© 1991 S. Karger AG. Basel 0042-1138/91/0462—0 167S2.75/0
Urol Int 1991;46:167-171
Treatment of Symptomatic Metastatic Prostatic Cancer with Cyproterone Acetate versus Orchiectomy: A Prospective Randomized Trial Paul Ostri, Tom Bonnesen, Tove Nilsson, Cai Frimodt-Moiler Department of Urology, Gentofte Hospital, University of Copenhagen, Denmark
Key Words. Prostatic cancer • Cyproterone acetate • Orchiectomy • Antiandrogenic treatment
Introduction Prostatic cancer is the second-most common cancer of men in Denmark, with about 1,100 new cases re ported a year. In autopsy materials, the prevalence of latent cancer is about 20% in men aged 50 years, and the prevalence is increasing with age. At the time of diagno sis, most of the patients present advanced diseases with carcinomas extending beyond the boundary of the pros tate. Since the observation of the androgen dependency of the tumor in the early forties [1], the therapy of prostatic cancer has been focused on the suppression of the testic ular androgens. Numerous studies based on this princi ple have shown symptom relief and some regression in about 60-80% of patients, but no improvement in sur vival rates [2-4]. Therefore, in Denmark, the attitude towards the treatment of prostatic cancer has been conservative until
now. Therapy is deferred until symptoms of cancer are detectable. Infravesical obstructions are treated with pal liative transurethral resections, and hormonal therapy is deferred until pain or other symptoms from dissemi nated disease occur. Until recently, the dominant form of endocrine therapy has been estrogens or orchiectomy. None of these treatments is ideal. For some patients, orchiectomy may be psychologically unacceptable, and estrogen therapy is followed by a high incidence of side effects such as cardiovascular complications, fluid reten tion, and gynecomasty [5]. In addition, none of these treatments suppress the adrenal androgens which may be responsible for treatment failure in some patients and for later relapse of the disease [6]. Cyproterone acetate (CPA) is a steroid molecule with antiandrogenic activity due to the competitive inhibi tion of the formation of the dihydrotestosterone-recep tor complex in the cytoplasm in the prostatic cells and elsewhere. In addition, CPA is antigonadotrophic by vir
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Abstract. During a 2-year period, 37 patients with symptomatic metastatic prostatic cancer were included in a prospective randomized phase-III trial. Nineteen patients were randomized to subcapsular orchiectomy, and 18 to cyproterone acetate (CPA) treatment with a dose of 50 mg b.i.d. The median age of the patients was 74 years (range 48-88 years), with no differences between the treatment groups. At 3, 6, and 12 months after initiation of the therapy and then every 6 months, patients were clinically and biochemically examined, and isotope scans and X-rays were performed. All patients were followed until death. Relief from symptoms was found following 3 months of treatment in 70.6% (95% confidence limits = 44.0-89.7%) of the patients treated with CPA, and in 83.3% (95% confidence limits = 58.6-96.4%) of the orchiectomized patients. The median time to relapse was 9 months in the CPA group, and 11 months in the orchiectomy group (p > 0.05). The median survival time was 13 months, with no differences between the groups. The treatment of advanced prostatic cancer with CPA is found to be a valuable alternative to orchiectomy.
168
Patients and Methods A prospective randomized controlled open study on patients with prostatic cancer was conducted from June 1982 to January 1984. Included in the study were patients with histologically verified adenocarcinomas, demonstrable métastasés (T |-T 4, Nx, M|) and symptoms of disseminated disease i.e. pain from métastasés, or locally advanced disease causing an obstruction of the upper urinary tract. Métastasés were demonstrated with isotope bone scanning and X-ray examinations, and ureteral obstructions with intravenous urography and l3lI-Hippuran diuresis renography (patients with obstructive uropathy due to infravesical obstruction were primarily treated with an indwelling catheter or transurethral resection of the prostate). Excluded from the study were patients with other malignancies, other rapidly progressing fatal illnesses, or with hépatologie dysfunc tion not based on prostatic cancer. Forty-one patients entered the study. None of them had pre viously received any systemic antiandrogenic treatment, and the expected survival time based on general health condition was at least 3 months. Following informed consent, 20 patients were randomized to subcapsular orchiectomy, and 21 to CPA treatment at a dose of 50 mg b.i.d. Once enrolled in the study, 4 patients were later excluded. One patient in the CPA group died before treatment was initiated, and 3 patients (2 in the CPA group and 1 in the orchiec tomy group) due to protocol violation. The median age of the patients was 74 years (range: 48-88 years), and there was no difference between the two treatment groups (median age in the orchiectomy group: 74.5, range 62-88 years; in the CPA group: 71, range 48-79 years). The clinical assessment of the therapeutic effect on the basis of symptoms and objective findings was made on entry to the study, following 3 and 6 months of treatment, and thereafter at intervals of 6 months. All patients were followed until the time of death. The following investigations were performed at each control: radioisotope bone scan (and if the interpretation of the bone scan was uncertain X-ray examinations), measurements of prostatic acid phosphatase (PAP), Hgb, creatinine, electrolyte concentrations, se rum testosterone, FSH, LH, and liver function tests. Intravenous urography was performed prior to treatment. If obstructive uropa thy was found, additional renographies were performed before treat ment and at the following controls. The patients were physically examined at each control. Perfor mance status, pain, and the use of analgesics were assessed, and side effects of treatment were recorded. The study was undertaken in accordance with the Helsinki declaration of 1975. Informed consent was obtained from all pa tients.
