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Ketoconazole in initial management and treatment of metastatic prostate cancer to spine
KETOCONAZOLE
IN INITIAL MANAGEMENT
AND TREATMENT
OF METASTATIC
PROSTATE CANCER TO SPINE MITCHELL
H. BAMBERGER,
FRANKLIN
C. LOWE,
M.D.
M.D.
From the Departments of Urology, St. Luke’s_Roosevelt Hospital Center, and Columbia University College of Physicians and Surgeons, New York, New York
ABSTRACT-Ketoconaxole in high doses cauSes castrate levels of testosterone within twenty-four to forty-eight hours; therefore it is extremely useful in the initial medical treatment of patients with metastatic prostate cancer who need a prompt therapeutic response. Review of 17 patients who presented with severe radicular pain or acute paraparesis/paraplegia showed that there was frequent delay in urologic consultation, pathologic confirmation, and initiation of efficacious therapy. In fact, 5 of 12 patients (42 %) who received radiation therapy prior to effective hormonal therapy suffered significant morbidity and mortality. The case is made for the use of ketoconaxole for initial empirical therapy for these patients.
Since 1941, the treatment of metastatic prostate cancer has been based on Huggins and Hodges’ observation that prostate carcinoma is androgen dependent. Approximately 40 percent of patients presenting with prostate cancer have metastatic disease.2 Among these patients is a group with a variety of complaints including lower back pain, numbness, or difficulty in ambulation. Parasthesia, paraparesis, and loss of bowel or bladder control are ominous signs of spinal cord involvement. The diagnosis of prostate cancer must be considered in the evaluation of these patients. Prompt and efficacious therapy must be initiated to prevent these neurologic deficits from progressing and becoming irreversible. Traditionally, patients with metastatic prostate cancer have been treated with oral estrogens or surgical castration by bilateral orchiectomy. Patients with impending spinal cord compression require immediate effective treatment of their prostate cancer. Although immediate orchiectomy has been the classic recommendation, radiation therapy in conjunction
UROLOGY
I
OCTOBER
1988
I
VOLUME
XXXII,
NUMBER
with steroids has been the most commonly used treatment in this clinical situation, with laminectomy being reserved for those patients who either fail to respond or who show signs of progressive neurologic deterioration.3 Unfortunately, the response and results to radiation therapy are unpredictable and variable.* A common alternative therapy is oral estrogens; however, this medication requires approximately two weeks to achieve castrate levels of testosterone and a longer period of time to observe for tumor regression.5 Surgical castration by bilateral orchiectomy provides prompt response, but it is not always readily acceptable to patients. Currently, a new modality, androgen synthesis blockade with ketoconazole, provides an acceptable alternative method for initial treatment of metastatic prostate carcinoma. This review of patients with newly diagnosed metastatic prostate cancer to the spine suggests that their management and treatment with either immediate castration or ketoconazole could have improved the course of their disease.
4
301
Material and Methods
TABLE I.
