Clinical and Biochemical Effect of Aminoglutethimide in the Treatment of Advanced Prostatic Carcinoma

0022-5347/83/1291-0051$02.00/0 Vol. 129, January Printed in U.S.A.

THE JOURNAL OF UROLOGY

Copyright© 1983 by The Williams & Wilkins Co.

CLINICAL AND BIOCHEMICAL EFFECT OF AMINOGLUTETHIMIDE IN THE TREATMENT OF ADVANCED PROSTATIC CARCINOMA T. J. WORGUL, * R. J. SANTEN, E. SAMOJLIK,t J. D. VELDHUIS, A. LIPTON, H. A. HARVEY, J. R. DRAGOt AND T. J. ROHNER From the Divisions of Endocrinology, Oncology and Urology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania

ABSTRACT

Treatment of male patients with advanced prostatic carcinoma and disease progression after initial endocrine therapy frequently is unsatisfactory. However, approximately 20 per cent of these patients respond to surgical adrenalectomy or hypophysectomy, indicating continued hormonal responsiveness. A total of 25 previously castrated men with stage D carcinoma received 1,000 mg. aminoglutethimide and 40 mg. hydrocortisone daily. The patients were evaluated using the criteria of the National Prostatic Cancer Project. One patient has had a complete response and is in remission after 275 weeks of therapy. A partial response was noted in 4 patients, while the disease was objectively stable in 6. Pre-treatment testosterone and dihydrotestosterone levels were measured in 9 of 25 patients and were significantly reduced statistically during aminoglutethirnide therapy (p <0.01). Response and drug toxicity are discussed. Adenocarcinoma of the prostate is the second most common malignancy and the third leading cause of cancer death in men >55 years old, with 66,000 new cases and 22,000 deaths yearly. 1 A total of 40 to 80 per cent of the patients present with metastases to lymph nodes, bone or viscera (stage D disease) and the mean survival is only 1.8 years. 2 • 3 Despite a 75 per cent response to primary hormonal ablative therapy, either orchiectomy or treatment with estrogens, further disease progression is associated with a 6-month survival of only 50 per cent. 2• 4 In men with progressive disease after primary therapy a variety of medical treatments, including chemotherapy, antiandrogens and enzyme inhibitors, as well as secondary major surgical ablative procedures, hypophysectomy and adrenalectomy have been used with more or less equal success. 5 Absolute comparison of the response to these various therapies is complicated by the wide variability in objective and subjective response criteria used by different investigators. We have developed a medical adrenalectomy regimen using aminoglutethimide, a potent inhibitor of adrenal steroid biosynthesis, and physiologic replacement doses of hydrocortisone as a medical alternative to major surgical ablative procedures on the pituitary and adrenal glands in the treatment of metastatic breast and prostate cancer. 6- 8 We herein present our clinical and biochemical reslJ,lts with aminoglutethimide-hydrocortisone in 25 previously castrated men with advanced stage D prostatic adenocarcinoma. Response criteria of the National Prostatic Cancer Project have been used to facilitate comparisons with several recent chemotherapy trials. 9

owing to lethargy associated with the soporific side effects of the drug. The average daily dose of aminoglutethimide was 250 mg. 3 times daily in this group. In initial studies dexamethasone was given for glucocorticoid replacement. However, hydrocortisone was substituted once aminoglutethimide was shown to accelerate the metabolism of dexamethasone. 10 Hydrocortisone was given at a dose of 100 mg. daily (20 mg. at 8 a.m., 20 mg. at 5 p.m. and 60 mg. at bedtime) for the first 2 weeks and 40 mg. (10 mg. at 8 a.m., 10 mg. at 5 p.m. and 20 mg. at bedtime) daily thereafter. To facilitate comparison of our results to those of other studies, the response criteria of the National Prostatic Cancer Project were used. 9 Blood samples (8 to 10 a.m.) were obtained before therapy and at 1 to 3-month intervals for measurements of testosterone and dihydrotestosterone. Patients whose hormone levels are given had been off prior estrogen therapy for at least 30 days. Testosterone and dihydrotestosterone were measured after ether extraction of plasma, celite chromatography and radioimmunoassay as described recently. 11 Statistics were performed using Student's t test. RESULTS

