Ketoconazole Therapy in Advanced Prostatic Cancer

0022-5347/84 / 1321-0061$02 .CO /0 THE ,JGURNAI~

Copyright

or

URO,LOG'!

1984 by The V/iEiarnf:

?lilki~s Co.

CANCER JOHN TRACHTENBERG From the Division of Urology, Department of Surgery, University of Toronto, Toronto, Ontario, Canada

ABSTRACT

To deterrn.ine the effect of keto.:rnaa:w1te a nonestrogenic antifungal agent, in patients with metastatic cancer 13 ·,vith symptomatic stage D2 prostatic cancer were administered 400 mg. ketoconazole every 8 hours. By 24 hours of treatment serum testosterone had decreased to the castrate level the adrenal androgens, androstenedione and dehydroepiandrosterone, also had decreased ~.,.,"""·--.. 1 week of treatment clinical response was evident in aH patients. Pain was improved and serum prostatic acid phosphatase levels had decreased significantly, and by 1 month acid phosphatase had reached the normal range. The patients have been followed for 3 to 10 months without relapse. Side effects were few. Because of the ease of administration, of action, and decrease of adrenal and testicular androgen levels, as well as the relative lack of side effects, ketoconazole may prove to be an important new drug in the treatment of prostatic cancer. Huggins and Hodges of the cancer the treatment vanced prostatic cancer relied on methods to lovver serum androgen levels. 1 Conventional methods to achieve this goal indude bilateral '""u-"m" or the administration of exogenous "";.,,,,.,o-<>v,c While both methods have Droved successful in lowering levels of testosterone" and inducing a clinical remission in the majority of patients they are associated with specific side effects. Many men with this disease are and infirm. Bilateral results in m,•wrurl,t'7 and men object to nw,0h,,<>r>trom easy to administer estrogens ~~ ..,,,w~,,·"~ basis and are associated intrinsic uo,uu,,,,,,u,, such as the development of tender the use of estrogens is associated increase in ~.~-'"'"''h, and to an increased incidence of thrombo-embolic events. Because of the side effects associated with estrogens a of nonestrogenic have been evaluated to deter· mine whether these agents confer the anticancer benefits of estrogens without the associated side effects. These include cac,v,,u, .lUl,
patient was being administered any form of steroid (glucocorticoid or estrogen) or cytotoxic therapy. The patients were on variety of other u"""""'"v.,rn. including (:l-blockers, didiuretics, analgesics and calcium channel blockers. No had active ulcer disease and none was on cimetidine. ± standard All men had "'~·,mu•n serum prostatic acid phosphatase levels as well as isotopic bone scan evidence of metastases. All patients had moderate to severe bone pain and a subnormal (<70) Karnofsky O to 100 performance scale. All patients initially were screened to ensure acceptability into the protocol. The initial biopsy was reviewed to confirm the diagnosis. Patients who had not had a recent (T<>n at 8 a.m., noon and 4 p.m. on day 1, and at 8 a.m. and 4 p.m. o:n 2. At weeks 1 to 4, 6 and 8, and every 4 weeks thereafter patients were evaluated as to pain and Karnofsky performance scale, and the laboratory evaluations done at 8 a.m. on day O were repeated. Bone scans and ultrasonic determinations of prostatic volume were repeated at 3-month intervals and were assessed according to the criteria of the National Prostatic Cancer Project. 8 Followup has ranged from 3 to 10 months. Statistical significance was assessed using the 2-sample t test with 5 per cent chosen as the level of significance. The term significant associated with numerical data implies statistical significance as described. W L • • • •,

introduced thetic imidazole dioxolane used in the treatment of """"·o-+,,-; and has been dern.onstrated to reduce adrenal and testicular ·-"-"'"--"' v~u,"c,vu in animals and men.4 " VI e have den10nstrated that dose ketoconazole and maintain a remission in a with cancer. 7 This is not an estrogen uc;cu1.c11n and in clinical trials to its feminizing characteristic has been the rare occurrence of gynecomastia. since this agent reduces markedly this further adrenal as well as testicular androgen rin,mw1.1 form of androgen ablation might confer a survival advantage for the patient. We have evaluated this agent in 13 men with symptomatic stage D2 prostatic cancer. a

PATIENTS AND METHODS

Thirteen men with previously untreated stage D2 symptomatic prostatic cancer (mean Gleason scale 6) were referred to us for hormonal therapy. All patients had intact testes. No Accepted for publication March 20, 1984. 61

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62

TRACHTENBERG TABLE 1. Changes in endocrine parameters

Time of Study -24 hrs.:j: -20 hrs. -16 hrs. 0 hrs. 4 hrs. 8 hrs. 24 hrs. 32 hrs. 1 wk.§ 4 wks. 12 wks.

