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Neurologic complications of ketoconazole therapy for advanced prostatic cancer
NEUROLOGIC
COMPLICATIONS
OF KETOCONAZOLE
THERAPY FOR ADVANCED PROSTATIC CANCER K. A. HANASH. M.D. From the King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
ABSTRACT-Ketoconaxole, an antifungal agent, has been recently used for the treatment of metastatic (Stage D) prostatic carcinoma. It acts by blocking the synthesis of androgens in the testes and adrenal glands. Its major side effects are gastrointestinal and hepatic. We describe a patient in whom severe mental disturbances developed following ketoconazole treatment. Symptoms improved after withdrawal of the drug.
Ketoconazole, an imidazole derivative, has a broad-spectrum antifungal activity. Recently it was found to inhibit testosterone synthesis in the testes and adrenal glands.’ 3 This prompted its use for the treatment of metastatic prostatic carcinoma.4 ’ iVe report a case of severe mental disturbances following ketoconazole treatment. Case Report A seventy-six-year-old Saudi man was hospitalized because of acute urinary retention of twenty-four hours’ duration. He had been complaining of marked obstructive urinary symptoms, lumbar pains, generalized weakness, namely in the lower extremities, for several months prior to admission. He had been treated for two years with digoxin and furosemide (Lasix) for chronic congestive heart failure. Physical examination revealed an enlarged, stony hard prostate and tenderness over the lumbar spine and sacrum. His bladder was distended up to the umbilicus. On neurologic examination he had marked weakness in the lower extremities with depressed deep tendon reflexes. He was catheterized and his residual urine was 800 cc. The catheter was left indwelling. Laboratory findings included a hematocrit of 32 per cent, a hemoglobin of 11 g/dL, serum creatinine 1.8 mg/dL, blood urea nitrogen (BUN) 40 mg/dL, serum glutamic oxaloacetic
466
transaminase (SGOT) 80 UlmL; serum acid phosphatase 75 King-Armstrong U/100 mL. A chest x-ray film showed cardiac enlargement. A technetium-99m methylene diphosphonate bone scan revealed multiple metastatic lesions in the lumbar spine, sacrum, and right ilium. A transrectal prostatic biopsy demonstrated a poorly differentiated adenocarcinoma. The patient refused a bilateral orchiectomy. Ketoconazole was administered at a dose of 400 mg 3 times daily, at eight-hour intervals for a total dose of 1,200 mg. About seventy-two hours after the start of ketoconazole the patient was found to be apathetic and severely disoriented in space and time. He was immobile in bed and refused oral feeding. He had no memory for recent events and could not handle abstractions or solve simple arithmetic problems. A neurologic examination, performed by a neurologist, failed to reveal any focal signs or sensory deficits. There was no bruit over the carotid arteries. A SMAC 20 revealed no abnormalities of the blood sugar, electrolytes, magnesium, or calcium. Arterial blood gases were within normal limits. There was moderate elevation of his SGOT to 120 U/mL. His serum creatinine and BUN were unchanged. Serum testosterone was 75 ng/lOO mL ( normal 400-1,200 ng/lOO mL) and serum cortisol 5.2 mg/dL (5-25 mg/lOO mL). A computerized tomography of the brain revealed bilateral moderate cerebral atrophy but
UROLOGY
i
JUNE 1989
i
VOLUME
XxX111, NUMBER
6
no other lesions. Ketoconazole was discontinued and the patient kept on intravenous fluids. About seventy-two hours later, he became fully alert and oriented, resumed normal feeding, and could be ambulated with assistance. A bilateral orchiectomy was performed under local anesthesia. Three weeks later, the catheter was removed and the patient was voiding with some diffcultv.
systems. Further studies are warranted to elucidate their cause. Patients and their families should be warned about the side effects of this drug. The future use of ketoconazole analogues may decrease the high incidence of side effects of the drug. This may influence the urologist to include them in the primary treatment of metastatic prostatic cancer or as a secondary therapy for estrogen-resistant tumors.