The clinical data of all 83 patients at St. Luke’s Hospital receiving external beam radiation therapy for spinal metastasis from prostate cancer from 1977 to 1986 were reviewed. Seventeen patients (20%) were found to have had no prior history or treatment of prostate cancer and were categorized as newly diagnosed Stage D-2 prostate cancer. The data on these 17 patients were carefully evaluated for presenting symptoms, length of time for urologic consultation, and for diagnostic confirmation. Treatment as well as response and morbidity were also analyzed. Results The most common complaint was either lower back or referred extremity pain in 13 patients (76 % ) . Neurologic symptoms including decrease in ambulation, parasthesia, and numbness was present in 4 patients (24 % ). The spinal metastases were almost equally divided between the lumbar, thoracic, and multiple areas. Urologic consultation was obtained at various times. Five patients were seen immediately. Overall, urologic consultation was obtained with a mean of 5.5 days and a median of 3.0 days after admission (Table I). Mean time for the initiation of hormonal therapy was 11.1 days for orchiectomy and 10.4 days for diethylstilbestrol. The timing of therapy for both external beam radiation therapy and hormonal manipulation was reviewed. Seven patients (41%) received external beam radiation therapy prior to hormonal therapy. Eight (47 % ) had external beam radiation therapy started after the initiation of hormonal manipulation; however, only 4 patients had orchiectomies. Another patient received external beam radiation therapy and diethylstilbestrol simultaneously. Therefore, 12 of 17 patients (71%) were treated with radiation therapy prior to the onset of effective hormonal therapy (oral diethylstilbestrol takes approximately 14 days to achieve castrate levels of testosterone). Five of these 12 patients suffered significant complications: 3 had laminectomies/ paraplegia and 2 died. None of the other group had significant early complications. Comment In approximately 50 percent of all patients with prostate cancer, bone metastasis even-
302
Days until urologic consultation
No. of Days
No. of Patients
0 l-3 over 5 over 30
5 7 3
2
tually develops.4 Pain, the most frequent symptom, is caused by a combination of stretching of the periosteum, nerve entrapment, tumor expansion, and pressure on the nerve roots. Vertebral body destruction is often associated with extradural spinal cord compression and can lead to irreversible neurologic changes if not recognized and treated early. The goal of treatment of metastatic disease is relief of pain and prevention of permanent neurologic deficits. Localized radiation therapy is useful in treating pain secondary to bone metastasis, but it is controversial in its efficacy.4 Reports show from 73 to 96 percent of patients receiving radiation therapy achieved partial or complete pain relief; however, the duration of the beneficial response has not been adequately evaluated or assessed.4 Systemic treatment for relief of bone pain may be preferable to localized external beam radiation therapy in patients with rapidly progressive disease. Neurologic changes may become irreversible if not treated emergently. Iacovou and associates3 evaluated 37 patients who underwent laminectomy for metastatic prostate cancer; 29 percent had cord compression as the initial presentation. Their evaluation revealed several important findings: (1) those able to walk prior to laminectomy were longterm survivors and remained ambulatory; (2) the advent of immobility in less than twentyfour hours was associated with poor results; (3) preoperative paraplegia was a consistently accurate indicator of poor prognosis; (4) patients with paraplegia received no benefit from surgery; (5) diagnosis of prostate cancer was considered to be delayed if it was not made within forty-eight hours after admission; and (6) delay in diagnosis usually resulted in permanent functional loss. Thus, prompt and accurate diagnosis needs to be made as soon as possible, preferably in less than forty-eight hours, to initiate therapy to prevent further irreversible neurologic deficits. When acute paraparesis/paraplegia is noted, immediate effective therapy is required. Classic teachings recommend emergent bilateral orchiectomy .because elimination of 90 percent of
UROLOGY
I
OCTOBER 1988 I
VOLUME XXXII, NUMBER 4
