Urologist, Not Tumor, Drives Androgen Deprivation Therapy

GALVESTON, Tex., June 20 ? Whether a man with prostate cancer is treated with androgen deprivation may depend more on his choice of urologist than on the nature of his tumor or his age, researchers here suggested.

"The use of androgen deprivation therapy for prostate cancer has been increasing, even in settings for which there is weak or no evidence of efficacy," wrote Vahakn B. Shahinian, M.D., M.S., and colleagues, of the University of Texas Medical Branch here, in the June 21 issue of Journal of the National Cancer Institute.

Some of the androgen deprivation therapy may be attributable to uncertainties about how who is most likely to benefit, the investigators commented. But it could also be due to urologist response to patient pressures for overt action, financial incentives to use gonadotropin-releasing hormone (GnRH) agonists, or to the influences of local thought leaders.

The reason this is important, they said, is that although androgen deprivation combined with radiation therapy has been shown to improve survival in men with locally advanced prostate cancer, the therapy is associated with significant side effects, including sexual dysfunction, osteoporosis, and fractures.

In addition, the therapy isn't cheap, the investigators pointed out.

"Androgen deprivation therapy in the form of GnRH agonists is very costly, making it the second highest Medicare Part B expenditure, at approximately .2 billion in 2003," they wrote.

To estimate the degree to which the decision to prescribe androgen deprivation was evidence-based, the investigators evaluated data on nearly 62,000 men with prostate cancer. They found that about one-fifth of the variation noted in the use of androgen deprivation therapy to treat the disease could be attributed to the decisions of urologists.

In contrast, less than one-tenth of the variance could be attributed to tumor characteristics such as stage or Gleason grade, or to patient characteristics such as age, race, or performance status, the investigators found.

"The substantial variations in rates of androgen deprivation use between urologists raise concerns about whether the therapy is being used appropriately," they wrote.

In an accompanying editorial, Paul F. Schellhammer, M.D., a professor of urology at Eastern Virginia Medical School, in Norfolk, acknowledged the uncertainties surrounding androgen deprivation/blockade for prostate cancer.

"The timing of androgen deprivation therapy in the absence of symptoms presents the urologist with the following dilemma," he wrote. "Should androgen deprivation therapy be withheld because of the paucity of evidence-based trials demonstrating survival benefits, or should it be administered because it could provide, at the minimum, a temporary dramatic biochemical, radiologic, or clinical response?"

But Dr. Schellhammer took issue with how the Galveston group determined disease severity in the patients studied, arguing that they may have underestimated the risk category for a significant number of the men included in the study.

The Galveston researchers assembled a retrospective population-based cohort of men with incident prostate cancer using the Medicare linked Surveillance, Epidemiology and End-Results (SEER) database.

They identified 61,717 men age 65 years and older who were diagnosed with prostate cancer from the beginning of 1992 through the end of 1999, and 1,802 urologists who cared for these patients within one year of diagnosis.

They used multilevel analyses to create estimates of the relative contributions of urologists' choices, tumor characteristics, and patient characteristics to the decision to use androgen deprivation therapy within six months of diagnosis.

The study cohort was divided into two groups based on year diagnosed (1992 to 1996, and 1997 to 1999). They did so because of publication in 1997 of a study showing a survival advantage for men with locally advanced prostate cancer who were treated with both radiation therapy and androgen deprivation.

The investigators also divided the cohort into men for whom the androgen deprivation therapy was presumably evidence-based, and those in whom the treatment was of uncertain benefit.

They found that "the percentage of the total variance in the use of androgen-deprivation therapy attributable to the urologist was consistently higher than that attributable to tumor or patient characteristics."

The pattern was most pronounced for those patients who were diagnosed during the last three years studied (Jan. 1, 1997, through Dec. 31, 1999), during which 22.56% of the total variance in use of androgen deprivation therapy was attributable to the urologist, 9.71% could be chalked up to tumor characteristics (stage or Gleason grade), and 4.29% could be pinned on patient characteristics (age, ethnicity, socio-economic status, comorbidity, geographic region, or year of diagnosis).

Dr. Shahinian and colleagues offered several possible explanations for the variance in androgen deprivation use they saw, such as uncertainty about the benefit of the therapy.

"For instance, in a national survey of urologists about recommended treatment for patients with localized prostate cancer who were older than 70 (in which more than one response could be selected), 74% chose radiation, 48% chose radical prostatectomy, 31% chose androgen deprivation therapy, and 38% chose observation only," they wrote.

Anther potential factor could be that clinical indications for the use of androgen deprivation during the study period broadened.

Still other possibilities include "financial incentives for the urologist to prescribe GnRH agonists, pressure from patients to prescribe something in the face of a cancer diagnosis, or influences from local opinion leaders," the investigators wrote. "Physicians may differ in their response to these influences, and these differences may contribute to the variance in use of androgen deprivation therapy."

In his editorial, Dr. Schellhammer noted that the authors used Gleason sums rather than Gleason scores to estimate risk category, an approach that may undercount men in higher risk categories for whom androgen deprivation would be appropriate.

In addition, they did not have access to data on prostate specific antigen levels.

"They state that, because neither grade nor stage influenced their variance analysis, they assumed that PSA data would not either," Dr. Schellhammer wrote. "I disagree. PSA data may have provided information to expand the high-risk evidence-based cohort and thus decrease the variance attributed to the urologist."

He added that "there are few strategies for the treatment of non-germ-cell solid tumors that can so rapidly lower a disease-related serum marker (such as PSA) to undetectable levels and that can produce such dramatic subjective and objective responses for as long as a decade."