prostate Research Endeavor (CaPSURE).
"In the past, many clinicians thought that these patients were incurable and should be treated with androgen-deprivation therapy alone," Dr. Warde explained at the time.
This study shows that adding radiation to ADT significantly improves survival. 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 (P = .033).
The combination therapy also reduced the risk of dying from prostate cancer. The 7-year cumulative disease-specific deaths were 9% for patients receiving ADT plus radiation therapy and 19% for patients receiving ADT alone (P = .001).
Furthermore, many fewer patients treated with combination therapy developed progressive disease. A total of 346 patients developed progressive disease — 251 treated with ADT alone and 95 treated with ADT plus radiation therapy.
All 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, which was the standard dose when the trial started in the 1990s, with or without radiation to seminal vesicles. If needed, 45 Gy was delivered to the pelvic nodes.
"Today, we would use 74 to 78 Gy and 45 to 50 Gy to the nodes," Dr. Warde said at the ASCO meeting, explaining that the study probably "underestimates the value of radiation therapy," because radiation technology and doses were less potent than those currently used.
Strongest Evidence to Date
In an accompanying comment, an American prostate cancer expert not involved with the study praised the findings.
"This study has provided the strongest evidence to date that androgen-deprivation therapy alone for men with high-risk prostate cancer is not adequate. These patients require an aggressive multimodal approach, incorporating prostate-directed local therapy," said Matthew Cooperberg, MD, from the Department of Urology at the University of California, San Francisco.
The study improves on the major SPCG-7 trial, he reports. That study used antiandrogens rather than surgical or medical castration, and was thus dated in its approach, he says. In addition, the patients in the study by Dr. Warde and colleagues — a joint venture of European and North American cooperative groups — had less favorable prognoses.
Reporting of Adverse Events Questioned
Dr. Cooperberg also voiced some important disclaimers about the study.
First, he noted that it is not clear whether radiation therapy plus ADT is the best initial treatment for these men.
"The crucial question — whether the optimum initial strategy should include radiation combined with androgen-deprivation therapy, or surgery followed by selective radiation on the basis of pathological findings and early biochemical outcomes — is still open," he writes.
More important, Dr. Cooperberg questions the toxicity findings.
The study authors reported that toxicity and health-related quality-of-life results showed a "small effect" of radiation on late gastrointestinal toxicity: 3 patients (0.5%) in the ADT group and 2 patients (0.3%) in the combination group developed rectal bleeding of grade 3 or higher; 4 patients (0.7%) in the ADT group and 8 patients (1.3%) in the combination group developed diarrhea of grade 3 or higher; and 14 patients (2.3%) in each treatment group developed urinary toxicity of grade 3 or higher.
"Warde and colleagues' assertion...that the benefit of radiation comes at no expense to long-term urinary or bowel effects challenges clinical experience and many other studies," says Dr. Cooperberg.
The questionnaires used to assess patient-reported toxicities are relatively insensitive, compared with newer measures, he says. Plus, the Functional Assessment of Cancer Therapy–Prostate instrument, completed by the large majority of patients in the trial, does not capture bowel symptoms; the instrument used for those symptoms was completed by only 10% of the patients, he points out.
Debate About Standard of Care
At the ASCO meeting, there was some disagreement among prostate cancer experts about what the current standard of care in the field is.
"It's what we are already doing," said Oliver Sartor, MD, from the Tulane Cancer Center in New Orleans, Louisiana, about radiation combined with ADT.
"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 previous 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 design raises 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," he said.
Not all men with locally advanced disease should receive radiation, Dr. Warde noted at the ASCO meeting. The general rule is that in men with a life expectancy of 5 to 10 years should receive both hormone therapy and radiation. However, in older men with few years of life remaining and in men with considerable comorbidities, especially those of a cardiovascular nature, radiation should be avoided.
The study authors, Dr. Cooperberg, 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.
Lancet. Published online November 3, 2011. Abstract, Comment
The benefits of this combined treatment "should be discussed with all patients with locally advanced prostate cancer," say the study authors, led by Padraig Warde, MBChB, from the University of Toronto's Princess Margaret Hospital in Ontario, Canada.
