Edited comments by Laurence Klotz, MD

Prostate Cancer Prevention Trial

Three observations from the Prostate Cancer Prevention Trial (PCPT) are important with respect to prostate cancer management. The first is the 25 percent reduction in the rate of prostate cancer diagnosis in the finasteride- treated group. The second is that at the end of seven years, 25 percent of the patients in the placebo group had a positive biopsy. The third is the loss of libido and erectile function in the placebo group during the seven years of the trial.

Overdetection of early, low-risk prostate cancer

The high rate of prostate cancer detection in the PCPT is the latest piece of evidence indicating that screening may lead to increased rates of prostate cancer diagnosis. Another piece of evidence comes from the European Randomized Screening for Prostate Cancer (ERSPC) trial in which the rate of diagnosis in the screened arm was seven times higher than in the control arm, but mortality was the same. The inescapable conclusion is that we are diagnosing more patients with prostate cancer than the number of patients who are at risk of death from prostate cancer.

I don't believe we should stop screening just because we've had a phenomenal stage migration. However, we need to change the way we approach patients with favorable-risk, localized prostate cancer — patients with a mild PSA elevation or a normal PSA whose biopsies reveal small-volume, well-differentiated prostate cancer. Those patients are not likely to die from prostate cancer and should probably be followed rather than treated aggressively.

Regardless of age, the patient with a small microfoci of well-differentiated prostate cancer very possibly has minimal disease and may not need to be treated. Before the PCPT trial, it was believed that when the PSA went up, it reflected a larger volume of disease, which led to a biopsy. We've learned from the PCPT that we're diagnosing the 25 or 30 percent of patients with microfoci, and most of them should not be treated.

Effect of finasteride on the rate of prostate cancer and on tumor grade

The PCPT trial was unequivocally positive. In fact, it was stopped early because the results were so positive. Although 18,000 patients were enrolled, the results are based on the first 9,000 patients who underwent a biopsy. Compared to the patients receiving placebo, those treated with finasteride had a 25 percent reduction in the incidence of prostate cancer.

The rate of high-grade cancer was greater in the patients treated with finasteride. Two reasons may account for this difference in cancer grade. First, finasteride may artificially change the cancer grade. It's widely accepted that androgen deprivation therapy causes an upgrading of the Gleason score. Pathologists agree that a Gleason score can't be assigned after androgen deprivation therapy. It's also possible that finasteride interferes with androgen receptor function and predisposes patients to a higher-grade cancer.

Deciding whether patients should receive finasteride for prostate cancer prevention

To determine the value of finasteride in prostate cancer prevention, the results from the Medical Therapy of Prostatic Symptoms (MTOPS) trial must be considered. MTOPS was a large, four-arm, placebo-controlled trial in patients with benign prostatic hyperplasia (BPH) that evaluated an alpha-blocker (doxazosin) and finasteride. It demonstrated a definite benefit from treatment with the combination of an alpha-blocker and finasteride compared to either drug alone, and in terms of a reduced need for surgery, reduced urinary retention and improvement in symptoms.

Two positive trials evaluating the role of finasteride one in patients with BPH and one in patients with prostate cancer are relevant to the middle-aged man who's worried about prostate cancer. In a patient who has some enlargement of the prostate and is symptomatic, finasteride may reduce the symptoms and the likelihood of needing surgical intervention.

Use of finasteride is associated with a 25 percent reduction in the rate of prostate cancer, and it facilitates regrowth of hair. The potential downsides to finasteride include its impact on erectile function, which is uncommon and reversible, and a possible increased risk of high-grade prostate cancer. However, only two to four patients out of 1,000 actually develop higher-grade cancer.

Adjuvant hormonal therapy for patients with high-risk prostate cancer

Controversy exists about the management of patients with high-risk prostate cancer. The closest thing to a standard of care is external beam radiation plus two to three years of adjuvant hormonal therapy. However, data from several sources indicate that surgery may have a role for patients with high-risk disease. A randomized trial by Akakura et al from Japan demonstrated a survival benefit for patients with locally advanced prostate cancer who were treated with hormonal therapy and surgery compared to patients treated with hormonal therapy and radiation therapy.

Data from the Early Prostate Cancer (EPC) trial of adjuvant bicalutamide from Scandinavia demonstrated a survival benefit with bicalutamide compared to placebo in patients with locally advanced disease. These data support the idea that patients with high-risk disease may derive benefit from adjuvant androgen deprivation even those who have undergone radical prostatectomy. Data from Quebec indicate that patients treated with neoadjuvant hormonal therapy and surgery have a superior outcome compared to patients treated with hormonal therapy and radiation.

This whole concept of adjuvant hormonal therapy needs to be clarified. Based on a number of trials, early hormonal therapy offers a survival benefit. It has a role in patients with high-risk disease treated with radiation therapy. However, its role in patients who are treated with surgery is unknown. Conventional thinking indicates that in a small population of prostate cancer cells, a single androgen-independent cancer cell will eventually predominate despite androgen deprivation therapy.

However, the model of the "bystander effect" would suggest that an isolated androgen-independent cancer cell requires androgen-dependent cancer cells to survive. Hence, a role for more aggressive early therapy may exist, although it has yet to be proven. Over the next few years I foresee a shift toward earlier use of androgen deprivation therapy after radical prostatectomy in the adjuvant setting.

Meta-analysis of trials evaluating maximum androgen blockade

We've sold ourselves short in urology by discounting minor survival benefits. Paul Goss, at our center in Toronto, recently published a trial of letrozole in approximately 6,000 patients with breast cancer who were treated with five years of adjuvant tamoxifen. His trial demonstrated a very small disease-free survival benefit for letrozole that has been widely touted as being important.

In urology, we have comparable differences with maximum androgen blockade (MAB). There are at least six meta-analyses of nilutamide or flutamide plus medical or surgical castration versus castration alone. They all demonstrated approximately a 10 percent reduction in the hazard ratio for death at five years, which relates to about a three percent absolute survival benefit.

One study with 800 patients with a two-by-two factorial design bicalutamide or flutamide combined with goserelin or leuprolide acetate demonstrated that bicalutamide was approximately 12 percent better than flutamide in terms of risk of death. So the question is, "What conclusions can be drawn from the meta-analyses and this large randomized study?"

The statisticians contend trial results cannot be mixed, but that's not entirely true if certain conditions are fulfilled. In a situation where Drug A has been shown to be better than Drug B, and Drug B is superior to Drug C, you can then say Drug A is better than Drug C if the inclusion criteria for the trials are similar. The mathematics are quite complex, but it turns out that bicalutamide is 10 percent better than flutamide when both are combined with an LHRH agonist. Flutamide is 10 percent better than placebo when used in MAB. Scientifically, there is a reasonably sound basis for asserting bicalutamide plus castration is 20 percent better than castration alone. This analysis will be presented at the 2004 AUA meeting for the first time.

Role of MAB in patients with high-risk disease

I primarily use MAB with bicalutamide in patients I consider to be at higher risk of death from prostate cancer, for whom I really want to provide every opportunity for long-term survival. The typical patient currently being treated with androgen deprivation is one who was initially treated with radiation therapy or a prostatectomy and three or four years later has a rise in his PSA. Since those patients have very long-term survival, they may be on androgen deprivation for eight, 10 or 15 years. Hence, I'm a little reluctant to add more to their therapy. However, in the patients with higher-risk disease, such as those with metastatic disease or a rapidly rising PSA, I'm much more aggressive with MAB than I was a year or two ago.

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