[CANCER RESEARCH 47, 4736-4739, September 1, 1987) Adrenal Steroid Levels in Castrated Men with Prostatic Carcinoma Treated with Aminoglutethimide plus Hydrocortisone1 Frederick R. Minianti, ' E. David Crawford, Willi Kreis, Yvan Levasseur, and The Aminoglutethimide Study Group
Section of Hematology and Oncology, Tucson VA Medical Center, Tucson 85723 and University of Arizona School of Medicine, Tucson 85724 [F. R. A.J Arizona; Division of Urology, University of Colorado Health Sciences Center, Denver, Colorado 80262 [D. C.J;Northshore University Hospital, Cornell University Medical Center, Manhasset, New York 11030 [W. K.J; and Ciba-Geigy Pharmaceuticals, Summit, New Jersey 07901 [Y. L.J
ABSTRACT in 94 of 129 castrated men with metastatic prostatic carcinoma treated with aminoglutethimide plus hydrocortisone. Monthly serum dehydroepiandrosterone sulfate, androstenedione, tes tosterone, dihydrotestosterone, and free testosterone levels were mea sured in 94 of 129 patients with castration resistant prostatic carcinoma MATERIALS AND METHODS treated on a clinical protocol with aminoglutethimide (1000 mg/day) plus hydrocortisone (40 mg/day) Base-line steroid levels were not found to be Study Group and Clinical Trial Design. The Aminoglutethimide Study age related. Therapy reduced the median levels of all monitored steroids Group (Appendix A) is composed of IS institutions who instituted a but this suppression was not uniform. Although 87% of dehydroepian Phase II clinical trial in 1983 to determine whether therapy with AGT drosterone sulfate levels were suppressed compared to base-line meas plus HC had significant clinical activity in previously castrated men urements, only 52% of androstenedione and 49% of testosterone levels with progressive, évaluable,ormeasurable, prostatic carcinoma. Addi were reduced. Androstenedione levels in 34% of patients actually rose to tional eligibility criteria included normal hematopoietic, renal, and greater than twice base-line levels with similar but less frequent rises hepatic function, histologically documented prostatic carcinoma, in seen in testosterone, free testosterone, and dihydrotestosterone levels. formed written consent, and a life expectancy in excess of 3 months. The highest testosterone level measured was 190 ng/ml. Neither the Therapy consisted of AGT at a dose of 250 mg p.o. twice a day for cause, the deviation, nor the clinical significance of the androgen rise 2 weeks with the dose then escalated to 250 mg four times a day. seen in these patients was established. Therapy with aminoglutethimide Hydrocortisone was concurrently administered p.o. at an initial total plus hydrocortisone as administered in this study may not uniformly daily dose of 100 mg with the dose then reduced to a maintenance dose achieve the objective of suppressing adrenal androgen production. of 40 mg/day after 2 weeks of therapy. All patients were initially treated for 3 months unless frank disease progression occurred. At the end of 3 months, measurable or évaluablediseaseparameters were reassessed INTRODUCTION and a response determination was made by using National Prostate Cancer Project criteria (12). Patients who achieved disease regression The suppression or elimination of testicular androgen pro (partial or complete) or disease stabilization were continued on AGT duction is the only proven effective systemic therapy for meta- plus HC therapy until disease progression was documented. Patients static prostatic carcinoma (1). Endocrine induced remissions with disease progression had their therapy discontinued and were persist for an average of less than 2 years and median survival removed from study. from the date of subsequent relapse is only 6 months (2). Adrenal Steroid Levels. Serum samples were collected on all patients Adrenal steroid production is also a source of androgen pro prior to initiation of therapy and 4, 8, and 12 weeks later with the study design calling for the blood sampling to be performed at approximately duction and is not affected by most primary therapies directed the same time each morning. Serum was stored frozen at -20°C.Assays toward the testes (3). Consequently, adrenal suppression has for levels of DHEA-S, AND, testosterone, DHT, and FT were carried become a proposed method of second line hormonal therapy in out at Nichols Institute Laboratories in San Juan Capistrano, CA. prostate cancer (4). DHEA-S levels were quantified by a direct RIA with the lower limit Although surgical adrenalectomy in patients with prostatic of sensitivity being 5 /¿g/dl.Separate RIAs were also used to measure carcinoma progressing after castration leads to a more complete