Overused: Androgen-Deprivation Therapy in Prostate Cancer

Nick Mulcahy

June 11, 2009

June 11, 2009 — Androgen-deprivation therapy (ADT) for prostate cancer is overused, according to experts who have written recent editorials in 2 major journals.

"It's becoming increasingly clear that androgen-deprivation therapy is overused in treating prostate cancer," writes William Dale, MD, PhD, in an editorial accompanying a new American study that indicates that ADT contributes to the development of diabetes. The study and editorial were published online June 8 in the Journal of Clinical Oncology. Dr. Dale is from the geriatrics and palliative medicine and hematology/oncology sections at the University of Chicago in Illinois.

No doubt there is gross overuse of androgen-deprivation therapy in the treatment of prostate cancer.

"No doubt there is gross overuse of androgen-deprivation therapy in the treatment of prostate cancer," said Peter Albertsen, MD, MS, in an interview with Medscape Oncology. Dr. Albertsen is the author of an editorial published in the June 11 issue of the New England Journal of Medicine that accompanies a new European study on the use of ADT in men with locally advanced prostate cancer. He is professor of surgery and chief of the Division of Urology at the University of Connecticut Health Center in Framingham.

Both Dr. Albertsen and Dr. Dale note that ADT has been shown to improve survival in men with metastatic prostate cancer, but that its survival benefits are mostly uncertain or unproven in other stages of the disease.

What's Driving the Overuse?

The overuse of ADT has been driven, in part, by clinicians in the United States overestimating the effectiveness of ADT, suggests Dr. Albertsen. "If it's good for advanced disease, there's a good chance it will work for localized disease — that's probably been the thinking," he explained.

Overuse was probably worse a few years ago.

Money has also been a driver. "Overuse was probably worse a few years ago when clinicians were making a lot of money off of it," Dr. Albertsen said about the administration of ADT and related follow-up care.

The desire to take action is another driver, said Dr. Dale. "There is a propensity to 'do something' about cancer that leads to starting a therapy that is not justified. This is particularly true for older men," he told Medscape Oncology.

Dr. Dale cited 2 "do something" settings in which data don't support the use of ADT. "Starting it early when PSA [prostate-specific antigen] first rises following surgery or radiation — versus waiting until later to start it — has not been shown to extend life. It is also being used increasingly in older men as primary therapy rather than surgery or radiation therapy," he noted.

I was struck by men who had their PSA rising and were going out of their minds with worry.

Dr. Dale, who is trained as a geriatrician and has an appointment in oncology, spent a month in an oncology clinic talking to clinicians and patients about their decisions to start ADT. "I was struck by men who had their PSA rising and were going out of their minds with worry," he noted. In a study coauthored by Dr. Dale (J Clin Oncol 2009; 27:1557-1563), patient anxiety was shown to be the primary reason men with rising PSA counts, or biorecurrence, decided to start ADT .

In their editorials and comments to Medscape Oncology, Drs. Albertsen and Dale encouraged clinicians to limit their use of ADT to appropriate patients.

They also reminded clinicians of the potential deleterious effects of treatment, including osteoporosis, fatigue, weakness, adiposity, worse cholesterol profiles, hot flashes, and now the development of diabetes.

ADT for Some, But Not All, Advanced Localized Disease

In the treatment of prostate cancer, ADT should "primarily be limited to men with advanced localized disease undergoing radiation therapy and to men with clear signs of systemic disease," writes Dr. Albertsen in his editorial.

"These are the patients most likely to benefit from either symptom relief or increased survival that would justify the compromise in quality of life that is associated with androgen-deprivation therapy," he notes.

Dr. Albertsen reached this conclusion based on the available literature, which now includes the European study of men with advanced localized disease published in the New England Journal of Medicine.

In the study, the definition of locally advanced disease was either tumor stages T1c to T2a–b and nodal stage N1 or N2, or tumor stages T2c to T4 and clinical nodal stages N0 to N2. Patients with clinical evidence of metastatic spread were excluded.

The study indicates that, following external-beam radiation for locally advanced prostate cancer, 6 months of ADT does not provide survival superior to 3 years of treatment; the now-published results were originally presented at the ASCO annual meeting in 2007 and reported on by Medscape Oncology at the time.

In short, the study says that 3 years of ADT, which is the standard in this setting, should remain the standard.

The results are not generalizeable to men with other stages of prostate cancer, emphasized Dr. Albertsen. He added that the results might not be very helpful when considering American men with advanced localized disease.

"In Europe, more men have T3 disease," Dr. Albertsen said, referring to roughly 70% of the men in the study. European countries do not screen for prostate cancer as aggressively as the United States, he said. As a consequence, Europe has more cancers detected clinically and thus a different pool of patients with locally advanced prostate cancer.

In the United States, many men with advanced local disease will have T1c disease, which is characteristic of screen-detected cancers, Dr. Albertsen continued. These men typically have prostate cancers of much smaller volume and lower grade than the men in the European study, he explained.

It is "unclear" whether the European findings apply to men who receive radiation and ADT and have smaller volume and lower grade tumors characteristic of so much of screen-detected T1c disease, writes Dr. Albertsen.

Thus, the term locally advanced disease might need some qualification when considering ADT in the United States, suggested Dr. Albertsen.

Balancing the Risks for Therapy and Disease

According to Dr. Dale, the best candidates for early use of ADT are, in addition to patients with overt metastasis, younger patients (under 65) with "high-risk" disease (high-grade prostate cancer, local spread of disease into lymph nodes) receiving external-beam radiation. His comments, in effect, echoed Dr. Albertsen's

Dr. Dale also suggested that otherwise healthy men with very high-risk features (Gleason grade of 8–10, PSA doubling times of less than 3 months, short time between primary therapy and rising PSA) could be started early.

However, older patients with moderate-grade or lower disease and long PSA doubling times should definitely not be started on it right away, he emphasized.

"We have to balance the risk of the prostate cancer with the risks of the therapy when making these decisions," said Dr. Dale, adding that mixed information exists about the role ADT plays in worsening cardiovascular disease or diabetes.

However, the new American study "convincingly supports the conclusion that ADT contributes to the development of [diabetes mellitus]," writes Dr. Dale in his editorial.

In the retrospective study of more than 19,000 patients, the investigators found an adjusted hazard ratio of 1.26 (95% confidence interval, 1.16 - 1.36) for the development of diabetes mellitus among men undergoing ADT, said Dr. Dale. The number needed to harm due to the use of ADT was 91, he added.

Dr. Dale and Dr. Albertsen have disclosed no relevant financial relationships.

J Clin Oncol. 2009. Published online ahead of print June 8, 2009.
N Engl J Med. 2009;360:2516-2525 and 2572-2574.

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