SWOG-S9921: Combined androgen deprivation with or without mitoxantrone and prednisone after radical prostatectomy

This ongoing trial, which is very important, randomly assigns men who have had a radical prostatectomy and are at high risk for recurrence to combined androgen blockade for two years with or without chemotherapy (3.1).

We have almost 500 patients enrolled on this study, and we need about 1,400 to complete it. SWOG-S9921 sets out to define whether adding something to radical prostatectomy makes a difference.

Neoadjuvant hormonal therapy trials

Years ago, studies of hormonal therapy administered prior to radical prostatectomy were conducted to determine if the positive surgical margin rate could be improved. Dr Soloway did a study in the United States (Soloway 2002), as did Dr Debruyne in Europe (Schulman 2000) and Dr Gleave in Canada (Gleave 2001).

These studies showed that the use of hormonal therapy for three or eight months before surgery significantly decreased the positive margin rate. However, at three, five and even six years, no differences in the PSA failure rates were noted (Schulman 2000; Soloway 2002; Aus 2002), which led people to believe that neoadjuvant hormonal therapy didn’t do anything. These trials, however, were not powered with enough numbers and follow-up time.

My prediction is that with time, some of these studies will show a difference in the PSA failure rates. In patients with local prostate cancer, we’re not going to obtain answers quickly. Sometimes it will take 10 or 15 years to observe a difference between the arms of a trial.

SWOG-S9916: Docetaxel/estramustine versus mitoxantrone/ prednisone in men with hormone-refractory metastatic disease

We reported at a plenary session at ASCO 2004 and published in the New England Journal of Medicine our large Phase III trial headed up by Dan Petrylak from Columbia, which compared docetaxel and estramustine to mitoxantrone and prednisone (Petrylak 2004a, b; [3.2]).

This was the first trial in my history in the Southwest Oncology Group to show a survival benefit (1.3), and we’ve studied every drug known to mankind. While the survival benefit in SWOG-S9916 was a couple months, it’s a big leap. The next leap, I think, is to use that as a basis for a platform to add new agents.

Intermittent versus continuous androgen deprivation: Goserelin/bicalutamide

SWOG-S9346, which has been ongoing for a number of years, has accrued about 2,000 patients. Men with newly diagnosed, untreated metastatic disease receive combined androgen ablation. At nine months, if their PSA drops below 4 ng/mL, they are randomly assigned to continuous or intermittent therapy.

With intermittent therapy, the patient resumes hormonal therapy when his PSA goes up to a predetermined level — usually half of the baseline level or 10 ng/mL.

The whole idea is to provide a hormonal therapy holiday to reduce toxicity and costs. Integrated in that trial is the use of bisphosphonates, particularly zoledronic acid, to evaluate its effect on bone disease.

We have enough data suggesting that intermittent therapy is probably not going to make the patient’s scenario worse; at least that’s what has been reported. Whether it’s going to be better is unknown. If it’s the same as continuous therapy, it’s a no-brainer that intermittent therapy would be the choice, since patients can have a drug holiday with fewer side effects and less expense.

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Dr Crawford is a Professor of Surgery and Radiation Oncology and the Head of Urologic Oncology at the University of Colorado Health Sciences Center in Aurora, Colorado.