Scand J (It-01 Nephrol I?: 11.5-1 I X , 1978
TREATMENT OF PROSTATIC CARCINOMA WITH CYPROTERONE ACETATE
Scand J Urol Nephrol Downloaded from informahealthcare.com by University of Melbourne on 10/28/14 For personal use only.
K . I . Tveter.' €3. Otne\ and R. Hanne\tad
Sixteen patients with prostatic carcinoma were treated with 200 mg of Cyproterone acetate daily. N o other kind of hormonal treatment was administered. Increasing skeletal metastases were observed in 6 patients, whereas significant reduction of metastases took place in 2 patients. Objective relief of stranguria was observed only in 3 patients. The amount of residual urine increased in 3 patients and was reduced in 5 . In about one third of the patients. the prostate gland became smaller and softer. The acidic phosphatases decreased from pathological to normal values in 7 patients. There were no observed hepatic, renal o r haemotological side-effects. However, serious cardio-vascular complications occurred in 6 patients. while arterial hypertension developed in 4. I t is suggested that Cyproterone acetate cannot be recommended as the only kind of hormonal treatment of prostatic cancer.
Ahstriict.
The pioneer and original work of Charles Huggins and collaborators about three decades ago. established the value of estrogens in the treatment of prostatic cancer (Huggins Rr Hodges, 1941). Still estrogens are among our most important drugs in the hormonal treatment of prostatic malignancies. Estrogens may, however, cause serious sideeffects. Thus, cardio-vascular complications seem to be significantly higher in patients treated with estrogens (Veterans Administration Group, 1967). Systematic research work has therefore been carried out in order to obtain compunds with the same antiandrogenic potency as estrogens, but without their feminizing and cardio-vascular side-effects. One such synthetic antiandrogen is Cyproterone acetate (Steinbeck. Mehring & Neumann. 1971). The purpose of the present work was to investigate the clinical effect of Cyproterone acetate i n patients with prostatic cancer. MATERIAL The material consists of 16 men with histologically verified prostatic cancer. average age 70 years (48-83 years).
Fifteen were stage 111 and IV carcinomas and one patient had stage I tumor. They were all treated wjith Cyproterone acetate orally in a dosage of 50 mg four times daily. N o other kind of hormonal treatment was given. Thus. they were neither treated with estrogens nor with orchiectomi. The treatment lasted from 3 to 16 months. with an average of 9 months. The various following parameten were studied before and at regular intervals during the treatment: X-ray of the lungs, the pelvis and I,-S spine; isotope scanning of the skeleton, tiroflowmetry. determinations of residual urine, measurements of the siLe. consistency and fixation of the prostatic gland. Likewise. the level of acidic phosphatase was studied, and the function of the bone marrow (haemoglobin. leucocytes, erythrocytes. thrombocytes). the kidney (creatinine and urea) and the liver ( A L A T , ASAT, alkaline phosphatase. normotest). Special attention was drawn to the cardiopulmonary status of the patients, and the blood pressure was controlled regularly. Follow-up was done I , ?, 3 . 6 . 9, I ? and 18 months after initiation of the treatment. The treatment was discontinued as soon as side-effects occurred, o r when no effect on the cancer could be demonstrated. the patient was then either treated with estrogens o r by orchiectomi.
RESULTS X-rrrq and scYtitigrtrpiiic ( ~ x u t r i i i i t ~ t i o n of' tll e . s X c l l ~ t o n
During the treatment. increasing metastases were recorded in 6 patients. In two patients there was significant reduction of bony metastases, whereas in one patient the metastases seemed t o be unchanged. Seven patients had apparently n o metastases, either before or during the treatment. None of the patients had pulmonary metastases.
' Present adress: Professor K . J. 'Iveter. Surgical Dept., University Hospital of Trondheim, 7000 Trondheim, Norway.
No. of pats.
Scand J Urol Nephrol Downloaded from informahealthcare.com by University of Melbourne on 10/28/14 For personal use only.