Patients. We studied 25 men with progressive stage D prostatic adenocarcinoma. Mean patient age was 70.1 ± 1.5 years (standard error), with a range of 53 to 85 years. Organ involvement before aminoglutethimide-hydrocortisone therapy included bone in 25 patients, ureteral obstruction in 2, liver in 1, lung in 1 and inferior vena cava in 1. Sixteen patients complained of anorexia and weight loss. Pain occurred in 7 patients who required nonnarcotic analgesics and in 18 who required narcotics for relief. Of the patients 15 were fully ambulatory but with symptoms, while 8 were confined to bed <50 per cent and 2 >50 per cent of the time. Previous therapy included orchiectomy in 25 patients, estrogens in 23, chemotherapy in 2 and flutamide in 3. A total of 15 men had received prior radiation therapy for bone pain. Clinical response. Of the 25 patients who initially began treatment 1 was lost to followup and drug toxicity occurred in 1, leaving 23 evaluable patients. Using the criteria of the National Prostatic Cancer Project an objective response was noted in 11 patients (47.8 per cent), while 12 suffered progression. Of the 11 patients with an objective response 1 continues to be free of disease on therapy after 275 weeks (complete response),

METHODS

Men with biopsy-proved stage D adenocarcinoma of the prostate and disease progression after orchiectomy were eligible for study after informed consent was obtained. Arninoglutethimide was given at a dose of 250 mg. twice daily for the first 2 weeks and 4 times daily thereafter. Chronically, the dose of aminoglutethimide was adjusted downward in some patients Accepted for publication April 2, 1982. Supported in part by grants T32-AM07287 and NO-l-CB-53851. * Current address: 1128 Louisiana Ave., Shreveport, Louisiana 71101. t Current address: Department of Medicine, Tremont and South Center St., East Orange, New Jersey 07019. t Requests for reprints: Division of Urology, Milton S. Hershey Medical Center, Pennsylvania State University, P.O. Box 850, Hershey, Pennsylvania 17033. 51

52

WORGUL AND ASSOCIATES

CASE REPORT 1.0 " NON RESPONDERS

o RESPONDERS

>>:::;

.8


"'


.6

0:: 0..

----'

<(

>

.4

> 0::

:::,

en

.2

20

40

60

80

100

120

140

160

250

WEEKS

Fm. 1. Survival probability curves for patients with and without objective response to aminoglutethimide-hydrocortisone therapy (p <0.01).

Testosterone

R. W., a 64-year-old man, presented in November 1970 with a prostate nodule containing well differentiated adenocarcinoma. In June 1971, 6,000 rad radiotherapy were delivered to the prostate. Mild nocturia developed in January 1974 and hematuria occurred in September 1975. The patient received 5 mg. diethylstilbestrol daily. The prostate again was enlarged in December. In January 1976 skeletal x-rays revealed a single osteoblastic lesion in the body of Tl2 and an acid phosphatase level of 0.9. A bone scan was not obtained. Bilateral orchiectomy was done and the diethylstilbestrol was increased to 5 mg. 3 times daily. The symptoms stabilized for 3 months and then increased markedly. The patient noticed generalized fatigue and weakness, and increased pain in the right shoulder, elbows, knees, lumbar spine and pelvis, which required codeine for relief and rendered him nearly bedridden for 3 months before hospitalization in June. There were paresthesia and weakness of the left hand, and the patient had lost 40 pounds during the last 6 months.

Dihyd rotestosterone

50

40 E 0 0

30

,---<

DD ------C

20

I

10

Basal

Treatment

Basal

Treatment

Fm. 2. Serum testosterone and dihydrotestosterone concentrations before and after aminoglutethimide-hydrocortisone therapy. Significant suppression was observed for testosterone (p <0.005) and dihydrotestosterone (p <0.025).

