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Ketoconazole Therapy in Advanced Prostatic Cancer
D02:2-5347 /87 /1375-0958$02,00/0
Vol. 137.
THE ~TOURNAL GF UROLOGY
Copyright CG 1987 by The TNilliams
Vi/ilkins Co.
Printed in
Editorial KETOCONAZOLE THERAPY IN ADVANCED PROSTATIC CANCER The discovery in 1941 that androgen ablation could cause the regression of human prostatic cancer ushered in a new era in the treatment of advanced solid tumors and promised to offer a cure for patients afflicted with metastatic cancer.' Many clinical trials that followed this pioneering report hoped to demonstrate complete and lasting regression of advanced forms of this disease but these trials uniformly have failed. The decades that followed these disappointing results have seen many different agents with differing modes of action introduced only ultimately to produce similar results. Thus, 2 predominant concepts have emerged regarding hormonal therapy of prostatic cancer. First, that this is a valuable palliative maneuver and, thus, it should be used only when minimal morbidity and clear gains in the quality of life can be assured. The other diametrically opposed concept is that failure of this form of therapy is owing to inadequate hormonal ablation and not to failure of the concept itself. Those who pursue the latter course believe that modifications in the type and delivery of hormonal therapy will yield improved results. All of the new agents that have undergone recently clinical trials, have been evaluated with respect to the aforementioned hypotheses. Flutamide, a nonsteroidal antiandrogen, was reported to be as effective as conventional therapy with less morbidity. Similar results have been reported for leuprolide, a luteinizing hormone-releasing hormone agonist, and cyproterone acetate, a progestational antiandrogen. No evidence of increased survival has been demonstrated with any of these agents. 2 In this issue of the Journal 3 separate articles document the potential uses and problems of another new agent in the treatment of prostatic cancer. Ketoconazole, which is an orally active systemic antifungal agent, was noted to inhibit rapidly testicular and adrenal androgen production when used in high doses. Subsequently, it was demonstrated to be active in the treatment of prostatic cancer. 3 V anuytsel and associates (page 905) have documented their experience with fixed high dose ketoconazole in 22 ;.mo,vno~ with metastatic Of these patients previous forms of hormonal in 4. The responses achieved with this regimen untreated patients were comparable to those experienced other forms of hormonal therapy. Of interest was the unexpected long duration of secondary re,;pcms:e in 2 of 3 patients in whom prior hormonal 1-h,,.,,,n" had The high effects) documented in this profile (32 per cent significant report suggests that without some clear-cut survival benefit this regimen is not the most appropriate form of palliative hormonal therapy. Pont (page 902) has reported a similar experience with the use of this agent in untreated patients. He has attempted to modify the toxicity profile by varying the dose of ketoconazole and by supplementing patients with glucocorticoidso His results in regard to response and toxicity are not significantly different than those of Vanuytsel and associates" Pont also reports
impressive subjective (5 of 11) responses in patients in whom other forms of hormonal therapy had failed. Lowe and Somers (page 1000) report on the short-term use of ketoconazole in a patient with disseminated intravascular coagulation associated with prostatic cancer. Because of a bleeding diathesis this patient was not fit for surgery and required rapid reduction of serum androgens to control the primary and secondary disease. The authors concluded that of the agents available to reduce serum testosterone ketoconazole would result in the most rapid reduction in androgen production. Indeed, within 96 hours of the introduction of ketoconazole the serum testosterone was in the castrate range and the patient had improved substantially. Ketoconazole represents a new class of agents that decrease androgen production by direct inhibition of the enzymes of steroidogenesis. The data in these articles suggest that ketoconazole is effective in the induction and maintenance of a clinical remission, and that its speed and multiple sites of action as well as its potential use in patients in whom primary therapy has failed may offer unique advantages, Nevertheless, the high toxicity profile of this agent as monotherapy in the aforementioned doses precludes its routine chronic use as a palliative agent at this time. Furthermore, the present studies clearly fail to demonstrate any survival advantage of this mode of therapy. Further studies must determine whether modifications in dose, method of administration, concomitant medication or the development of analogues of the agent will decrease the incidence of side effects or increase the duration of response. In addition, these studies may define further the nonhormonal cytotoxic role of cytochrome P450 inhibitors in the treatment ofprostatic malignancy. Recently, several studies have demonstrated direct in vitro cytotoxicity to hormone independent cell lines, including human prostatic and pancreatic cancer. In addition, these studies have shown that ketoconazole acts synergistically with conventional chemotherapeutic agents. 4 Thus, the aforementioned preliminary studies should direct the further development of this interesting class of John Trachtenberg Division of Urology of Toronto 1. Huggins, C, and Hodges, C. V.: Studies on prostatic cancer. I. The
effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res., 1: 293, 1941. 2. Smith, J. Ao, Jr.: New methods of endocrine management of prostatic cancer. J. Urol., 137: 1, 1987. 3. Trachtenberg, J.: Ketoconazole therapy in advanced prostatic cancer. J. Urol., 132: 61, 1984. 4. Rochlitz, C. H., Russi, M. B., Damon, L. E., Geddes, A. and Cadman, E. C.: Cytotoxicity and effect of ketoconazole and VP16 action and cellular uptake in malignant cells. Clin. Res., 35: 168A, 1987.