testosterone occurs within two to six hours (mean of 3 hours). 5 Rapid clinical response can be seen in approximately 80 percent to 85 percent of patients. Bilateral orchiectomy is the fastest and most effective method to produce castrate levels of testosterone whenever rapid treatment is indicated. Although the classic teachings recommend immediate orchiectomy for those patients with acute onset of paraparesis/paraplegia presumably secondary to metastatic prostate cancer, this study showed that the realities of clinical medicine are completely different. A urologic consultation was obtained within a mean of 5.5 days and a median of 3.0 days after admission. Besides the delays in consultation, scheduling biopsies, waiting for pathology reports, and scheduling surgery, obtaining patient/family acceptance for castration were frequently important issues. Thus, hormonal therapy was not initiated promptly, with a mean of 11.1 days for orchiectomy and 10.4 days for diethylstilbestrol. Obviously, alternative forms of initial efficacious hormonal therapy are needed. Ketoconazole is the perfect alternative for initial empirical hormonal therapy for these patients.6 Numerous reports have shown ketoconazole to be an effective hormonal agent for metastatic prostate cancer.e-10 In doses of 400 mg orally every eight hours, serum testosterone levels were within 30 percent of baseline within twenty-four hours and castrate by forty-eight hours.lOJ1 Its mechanism of action is by inhibition of steroid synthesis by blocking P-450 cytochrome oxidase transport of the C 17-20 lyase enzymes, 11.12Its responses have been reported to occur within twenty-four to ninety-six hours after the initiation of therapy.6J0 Therefore, ketoconazole produces almost as rapid an effect as orchiectomy. Its effects are reversible within eight to twelve hours after discontinuing the medicine; therefore, it is an excellent choice for initial and empirical therapy. Ketoconazole also provides a good alternative when either orchiectomy or estrogen therapy is contraindicated. The data presented showed that 5 of 12 patients who were treated with radiation therapy prior to the onset of efficacious hormonal therapy had rapid progression of their disease leading to paraplegia and/or death. These complications might have been averted with earlier effective hormonal therapy, either orchiectomy or ketoconazole. Therefore, ketoconazole provides an excellent initial medical therapy for
UROLOGY
/
OCTOBER
1988
/
VOLUME xXx11,
these patients. As a result of this review, we have initiated a protocol at our institution using ketoconazole in conjunction with corticosteroids and/or radiation therapy for initial empirical therapy for patients with possibly newly diagnosed metastatic prostate cancer involving the spine. Obviously, for those patients who have been previously diagnosed and treated hormonally, the combination of corticosteroids and radiation therapy is the appropriate therapy. Conclusion In patients with obstructive voiding patterns, radicularlback pain, and new-onset neurologic signs, metastatic prostate cancer must be considered. Prompt urologic consultation and diagnosis should be made. Ketoconazole should be initiated empirically in an attempt to prevent irreversible neurologic damage. Subsequently, ketoconazole can be discontinued if the etiology was found not to be metastatic prostate cancer or when orchiectomy is performed for long-term hormonal therapy. St. Luke’s Hospital New York, New York 10025 (DR. LOWE) References 1. Huggins C, and Hodges CU: Studies on prostate cancer. The effect of castration, of estrogen and of androgen injection on serum phosphatase in metastatic carcinoma of the prostate, Cancer Res 1: 293 (1941). 2. Jacobs SC: Spread of prostatic cancer to bone, Urology 21: 337 (1983). 3. Iacovou W, et al: Cord compression and carcinoma of the prostate: Is laminectomy justified? Br J Uro157: 733 (1985). 4. Mauch PM, and Drew MA: Treatment of metastatic cancer to bone in cancer, in Devita V, Hellman S, and Rosenberg S (Eds): Principles and Practice of Oncology, 2nd ed, Philadelphia, J.B. Lippincott Co., 1983. 5. Maatman TJ, Gupta MK, and Montie JE: Effectiveness of castration versus intravenous estrogen therapy in producing rapid endocrine control of metastatic cancer of the prostate, J Urol133: 626 (1985). 6. Lowe FC, and Somers WJ: The use of ketoconazole in the emergency management of disseminated intravascular coagulation due to metastatic prostate cancer, J Urol 137: 1966 (1987). 7. Nicolle P Pontin A, and Sarembock L: High-dose ketoconazole therapy in prostatic cancer. A pilot study, South Afr Med J 67: 888 (1985). 8. Debruyne FMJ, and Witzes FJ, members of South East Cooperative Study Group: Ketoconazole high dose in management of metastatic prostatic carcinoma, J Urol135: 293A (1986). 9. Point A: Long term experience with high dose ketoconazole therapy for prostate cancer, J Urol 137: 962 (1987). 10. Tractenberg J, Halpern N, and Pont A: Ketoconazole: a novel and ranid treatment for advanced nrostatic cancer, I Urol 130: 152 (1983). 11. Denis L, Chaban M, and Mahler C: Clinical applications of ketoconazole in nrostatic cancer, in EORTC Genitourinary Group Monograph iPart A: Therapeutic Principles in Metastatic Prostate Cancer, New York, Alan R. Liss, Inc, 1985 12. Pont A, et al: Ketoconazole block adrenal steroid synthesis, Ann Intern Med 97: 370 (1982).