4 have had a partial response for 8, 41, 122 and 157 weeks, respectively, and 6 have had objectively stable disease for 16, 20, 20, 23, 23 and 32 weeks, respectively. Survival was significantly longer for patients with an objective response by the Mantel-Cox and Breslow tests (p <0.01) (fig. 1). 12 • 1'3 Of the 25 patients 13 (52 per cent) had at least 1 side effect of aminoglutethimide therapy, including lethargy in 11 patients (44 per cent), nausea in 9 (36 per cent), ataxia in 4 (16 per cent), skin rash in 1 (4 per cent) and hypothyroidism in 1 (4 per cent). In 1 patient therapy had to be stopped after 2 days owing to intolerable lethargy. Lethargy in these patients was somewhat more pronounced than that in women receiving aminoglutethimide-hydrocortisone for metastatic breast cancer in our clinic, and may be related to the greater age and extent of disease, and decreased renal function (major site of drug clearance) in these patients. Generally, however, the remainder of the side effects were mild and occurred primarily in the first 6 weeks of therapy. Hormonal response. Serum testosterone (p <0.005) and dihydrotestosterone (p <0.025) concentrations were below the basal level in 9 patients (fig. 2). Owing to the small number of patients there were insufficient data to compare androgen levels in patients with and without response.

FIG. 3. Skeletal x-rays of patient R. W. before therapy (June 1976) with aminoglutethimide-hydrocortisone.

53

AMINOGLUTETHIMIGE

Since that tirtte;; dlllHJlV~:1uce•LHJLlHlUt as an inhibitor of steroidogenesis. cc,,u,uu.~~ blocks several cu•ALtu,11e P-450 mediated steps, including the cholesterol side chain cleav(formation of pregnenolone from cholesterol) and 11-hydroxylase and 21-hydroxylase encortisol production aminoglutethimide tn,·-rrnntQ the negative-feedback loop, allowing adrenocorticoHv,.u.,vo,~ to increase sufficiently to overcome the druginduced blockade. 1"· 17 Administration of replacement amounts of rr., m·rrn, prevents the reflex increase in adrenocorti-~,h,ffrn~ hormone and allows persistent adrenal blockade with aminoglutethimide. With these concepts a drug regimen using aminoglutethimide and replacement doses of hydrocortisone was developed to produce a medical adrenalectomy as a substitute for bilateral adrenalectomy in the treatment of patients with carcinoma of the breast and prostate. 0- 8 • 10 The role of further hormonal therapy in patients with recurrent advanced prostatic cancer after orchiectomy has been doubtful. 18 Plasma testosterone levels are decreased 90 per cent on:hi,ectoinv and no late increase in testosterone levels has been in men with recurrent disease. rn, 2° Furthermore, several investigators were unable to detect any further decrease in testosterone levels after adrenalectomy in patients who pre21 ' 22 What, then, is the had m(:le1·go,ne evidence that recurrent tumors after orchiectomy still hormonally re:srn)n:s1v and ex1;ratec,t1c:ul,11 androgen cancer. Although criteria have been and subjective responses, adrenalectomy and uQioC't.mr"' are associated with 36 to 70 and 35 to 80 per cent response rates, respectively. 5 These results indicate that some prostatic tumors remain at least partially horAdrenal testosterone production in castrated cancer has been studied. With selective adrenal catheterization techniques, direct adrenal gland secretion of testosterone varies from 16 to 217 µ,g. per day and another 228 to 294 µg. per day of testosterone is produced by direct conversion from androstenedione, 23 indicating that patients who ,a~,mr,nc< to further hormonal manipulations may have ;;u:rn.11c:m.1c Ciur duce a medical a.ure11a1ec showed a 47.8 per cent eo1Ju11,;e rate in 23 men with prostatic cancer unresponsive to rnn+.m=u (1 '"•-~:.,'";,,'S.'.~,'S'8, 4 rP.
ov,,ov,c:r,uol"

0

1979) 1;vith

tion of blastic bony 1netastases.

