Clinical use of intermittent androgen deprivation therapy

I think the role of intermittent androgen deprivation therapy for patients with D2 disease is not that compelling (1.1). Of course, the more common situation is a rising PSA after the failure of local therapy, and the majority of these patients are being treated with hormonal therapy too early and aggressively. Many of them, such as a 75-year-old man who received radiation therapy five years ago and now has a PSA of 3 ng/mL, are probably not at risk of death from prostate cancer. Opinions vary, but my view is that many of these patients are not at risk. The data are clear that these patients do not need to be treated at that point.

If they are going to be treated, however, the less treatment the better, and intermittent androgen deprivation therapy is appropriate, even if the trials show a modest adverse effect on survival. I think the patients who are at risk of not doing well on intermittent androgen deprivation therapy are those with quite advanced, relatively rapidly progressing, life-threatening disease.

Use of bicalutamide 150 mg

Certainly, people talk about the benefit of bicalutamide 150 mg in terms of sparing libido, but I think the bone mineral density story is more compelling. Bicalutamide 150 mg actually increases bone mineral density (Smith 2004; [1.2]) because the high levels of testosterone are converted into estrogen, which is a bone mineral density-sparing hormone. To me, that is really the strong argument for its use.

There are two caveats, however. First is the question of whether bicalutamide 150 mg is equivalent in terms of duration of survival. The second issue is gynecomastia. A number of my patients who are on the bicalutamide EPC trial (Wirth 2004) have had breast reduction surgery. They’re quite happy, but this was definitely an issue for them.

I have not used much prophylactic radiation in these patients. I probably should use more of it, but it doesn’t work in everyone, and it’s radiation to the chest. The patients aren’t too keen about it, so I haven’t really employed it. There are studies using tamoxifen (Perdona 2005; Saltzstein 2005; Boccardo 2005), but one of the problems is that if it’s the estrogen that’s contributing to the increase in bone mineral density, maybe by using tamoxifen to block gynecomastia, you’re blocking the benefit on bone mineral density. From a theoretical perspective, it is possible tamoxifen will have an adverse effect.

Docetaxel for patients with hormone-refractory prostate cancer

In patients with metastatic disease, two trials have shown a survival benefit with docetaxel. This was widely acknowledged to be a huge step forward because, up to that point, chemotherapy provided just a quality-of-life benefit. A survival benefit is a major event. Of course, the size of that benefit was somewhere around two and a half months (Petrylak 2004; Tannock 2004; [1.3]). The trials compared docetaxel against other chemotherapy regimens. Hence, it’s definitely a significant event in the history of the management of prostate cancer.

Clearly, the standard of care is now docetaxel, and it should be offered to patients who have hormone-refractory metastatic prostate cancer. The controversy involves whether it should be offered earlier, and those studies are being conducted. If a patient has a rapidly rising PSA with hormone-refractory metastatic disease — whether he’s symptomatic or not — I think it’s reasonable to treat him with docetaxel. I use the PSA doubling time as a surrogate marker for symptomatic progression, because I know that the patient is going to have symptoms soon. If he has hormone-refractory disease without evidence of recurrence, I don’t treat him.

Tolerability of docetaxel

Docetaxel is very well tolerated, and the mortality rate from toxicity is extremely low. I have been very impressed with the favorable toxicity profile of docetaxel. I also think that elderly patients tolerate it quite well. The toxicity associated with chemotherapy is acute, while the toxicity associated with hormonal therapy is chronic, long term and insidious. Patients receive chemotherapy for a much shorter period of time, as a rule.

Benefits of MAB with bicalutamide in patients with metastatic disease

We integrated the results from trials with a common treatment arm in situations in which it’s no longer feasible to conduct a placebo-controlled trial. Dr Schellhammer compared bicalutamide to flutamide with goserelin or leuprolide and demonstrated a 13 percent reduction in the risk of death for the patients receiving bicalutamide compared to those receiving flutamide (Schellhammer 1997).

We integrated those data with the results from the meta-analysis of the Prostate Cancer Trialists’ Collaborative Group, which demonstrated a significant eight percent reduction in the risk of death for patients treated with flutamide plus castration compared to those treated with castration alone (Prostate Cancer Trialists’ Collaborative Group 2000). The flutamide/castration arm can be canceled out, and you end up with a comparison of bicalutamide plus castration to castration alone even though they have never been directly compared. This analysis demonstrated a 20 percent reduction in the risk of death for patients treated with bicalutamide plus castration.

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Dr Klotz is a Professor of Surgery at the University of Toronto and Chief of the Division of Urology at Sunnybrook and Women’s College Health Sciences Centre in Toronto, Ontario.