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Flutamide

Flutamide is an oral antiandrogen drug primarily used to treat prostate cancer. It competes with testosterone and its powerful metabolite, dihydrotestosterone (DHT) for binding to androgen receptors in the prostate gland. By doing so, it prevents them from stimulating the prostate cancer cells to grow. Flutamide has been largely replaced by a newer member of this class, bicalutamide, due to a better side-effect profile. Flutamide may also be used to treat excess androgen levels in women. It is marketed under the brand name Eulexin. more...

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Structure

Unlike the hormones with which it competes, flutamide is not a steroid; rather, it is a substituted anilide. After absorption, the molecule is quickly α-hydroxylated to its primary active form, hydroxyflutamide. Flutamide is excreted in various forms in the urine, the primary form being 2-amino-5-nitro-4-(trifluoromethyl) phenol.

Use in prostate cancer

Gonadotropin-releasing hormone (GnRH) is released by the hypothalamus in a pulsatile fashion; this causes the anterior pituitary to release leutinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates the testes to produce testosterone, which is metabolized to DHT by the enzyme 5α-reductase. DHT, and to a much smaller extent, testosterone, stimulate prostate cancer cells to grow. Therefore, blocking these androgens can provide powerful treatment for prostate cancer, especially metastatic disease. Normally administered are analogues of GnRH, such as leuprolide or goserilin. Although they stimulate the same receptors that GnRH does, since they are present continuously and not in a pulsatile manner, they serve to inhibit the pituitary and therefore block the whole chain. However, they initially cause a surge in activity; this is not solely a theoretical risk but may cause the cancer to flare. Flutamide was initially used at the beginning of GnRH-analogue therapy to block this surge, and it and other nonsteroidal anti-androgens continue in this use.

There have been studies to investigate the benefit of adding an anti-androgen to surgical orchiectomy or its continued use with a GnRH analogue (combined androgen blockade, CAB). Adding anti-androgens to orchiectomy showed no benefit, while a small benefit was shown with adding anti-androgens to GnRH.

Unfortunately, therapies which lower testosterone levels, such as orchiectomy or GnRH-analogue administration, also have signficant side effects. Compared to these therapies, treatment with antiandrogens exhibits "fewer hot flashes, less of an effect on libido, less muscle wasting, fewer personality changes, and less bone loss." However, antiandrogen therapy alone is less effective than surgery. Nevertheless, given the advanced age of many with prostate cancer, as well as other features, many men may choose antiandrogen therapy alone for a better quality of life.

Side effects

In addition to the effects previously mentioned, flutamide may also induce gynecomastia. Tamoxifen can partially counteract this effect. Some patients experience mild liver injury, which resolves when the drug is discontinued. It may also cause gastrointestinal side effects; one reason bicalutamide is replacing flutamide is that it appears to exhibits these to a lesser degree.

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Metastatic Prostate Cancer: Is Adding Flutamide Beneficial?
From American Family Physician, 2/15/99 by Jeffrey T. Kirchner

Prostate cancer is currently the most commonly diagnosed neoplasm in the United States. The median survival rate in men with metastatic disease ranges from 24 to 36 months. Because the growth of prostate cancer requires androgens, surgical castration is often performed in patients with advanced disease to suppress androgens and provide palliative effect. However, androgens are also produced by the adrenal glands. To counteract the effects of these androgens, agents such as leuprolide acetate and flutamide have been used. In an earlier study, Eisenberger and colleagues found that treatment with a combined androgen blockade of leuprolide acetate with flutamide improved patients' survival. In this double-blind, randomized study, the authors further evaluated the effects of this androgen blockade plus bilateral orchiectomy in the treatment of patients with metastatic prostate cancer.

Eligible patients had confirmed adenocarcinoma of the prostate with bone or distant soft-tissue metastases. All patients underwent early bilateral orchiectomy but received no previous or concomitant hormonal treatment, chemotherapy or biologic-response modifier therapy. Patients were still eligible for the study if they had received palliative radiation at sites of distant metastases. Baseline measurements of serum creatinine, prostate-specific antigen (PSA), liver enzymes, serum alkaline phosphatase, and serum testosterone levels were obtained. These measurements were repeated at one month and then every three months during the trial. Other diagnostic studies included a chest radiograph, a bone scan and a computed tomographic scan of the pelvis and abdomen at baseline and at six-month intervals for two years. Patients were randomized to either a treatment group, where they received two 125-mg capsules of flutamide three times a day until progression of the disease was noted, or a control group. The primary end point was death. Secondary end points included progression-free survival and PSA response.

During the five-year study period, 698 patients were randomly assigned to receive flutamide, and 687 were assigned to receive placebo. Patients had a mean age of 71 years. Twenty-two percent of the patients were black. The mean survival rate in the treatment group was 33.5 months compared with 29.9 months in the placebo group. This difference was not statistically significant. The median progression-free survival time was 20.4 months in the treatment group and 18.6 months in the placebo group. The percentage of PSA responses was higher in the treatment group (74 percent) than in the placebo group (61.5 percent). Despite this finding, patients in the flutamide group did not have better survival rates.

The authors conclude that flutamide offers no additional benefit to patients with metastatic prostate cancer following bilateral orchiectomy. This finding is in contrast to results of their previous study in which they found a 25 percent improvement in median survival in men with metastatic prostate cancer who were given flutamide with leuprolide acetate. In view of this, the authors recommend a reevaluation of medical and surgical options of castration, either alone or in combination with flutamide or other antiandrogen agents. The results cited in this study suggest that the benefits of combined androgen blockade in patients with metastatic prostate cancer are negligible.

Eisenberger MA, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med October 8, 1998;339:1036-42.

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