Androstenedione (nmol./1.)

Testosterone (nmol./1.) 17.7 ± 14.5 ± 14.6 ± 17.7 ± 5.6 ± 3.2 ± 1.4 ± 1.2 ± 2.6 ± 2.4 ± 2.1 ±

4.3 ± 3.6 ± 2.5 ± 4.0 ± 2.1 ± 1.7 ± 1.8 ± 0.9 ± 1.1 ± 0.9 ± 1.1 ±

1.3 0.8 0.7 1.4 0.5 0.4 0.6 0.3 0.3 0.2 0.2

0.7 0.8 0.6 0.4 0.2 0.1 0.1 0.2 0.2 0.8 0.7

Dehydroepiandrosterone (µmol./1.) 6.2 5.5 4.0 5.1 2.5 2.5 2.1 2.0 1.5 1.8 1.6

± ± ± ± ± ± ± ± ± ± ±

Progesterone (nmol./1.)

0.9 0.6 1.0 0.7 0.3 0.4 0.5 0.3 0.3 0.4 0.8

17-Hydroxy Progesterone (nmol./1.)

3.5 ± 0.6

4.0 ± 0.9

9.8 ± 1.6 11.4 ± 2.2

10.9 ± 1.8 12.0 ± 2.2

Luteinizing Hormone (IU/1.) 3.1 ± 3.1 ± 3.2 ± 3.7 ± 5.5 ± 6.4 ± 6.9 ± 6.4 ± 9.6 ± 15.6 ± 17.2 ±

0.8 1.0 1.0 0.5 0.4 0.3 0.6 0.4 0.2 4.0 0.4

17-Ketosteroids (µmol./mmol. creatinine)*

Urinary Free Cortisol (nmol./mmol. creatinine)t

4.0 ± 0.7

30.8 ± 4.3

1.7 ± 0.4 1.8 ± 0.7 1.5 ± 0.6

22.0 ± 5.8 23.3 ± 4.4 22.9 ± 2.9

Data are reported as mean ± standard error for 13 patients. All serum steroid and luteinizing hormone assays were performed by clinical radioimmunoassay. Normal values are testosterone 10 to 35 nmol./1., androstenedione 2 to 7 nmol./1., dehydroepiandrosterone 2.5 to 10 µmol./1., progesterone 3 to 9 11mol./l., 17-hydroxy progesterone 3 to 8 nmol./1. and luteinizing hormone 1 to 4 IU /1. * 24-hour urinary 17-ketosteroids (normal 3 to 8 µmol./mmol. urinary creatinine). t 24-hour urinary free cortisol (normal 7.5 to 40 nmol./mmol. urinary creatinine). :j: Hours after start of ketoconazole at 400 mg. orally every 8 hours. § Weeks of treatment with 400 mg. ketoconazole every 8 hours. TABLE 2.

Patient response to ketoconazole therapy Interval on Therapy 0 Hrs.

Prostatic acid phosphatase (IU /

14.9 ± 1.1

1 Wk.

4 Wks.

1.8 ± 0.4

0.8 ± 0.1

12 Wks. 0.9 ± 0.2

I.)*

Bone scan (No. pts.) Prostatic volume (cm. 3)t Performance:j: Response (No. pts.)§

Multiple metastases (13) 57.0 ± 4

Improved (8), no change (5) 23.0 ± 8

58.0 ± 11

92.0 ± 8 Partial (12), objectively stable (1)

Data are reported as mean ± standard error for 13 patients. * Performed enzymatically using paranitrophenyl phosphatase as substrate (normal <1.1 IU/1.) t Determined by transabdominal real-time ultrasound. :j: Karnofsky scale O (moribund) to 100 (full activity without restrictions). § National Prostatic Cancer Project criteria. RESULTS