Acute cholecystitis Increasing dyspnea and edema ‘* FI tis hing” Mors subita Thrombosis cerebri Infarctus cordis
Ptittcrtr
I 3 (4?) I I I I
One patient was treated with TUR o f t h e prostate at the same time a s he entered the trial. and he is therefore omitted from this part of the study. Of the following 15 patients. three patients had improved voiding. Some or uncertain improvement was recorded in two other patients. The urotlowmetric findings were worse in two patients. and in one patient the uroflowmetry showed no alteration. Two patients had normal voiding pattern througho u t the study. The remaining five patients had total urinary retention from the very beginning of the investigation and in all these five patients total urinary retention persisted after 2-3 months of treatment. and ii TUR of the prostate was then carried out. Three more patients had significant stranguria. with n o response t o the treatment even after several months, and were treated with TUR. Thus, T U R was carried out in a total of 8 patients. Three patients experienced transient improvement during the first 2-6 months of treatment. Thereafter stranguria recurred. R i)si d i i ti 1 ii ritr 1, During the treatment residual urine was reduced in 5 patients. in 5 other patients the amount of residual urine was unchanged, while 3 had increased residual urine. The remaining patients had n o residual urine. i n the prosttitt> glwitl
The changes in the size of the prostate as evidenced by determination of the width of the gland were as fol lo w s : Significant reduction Reduction Unchanged Larger
Unchanged Less fixation Increasing fixation
1 pat. 6 pats. 7 pats. 2 pats.
10 pats. 4 pats.
7 pats.
Changes in the consistency of the prostate during the treatment were as fc)llows: Unchanged Softening Transient softening (after 1-3 months)
of tnictiiritiotr
Cliritigc..c
Determination of the degree of fixation of the gland and infiltration of the neighbout-ing structures revealed:
10 pats. 4 pats.
z pats.
Vtirioii.~ blood i ~ r i l i r c s
A ~,.i d i cphosphatase activity: The changes in the ’
acidic phosphatase activity of the I6 patients were: Increasing. but still normal values Increasing. to pathological values Decreasing. from pathological t o normal values Unchanged nlwmal values
3 pats. I pat.
7 pats. 5 pats.
The changes in the specific prostatic acidic phosphatase activity were almost the same a s for the total acidic ph o s p ha t a se . The treatment with Cyproterone acetate had apparently no adverse effects o n the bone m;u-row. The heamoglobin values. the number of erythrocytes. leucocytes and thrombocytes were n o t altered during the treatment period. The kidney function a s determined by serum creatinine and blood urea values. was not effected by the treatment. All patients had normal kidney function throughout the study. The liver function tests were normal in all patients throughout the investigation. The general condition of the patient. a s judged from his own observations. improved in 5 and was significantly better in 7 , while I patient experienced increasing fatigueness. The general condition of the remaining patients was not influenced by Cyproterone acetate. SkPlctlil
pClit1.s
Ten patients had no skeletal pains. One patient got increasing pains during the treatment. In 2 patients the skeletal pains disappeared after one and three months, respectively. Another 3 patients experienced transient improvement during the first 2 4 months of the treatment.
Fi,t~iitiiti;~(it;oti
N o patients complained ofgynaemastia. Libido was reduced in 6 . unchanged in 5 , while 5 patients could give no expression on the effects o n libido. Potency was reduced in 6 patients and unchanged in 5 . whereas 5 patients were unable t o give any information.
Scand J Urol Nephrol Downloaded from informahealthcare.com by University of Melbourne on 10/28/14 For personal use only.
Cot~~/’lic~trt;otl~s
During the treatment significant cardio-vascular alterations were noted in several patients (Table I). The most serious of these include 1 case of sudden death. I case with coronary infarction and 1 case with acute cerebral vascular attack. Blood prcssiirc, The blood pressure was significantly increased in 4 patients. In 10 patients the blood pressure was unaltered. In the remaining 2 patients there is unfortunately no data concerning the blood pressure before they entered the trial.