The findings from the randomized trial of 1205 men are published online November 3 in the Lancet. They were first presented at the 2010 annual meeting of the American Society of Clinical Oncology (ASCO), and were reported by Medscape Medical News at the time.
At that ASCO meeting, Dr. Warde said that "up to 45%" of patients with high-risk locally advanced prostate cancer are treated with ADT alone, citing information from the Cancer of the Prostate Research Endeavor (CaPSURE).
"In the past, many clinicians thought that these patients were incurable and should be treated with androgen-deprivation therapy alone," Dr. Warde explained at the time.
This study shows that adding radiation to ADT significantly improves survival. 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 (P = .033).
The combination therapy also reduced the risk of dying from prostate cancer. The 7-year cumulative disease-specific deaths were 9% for patients receiving ADT plus radiation therapy and 19% for patients receiving ADT alone (P = .001).
Furthermore, many fewer patients treated with combination therapy developed progressive disease. A total of 346 patients developed progressive disease — 251 treated with ADT alone and 95 treated with ADT plus radiation therapy.
All 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, which was the standard dose when the trial started in the 1990s, with or without radiation to seminal vesicles. If needed, 45 Gy was delivered to the pelvic nodes.
"Today, we would use 74 to 78 Gy and 45 to 50 Gy to the nodes," Dr. Warde said at the ASCO meeting, explaining that the study probably "underestimates the value of radiation therapy," because radiation technology and doses were less potent than those currently used.
Strongest Evidence to Date
In an accompanying comment, an American prostate cancer expert not involved with the study praised the findings.
"This study has provided the strongest evidence to date that androgen-deprivation therapy alone for men with high-risk prostate cancer is not adequate. These patients require an aggressive multimodal approach, incorporating prostate-directed local therapy," said Matthew Cooperberg, MD, from the Department of Urology at the University of California, San Francisco.
The study improves on the major SPCG-7 trial, he reports. That study used antiandrogens rather than surgical or medical castration, and was thus dated in its approach, he says. In addition, the patients in the study by Dr. Warde and colleagues — a joint venture of European and North American cooperative groups — had less favorable prognoses.
Reporting of Adverse Events Questioned
Dr. Cooperberg also voiced some important disclaimers about the study.
First, he noted that it is not clear whether radiation therapy plus ADT is the best initial treatment for these men.
"The crucial question — whether the optimum initial strategy should include radiation combined with androgen-deprivation therapy, or surgery followed by selective radiation on the basis of pathological findings and early biochemical outcomes — is still open," he writes.
More important, Dr. Cooperberg questions the toxicity findings.
The study authors reported that toxicity and health-related quality-of-life results showed a "small effect" of radiation on late gastrointestinal toxicity: 3 patients (0.5%) in the ADT group and 2 patients (0.3%) in the combination group developed rectal bleeding of grade 3 or higher; 4 patients (0.7%) in the ADT group and 8 patients (1.3%) in the combination group developed diarrhea of grade 3 or higher; and 14 patients (2.3%) in each treatment group developed urinary toxicity of grade 3 or higher.
"Warde and colleagues' assertion...that the benefit of radiation comes at no expense to long-term urinary or bowel effects challenges clinical experience and many other studies," says Dr. Cooperberg.
The questionnaires used to assess patient-reported toxicities are relatively insensitive, compared with newer measures, he says. Plus, the Functional Assessment of Cancer Therapy–Prostate instrument, completed by the large majority of patients in the trial, does not capture bowel symptoms; the instrument used for those symptoms was completed by only 10% of the patients, he points out.
Debate About Standard of Care
At the ASCO meeting, there was some disagreement among prostate cancer experts about what the current standard of care in the field is.
"It's what we are already doing," said Oliver Sartor, MD, from the Tulane Cancer Center in New Orleans, Louisiana, about radiation combined with ADT.
"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 previous 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 design raises 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," he said.
Not all men with locally advanced disease should receive radiation, Dr. Warde noted at the ASCO meeting. The general rule is that in men with a life expectancy of 5 to 10 years should receive both hormone therapy and radiation. However, in older men with few years of life remaining and in men with considerable comorbidities, especially those of a cardiovascular nature, radiation should be avoided.
The study authors, Dr. Cooperberg, 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.
Lancet. Published online November 3, 2011. Abstract, Comment
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