The

Jobe of the :Jrostate ,,,,,GHow., x -rays revealed

osteoblastic lesions cervicat thoracic a.Ld lumbar ribs shoulder, and both fe1nurs 3)0 A bone scan increased in the thoracolurnbar disease. The The and 40 mg. h,;orlrnl'n1'"hc:on which resolved had 25 weakness and hematuria had resolved The prostate had decreased in size . .,_,,,m.up,~c of skeletal x-rays before and after aminoglutethimide are shown in figures 3 and 4. The patient has active and free of disease, and continues on therapy. 0

1

DISCUSSION

Aminoglutethimide, introduced initially as an anticonvulsant in 1960, was removed from the market in 1966 after the uc';',c:,~,·e,·r,•+ of adrenal insufficiency in several pa-

below basal values in men treated Demonstration of <>H
54

WORGUL AND ASSOCIATES

tion in testosterone levels, which before treatment are only 3 to 7 per cent of the rate in nonorchiectomized patients. 23 In a parallel situation women with hormone-dependent breast carcinoma who had undergone oophorectomy respond to surgical adrenalectomy. The estrogen levels are low in these patients before adrenalectomy (that is 5.5 ng./100 ml. estrone and 1.5 ng./100 ml. estradiol) and decrease further after adrenal ablation (that is 1.2 ng./100 ml. estrone and 0.7 ng./100 ml. estradiol).26 One explanation for these observations in breast and prostatic carcinoma is that the hormone-dependent neoplastic cells are exquisitely sensitive to the respective sex steroids. It may be a general phenomenon that endocrine responsive tissues develop a higher level of hormone sensitivity when deprived of hormone stimulation for a prolonged interval. This would be analogous to the denervation hypersensitivity that long has been described for neural tissues. As an example of this phenomenon postmenopausal women or prepubertal girls are exquisitely sensitive to estrogen with respect to gonadotropin suppression. 27 · 28 Administration of replacement steroid later diminishes the level of sensitivity to estrogen in these patients. 29 Thus, deprivation of the testicular source of androgens in men with prostatic carcinoma may result in enhanced sensitivity of the neoplastic cells to the lower levels of adrenal androgens. This possibility, while highly speculative, can be tested with currently available methods. Alternatively, the decrease of androgens observed in this study may not explain the clinical responses. Other possible explanations are that the aromatase inhibitory properties of aminoglutethimide cause an inhibition of estrogen production. 30 It recently has been shown that tamoxifen, an antiestrogen, causes apparent tumor regression in patients with prostatic carcinoma31 and that estrogens may be important for maintenance of androgen receptors in dog prostatic tissues.'12 It further is possible that the hydrocortisone administered produced the responses observed through antiinflammatory or other nonspecific effects. Each of these possibilities must be tested rigorously before definitive conclusions can be made. Hydrocortisone was administered along with aminoglutethimide in this study. It is possible that the decrease in androgens observed was produced strictly by hydrocortisone. A similar possibility recently has been examined in castrated women treated with aminoglutethimide and hydrocortisone in whom hydrocortisone alone was shown to reduce estrogen levels to a lesser extent than the combination of aminoglutethimide and hydrocortisone.:i:i Such a study has not been done to examine the effects of hydrocortisone versus hydrocortisone plus aminoglutethimide in men with prostatic carcinoma. Further studies must now evaluate the comparative effects of both of these regimens in men with prostatic carcinoma randomized to receive these 2 treatments. Presently, therapy of advanced prostatic carcinoma is discouraging and remains palliative at best. Further refinement of the use of androgen receptors or nuclear dihydrotestosterone concentrations may allow selection of patients more likely to respond to hormonal therapy.'14 In the future extensive combination hormonal-chemotherapy may provide greater relief for these patients. REFERENCES 1. Silverberg, E.: Cancer statistics, 1980. CA, 30: 23, 1980. 2. Klein, L. A.: Prostatic carcinoma. New Engl. J. Med., 300: 824,

