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First-line therapies for advanced disease

The medical treatment of prostate cancer begins when a patient has either not responded to local treatment efforts or presents with advanced disease that cannot be treated effectively with surgery or radiation therapy. First-line therapy for advanced disease is surgical or medical castration.

In this Section:

• Bilateral orchiectomy
• LHRH analogs
• Antiandrogens
• Combined androgen blockade
• Diethylstibestrol (DES)
• Treatment recommendations

 

Bilateral orchiectomy

The testes normally produce approximately 95% of the testosterone in human males, and bilateral orchiectomy reduces plasma testosterone levels by approximately 93%. Although there are other ways besides castration to lower serum testosterone (primarily through the estrogen action of LHRH analogs; see below), bilateral orchiectomy has distinct advantages. These include the lack of compliance problems or the need to adjust dose to the patient's metabolic state, and the absence of the potentially fatal cardiovascular complications that are often seen with high-dose estrogen therapy. Medical treatment also must be maintained for life and can be very costly. The psychological impact of castration is severe; however, and many men opt for medical therapy if given a choice.

 

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LHRH analogs

LHRH agonists, such as leuprolide acetate and goserelin acetate, regulate the release of LH and thereby produce chemical castration. These agents spare the patient the psychological trauma of an orchiectomy and also are devoid of the cardiovascular side effects associated with estrogen treatment (Table 3).

Because LHRH analogs can cause a transient increase in testosterone and induce a 'flare' response, an antiandrogen, such as flutamide, bicalutamide, and nilutamide, is utilized during the first month of LHRH therapy.

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Antiandrogens

Antiandrogens block the effects of androgens at the prostate tissue level. These compounds appear to interfere with the binding of the active metabolite of testosterone, dihydrotestosterone, to its receptor within the prostate.

The most commonly used antiandrogens are cyproterone acetate (Androcur), flutamide, megestrol acetate, bicalutamide, and nilutamide. Ketoconazole (Nizoral), an antifungal agent, is also often used. As mentioned above, antiandrogens are added to LHRH analogs to block any transient stimulation of testosterone by these agents or to directly block any remaining androgens that may affect the prostate.

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Combined androgen blockade

Surgical or medical castration decreases circulating testosterone by 90% - 95%. It has been demonstrated that the remaining androgens result from peripheral conversion of adrenal steroids. Several investigators have suggested that complete androgen blockade (CAB) or total androgen blockade (TAB), achieved by adding flutamide (250 mg PO tid), bicalutamide (50 mg PO daily), or nilutamide (150 mg PO daily) to castration, results in better disease control.

Although controversial, CAB is most likely beneficial only in patients with minimal symptoms and minimal disease on bone scan. Patients who present with widespread advanced disease and/or poor performance status do not appear to benefit from this approach.

 

Diethylstilbestrol (DES)

Estrogen administration, in the form of DES, also produces chemical castration. DES inhibits prostate growth, primarily through inhibition of the hypothalamic-pituitary-gonadal axis, which blocks testicular synthesis of testosterone and thus lowers plasma testosterone. Since doses over 3 mg/d cause significant cardiovascular mortality, DES has fallen out of favor as a first-line therapy to induce castration.

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Treatment recommendations

A patient who presents with advanced prostate cancer requires medical or surgical castration. Although this has not definitely been demonstrated to increase the patient's life-span, the quality-of-life benefits gained from disease control are unquestioned. Controversy exists over whether to start treatment early, when a patient is still asymptomatic, or to wait until symptoms develop. However, it is generally accepted that treatment should begin early. The primary goal of early androgen deprivation should be prolongation of survival or prevention of catastrophic consequences of advanced disease.

In patients with minimal bone involvement (usually defined as fewer than five lesions) and minimal symptoms, CAB is the treatment of choice. This can be accomplished by orchiectomy or the use of depot injections of leuprolide (7.5 mg SC monthly) or goserelin (3.6 mg SC monthly). Further androgen blockade is accomplished by the addition of an antiandrogen, such as flutamide (250 mg PO tid), bicalutamide (50 mg PO daily), or nilutamide (150 mg PO daily).

Patients presenting with widespread bone or soft-tissue disease can be treated with surgical castration alone. If medical castration therapy is used, treatment with an antiandrogen for one month after the initiation of castration therapy is recommended. This can be accomplished with flutamide, bicalutamide, nilutamide, or ketoconazole (400 mg PO tid).

Recently, the efficacy of bicalutamide monotherapy (150 mg/d) compared with flucamide + goserelin was tested in a randomized study of patients with histologically proven C or D disease. Fewer patients in the bicalutamide group experienced loss of libido (P=.O01) and of erectile dysfunction (P=.002). Significant trends also were noted in the bicalutamide-treated patients with respect to their quality of life and social functioning, vitality, emotional well-being, and physical capacity. Bicalutamide monotherapy may represent a major advance in the treatment of hormone-naive advanced prostate cancer.

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