July 11, 2008 — Primary androgen-deprivation therapy (ADT), used alone instead of surgery or radiation, does not improve survival, over conservative management, in the majority of elderly men with localized prostate cancer.

This finding, from an analysis of data from 19,271 men, appears in the July 9 issue of the Journal of the American Medical Association.

The study calls into question the increasingly common use of primary ADT, especially considering its significant adverse effects and cost, say the researchers. The findings contrast those for adjuvant ADT used alongside radiation and/or surgery, which does improve overall survival.

"I think that the bottom line is that primary androgen-deprivation therapy does not appear to benefit the average man with localized prostate cancer," senior author Siu-Long Yao, MD, from the Cancer Institute of New Jersey, in New Brunswick, told Medscape Oncology. "It is possible that certain subsets of men, such as those with poorly differentiated cancer, might derive some benefit, but you must carefully consider and justify the rationale for primary androgen-deprivation therapy if you are going to proceed with it."

"My conclusion would be that primary androgen-deprivation therapy does not appear to be a good alternative to surgery or radiation; outcomes appear to be no better than conservative management or watchful waiting," Dr. Yao commented.

"This study further reduces enthusiasm for the use of hormonal therapy in early-stage prostate cancer, and suggests that such treatment, if used at all, should be limited to high-grade disease, as defined by SEER [Surveillance, Epidemiology, and End Results]," commented Martin G. Sanda, MD, from the Beth Israel Deaconess Medical Center, in Boston, Massachusetts. Dr. Sanda was not involved in the study.

"Their findings of no survival benefit in intermediate- or low-risk disease add to other recent publications that elucidated flaws in hormonal therapy related to its adverse effects on quality of life and cardiac events among men with prostate cancer," Dr. Sandra added.

No Improvement in Overall or Cancer-Specific Survival

Primary ADT has become an increasingly popular option for localized prostate cancer, especially among older men, and is used in place of surgery, radiation, or conservative management, Dr. Yao and colleagues comment. However, the popularity of this option is not backed up by data; this is not a standard treatment approach, nor is it sanctioned by any major groups or guidelines, they point out.

And now they have shown that primary ADT is no better than conservative management.

Dr. Yao and colleagues performed an instrumental variable analysis on a population-based cohort of 19,271 men, aged 66 years or older, with clinical stage T1 or T2 prostate cancer. All the men were covered by Medicare and none received definitive local therapy; 7867 (41%) men received primary ADT, and the remainder were followed with conservative management.

The 10-year overall survival was practically identical — 30.2% with ADT vs 30.3% with conservative management (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.96 - 1.05).

The 10-year prostate-cancer-specific survival was also very similar (80.1% with ADT vs 82.6% with conservative management; HR, 1.17; 95% CI, 1.03 - 1.33).

However, ADT has significant adverse effects and is costly, the researchers point out. Previous studies have suggested a 10% to 50% increase in the risk for fracture, diabetes, coronary heart disease, myocardial infarction, and sudden cardiac death; a 500% increase in the risk for gynecomastia and hot flashes; and a 267% increase in the risk for impotence. In the United States, ADT cost $1.2 billion in 2003 and was the second-highest Medicare Part B drug expenditure.

In light of significant adverse effects, cost, and lack of improvement in survival, Dr. Yao and colleagues suggest that clinicians "carefully consider the rationale for initiating primary ADT in elderly patients with T1–T2 prostate cancer."

Ongoing Controversy — To Treat or Not to Treat

"This has been an ongoing controversy for a long time — to treat or not to treat elderly men with prostate cancer," commented Kevin Kelly, DO, from the Yale Cancer Center, in New Haven, Connecticut. Dr. Kelly was not involved in the study.

"There are 2 things that I consider when I treat these older men," he explained. "Number 1 is the extent/grade of the current prostate cancer, and number 2 is the projected longevity of the patient. If the patient has a high-grade tumor and locally advanced disease, he will have disease progression, morbidity, and/or mortality from the cancer in 5 years. Therefore, this is a reasonable subset of patients to treat if they are expected to live the 5 years."

"At the end of the day, it is proper patient selection and understanding what you want to accomplish with androgen-deprivation therapy," Dr. Kelly commented. "Perhaps survival is not the only end point we should look at."

This study was supported in part by the US Army Medical Research Acquisition Activity, Fort Detrick, Maryland, and the Cancer Institute of New Jersey; the Department of Defense, Ohl Foundation; and by the National Cancer Institute and the Cancer Institute of New Jersey. Dr. Yao and coauthors have disclosed no relevant financial relationships.

JAMA. 2008;300:173-181.

Clinical Context

Study Highlights

• Study data were obtained from the Surveillance, Epidemiology, and End Results program database, which has followed up 26% of the United States' population after 2001.
• The current study cohort consisted of 89,877 men age 66 years or older who were diagnosed with stage T1 or T2 prostate cancer between 1992 and 2002. Men who received definitive local therapy such as surgery or radiation or who died within 180 days of the diagnosis of prostate cancer were excluded from study analysis.
• Researchers used Medicare claims data to find participants treated with primary ADT, as defined by orchiectomy or the use of luteinizing hormone–releasing hormone agonists.
• The main outcome of the study was the rate of overall and prostate cancer–specific survival among subjects receiving primary ADT vs conservative management (no definitive localized therapy or ADT). This result was adjusted for potential confounders, including family history, diet, weight, and prostate-specific antigen levels.
• 19,271 men were included in the study analysis. The median age was 77 years, and the median follow-up duration was 81 months.
• 41% of these subjects received primary ADT. Compared with subjects receiving conservative treatment, men receiving primary ADT were older (mean age, 79 vs 77 years) and were more likely to have poorly differentiated or T2 prostate cancer.
• There were a total of 1560 deaths related to prostate cancer and 11,045 total deaths during follow-up.
• Primary ADT was associated with a 17% decrease in prostate cancer–specific survival vs conservative management (80.1% vs 82.6%, respectively).
• The incidence of overall 10-year mortality was 30.2% and 30.3% in the conservative management and primary ADT groups, respectively, a nonsignificant difference.
• The main results of the study appeared independent of other comorbidities.
• Among patients with poorly differentiated prostate cancer, primary ADT was associated with a borderline improvement in prostate cancer–specific survival (hazard ratio, 0.84). Primary ADT did not reduce the risk for overall mortality in this subgroup.
• Primary ADT was not beneficial among men with moderately differentiated prostate cancer.

Pearls for Practice

• ADT has been demonstrated to reduce mortality rates as an adjuvant treatment of high-risk prostate cancer, and it is frequently used as a primary treatment of localized prostate cancer. However, ADT has also been associated with higher risks for fracture, coronary heart disease, and diabetes.
• In the current study, primary ADT did not improve prostate cancer–specific survival or overall survival vs conservative treatment among older men with localized prostate cancer.

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