Comment
6845 Elm Street
Ketoconazole acts by inhibiting the synthesis of cholesterol and interfering with cytochrome P-450 enzyme systems in several organs and namely the testes and adrenal glands.‘.2.8 The major site of action appears to be the C17-20 lyase. It blocks cholesterol side chain cleavage in both testes and adrenals.s High concentrations of the drug are required to inhibit androgen synthesis. The most commonly reported side effects are gastrointestinal disturbances, hepatic dysfunction and hepatitis, pruritis, impotence, gynecomastia, adrenal insufficiency, and hypocalcemia. 8_12The drug had to be discontinued because of severe adverse reactions, namely gastroenterologic, in 32 of 40 percent of the cases.s7 An asthenia syndrome, characterized by muscle weakness, fatigue, apathy, and anorexia has been reported to occur frequently in up to 58 percent of the cases in one series.6-1”.14One case, similar to our patient, developed mental disturbances with confabulation and disorientation which improved after withdrawal of the drug.6 All patients with the asthenia syndrome regained their pretreatment performance status, rapidly (within one week) after ketoconazole withdrawal. The pathogenesis of the neurologic disturbances is unknown. They may be attributed to acute adrenal insufficiency, secondary to inhibition of cortisol production, under stress. Nevertheless: cortisol levels were found to be within normal limits in those patients, such as in our case.fi.‘3.1s Another possible mechanism may be related to the interference with P450 enzyme
UROLOGY
/ JUNE 1989
/ VOLUME
XxX111, NUMBER
Suite 603 McLean, Virginia 22101
References 1. Pont A, ef al: Ketocunazolc blocks testosterone synthesis, Arch Intern Med 142: 2137 (1982). 2. Pont A, ef al: Ketoconazole blocks adrenal steroid synthesis, Ann Intern Med 97: 370 (1982). 3. DeCoster R. et al: Effects of high dose ketoconazolc therapy on the main plasma testicular and adrenal steroids in previousI\ untreated prostatic cancer patients. Clin Endocrinol 24: 657 (1986). 4. Trachtenherg J, and Pont A: Ketoconazole therapy for advanced prostate cancer, Lancet 2: 433 (1984). 5. Pont A: Long-term experience with high dose ketoconazolc therapy in patients with Stage D2 prostatic carcinoma. J Urol 137: 902 (1987). 6. Vanuytsel L, et al: Ketoconazole therapy for advanced prostatic cancer: feasihility and treatment results. J Urol 137: ROrj (1987). 7. Zadra J, Duffy P, and Trachenberg J: The treatment of metastatic prostatic cancer with ketoconazole (ahst 103X). J Urol 133: 272A (1985). 8. Sonino N: The use ketoconazole as an inhibitor of steroid production, N Engl J Med 317: 812 (1987). 9. Williams G: Ketoconazole for prostate cancer. Letter to the Editor, Lancet 2: 696 (1984). 10. Denis I,, Chahan M, and Mahlcr C: Clinical application of ketoconazole in prostatic cancer. Prog Clin Biol Rrs 185A: 319 (1985). 11. Williams C. cf ul: Objective rcsp~mscs to ketoconazole therapy in patients with relapsed progressive prostatic cancer, Br J Urol 58: 45 (1986). 12. Pont A: Long-term experience with high dose ketoconazole therapy for prostate cancer (ahst 389), J Urol 135: 201A (1986). 13. Trachtenherg J: Ketoconazole therapy in advanced prostatic cancer, J Ural 132: 61 (1984). 14. White MC, and Kendall-Taylor P: Adrenal hypofunction in patients with Ketoconazole. I,etter to the Editor. I,ancct 1: 13 (1985). 15. Williams 6, and Bloom SR: Treatment of advanced carcinoma of the prostate. Br Med J 289: ,571 (1984).