All patients demonstrated normal serum steroid parameters at the start of therapy. Serum testosterone was 17. 7 ± 1.3 nmol./1. (mean ± standard error) (normal 10 to 35 nmol./1.). Serum luteinizing hormone was 3.1 ± 0.8 IU/1. (normal 1 to 4 IU/1.). Serum adrenal androgens, androstenedione and dehydroepiandrosterone sulfate, demonstrated the expected diurnal variation. The 24-hour urinary excretion of 17-ketosteroids and free cortisol were within normal limits, as were baseline serum progesterone and serum 17-hydroxy progesterone (table 1). There was a significant decrease in serum testosterone levels by 4 hours of treatment and by 24 hours all serum androgen levels had decreased significantly. At 1 week of treatment serum testosterone was 2.6 ± 0.3 nmol./1., and the 8 a.m. androstenedione and dehydroepiandrosterone sulfate levels were 1.1 ± 0.2 nmol./1. and 1.5 ± 0.3 µmol./1., respectively. Urinary 17-ketosteroids mirrored these changes and decreased >50 per cent. Serum luteinizing hormone levels increased at 1 week to 9.6 ± 0.2 IU /1. Serum androgen levels remained significantly suppressed, while serum luteinizing hormone continued to increase and reached a peak of 17.2 ± 0.4 by 3 months. Serum progesterone and 17-hydroxy progesterone levels increased 300 per cent over baseline by 1 month and remained at that level at 3 months. The 8 a.m. serum cortisol levels never changed from baseline (not shown) but at 1 week of treatment and thereafter 24-hour urinary free cortisol was reduced approximately ·25 per cent but still remained within the normal range. All 13 patients responded to therapy and all remarked that the pain had disappeared greatly by 1 week of treatment. The mean Karnofsky performance index increased from an initial value of 58 ± 11 to 92 ± 8 by 3 months. Serum prostatic acid

phosphatase decreased in all patients from an initial value of 14.9 ± 1.1 IU/l. (mean± standard error, normal <1.1 IU/1.) to 1.8 ± 0.4 IU /l. by 1 week of treatment and continued to decrease towards normal thereafter (table 2). By 3 months of treatment 8 of 13 patients demonstrated improvement on the bone scan, while 5 scans showed stable disease and none showed progression. All patients demonstrated decreased prostatic size on ultrasound and digital rectal examination. At the 3-month reevaluation 12 patients were judged to have a partial response and 1 had objectively stable disease. No patient had progression. At the initiation of therapy the 2 oldest patients (83 and 84 years old, respectively) complained of marked weakness and lethargy. No changes were noted in the 8 a.m. serum cortisol levels, or in the serum electrolytes or liver function tests. However, serum adrenocorticotropic hormone was elevated markedly over baseline (195 and 135 IU, respectively, normal <24 IU/1.). The dose of ketoconazole was lowered to 300 mg., with resolution of all symptoms and return of serum adrenocorticotropic hormone to normal. At 2 to 4 weeks of treatment 6 of the 13 patients noticed vague abdominal pains and a low grade fever. There was no change in the liver function tests nor was eosinophilia noted. In the first patient treated therapy was interrupted for 3 days in search of a cause but none was found. The symptoms disappeared and therapy was resumed in this patient. In 5 subsequent patients with similar symptoms therapy was not stopped but the dose of ketoconazole was lowered to 300 mg. every 8 hours for 1 week. The symptoms also disappeared in these patients without evidence of liver, renal or bone marrow toxicity, and the dose of ketoconazole was returned to the initial level. Thereafter, all patients have been asymptomatic. Ketoconazole has been associated with liver toxicity. 9 • 10 In the 13 patients treated with high doses of ketoconazole we have not noted any evidence of hepatotoxicity. No patient had clinical hepatitis and no changes were noted in the serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminiase, lactic dehydrogenase or total bilirubin throughout the course of treatment (table 3). However, an increase, which was not statistically significant, was noted in serum creatinine levels. Blood urea nitrogen (BUN) did not change. No patient had gynecomastia, changes in blood pressure, rashes, peripheral edema, headaches or evidence of phlebitic changes. No other abnormalities were noted. DISCUSSION