DISC USSlON Cyproterone acetate is a potent antiandrogenic compound. The efficiency of the substance has been documented by several animal experiments (Neuman. vun Bersvordt-Wallrabe. Elger & Steinbeck, 1970). The drug will reduce the uptake of androgens in the prostate due to competitive affinity for the androgen receptor sites in the prostatic epithelial cells (Hansson & Tveter. 1971). Cyproterone acetate will also reduce plasma testosterone, but has no effect on plasma LH level (Geller. Fishman & Cantor. 1975). Electron microscopic studies has shown that Cyproterone acetate is able to induce distinct regressive changes in the prostatic epithelium of rats (Dahl & Tveter. 1974). Cyproterone acetate has also antiandrogenic properties in patients with prostatic diseases, both hyperplasia as well as cancer (Scott & W a d e , 1969: Wein & Murphy, 1973: Smith, Walsh & Goodwin, 1973; Jameson. 1976). In the present study where 16 patients with prostatic cancer were treated with Cyproterone acetate, only 3 patients had objective improvement of the micturition pattern, as observed by uroflowmetry. In the great majority of the patients, the voiding pattern was unaltered o r even worse. The amount of residual urine was reduced in 5
patients. and significantly increased in 3. According t o the patient’s own experience, 4 obtained relicf of dysuria and frequency. Our results therefore indicate that Cyproterone acetate in an oral dose of 50 mg 4 times daily. is not capable of eliminating or significantly reducing the micturition difficulties in patients with prost a t i c carcinoma . The siLe and consistency of the prostate gland were to some extent affected by the treatment. Thus. in 4 patients the fixation of the prostate t o the stirrounding tissues became less, and the consistency was also softer in 4 patients. The size of the prostate was considered to be reduced in 7 patients. Both the softening and the reduction in size seemed to occur after 1-3 months. If there were n o changes after this time, n o atrophic signs appeared at later intervals. I t is worth noting that in some patients there was some reduction and softening after the first and second control examination. Later on. however. the gland became larger and the consistency harder. Determination of the acidic phosphatase activity revealed significant reduction from pathological to normal values in as much a s 7 patients, indicating regressive changes of the disseminated cancer cells. The degree and incidence of skeletal metastases increased considerably during the treatment period in as many as h patients, while in 2 patients nondisputable regression of metastatic tissue was demonstrated. The lack of effect on metastases lends support to the suggestion that Cyproterone acetate in the dosage used in this study is n o t suffic i e n t I y potent for treat i ng disseminated pros t a t i c cancer. There was n o adverse effects on the liver, kidney o r bone marrow during the trial. On the other hand. there appeared to be significant increase in cardiovascular complications. Thus, three or possibly four of the patients experienced increased water retention, with dyspnea and declive edema. Four patients got significantly increased blood pressure during the treatment. One patient had an apoplectic cerebral injury. one an acute coronary infarction and one patient died suddenly, probably of cardiac arrest. These observations, although not conclusive. indicate that Cyproterone acetate may cause serious cardio-vascular complications in elderly patients with prostatic cancer. The frequency of such complications in the present series seems to be an absolute contraindication for using this drug in elderly patients.
Scand J Urol Nephrol Downloaded from informahealthcare.com by University of Melbourne on 10/28/14 For personal use only.
CON (.' L U S 1O N The p r e s e n t material i \ small a n d t h e t r e a t m e n t period too s h o r t t o d r a w safe c o n c l u s i o n s . However. i t a p p e a r s t h a t C y p r o t e r o n e a c e t a t e in a n oral d o s e of 200 mg daily m a y n o t b e r e c o m m e n d e d ;is t h e o n l y kind of h o r m o n a l t r e a t m e n t of p r o s t a t i c c;incer. First. t h e p o t e n c y of t h e d r u g in t h e d o s e s used is n o t sufficient t o cause o b j e c t i v e signs of r e g r e s s i o n of t h e c a n c e r . S e c o n d l y . t h e t r e a t m e n t , h a s in t h e p r e s e n t material b e e n a s s o c i a t e d with serious c a r d i o - v a s c u l a r c o m p l i c a t i o n s in a s m a n y a s 6 7 o u t o f a total of 16 p a t i e n t s . REFERENCES I h h l . E. & 'I'veter. K . J . 1974. The ultrastructure of the accewory sex organ\ o f the male rat. V. Effect of the antiandrogen compound Cyproterone acetate. J Enc i r ~ r i n62. 25 I , Geller. J.. Fishman. J . & Cantor. T. L. 1975. Effect of Cyproterone acetate on clinical. endocrine and pathological features of benign prostatic hypertrophy. J Src,roirl Eioc,heiii 6. X37.