NUMBER 4
303
IN INITIAL MANAGEMENT
AND TREATMENT
OF METASTATIC
PROSTATE CANCER TO SPINE MITCHELL
H. BAMBERGER,
FRANKLIN
C. LOWE,
M.D.
M.D.
From the Departments of Urology, St. Luke’s_Roosevelt Hospital Center, and Columbia University College of Physicians and Surgeons, New York, New York
ABSTRACT-Ketoconaxole in high doses cauSes castrate levels of testosterone within twenty-four to forty-eight hours; therefore it is extremely useful in the initial medical treatment of patients with metastatic prostate cancer who need a prompt therapeutic response. Review of 17 patients who presented with severe radicular pain or acute paraparesis/paraplegia showed that there was frequent delay in urologic consultation, pathologic confirmation, and initiation of efficacious therapy. In fact, 5 of 12 patients (42 %) who received radiation therapy prior to effective hormonal therapy suffered significant morbidity and mortality. The case is made for the use of ketoconaxole for initial empirical therapy for these patients.
Since 1941, the treatment of metastatic prostate cancer has been based on Huggins and Hodges’ observation that prostate carcinoma is androgen dependent. Approximately 40 percent of patients presenting with prostate cancer have metastatic disease.2 Among these patients is a group with a variety of complaints including lower back pain, numbness, or difficulty in ambulation. Parasthesia, paraparesis, and loss of bowel or bladder control are ominous signs of spinal cord involvement. The diagnosis of prostate cancer must be considered in the evaluation of these patients. Prompt and efficacious therapy must be initiated to prevent these neurologic deficits from progressing and becoming irreversible. Traditionally, patients with metastatic prostate cancer have been treated with oral estrogens or surgical castration by bilateral orchiectomy. Patients with impending spinal cord compression require immediate effective treatment of their prostate cancer. Although immediate orchiectomy has been the classic recommendation, radiation therapy in conjunction
UROLOGY
I
OCTOBER
1988
I
VOLUME
XXXII,
NUMBER
with steroids has been the most commonly used treatment in this clinical situation, with laminectomy being reserved for those patients who either fail to respond or who show signs of progressive neurologic deterioration.3 Unfortunately, the response and results to radiation therapy are unpredictable and variable.* A common alternative therapy is oral estrogens; however, this medication requires approximately two weeks to achieve castrate levels of testosterone and a longer period of time to observe for tumor regression.5 Surgical castration by bilateral orchiectomy provides prompt response, but it is not always readily acceptable to patients. Currently, a new modality, androgen synthesis blockade with ketoconazole, provides an acceptable alternative method for initial treatment of metastatic prostate carcinoma. This review of patients with newly diagnosed metastatic prostate cancer to the spine suggests that their management and treatment with either immediate castration or ketoconazole could have improved the course of their disease.
4
301
Material and Methods
TABLE I.