levels of AND, DHT, and testosterone levels. The lower limits of reduction in serum androgen levels (5), the significant morbidity sensitivity for these assays were 6 ng/dl for AND, 3 ng/dl for DHT, and mortality risk of this major surgical procedure has pre and 1 ng/dl for testosterone. FT was quantified after equilibrium cluded its routine application (6). AGT3 is an aromatase inhib dialysis with a lower limit of sensitivity of 1.2 pg/ml. itor and a potent inhibitor of adrenal corticosteroid synthesis Statistical Methodology. Timed steroid levels for the entire popula (7). Although all the effects of aminoglutethimide on the com tion and subpopulations were recorded as means and medians. A two- plex metabolic pathways in the adrenals have not been deline sided Wilcoxon signed rank test adjusted for ties and zeroes was applied to determine the significance of any change in median steroid levels ated, a major site of action is in the cortex where the conversion over time (13). A relationship between clinical variables and steroid of cholesterol to pregnenolone is inhibited (8). levels was assessed by linear regression analyses (14). A \2 table was Studies conducted primarily in women with breast carcinoma used to determine the significance of relationships between therapy have demonstrated that this drug can suppress some adrenal response rates and rising or falling adrenal steroid levels (15). steroid levels (9). However, uncertainty exists over whether aminoglutethimide can significantly inhibit the production of RESULTS androgenic steroids by the adrenal cortex (10, 11). We report herein the results of serial serum adrenal steroid measurements Clinical Results. Detailed results from the clinical trial are reported elsewhere." In brief, 129 patients were enrolled and 86 Received 5/19/86; revised 5/7/87; accepted 6/2/87. The costs of publication of this article were defrayed in part by the payment (67%) were évaluablefor response. Using National Prostate of page charges. This article must therefore be hereby marked advertisement in Cancer Project response criteria, partial tumor regressions were accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1Supported by a grant from Ciba-Geigy Pharmaceuticals. seen in 11 patients (13%). Stable disease criteria were docu 2To whom requests for reprints should be addressed, at Section of Hematology mented in 41 patients (48%), and frank disease progression was and Oncology, 111-D, Tucson VA Medical Center, Tucson, AZ 85723. 3The abbreviations used are: AGT, Aminoglutethimide; HC, hydrocortisone; 4 D. Crawford, F. R. Ahmann, W. Kreis, M. A. Davis, Y. J. Levasseur, and DHEA-S, dehydroepiandrosterone sulfate; AND, androstenedione; DHT, dihy- the Aminoglutethimide Study Group. Aminoglutethimide and hydrocortisone in drotestosterone; FT, free testosterone; RIA, radioimmunoassay; ACTH, adreno- the treatment of hormone refractory advanced adenocarcinoma of the prostate, corticotropic hormone. submitted to J. Clin. Oncol., 1986. 4736
Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1987 American Association for Cancer Research. ACT AND ADRENAL STEROID LEVELS documented in 34 patients (39%). Overall mean survival for the 50 entire study group was 13.3 ±9.3 (SD) months. Mean survival for partial responders was 20.1 ±8.1 months in comparison to 40 17.1 ±8.8 months for patients with stable disease and 10.5 ± 6.8 months for patients not responding to ACT plus HC. Therapy was well tolerated with toxicities including lethargy 30 (16%), rash (9%), nausea (12%), and edema (18%). Clinical findings of adrenal insufficiency were documented in four cases mcg/dl (5%). 20 Adrenal Steroid Levels. Of the 129 patients enrolled on study, a complete serum steroid level profile of 4 samples was obtained in 69 (53%) and a base-line and at least one follow-up study 10 after 2 months or more of ACT plus HC therapy was obtained X « in 94 (73%) of study entrants. Fig. \A displays a linear regres sion of base-line testosterone and Fig. IB displays base-line \14 i12 01 8Time AND levels as a function of age in these castrated men. The (weeks)— slopes of the generated lines for these adrenal androgens were Fig. 2. Serial median DHEA-S levels with 95% confidence limits in 69 patients not significantly different from zero. Hence, in these castrated treated with ACT plus HC for at least 3 months. A 80r-
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* •••*••••• ',*,*•-.*. 1 ' »* .i •\il»ì».~t•*?:» i L_± «-i* "i . i * Time (weeks) 0•'!•_ 35 41 47 53 59 65 71 77 83 89 Fig. 3. Serial median AND levels with 95% confidence limits in 64 patients treated for at least 3 months with ACT plus HC.