6
467
COMPLICATIONS
OF KETOCONAZOLE
THERAPY FOR ADVANCED PROSTATIC CANCER K. A. HANASH. M.D. From the King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
ABSTRACT-Ketoconaxole, an antifungal agent, has been recently used for the treatment of metastatic (Stage D) prostatic carcinoma. It acts by blocking the synthesis of androgens in the testes and adrenal glands. Its major side effects are gastrointestinal and hepatic. We describe a patient in whom severe mental disturbances developed following ketoconazole treatment. Symptoms improved after withdrawal of the drug.
Ketoconazole, an imidazole derivative, has a broad-spectrum antifungal activity. Recently it was found to inhibit testosterone synthesis in the testes and adrenal glands.’ 3 This prompted its use for the treatment of metastatic prostatic carcinoma.4 ’ iVe report a case of severe mental disturbances following ketoconazole treatment. Case Report A seventy-six-year-old Saudi man was hospitalized because of acute urinary retention of twenty-four hours’ duration. He had been complaining of marked obstructive urinary symptoms, lumbar pains, generalized weakness, namely in the lower extremities, for several months prior to admission. He had been treated for two years with digoxin and furosemide (Lasix) for chronic congestive heart failure. Physical examination revealed an enlarged, stony hard prostate and tenderness over the lumbar spine and sacrum. His bladder was distended up to the umbilicus. On neurologic examination he had marked weakness in the lower extremities with depressed deep tendon reflexes. He was catheterized and his residual urine was 800 cc. The catheter was left indwelling. Laboratory findings included a hematocrit of 32 per cent, a hemoglobin of 11 g/dL, serum creatinine 1.8 mg/dL, blood urea nitrogen (BUN) 40 mg/dL, serum glutamic oxaloacetic
466
transaminase (SGOT) 80 UlmL; serum acid phosphatase 75 King-Armstrong U/100 mL. A chest x-ray film showed cardiac enlargement. A technetium-99m methylene diphosphonate bone scan revealed multiple metastatic lesions in the lumbar spine, sacrum, and right ilium. A transrectal prostatic biopsy demonstrated a poorly differentiated adenocarcinoma. The patient refused a bilateral orchiectomy. Ketoconazole was administered at a dose of 400 mg 3 times daily, at eight-hour intervals for a total dose of 1,200 mg. About seventy-two hours after the start of ketoconazole the patient was found to be apathetic and severely disoriented in space and time. He was immobile in bed and refused oral feeding. He had no memory for recent events and could not handle abstractions or solve simple arithmetic problems. A neurologic examination, performed by a neurologist, failed to reveal any focal signs or sensory deficits. There was no bruit over the carotid arteries. A SMAC 20 revealed no abnormalities of the blood sugar, electrolytes, magnesium, or calcium. Arterial blood gases were within normal limits. There was moderate elevation of his SGOT to 120 U/mL. His serum creatinine and BUN were unchanged. Serum testosterone was 75 ng/lOO mL ( normal 400-1,200 ng/lOO mL) and serum cortisol 5.2 mg/dL (5-25 mg/lOO mL). A computerized tomography of the brain revealed bilateral moderate cerebral atrophy but
UROLOGY
i
JUNE 1989
i
VOLUME
XxX111, NUMBER
6
no other lesions. Ketoconazole was discontinued and the patient kept on intravenous fluids. About seventy-two hours later, he became fully alert and oriented, resumed normal feeding, and could be ambulated with assistance. A bilateral orchiectomy was performed under local anesthesia. Three weeks later, the catheter was removed and the patient was voiding with some diffcultv.
systems. Further studies are warranted to elucidate their cause. Patients and their families should be warned about the side effects of this drug. The future use of ketoconazole analogues may decrease the high incidence of side effects of the drug. This may influence the urologist to include them in the primary treatment of metastatic prostatic cancer or as a secondary therapy for estrogen-resistant tumors.