Hansson. V. & I'veter. K . J . 1971. Effect of antiandrogens on the uptake and binding of androgen by human benign nodular prostatic hyperplasia in vitro. Ac.tn E t i i h ~ (r K h l i . ) 68. 69.
Huggins. C . & Hodges. C. V. 1941. Sttidies on prostatic cancer: Effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of prostate. Cnncer Res I . 293. Jameson. R. M. 1976. Regression of penile metastases of prostatic carcinoma with Cyproterone acetate therapy. Er J Urol48. 268. Neumann. F.. von Berswordt-Wallrabe. R., Elger. W. & Steinbeck. H . 1970. Aspects of androgen-dependent events as studied by antiandrogens. Re H o r m Rc,s 26, 337. Scott. W. W. & Wade. J . C . 1969. Medical treatment of benign nodular prostatic hyperplasia with Cyproterone acetate. J Urol 101. 81. Smith. R . B.. Walsh, P. C . & Goodwin. W . E. 1973. Cyproterone acetate in the treatment of advanced carcinoma of the prostate. J Ur1d 110, 106. Steinbeck, H.. Mehring, M. & Neumann. F. 1971. Comparison of the effects of Cyproterone. Cyproterone acetate and estradiol on testicular function. accessory sexual glands and fertility in a long-term study on rats. J Reproti Fwtil26. 65 I . The Veterans Administration Cooperative Urological Rcsearch Group, 1967. Treatment and survival of patients with cancer of the prostate. Surg G y n c ~ , oOh.stc,t l 124. 1011. Wein. A . J. & Murphy, J . J. 1973. Experience in the treatment of prostatic carcinoma with Cyproterone acetate. J Urol 109, 68.
TREATMENT OF PROSTATIC CARCINOMA WITH CYPROTERONE ACETATE
Scand J Urol Nephrol Downloaded from informahealthcare.com by University of Melbourne on 10/28/14 For personal use only.
K . I . Tveter.' €3. Otne\ and R. Hanne\tad
Sixteen patients with prostatic carcinoma were treated with 200 mg of Cyproterone acetate daily. N o other kind of hormonal treatment was administered. Increasing skeletal metastases were observed in 6 patients, whereas significant reduction of metastases took place in 2 patients. Objective relief of stranguria was observed only in 3 patients. The amount of residual urine increased in 3 patients and was reduced in 5 . In about one third of the patients. the prostate gland became smaller and softer. The acidic phosphatases decreased from pathological to normal values in 7 patients. There were no observed hepatic, renal o r haemotological side-effects. However, serious cardio-vascular complications occurred in 6 patients. while arterial hypertension developed in 4. I t is suggested that Cyproterone acetate cannot be recommended as the only kind of hormonal treatment of prostatic cancer.
Ahstriict.
The pioneer and original work of Charles Huggins and collaborators about three decades ago. established the value of estrogens in the treatment of prostatic cancer (Huggins Rr Hodges, 1941). Still estrogens are among our most important drugs in the hormonal treatment of prostatic malignancies. Estrogens may, however, cause serious sideeffects. Thus, cardio-vascular complications seem to be significantly higher in patients treated with estrogens (Veterans Administration Group, 1967). Systematic research work has therefore been carried out in order to obtain compunds with the same antiandrogenic potency as estrogens, but without their feminizing and cardio-vascular side-effects. One such synthetic antiandrogen is Cyproterone acetate (Steinbeck. Mehring & Neumann. 1971). The purpose of the present work was to investigate the clinical effect of Cyproterone acetate i n patients with prostatic cancer. MATERIAL The material consists of 16 men with histologically verified prostatic cancer. average age 70 years (48-83 years).