This report confirms and expands upon our initial observation that ketoconazole might have an important role in the treatment of advanced prostatic cancer. 7 With 400 mg. ketoconazole taken every 8 hours all patients demonstrated an

CO

l(ETOCONAZOLE 'THERAPY H\J ADV.AJ:.JCED PR0STAT1C CANCER TABLE

D0

3. Hepatic and renal changes with high dose ketoconazole therapy Intervai on Therapy

Serum glutmnic oxaloacetic transaminase (normal <60 IU/L) Serum glutamic pyruvic transaminase (normal <50 lU/L) Lactic dehydrogenase (normal 110-230 lU/L) Total bilirubin (normal 2-20 µmoL/L) BUN (normal 3-7 mmoL/L) Creatinine (normal 60-110 mmoL/L)

0 Hrs.

1 Wk.

4 Wks.

12 Wks.

33.0 ± LO

28.0 ± 2.3

3LO ± L7

no± 2.6

lLO ± 1

13.0 ± 3

13.0 ± 4

15.0 ± 4

123.0 8.0 6.3 112.8

± ± ± ±

6

0.5 OA 6A

110.0 5.0 6.3 106.0

± 8 ± OA ± L2 ± 6.0

125.0 9.0 7.9 112.7

± 9 ± 0.3 ± 0.6 ± 16.0

120.0 8.0 7.7 163.7

±4 ± 0.7 ± 0.1 ± 23.0

Data are reported as mean ± standard error for 13 patients.

extremely rapid and sustained decrease in the serum testosterone as well as serum adrenal androgen levels (androstenedione and dehydroepiandrosterone sulfate). These effects have been maintained for as long as the patients have been studied (3 to 10 months). The patients displayed the characteristic response of prostatic cancer to androgen ablation, namely a decrease in serum prostatic acid phosphatase, improvement in bone scan, decrease in prostatic volume, and subsequent improvement in bone pain and performance. 1 This effect was accomplished without the customary lag phase associated with estrogen administration and, indeed, paralleled the clinical course of improvement seen in patients with advanced prostatic cancer after bilateral orchiectomy. Furthermore, ketoconazole therapy was not associated with any of the traditional feminizing or cardiovascular side effects of estrogen administration. Recently, controversy has arisen as to the effect of residual adrenal androgens after castration. Labrie and associates have postulated that these residual androgens may contribute to the emergence of hormonally resistant prostatic cancer. Therefore, they have suggested that these remaining androgens be neutralized by combining luteinizing hormone releasing hormone analogue agonists or castration with antiandrogens. 11 Were this to be true and a survival benefit to be accrued from this mode of combination therapy then, because of its decrease of adrenal androgen production, ketoconazole alone might achieve beneficial results. Side effects of therapy have been few in the 13 patients. In 2 elderly patients we have noted weakness and lethargy, which stopped on reduction of treatment dose. Ketoconazole has been shown to reduce cortisol reserve.' Although no serum changes consistent with an Addison-like syndrome were noted, because of the observed elevation in serum adrenocorticotropic hormone, it is possible that in these elderly patients cortisol reserve is minimal and full dose ketoconazole therapy was sufficient to reduce this reserve to produce an Addison-like syndrome during stress. It is believed that ketoconazole exerts its effect through interference with cytochrome P450-dependent 14-demethylathereby interfering with the conversion of lanosterol to cholestero!. 4 In these ~~,_,c,~•~ the predominant effect is an inhibition of the , v , . u , ~ u , v u of androstenedione, uxhV•d.HX',~" drosterone and testosterone. There is a much less apparent effect on the production of the cortisol although tests of glucocorticoid reserve were not performed and have been noted to be reduced by others. 4 This concept is reinforced by the marked decrease in 24-hour urinary 17-ketosteroids compared to 24hour urinary free cortisol. Furthermore, serum progesterone and 17-hydroxy progesterone were elevated. Therefore, our data suggest that an additional and major effect of ketoconazole is to inhibit partially 17-20 desmolase, another P450-dependent enzyme, in the conversion of the C21 steroids to Cl9 steroids. A type of congenital male pseudohermaphroditism secondary to partial 17-20 desmolase deficiency has been described, which possesses many of the hormonal characteristics induced by ketoconazole. 12 • 10 In these patients serum testosterone, androstenedione and dehydroepiandrosterone are reduced with an