1979. 3. Schoonees, R., Palma, L. D., Gaeta, J. F., Moore, R.H. and Murphy, G. P.: Prostatic carcinoma treated at categorical center. Clinical and pathologic observations. N. Y. State J. Med., 72: 1021, 1972. 4. Johnson, D. E., Scott, W.W., Gibbons, R. P., Prout, G. R., Schmidt, J. D., Chu, T. M., Gaeta, J., Saroff, J. and Murphy, G. P.: National randomized study of chemotherapeutic agents in advanced prostatic carcinoma: a progress report. Cancer Treat. Rep., 61: 317, 1977. 5. Resnick, M. I. and Grayhack, J. T.: Treatment of stage IV carcinoma of the prostate. Ural. Clin. N. Amer., 2: 141, 1975.

6. Santen, R. J., Worgul, T. J., Samojlik, E., Interrante, A., Boucher, A. E., Lipton, A., Harvey, H. A., White, D. S., Smart, E., Cox, C. and Wells, S. A.: A randomized trial comparing surgical adrenalectomy with aminoglutethimide plus hydrocortisone in women with advanced breast cancer. New Engl. ,J. Med., 305: 545, 1981. 7. Santen, R. J., Worgul, T. J., Harvey, H., Lipton, A., Smart, E., Boucher, A., White, D. and Wells, S.: Aminoglutethimide as treatment of postmenopausal women with advanced breast carcinoma: correlation of clinical and hormonal responses. Ann. Intern. Med., 96: 94, 1982. 8. Sanford, E. J., Drago, J. R., Rohner, T. J., Jr., Santen, R. and Lipton, A.: Aminoglutethimide medical adrenalectomy for advanced prostatic carcinoma. J. Urol., 115: 170, 1976. 9. Schmidt, J. D.: Chemotherapy of hormone-resistant stage D prostatic cancer. J. Ural., 123: 797, 1980. 10. Santen, R. J., Wells, S. A., Runic, S., Gupta, C., Kendall, J., Ruby, E. B. and Samojlik, E.: Adrenal suppression with aminoglutethimide. I. Differenlial effects of aminoglutethimide on glucocorticoid metabolism as a rationale for use of hyclrocortisone. J. Clin. Endocr. Metab., 45: 469, 1977. 11. Samojlik, E. and Santen, R. J .: Adrenal suppression with aminoglutethimide. III. Comparison of plasma t.4 - and t.''-steroids in postmenopausal women treated for breast carcinoma. J. Clin. Endocr. Metab., 4 7: 717, 1978. 12. Mantel, N.: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother. Rep., 50: 163, 1966. 13. Breslow, N.: A generalized Kruksal-Wallis test for comparing K samples subject to unequal patterns of censorship. Biometrika, 57: 579, 1970. 14. Hughes, S. W. and Burley, D. M.: Aminoglutethimide: a "sideeffect" turned to therapeutic advantage. Postgrad. Med. J., 46: 409, 1970. 15. Santen, R. J., Samojlik, E. and Worgul, T. J.: III. Aminoglutethimide. Product profile. In: Pharmanual: A Comprehensive Guide to the Therapeutic Use of Aminoglutethimide. Edited by R. J. Santen and I. C. Henderson. Basel, Switzerland: S. Karger, p. 101, 1982. 16. Dexter, R. N., Fishman, L. M., Ney, R. L. and Liddle, G. W.: Inhibition of adrenal corticosteroid synthesis by aminoglutethirnide: studies of the mechanism of action. J. Clin. Endocr. Metab., 27: 4 73, 1967. 17. Fishman, L. M., Liddle, G. W., Island, D. P., Fleischer, N. and Ki.ichel, 0.: Effects of amino-glutethimide on adrenal function in man. ,J. Clin. Endocr. Metab., 27: 481, 1967. 18. Menon, M. and Walsh, P. C.: Hormonal therapy for prostatic cancer. In: Prostatic Cancer. Edited by G. P. Murphy. Littleton, Massachusetts: PSG Publishing Co., chapt. 11, p. 175, 1979. 19. Young, H. H., II and Kent, J. R.: Plasma testosterone levels in patients with prostatic carcinoma before and after treatment. J. Urol., 99: 788, 1968. 20. Shearer, R J., Hendry, W. F., Sommerville, I. F. and Fergusson, J. D.: Plasma testosterone: an accurate monitor of hormone treatment in prostatic cancer. Brit. J. Urol., 45: 668, 1973. 21. Bhanalaph, T., Varkarakis, M. J. and Murphy, G. P.: Current status of bilateral adrenalectomy for advanced prostatic carcinoma. Ann. Surg., 179: 17, 1974. 22. Reynoso, G. and Murphy, G. P.: Adrenalectomy and hypophysectomy in advanced prostatic carcinoma. Cancer, 29: 941, 1972. 23. Sanford, E. J., Paulson, D. F., Rohner, T. J., Jr., Drago, J. R., Santen, R. J. and Bardin, C. W.: The effects of castration on adrenal testosterone secretion in men with prostatic carcinoma. J. Urol., 118: 1019, 1977. 24. Torti, F. M. and Carter, S. K.: The chemotherapy of prostatic adenocarcinoma. Ann. Intern. Med., 92: 681, 1980. 25. Samojlik, E., Veldhuis, J. D., Wells, S. A. and Santen, R. J.: Preservation of androgen secretion during estrogen suppression with aminoglutethimide in the treatment of metastatic breast carcinoma. J. Clin. Invest., 65: 602, 1980. 26. Worgul, T. J., Santen, R J., Samojlik, E. and Wells, S. A.: How effective is surgical adrenalectomy in lowering steroid hormone concentrations? J. Clin. Endocr. Metab., 54: 22, 1982. 27. Utian, W. H., Katz, M., Davey, D. A. and Carr, P. J.: Effect of premenopausal castration and incremental dosages of conjugated equine estrogens on plasma follicle-stimulating hormone, luteinizing hormone, and estradiol. Amer. ,J. Obst. Gynec., 132: 297, 1978. 28. Wise, A. J., Gross, M.A. and Schaich, D.S.: Quantitative relationships of the pituitary-gonadal axis in postmenopausal women. J.