Vol. 137.
THE ~TOURNAL GF UROLOGY
Copyright CG 1987 by The TNilliams
Vi/ilkins Co.
Printed in
Editorial KETOCONAZOLE THERAPY IN ADVANCED PROSTATIC CANCER The discovery in 1941 that androgen ablation could cause the regression of human prostatic cancer ushered in a new era in the treatment of advanced solid tumors and promised to offer a cure for patients afflicted with metastatic cancer.' Many clinical trials that followed this pioneering report hoped to demonstrate complete and lasting regression of advanced forms of this disease but these trials uniformly have failed. The decades that followed these disappointing results have seen many different agents with differing modes of action introduced only ultimately to produce similar results. Thus, 2 predominant concepts have emerged regarding hormonal therapy of prostatic cancer. First, that this is a valuable palliative maneuver and, thus, it should be used only when minimal morbidity and clear gains in the quality of life can be assured. The other diametrically opposed concept is that failure of this form of therapy is owing to inadequate hormonal ablation and not to failure of the concept itself. Those who pursue the latter course believe that modifications in the type and delivery of hormonal therapy will yield improved results. All of the new agents that have undergone recently clinical trials, have been evaluated with respect to the aforementioned hypotheses. Flutamide, a nonsteroidal antiandrogen, was reported to be as effective as conventional therapy with less morbidity. Similar results have been reported for leuprolide, a luteinizing hormone-releasing hormone agonist, and cyproterone acetate, a progestational antiandrogen. No evidence of increased survival has been demonstrated with any of these agents. 2 In this issue of the Journal 3 separate articles document the potential uses and problems of another new agent in the treatment of prostatic cancer. Ketoconazole, which is an orally active systemic antifungal agent, was noted to inhibit rapidly testicular and adrenal androgen production when used in high doses. Subsequently, it was demonstrated to be active in the treatment of prostatic cancer. 3 V anuytsel and associates (page 905) have documented their experience with fixed high dose ketoconazole in 22 ;.mo,vno~ with metastatic Of these patients previous forms of hormonal in 4. The responses achieved with this regimen untreated patients were comparable to those experienced other forms of hormonal therapy. Of interest was the unexpected long duration of secondary re,;pcms:e in 2 of 3 patients in whom prior hormonal 1-h,,.,,,n" had The high effects) documented in this profile (32 per cent significant report suggests that without some clear-cut survival benefit this regimen is not the most appropriate form of palliative hormonal therapy. Pont (page 902) has reported a similar experience with the use of this agent in untreated patients. He has attempted to modify the toxicity profile by varying the dose of ketoconazole and by supplementing patients with glucocorticoidso His results in regard to response and toxicity are not significantly different than those of Vanuytsel and associates" Pont also reports
impressive subjective (5 of 11) responses in patients in whom other forms of hormonal therapy had failed. Lowe and Somers (page 1000) report on the short-term use of ketoconazole in a patient with disseminated intravascular coagulation associated with prostatic cancer. Because of a bleeding diathesis this patient was not fit for surgery and required rapid reduction of serum androgens to control the primary and secondary disease. The authors concluded that of the agents available to reduce serum testosterone ketoconazole would result in the most rapid reduction in androgen production. Indeed, within 96 hours of the introduction of ketoconazole the serum testosterone was in the castrate range and the patient had improved substantially. Ketoconazole represents a new class of agents that decrease androgen production by direct inhibition of the enzymes of steroidogenesis. The data in these articles suggest that ketoconazole is effective in the induction and maintenance of a clinical remission, and that its speed and multiple sites of action as well as its potential use in patients in whom primary therapy has failed may offer unique advantages, Nevertheless, the high toxicity profile of this agent as monotherapy in the aforementioned doses precludes its routine chronic use as a palliative agent at this time. Furthermore, the present studies clearly fail to demonstrate any survival advantage of this mode of therapy. Further studies must determine whether modifications in dose, method of administration, concomitant medication or the development of analogues of the agent will decrease the incidence of side effects or increase the duration of response. In addition, these studies may define further the nonhormonal cytotoxic role of cytochrome P450 inhibitors in the treatment ofprostatic malignancy. Recently, several studies have demonstrated direct in vitro cytotoxicity to hormone independent cell lines, including human prostatic and pancreatic cancer. In addition, these studies have shown that ketoconazole acts synergistically with conventional chemotherapeutic agents. 4 Thus, the aforementioned preliminary studies should direct the further development of this interesting class of John Trachtenberg Division of Urology of Toronto 1. Huggins, C, and Hodges, C. V.: Studies on prostatic cancer. I. The
effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res., 1: 293, 1941. 2. Smith, J. Ao, Jr.: New methods of endocrine management of prostatic cancer. J. Urol., 137: 1, 1987. 3. Trachtenberg, J.: Ketoconazole therapy in advanced prostatic cancer. J. Urol., 132: 61, 1984. 4. Rochlitz, C. H., Russi, M. B., Damon, L. E., Geddes, A. and Cadman, E. C.: Cytotoxicity and effect of ketoconazole and VP16 action and cellular uptake in malignant cells. Clin. Res., 35: 168A, 1987.