The role of ketoconazole in advanced prostate cancer
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Prostate cancer is the most common malignancy in American males above age 55. The cause of prostate cancer is not known. The most accepted risk factors are age, race and family history. Common signs and symptoms include dysuria, urethral obstruction, back or hip pain, and complications of advanced metastatic disease such as spinal cord compression and disseminated intravascular coagulation (DIC) syndrome.
The American Urological System of staging prostate cancer designates four stages of tumor growth, A through D, with each stage containing substages. Stage A is occult, nonpalpable; stage B is palpable, macroscopic tumor; stage C is tumor with extracapsular extension, but still clinically localized; and stage D is metastatic disease. The management of prostate cancer is greatly influenced by the stage of the disease but also by the patient’s age, physical condition, and response to prior therapy. Traditionally, prostatectomy or radiation therapy is considered for patients with stage A or B disease and hormonal therapies that suppress the body’s production of androgens have been a standard treatment for selected patients with stage C or stage D disease. In the past decade, however, studies have been suggested that earlier initiation of hormonal therapy for patients with early forms of metastatic disease may prolong disease-free survival and overall survival.
Androgens play an important role in promoting the growth of the prostate glands and about 80% of stage D prostatic tumors are androgen dependent. The hypothalamus secretes luteinizing-hormone-releasing hormone (LHRH) which in turn signals the pituitary gland to release luteinizing hormone (LH). Luteinizing hormone causes the testes to synthesize androgens, such as testosterone. After it is secreted by the testes, testosterone is metabolized into dihydrotestosterone (DHT) which then binds to its receptor to stimulate testicular protein production, cell division and growth. About 95% of testosterone is synthesized by the testes and the remaining 5% is released by the adrenal glands. The goal of hormonal therapy is to stabilize the disease or to provide regression, and this can be achieved by reducing testosterone to castrate level (<50 ng/mL). The most common hormonal therapies include bilateral orchiectomies, estrogen (e.g., diethylstilbestrol), LHRH agonists (e.g., leuprolide, buserelin, goserelin), progestins (e.g., megestrol acetate) and antiandrogens (e.g., flutamide, cyproterone, bicalutamide). The onset of action of these agents may take up to two weeks. It has recently been shown that ketoconazole can lower testosterone concentration to castrate levels within 48 hours. This prompt therapeutic onset of action has led to the investigation of ketoconazole as an antiandrogen agent.
Ketoconazole can lower testosterone concentration to castrate levels within 48 hours. Many studies show the agent inhibits two CYP450-dependent enzymes to block testosterone synthesis.
Ketoconazole is an imidazole antifungal agent. The antiandrogenic effects of this drug in mammalian cells were detected after the development of gynecomastia in some patients treated for fungal infections. Thereafter, many studies showed ketoconazole blocks the synthesis of testosterone by interfering with the cytochrome P-450-dependent enzymes of steroid biosynthesis. In the testes and the adrenal glands, cholesterol is converted to pregnenolone and progesterone. Both pregnenolone and progesterone are then transformed by a series of enzyme-controlled steps to dehydroepiandrosterone, androstenedione, and testosterone. Two cytochrome P-450-dependent enzymes, the 17-hydroxylase and the C17-20 lyase, catalyze this conversion. Ketoconazole inhibits both enzymes resulting in reduction of testosterone levels to reach castration levels in men.
First-Line Therapy
Trachtenber et al. examined the effects of oral ketoconazole 400 mg every 8 hours on 15 patients with advanced prostatic cancer.Two patients withdrew: one for personal reasons and one developed a paraspinal mass. Thirteen patients completed the study.After three days of therapy, the need for analgesics was greatly reduced in all patients. The mean serum testosterone concentrations decreased to near anorchid concentration. After six months of therapy, 13 patients were in remission and side effects of the drug were minimal. This study showed that ketoconazole was effective and well-tolerated.
In a study conducted by Aabo et al., the effect of ketoconazole was examined in 11 previously untreated prostatic cancer patients. High-dose ketoconazole 400 mg every 8 hours was reported effective in inducing complete response (elimination of pain and tumor cells) in two patients and partial response (reduction of pain, recalcification of osteolytic bone lesions) in four patients. The most common adverse reactions were nausea, anorexia and hypertension. A rebound increase in testosterone levels developed in five patients. The investigators concluded that adverse reactions and rebound increase in testosterone levels limit the use of high-dose ketoconazole as first-line therapy in advanced prostate cancer.