The clinical data of all 83 patients at St. Luke’s Hospital receiving external beam radiation therapy for spinal metastasis from prostate cancer from 1977 to 1986 were reviewed. Seventeen patients (20%) were found to have had no prior history or treatment of prostate cancer and were categorized as newly diagnosed Stage D-2 prostate cancer. The data on these 17 patients were carefully evaluated for presenting symptoms, length of time for urologic consultation, and for diagnostic confirmation. Treatment as well as response and morbidity were also analyzed. Results The most common complaint was either lower back or referred extremity pain in 13 patients (76 % ) . Neurologic symptoms including decrease in ambulation, parasthesia, and numbness was present in 4 patients (24 % ). The spinal metastases were almost equally divided between the lumbar, thoracic, and multiple areas. Urologic consultation was obtained at various times. Five patients were seen immediately. Overall, urologic consultation was obtained with a mean of 5.5 days and a median of 3.0 days after admission (Table I). Mean time for the initiation of hormonal therapy was 11.1 days for orchiectomy and 10.4 days for diethylstilbestrol. The timing of therapy for both external beam radiation therapy and hormonal manipulation was reviewed. Seven patients (41%) received external beam radiation therapy prior to hormonal therapy. Eight (47 % ) had external beam radiation therapy started after the initiation of hormonal manipulation; however, only 4 patients had orchiectomies. Another patient received external beam radiation therapy and diethylstilbestrol simultaneously. Therefore, 12 of 17 patients (71%) were treated with radiation therapy prior to the onset of effective hormonal therapy (oral diethylstilbestrol takes approximately 14 days to achieve castrate levels of testosterone). Five of these 12 patients suffered significant complications: 3 had laminectomies/ paraplegia and 2 died. None of the other group had significant early complications. Comment In approximately 50 percent of all patients with prostate cancer, bone metastasis even-
302
Days until urologic consultation
No. of Days
No. of Patients
0 l-3 over 5 over 30
5 7 3
2
tually develops.4 Pain, the most frequent symptom, is caused by a combination of stretching of the periosteum, nerve entrapment, tumor expansion, and pressure on the nerve roots. Vertebral body destruction is often associated with extradural spinal cord compression and can lead to irreversible neurologic changes if not recognized and treated early. The goal of treatment of metastatic disease is relief of pain and prevention of permanent neurologic deficits. Localized radiation therapy is useful in treating pain secondary to bone metastasis, but it is controversial in its efficacy.4 Reports show from 73 to 96 percent of patients receiving radiation therapy achieved partial or complete pain relief; however, the duration of the beneficial response has not been adequately evaluated or assessed.4 Systemic treatment for relief of bone pain may be preferable to localized external beam radiation therapy in patients with rapidly progressive disease. Neurologic changes may become irreversible if not treated emergently. Iacovou and associates3 evaluated 37 patients who underwent laminectomy for metastatic prostate cancer; 29 percent had cord compression as the initial presentation. Their evaluation revealed several important findings: (1) those able to walk prior to laminectomy were longterm survivors and remained ambulatory; (2) the advent of immobility in less than twentyfour hours was associated with poor results; (3) preoperative paraplegia was a consistently accurate indicator of poor prognosis; (4) patients with paraplegia received no benefit from surgery; (5) diagnosis of prostate cancer was considered to be delayed if it was not made within forty-eight hours after admission; and (6) delay in diagnosis usually resulted in permanent functional loss. Thus, prompt and accurate diagnosis needs to be made as soon as possible, preferably in less than forty-eight hours, to initiate therapy to prevent further irreversible neurologic deficits. When acute paraparesis/paraplegia is noted, immediate effective therapy is required. Classic teachings recommend emergent bilateral orchiectomy .because elimination of 90 percent of
UROLOGY
I
OCTOBER 1988 I
VOLUME XXXII, NUMBER 4