Fifteen were stage 111 and IV carcinomas and one patient had stage I tumor. They were all treated wjith Cyproterone acetate orally in a dosage of 50 mg four times daily. N o other kind of hormonal treatment was given. Thus. they were neither treated with estrogens nor with orchiectomi. The treatment lasted from 3 to 16 months. with an average of 9 months. The various following parameten were studied before and at regular intervals during the treatment: X-ray of the lungs, the pelvis and I,-S spine; isotope scanning of the skeleton, tiroflowmetry. determinations of residual urine, measurements of the siLe. consistency and fixation of the prostatic gland. Likewise. the level of acidic phosphatase was studied, and the function of the bone marrow (haemoglobin. leucocytes, erythrocytes. thrombocytes). the kidney (creatinine and urea) and the liver ( A L A T , ASAT, alkaline phosphatase. normotest). Special attention was drawn to the cardiopulmonary status of the patients, and the blood pressure was controlled regularly. Follow-up was done I , ?, 3 . 6 . 9, I ? and 18 months after initiation of the treatment. The treatment was discontinued as soon as side-effects occurred, o r when no effect on the cancer could be demonstrated. the patient was then either treated with estrogens o r by orchiectomi.
RESULTS X-rrrq and scYtitigrtrpiiic ( ~ x u t r i i i i t ~ t i o n of' tll e . s X c l l ~ t o n
During the treatment. increasing metastases were recorded in 6 patients. In two patients there was significant reduction of bony metastases, whereas in one patient the metastases seemed t o be unchanged. Seven patients had apparently n o metastases, either before or during the treatment. None of the patients had pulmonary metastases.
' Present adress: Professor K . J. 'Iveter. Surgical Dept., University Hospital of Trondheim, 7000 Trondheim, Norway.
No. of pats.
Scand J Urol Nephrol Downloaded from informahealthcare.com by University of Melbourne on 10/28/14 For personal use only.
Acute cholecystitis Increasing dyspnea and edema ‘* FI tis hing” Mors subita Thrombosis cerebri Infarctus cordis
Ptittcrtr
I 3 (4?) I I I I
One patient was treated with TUR o f t h e prostate at the same time a s he entered the trial. and he is therefore omitted from this part of the study. Of the following 15 patients. three patients had improved voiding. Some or uncertain improvement was recorded in two other patients. The urotlowmetric findings were worse in two patients. and in one patient the uroflowmetry showed no alteration. Two patients had normal voiding pattern througho u t the study. The remaining five patients had total urinary retention from the very beginning of the investigation and in all these five patients total urinary retention persisted after 2-3 months of treatment. and ii TUR of the prostate was then carried out. Three more patients had significant stranguria. with n o response t o the treatment even after several months, and were treated with TUR. Thus, T U R was carried out in a total of 8 patients. Three patients experienced transient improvement during the first 2-6 months of treatment. Thereafter stranguria recurred. R i)si d i i ti 1 ii ritr 1, During the treatment residual urine was reduced in 5 patients. in 5 other patients the amount of residual urine was unchanged, while 3 had increased residual urine. The remaining patients had n o residual urine. i n the prosttitt> glwitl
The changes in the size of the prostate as evidenced by determination of the width of the gland were as fol lo w s : Significant reduction Reduction Unchanged Larger
Unchanged Less fixation Increasing fixation
1 pat. 6 pats. 7 pats. 2 pats.
10 pats. 4 pats.
7 pats.
Changes in the consistency of the prostate during the treatment were as fc)llows: Unchanged Softening Transient softening (after 1-3 months)
of tnictiiritiotr
Cliritigc..c
Determination of the degree of fixation of the gland and infiltration of the neighbout-ing structures revealed:
10 pats. 4 pats.
z pats.
Vtirioii.~ blood i ~ r i l i r c s
A ~,.i d i cphosphatase activity: The changes in the ’
acidic phosphatase activity of the I6 patients were: Increasing. but still normal values Increasing. to pathological values Decreasing. from pathological t o normal values Unchanged nlwmal values
3 pats. I pat.
7 pats. 5 pats.