Age at Entry (years) men, adrenal production of these androgens showed no trend B 20 to decline with age. Figs. 2 and 3 display serial median DHEA-S and AND levels, 18 respectively, from the 69 patients in whom a complete, 3-month 16 steroid level profile was obtained. Using a two-sided Wilcoxon signed rank test adjusted for ties and zeroes, the fall in the 14 median DHEA-S level was significant with P < 0.001, whereas the change in median AND levels was not significantly altered 12 by our therapy. The suppression of median base-line testoster o one, DHT, and FT levels were 9 ng/dl, 6.0 ng/dl, and 0.8 pg/ 10 ml, respectively, with values after 12 weeks of therapy falling I to median levels of 6.5 ng/dl, 5.0 ng/dl, and 0.7 pg/dl. o Table 1 displays the effects of 2 to 3 months of therapy with ACT plus HC on mean adrenal steroid levels. This larger population (up to 94 patients) includes 25 patients who devel oped progressive disease after only 2 months of therapy, were removed from study and, hence, did not complete the entire 3- month protocol as did the 69 patients shown in Fig. 1. While 1 1 1 DHEA-S levels fell in 87% of this larger group, close to 50% 384348535863 6873788388 of patients had increases in AND, testosterone, DHT, and FT levels while on AGT plus HC, with the largest changes seen in Age at Entry (years) AND levels. Fig. 1 I, a linear regression analysis of patient age to base-line testosterone levels; lì.a linear regression analysis of patient age to base-line androstenedione Fig. 4 displays linear regression analyses of the relationship levels. of AND and testosterone levels after 1 month (Fig. 4/4), 2 4737
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Table 1 Adrenal steroid levels before and after aminoglutethimide plus hydrocortisone therapy Testosterone DHEA- AND (ng/dl) (ng/dl) DHT (ng/dl) FT (pg/dl) Overall effect No. Base line (mean ±SD) 48.2 ±50.8 44.7 ±36.1 10.9 ±6.4 7.2 ±3.9 1.0 ±1.0 Ontherapy"Steroid 13.4±18.782 104.2 ±185.848 6.4 ±22.646 6.3 ±4.049 1.3 ±1.247 reduction No. (%) (87%) (52%) (49%) (55%) (54%) Base line (mean ±SD) 53.8 ±51.8 47.7 ±38.6 12.8 + 7.0 8.5 ±4.3 1.1 ±0.5 OntherapySteroid 12.9±18.312(13%) 17.6±13.644 4.4 ±3.447(51%) 4.9 ±1.840 0.6 ±0.440 elevation or no change No. (%) (48%) (45%) (46%) Base line (mean ±SD) 9.8 ±13.8 41.7 ±33.4 9.0 ±5.2 5.6 ±2.5 0.7 ±0.5 On2.2* therapy (mean ±SD)94 16.8 ±21.992 190.4 ±234.393 23.5 ±29.089 7.9 ±5.187 2.1 ± On therapy, after 8 to 12 weeks of aminoglutethimidine plus hydrocortisone.
1 month of therapy months (Fig. 4B), and 3 months (Fig. 4C) of ACT plus HC n =18 therapy in those patients whose AND level increased to at least r =0.89 5 times the base-line level. The respective rvalues for the curves are 0.89, 0.63, and 0.89. A similar relationship was found for AND, DHT, and FT levels. Correlation of Steroid Levels with Clinical Results. An anal ysis was carried out to determine if the adrenal steroid effects from therapy (ACT plus HC) affected clinical outcome. There were 23 patients évaluablefor clinical response who had an AND rise to greater than twice base-line values. In this group only one partial response (4%) was seen. However, by x2 anal ysis, this response rate was not significantly less than the 15% 18 27 36 45 54 63 72 response rate seen in all other patients (P = 0.2). Also not Androstenedione Levels Ing/dll significant was the trend for a higher response rate (19%) seen in the 47 patients whose AND levels actually fell during ACT plus HC therapy. _ 2 months of therapy 18 r =0.63 16 - n =16 DISCUSSION i 14 These endocrine studies demonstrate several findings. First, I 12 in castrated men androstenedione and testosterone levels do not appear to decrease with age. Other investigators have noted £ 10 age related declines in DHEA-S levels but conflicting data have been published regarding the effect of age in AND levels (16, 17). Second, in the doses studied, ACT plus HC does influence adrenal steroid synthesis. In 87% of patients, DHEA-S levels were reduced to the lower detection limits of the RIA. The overall effect observed on AND, testosterone, DHT, and FT J_ IIII _L JL was toward lowered levels. However, the effect on these steroids 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 12.0 was variable with up to 34% of patients actually experiencing a Androstenedione Levels (ng/dl) doubling or more in their base-line AND levels on therapy. And finally, while there was a trend for patients with a doubling or more of base-line AND levels to have a reduced incidence of a
3 months of therapy clinical response to ACT plus HC therapy, this association was 84 n=13 not significant. 72 r =0.89 The effect of ACT plus HC on adrenal androgen levels was 60 unclear. In postmenopausal women this drug alone failed to lower testosterone and DHT levels and has had variable effects 48 in AND levels (10,11). The ability of ACT plus HC to suppress 36 AND, testosterone, and DHT in castrated men has been sug