Comment
6845 Elm Street
Ketoconazole acts by inhibiting the synthesis of cholesterol and interfering with cytochrome P-450 enzyme systems in several organs and namely the testes and adrenal glands.‘.2.8 The major site of action appears to be the C17-20 lyase. It blocks cholesterol side chain cleavage in both testes and adrenals.s High concentrations of the drug are required to inhibit androgen synthesis. The most commonly reported side effects are gastrointestinal disturbances, hepatic dysfunction and hepatitis, pruritis, impotence, gynecomastia, adrenal insufficiency, and hypocalcemia. 8_12The drug had to be discontinued because of severe adverse reactions, namely gastroenterologic, in 32 of 40 percent of the cases.s7 An asthenia syndrome, characterized by muscle weakness, fatigue, apathy, and anorexia has been reported to occur frequently in up to 58 percent of the cases in one series.6-1”.14One case, similar to our patient, developed mental disturbances with confabulation and disorientation which improved after withdrawal of the drug.6 All patients with the asthenia syndrome regained their pretreatment performance status, rapidly (within one week) after ketoconazole withdrawal. The pathogenesis of the neurologic disturbances is unknown. They may be attributed to acute adrenal insufficiency, secondary to inhibition of cortisol production, under stress. Nevertheless: cortisol levels were found to be within normal limits in those patients, such as in our case.fi.‘3.1s Another possible mechanism may be related to the interference with P450 enzyme
UROLOGY
/ JUNE 1989
/ VOLUME
XxX111, NUMBER
Suite 603 McLean, Virginia 22101
References 1. Pont A, ef al: Ketocunazolc blocks testosterone synthesis, Arch Intern Med 142: 2137 (1982). 2. Pont A, ef al: Ketoconazole blocks adrenal steroid synthesis, Ann Intern Med 97: 370 (1982). 3. DeCoster R. et al: Effects of high dose ketoconazolc therapy on the main plasma testicular and adrenal steroids in previousI\ untreated prostatic cancer patients. Clin Endocrinol 24: 657 (1986). 4. Trachtenherg J, and Pont A: Ketoconazole therapy for advanced prostate cancer, Lancet 2: 433 (1984). 5. Pont A: Long-term experience with high dose ketoconazolc therapy in patients with Stage D2 prostatic carcinoma. J Urol 137: 902 (1987). 6. Vanuytsel L, et al: Ketoconazole therapy for advanced prostatic cancer: feasihility and treatment results. J Urol 137: ROrj (1987). 7. Zadra J, Duffy P, and Trachenberg J: The treatment of metastatic prostatic cancer with ketoconazole (ahst 103X). J Urol 133: 272A (1985). 8. Sonino N: The use ketoconazole as an inhibitor of steroid production, N Engl J Med 317: 812 (1987). 9. Williams G: Ketoconazole for prostate cancer. Letter to the Editor, Lancet 2: 696 (1984). 10. Denis I,, Chahan M, and Mahlcr C: Clinical application of ketoconazole in prostatic cancer. Prog Clin Biol Rrs 185A: 319 (1985). 11. Williams C. cf ul: Objective rcsp~mscs to ketoconazole therapy in patients with relapsed progressive prostatic cancer, Br J Urol 58: 45 (1986). 12. Pont A: Long-term experience with high dose ketoconazole therapy for prostate cancer (ahst 389), J Urol 135: 201A (1986). 13. Trachtenherg J: Ketoconazole therapy in advanced prostatic cancer, J Ural 132: 61 (1984). 14. White MC, and Kendall-Taylor P: Adrenal hypofunction in patients with Ketoconazole. I,etter to the Editor. I,ancct 1: 13 (1985). 15. Williams 6, and Bloom SR: Treatment of advanced carcinoma of the prostate. Br Med J 289: ,571 (1984).
6
467