AlV£IJ:,.JOGLUTETI--Il1VrIDE

Lab. Ciin. 1VIed. 81: 28, 197:3. 29. lviaruca) ,J. Kulin H. E. and Santner) S.: the onaaorro1pn1-g:oriacia1 negative feedback axis in with gonadal dysgenesis (G.D.) undergoing initial estrotreatment. Read at annual of the Endocrine Society, Ohio, abstract 492, 1981. 30. Santen, R J., Santner, S., Davis, E.: Aminoglutethimide inhibits extraglandular estrogen 'Nomen with breast carcinoma. J. 47: 1257, 1978. 31. Glick, J. H., Wein, A., Padavic, K, Negedank, W., Harris, D. and Brodovsky, H.: Tamoxifen in refractory metastatic carcinoma of 1

1

1

:?ROSTATE CAiiCER

the prostate. Cancer Treat. 64: 813, 1980. 32. tv'!oore, R. J., Gazak, J. M. Wilson, J. D.: Regulation of dihydrotestosterone binding in dog prostate by 17/JJ. Clin. Invest., 63: 351, 1979. 33. Parideans, R., Vermeulen, A. and Henson, J.C.: Respective effects of hydrocortisone and aminoglutethimide on circulating sex steroids in postmenopausal patients with advanced breast cancer. In: Program and Abstracts. Aromatase: New Perspectives for Breast Cancer, Key Biscayne, Florida, December 6-9, abstract P-10, 1981. 34. de Vere White, R and Olsson, C. A.: Androgen receptors in prostate cancer. Urology, suppl., 17: 24, 1981.