increase in 17-hydroxy progesterone, luteinizing hormone and follicle-stimulating hormone. The diagnosis is strengthened by human chorionic gonadotropin or adrenocorticotropic hormone stimulation tests, which show a disproportionate increase in C21 versus Cl9 steroids. Many of these characteristics are common in patients treated with ketoconazole. Further studies are necessary to determine the mode of action of ketoconazole and specific enzyme blocks in impairing androgen production in endocrinologically normal patients. Ketoconazole is a potential addition to the treatments available for the hormonal manipulation of prostatic cancer. Its benefits include its ease of administration, rapidity of action, profound impairment of adrenal and testicular androgen production, and relative lack of side effects. Long-term testing is needed to evaluate further this mode of therapy and its relative benefits over conventional hormonal therapy. REFERENCES

L Walsh, P. C.: Physiologic basis for hormonal therapy in carcinoma of the prostate. UroL Clin. N. Amer., 2: 125, 1975. 2. Glashan, R. W. and Robinson, M. R. G.: Cardiovascular complications in the treatment of prostatic carcinoma. Brit. J. UroL, 53: 624, 198L 3. Trachtenberg, J.: Non-estrogenic pharmacologic therapy for advanced prostatic cancer. Sem. UroL, voL 1, No. 4 (Nov.) 1983. 4. Pont, A., Williams, P. L, Azhar, S., Reitz, R K, Bochra, C., Smith, K R and Stevens, D. A.: Ketoconazole blocks testosterone synthesis. Arch. Intern. Med., 142: 2137, 1982. 5. Pont, A., Williams, P. L., Loose, D. S., Feldman, D., Reitz, R. K, Bochra, C. and Stevens, D. A.: Ketoconazole blocks adrenal steroid synthesis. Ann. Intern. Med., 97: 370, 1982. 6. Pont, A., Williams, P. L, Loose, D. S., Feldman, D., Bochra, C., Reitz, R E. and Stevens, D. A.: Ketoconazole inhibits adrenal steroid synthesis. Clin. Res., abstract, 30: 520A, 1982. 7. Trachtenberg, J., Halpern, N. and Pont, A: Ketoconazole: a novel and rapid t:reatment for advancedprostatic cancer. J. UroL, 130: 152, 1983. 8. Schmidt, J. D., Scott, W. W., Gibbons, R., Johnson, D. E., Prout, G. R, Jr., Loening, S., Soloway, M., deKemion, J. R, Pontes, J. E., Slack, N. H. and Murphy, G. P.: Chemotherapy programs of the National Prostatic Cancer Project (NPCP). Cancer, suppL 7, 45: 1937, 1980. 9. Huebner, G.D.: Advisory on hepatocellular dysfunction associated with ketoconazole therapy. Janssen Pharmaceutica, Beerse, Belgium, March l, 1982. 10. Stevens, D. A., Williams, P. L, Sugar, A. M. and Pont, A.: Ketoconazole effects. Letter to the Editor. Ann. Intern. Med., 92: 284, 1982.

lL Labrie, F., Dupont, A., Belanger, A., Cusan, L, Lacourciere, Y., Monfette, G., Laberge, J. G., Emond, J. P., Fazekas, A T. A., Raynaud, J. P. and Husson, J. M.: New hormonal therapy in prostatic carcinoma: combined treatment with an LHRH agonist and an antiandrogen. Clin. Invest. Med., 5: 267, 1982. 12. Zachmann, M., Viillmin, J. A., Hamilton, W. and Prader, A: Steroid 17,20-desmolase deficiency: a new cause of male pseudohermaphroditism. Clin. Endocr., l: 369, 1972. 13. Goebelsmann, U., Zachmann, M., Davajan, V., Israel, R., Mestman, J. H. and Mishell, D. R: Male pseudohermaphroditism consistent with 17,20-desmolase deficiency. Gynec. Invest., 7: 138, 1976.