24 gested by others in smaller series (18, 20). It may be that ACT plus HC affects adrenal steroid synthesis differently in men 12 than in women. J! II i I O 1.3 2.5 3.8 5.0 6.3 7.5 8.8 10.0 We monitored adrenal steroid levels for only the first 3 months of AGT plus HC therapy. It has been suggested that in Androstenedione Levels (ng/dl) postmenopausal women with breast carcinoma the acute effects Fig. 4. I. a linear regression analysis of testosterone and AND levels after 1 of AGT plus HC on adrenal steroid synthesis differ from the month of ACT plus HC therapy; B, a linear regression analysis of testosterone and AND levels after 2 months of ACT plus HC therapy; C, a linear regression chronic effects (21 ). It is uncertain whether the variable effects analysis of testosterone and AND levels after 3 months of ACT plus HC therapy. on AND and other adrenal androgen levels reflect a stable state 4738
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2. Blackard, C. E. The Veterans Administration Cooperative Urologica! Re or rather is a transitory phenomenon. While our study called search Group Studies of Carcinoma of the Prostate: a review. Cancer <'hem for a morning collection time, an additional potential factor in other. Rep., 59: 225-227, 1975. the way in steroid levels is the temporal periodicity of adrenal 3. Sanford, E. F., Paulson, D. F., Rohner, T. J., Drago, J. R., Santen, R. J., steroid production. Possible explanations for a rise in AND and Bardin, C. W. The effects of castration on adrenal testosterone secretion in men with prostatic carcinoma. J. Urol., ¡IS:1019-1021, 1977. and other androgen levels in some patients include a lack of 4. Muggins, C., and Scott, W. W. Bilateral adrenalectomy in prostatic cancer. patient compliance, effects of ACT plus HC on prolactin, or Clinical features and urinary excretion of 17-ketosteroids and estrogens. Ann. inadequate suppression of ACTH by 40 mg/day of HC. A Surg., 122:1031-1051, 1945. 5. Bhanalaph, T., Varkarakis, M. J., and Murphy, G. P. Current status of differential effect of ACTH on various steps in adrenal steroid bilateral adrenalectomy on advanced prostatic carcinoma. Ann. Surg., 179: synthesis had been recognized (22) and prolactin has been 17-23, 1973. 6. Schoonees, R., Schalach, D. S., Reynoso, G., and Murphy, G. P. Bilateral suggested by some workers to directly influence adrenal andro adrenalectomy for advanced prostatic carcinoma. J. Urol., Itili: 123-125, gen secretion (23). Only by long term monitoring of prolactin, 1972. 7. Salhanick, M. A. Basic studies on aminoglutethimide. Cancer Res., 42: ACTH, and other pituitary axis hormones, as well as adrenal 3315s-3321s, 1982. steroids, will the mechanism of the rises in AND and other 8. Dexter, R. N., Fishman, L. M., Ney, R. L., and Liddle, G. W. Inhibition of adrenal androgens be clearly understood. adrenal conicosteroid synthesis by aminoglutethimide. Studies of the mech anism of action. J. Clin. Endocrino!. Metab., 27:473-481, 1967. Of concern is the potential clinical effect of actually increas 9. Santen, R. J., Santner, S., Davis, B., Veldhuis, J., Samojlik, E., and Ruby, ing body androgen production in some patients with metastatic E. Aminoglutethimide inhibits extraglandular estrogen production in post- prostatic carcinoma treated with ACT plus HC. Although menopausal women with breast carcinoma. J. Clin. Endocrino!. Metab., 47: 1257-1265, 1978. prostate cancer eventually progresses after an orchiectomy, 10. Santen, R. J., Worgul, T. J., Lipton, A., Harvey, H., Boucher, A., Samojlik, there is significant evidence to suggest that these tumors remain E., and Wells, S. A. Aminoglutethimide as treatment of postmenopausal women with advanced breast cancer. Ann. Intern. Med., 96:94-101, 1982. sensitive to androgen stimulation (1). Marked symptomatic 11. Samojlik, E., Veldhius, J. D., Wells, S. A., and Santen, R. J. Preservation of progression has been documented in most patients receiving androgen secretion during estrogen suppression with aminoglutethimide in exogenous testosterone either as an adjunct to 32Ptherapy (24) the treatment of metastatic breast carcinoma. J. Clin. Invest., 65: 602-612, 1980. or when given as a cell synchronization maneuver prior to the 12. Slack, N. H., Mittelman, A., Brady, M. F., and Murphy, G. P. Investigators administration of cytotcxic chemotherapy (25). It is possible in the National Prostatic Cancer Project. The importance of the stable category for chemotherapy treated patients with advanced and relapsing that the clinical efficacy of ACT plus HC in castration resistant prostate cancer. Cancer
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Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1987 American Association for Cancer Research. Adrenal Steroid Levels in Castrated Men with Prostatic Carcinoma Treated with Aminoglutethimide plus Hydrocortisone
Frederick R. Ahmann, E. David Crawford, Willi Kreis, et al.
Cancer Res 1987;47:4736-4739.
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