Cersosimo et al. reviewed a number of small studies in which ketoconazole 400 mg was given every 8 hours to a total of 88 patients. Complete and partial remissions were achieved in three and 15 patients, respectively. Adverse reactions included nausea and vomiting (33%), impotence, gynecomastia (10-15%), dry skin, elevation of hepatic aminotransferases and occasionally severe hepatitis.
Second-Line Therapy
Almost all patients will eventually no longer respond to conventional androgen deprivation therapy (orchiectomy, estrogens, LHRH agonists, etc.) and relapse. This syndrome has been termed the “antiandrogen withdrawal syndrome.” Recent reports have suggested that, in these situations, the administration of ketoconzole may be of some benefit. The rationale behind this therapy is based on the hypothesis that, after testicular castration, adrenal androgens play a significant role in prostatic tumor cell stimulation. Ketoconazole inhibits both testicular and adrenal androgenesis. Therefore, it can provide further androgen ablation.
Witjes et al. examined the efficacy of oral ketoconazole 400 mg every 8 hours or 600 mg every 12 hours daily in 28 patients. All patients had relapsing metastatic prostatic disease that was initially responsive to hormonal therapy. At the end of nine months of treatment, 13 patients died from metastatic disease. Nine patients withdrew: seven because of gastrointestinal (GI) side effects and two due to progressive disease. One patient was unevaluable. Five patients remained in the study: four were objectively stable and one had progressive disease. The clinical and biochemical results in both treatment regimens (400 mg every 8 hrs., 600 mg every 12 hrs.) were similar. Serum ketoconazole concentrations were within therapeutic levels (at least 4 µg/mL to achieve testosterone concentration within the castrate range) at 8 hrs. (400 mg every 8hrs. group) and 12 hours (600 mg every 12 hrs. group) after last ketoconazole intake. All five patients completed the study and were reported to be pain-free (required no analgesics). This study suggested that ketoconazole may be beneficial in the management of patients with relapsing metastatic prostate cancer. However, side effects of the drug may limit its use. Further studies are needed.
Small et al. studied the activities of ketoconazole in 50 patients who were refractory to flutamide and had progressive disease after flutamide withdrawal.Results of the study showed 30 patients had greater than 50% decrease in prostate specific antigen (PSA). The most common toxicities were GI upset, fatigue, edema, hepatotoxicity and rash. It was concluded that ketoconazole retained significant activity in patients who were refractory to antiandrogen therapy.
Emergency Management of disseminated intravascular coagulation (DIC) Syndrome
About 24% patients with prostatic cancer develop life-threatening disseminated intravascular coagulation syndrome, which requires emergency correction of the underlying disease. The triggering mechanism of this syndrome is due to the release of tissue factor by tumors into the circulation and activation of the coagulation cascade. This hypercoagulable state results in hemorrhage, thrombotic and embolic complications. Lowe and Somers reported the successful use of ketoconazole 400 mg every 8 hours in a 72-year-old black man with prostate cancer. Spontaneous bleeding from DIC stopped within 48 hours. Litt et al. also reported a similar case in an 84-year-old prostatic cancer patient. Ketoconazole 400 mg every 8 hours successfully reversed DIC syndrome in this patient after four days treatment and an orchiectomy was subsequently performed.
Conclusion
Ketoconazole inhibits the synthesis of androgens in both the testes and the adrenal glands by interfering with cytochrome P-450 enzymes. An effective dose appears to be 400 mg every 8 hours. At this level, the drug produces castrate levels of testosterone within 48 hours, produces subjective (e.g., significant pain relief) and objective (e.g., decrease in PSA levels and recalcification of osteolytic bone lesions) improvement in patients who have advanced prostate cancer. However, high incidence of adverse effects, such as severe GI intolerance, hepatic toxicity, impotence and gynecomastia may limit its routine use in this disease. Other disadvantages of ketoconazole include its short half-life that requires every-8-hour administration. Addisonian crises can occur in high-dose ketoconazole therapy and supplementation of dexamethasone may be necessary. Finally, rebound elevation of serum testosterone will occur after long-term (3–6 months) therapy.
Because of all these problems, ketoconazole is currently considered for a limited number of indications. Its major usefulness is in the group of patients who need a prompt therapeutic response, such as in disseminated intravascular coagulation (DIC) syndrome with advanced prostate cancer. It is an excellent modality for short-term use when orchiectomy, surgical or medical, or other forms of therapy, such as estrogens, are contraindicated. Finally, it can be used as initial empiric therapy to obtain prompt clinical relief during the diagnostic workup when prostate cancer is suspected. The role of ketoconazole in the treatment of patients with hormonal refractory disease has yet to be determined.
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