The changes in the specific prostatic acidic phosphatase activity were almost the same a s for the total acidic ph o s p ha t a se . The treatment with Cyproterone acetate had apparently no adverse effects o n the bone m;u-row. The heamoglobin values. the number of erythrocytes. leucocytes and thrombocytes were n o t altered during the treatment period. The kidney function a s determined by serum creatinine and blood urea values. was not effected by the treatment. All patients had normal kidney function throughout the study. The liver function tests were normal in all patients throughout the investigation. The general condition of the patient. a s judged from his own observations. improved in 5 and was significantly better in 7 , while I patient experienced increasing fatigueness. The general condition of the remaining patients was not influenced by Cyproterone acetate. SkPlctlil
pClit1.s
Ten patients had no skeletal pains. One patient got increasing pains during the treatment. In 2 patients the skeletal pains disappeared after one and three months, respectively. Another 3 patients experienced transient improvement during the first 2 4 months of the treatment.
Fi,t~iitiiti;~(it;oti
N o patients complained ofgynaemastia. Libido was reduced in 6 . unchanged in 5 , while 5 patients could give no expression on the effects o n libido. Potency was reduced in 6 patients and unchanged in 5 . whereas 5 patients were unable t o give any information.
Scand J Urol Nephrol Downloaded from informahealthcare.com by University of Melbourne on 10/28/14 For personal use only.
Cot~~/’lic~trt;otl~s
During the treatment significant cardio-vascular alterations were noted in several patients (Table I). The most serious of these include 1 case of sudden death. I case with coronary infarction and 1 case with acute cerebral vascular attack. Blood prcssiirc, The blood pressure was significantly increased in 4 patients. In 10 patients the blood pressure was unaltered. In the remaining 2 patients there is unfortunately no data concerning the blood pressure before they entered the trial.
DISC USSlON Cyproterone acetate is a potent antiandrogenic compound. The efficiency of the substance has been documented by several animal experiments (Neuman. vun Bersvordt-Wallrabe. Elger & Steinbeck, 1970). The drug will reduce the uptake of androgens in the prostate due to competitive affinity for the androgen receptor sites in the prostatic epithelial cells (Hansson & Tveter. 1971). Cyproterone acetate will also reduce plasma testosterone, but has no effect on plasma LH level (Geller. Fishman & Cantor. 1975). Electron microscopic studies has shown that Cyproterone acetate is able to induce distinct regressive changes in the prostatic epithelium of rats (Dahl & Tveter. 1974). Cyproterone acetate has also antiandrogenic properties in patients with prostatic diseases, both hyperplasia as well as cancer (Scott & W a d e , 1969: Wein & Murphy, 1973: Smith, Walsh & Goodwin, 1973; Jameson. 1976). In the present study where 16 patients with prostatic cancer were treated with Cyproterone acetate, only 3 patients had objective improvement of the micturition pattern, as observed by uroflowmetry. In the great majority of the patients, the voiding pattern was unaltered o r even worse. The amount of residual urine was reduced in 5
patients. and significantly increased in 3. According t o the patient’s own experience, 4 obtained relicf of dysuria and frequency. Our results therefore indicate that Cyproterone acetate in an oral dose of 50 mg 4 times daily. is not capable of eliminating or significantly reducing the micturition difficulties in patients with prost a t i c carcinoma . The siLe and consistency of the prostate gland were to some extent affected by the treatment. Thus. in 4 patients the fixation of the prostate t o the stirrounding tissues became less, and the consistency was also softer in 4 patients. The size of the prostate was considered to be reduced in 7 patients. Both the softening and the reduction in size seemed to occur after 1-3 months. If there were n o changes after this time, n o atrophic signs appeared at later intervals. I t is worth noting that in some patients there was some reduction and softening after the first and second control examination. Later on. however. the gland became larger and the consistency harder. Determination of the acidic phosphatase activity revealed significant reduction from pathological to normal values in as much a s 7 patients, indicating regressive changes of the disseminated cancer cells. The degree and incidence of skeletal metastases increased considerably during the treatment period in as many as h patients, while in 2 patients nondisputable regression of metastatic tissue was demonstrated. The lack of effect on metastases lends support to the suggestion that Cyproterone acetate in the dosage used in this study is n o t suffic i e n t I y potent for treat i ng disseminated pros t a t i c cancer. There was n o adverse effects on the liver, kidney o r bone marrow during the trial. On the other hand. there appeared to be significant increase in cardiovascular complications. Thus, three or possibly four of the patients experienced increased water retention, with dyspnea and declive edema. Four patients got significantly increased blood pressure during the treatment. One patient had an apoplectic cerebral injury. one an acute coronary infarction and one patient died suddenly, probably of cardiac arrest. These observations, although not conclusive. indicate that Cyproterone acetate may cause serious cardio-vascular complications in elderly patients with prostatic cancer. The frequency of such complications in the present series seems to be an absolute contraindication for using this drug in elderly patients.