testosterone occurs within two to six hours (mean of 3 hours). 5 Rapid clinical response can be seen in approximately 80 percent to 85 percent of patients. Bilateral orchiectomy is the fastest and most effective method to produce castrate levels of testosterone whenever rapid treatment is indicated. Although the classic teachings recommend immediate orchiectomy for those patients with acute onset of paraparesis/paraplegia presumably secondary to metastatic prostate cancer, this study showed that the realities of clinical medicine are completely different. A urologic consultation was obtained within a mean of 5.5 days and a median of 3.0 days after admission. Besides the delays in consultation, scheduling biopsies, waiting for pathology reports, and scheduling surgery, obtaining patient/family acceptance for castration were frequently important issues. Thus, hormonal therapy was not initiated promptly, with a mean of 11.1 days for orchiectomy and 10.4 days for diethylstilbestrol. Obviously, alternative forms of initial efficacious hormonal therapy are needed. Ketoconazole is the perfect alternative for initial empirical hormonal therapy for these patients.6 Numerous reports have shown ketoconazole to be an effective hormonal agent for metastatic prostate cancer.e-10 In doses of 400 mg orally every eight hours, serum testosterone levels were within 30 percent of baseline within twenty-four hours and castrate by forty-eight hours.lOJ1 Its mechanism of action is by inhibition of steroid synthesis by blocking P-450 cytochrome oxidase transport of the C 17-20 lyase enzymes, 11.12Its responses have been reported to occur within twenty-four to ninety-six hours after the initiation of therapy.6J0 Therefore, ketoconazole produces almost as rapid an effect as orchiectomy. Its effects are reversible within eight to twelve hours after discontinuing the medicine; therefore, it is an excellent choice for initial and empirical therapy. Ketoconazole also provides a good alternative when either orchiectomy or estrogen therapy is contraindicated. The data presented showed that 5 of 12 patients who were treated with radiation therapy prior to the onset of efficacious hormonal therapy had rapid progression of their disease leading to paraplegia and/or death. These complications might have been averted with earlier effective hormonal therapy, either orchiectomy or ketoconazole. Therefore, ketoconazole provides an excellent initial medical therapy for
UROLOGY
/
OCTOBER
1988
/
VOLUME xXx11,
these patients. As a result of this review, we have initiated a protocol at our institution using ketoconazole in conjunction with corticosteroids and/or radiation therapy for initial empirical therapy for patients with possibly newly diagnosed metastatic prostate cancer involving the spine. Obviously, for those patients who have been previously diagnosed and treated hormonally, the combination of corticosteroids and radiation therapy is the appropriate therapy. Conclusion In patients with obstructive voiding patterns, radicularlback pain, and new-onset neurologic signs, metastatic prostate cancer must be considered. Prompt urologic consultation and diagnosis should be made. Ketoconazole should be initiated empirically in an attempt to prevent irreversible neurologic damage. Subsequently, ketoconazole can be discontinued if the etiology was found not to be metastatic prostate cancer or when orchiectomy is performed for long-term hormonal therapy. St. Luke’s Hospital New York, New York 10025 (DR. LOWE) References 1. Huggins C, and Hodges CU: Studies on prostate cancer. The effect of castration, of estrogen and of androgen injection on serum phosphatase in metastatic carcinoma of the prostate, Cancer Res 1: 293 (1941). 2. Jacobs SC: Spread of prostatic cancer to bone, Urology 21: 337 (1983). 3. Iacovou W, et al: Cord compression and carcinoma of the prostate: Is laminectomy justified? Br J Uro157: 733 (1985). 4. Mauch PM, and Drew MA: Treatment of metastatic cancer to bone in cancer, in Devita V, Hellman S, and Rosenberg S (Eds): Principles and Practice of Oncology, 2nd ed, Philadelphia, J.B. Lippincott Co., 1983. 5. Maatman TJ, Gupta MK, and Montie JE: Effectiveness of castration versus intravenous estrogen therapy in producing rapid endocrine control of metastatic cancer of the prostate, J Urol133: 626 (1985). 6. Lowe FC, and Somers WJ: The use of ketoconazole in the emergency management of disseminated intravascular coagulation due to metastatic prostate cancer, J Urol 137: 1966 (1987). 7. Nicolle P Pontin A, and Sarembock L: High-dose ketoconazole therapy in prostatic cancer. A pilot study, South Afr Med J 67: 888 (1985). 8. Debruyne FMJ, and Witzes FJ, members of South East Cooperative Study Group: Ketoconazole high dose in management of metastatic prostatic carcinoma, J Urol135: 293A (1986). 9. Point A: Long term experience with high dose ketoconazole therapy for prostate cancer, J Urol 137: 962 (1987). 10. Tractenberg J, Halpern N, and Pont A: Ketoconazole: a novel and ranid treatment for advanced nrostatic cancer, I Urol 130: 152 (1983). 11. Denis L, Chaban M, and Mahler C: Clinical applications of ketoconazole in nrostatic cancer, in EORTC Genitourinary Group Monograph iPart A: Therapeutic Principles in Metastatic Prostate Cancer, New York, Alan R. Liss, Inc, 1985 12. Pont A, et al: Ketoconazole block adrenal steroid synthesis, Ann Intern Med 97: 370 (1982).
NUMBER 4
303