Scand J Urol Nephrol Downloaded from informahealthcare.com by University of Melbourne on 10/28/14 For personal use only.
CON (.' L U S 1O N The p r e s e n t material i \ small a n d t h e t r e a t m e n t period too s h o r t t o d r a w safe c o n c l u s i o n s . However. i t a p p e a r s t h a t C y p r o t e r o n e a c e t a t e in a n oral d o s e of 200 mg daily m a y n o t b e r e c o m m e n d e d ;is t h e o n l y kind of h o r m o n a l t r e a t m e n t of p r o s t a t i c c;incer. First. t h e p o t e n c y of t h e d r u g in t h e d o s e s used is n o t sufficient t o cause o b j e c t i v e signs of r e g r e s s i o n of t h e c a n c e r . S e c o n d l y . t h e t r e a t m e n t , h a s in t h e p r e s e n t material b e e n a s s o c i a t e d with serious c a r d i o - v a s c u l a r c o m p l i c a t i o n s in a s m a n y a s 6 7 o u t o f a total of 16 p a t i e n t s . REFERENCES I h h l . E. & 'I'veter. K . J . 1974. The ultrastructure of the accewory sex organ\ o f the male rat. V. Effect of the antiandrogen compound Cyproterone acetate. J Enc i r ~ r i n62. 25 I , Geller. J.. Fishman. J . & Cantor. T. L. 1975. Effect of Cyproterone acetate on clinical. endocrine and pathological features of benign prostatic hypertrophy. J Src,roirl Eioc,heiii 6. X37.
Hansson. V. & I'veter. K . J . 1971. Effect of antiandrogens on the uptake and binding of androgen by human benign nodular prostatic hyperplasia in vitro. Ac.tn E t i i h ~ (r K h l i . ) 68. 69.
Huggins. C . & Hodges. C. V. 1941. Sttidies on prostatic cancer: Effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of prostate. Cnncer Res I . 293. Jameson. R. M. 1976. Regression of penile metastases of prostatic carcinoma with Cyproterone acetate therapy. Er J Urol48. 268. Neumann. F.. von Berswordt-Wallrabe. R., Elger. W. & Steinbeck. H . 1970. Aspects of androgen-dependent events as studied by antiandrogens. Re H o r m Rc,s 26, 337. Scott. W. W. & Wade. J . C . 1969. Medical treatment of benign nodular prostatic hyperplasia with Cyproterone acetate. J Urol 101. 81. Smith. R . B.. Walsh, P. C . & Goodwin. W . E. 1973. Cyproterone acetate in the treatment of advanced carcinoma of the prostate. J Ur1d 110, 106. Steinbeck, H.. Mehring, M. & Neumann. F. 1971. Comparison of the effects of Cyproterone. Cyproterone acetate and estradiol on testicular function. accessory sexual glands and fertility in a long-term study on rats. J Reproti Fwtil26. 65 I . The Veterans Administration Cooperative Urological Rcsearch Group, 1967. Treatment and survival of patients with cancer of the prostate. Surg G y n c ~ , oOh.stc,t l 124. 1011. Wein. A . J. & Murphy, J . J. 1973. Experience in the treatment of prostatic carcinoma with Cyproterone acetate. J Urol 109, 68.