Table 1. Numbers of patients with different symptoms during treatment At entry
Improvements after 3 months
6 months
12 months
CPA Alive Pain Positive bone scan Urostasis
19 19 18 6
17 12 1 2
11 8 1 1
8 6 0 0
Orchiectomy Alive Pain Positive bone scan Urostasis
18 18 17 8
18 15 4 4
14 13 4 4
11 8 3 3
Statistics In the text, populations are described by medians and ranges. Comparative statistical analysis included the Fisher exact test, the Mann-Whitney rank sum test, and Wilcoxon’s matched-pair signedrank test, p < 0.05 was considered the level of significance.
Results The patients’ symptoms at entry and at the following controls in the first year are shown in table 1, demon strating that all were complaining of pain from the can cer, and that all but 1 patient in both groups were found to have métastasés on bone scans. There were no differences in the palliative effect of the two treatments. Following 3 months of treatment, 70.6% (95% confidence limits = 44.0-89.7%) of the patients alive in the CPA group and 83.3% (95% confi dence limits = 58.6-96.4%) of those in the orchiectomy group were found to have a marked reduction in pain and an increase in performance rate. No differences in the duration of the palliation were found between the treatment groups. In the orchiectomy group, the median time to relapse/progression was 9 months (range 3-24 months) versus 11 months in the CPA group (range 3-36 months). During treatment, partial remission (EORTC) was found in only 2 patients treated with orchiectomy and in 1 treated with CPA. No patients in either treatment group fulfilled the criteria for complete remission [7] at any control.
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tue of progestional activity, thereby affecting the hypothalamo-pituitary axis. The present prospective randomized study was per formed to analyze and compare the effects of CPA treat ment and orchiectomy in patients with symptomatic dis seminated prostatic carcinomas.
Ostri/Bonnesen/Nilsson/Frimodt-Mellcr
Treatment of Prostatic Cancer with Cyproterone Acetate versus Orchiectomy
Time after treatment, months
Fig. 1. PAP concentrations (median values) in patients treated with CPA (o) or orchiectomy (■) Fig. 2. Concentrations (median values) of FSH (■, •) and LH (□, o) in patients treated with CPA (•, o) or orchiectomy (■, □).
Fig. 3. Serum testosterone concentrations (median values) in patients treated with CPA (o) or orchiectomy (■). Fig. 4. Survival following treatment, d = All patients; ■ = orchiec tomy group; o = CPA group.
Regression on bone scans (i.e. a reduction in hot spot > 50%) was found in a few patients only (table 1), and no significant differences were found between the groups. A complete normalization of bone scans at 12 months was found in 2 patients treated by orchiectomy. Impaired renal function and stasis of the upper uri nary tract due to obstruction from the cancer were found in 14 patients at entry (table 1). Following 3 months of treatment, normalizations in serum creatinine levels and renographies were observed in approximately 50% in both treatment groups; again, no significant differences were found between the groups. The changes of PAP during treatment are shown in figure 1. In both treatment groups, a significant decline in concentration was found at the 3-month control, fol lowed by a slow but insignificant rise in the following 9 months. There were no differences in PAP concentra tions between the treatment groups at any time.
Significant rises in FSH and LH levels (fig. 2) and a decrease in serum testosterone (fig. 3; p < 0.001) were seen in the orchiectomized patients. In the patients treated with CPA, a decrease in serum testosterone con centrations was found, but the decline was significantly lower compared to the orchiectomy group. No signifi cant changes were seen in FSH and LH concentrations in the CPA group. At entry the median serum creatinine concentrations were 0.110 mmol/1 (range 0.043-0.558 mmol/1) in the orchiectomized group, and 0.105 mmol/1 (range 0.0780.186 mmol/1) in patients treated with CPA. During treatment, there was a slight, insignificant increase in the concentration to 0.129 mmol/1 in the orchiectomy group at the 12-month control, and an insignificant decrease to 0.082 mmol/1 in the CPA group. All patients were followed until death. The survival is shown in figure 4. There were no differences in the sur-
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Treatment time, months
169
170
Discussion Mortality and the duration of survival in patients with advanced metastatic prostatic cancer have not sig nificantly improved since the introduction of hormonal therapy. Labrie et al. [6] claimed that total androgen blockade resulted in better survival, but so far, no ran domized study has been able to prove this statement [810], The median arrival time in our study was 13 months, with no difference between the treatment groups. This survival time is shorter than that found in previous stud ies [2, 8, 11], but only in the present study, exclusively patients with symptomatic metastatic cancers were in cluded. When the prostatic cancer is disseminated, the chances of prolonging life are minimal, and the strategy of therapy must be aimed at relieving the symptoms with minimal side effects. In the present study, subjective improvement was found in 77.1% of the patients, with no significant dif ference between the treatment groups. This is in accor dance with the palliative response rates found in patients treated with orchiectomy [12, 13], estrogens [14], or other ways of androgen deprivation including patients treated with ‘complete androgen blockage’ [8, 10], The median duration of the improvement was 10 months, and again no difference was found between patients treated with orchiectomy or CPA. A significant reduction in PAP was measured in both treatment groups, and a high correlation was found between relief from symptoms and decline in PAP con centrations. Relapse was correlation with but not pre ceded by a rise in PAP. Only in a few patients was remis sion of bone metastases detectable, and again, there was no difference between the two groups. None of the patients fulfilled the EORTC criteria for complete remis
sion, and only 2 patients treated by orchiectomy and 1 treated with CPA fulfilled the criteria for partial remis sion. This remission rate is lower than those found in earlier studies [2, 14, 15], but the patients in this study probably presented more advanced disease before treat ment, as only patients with symptomatic cancers were included. During CPA treatment, serum testosteione decreased to about one third of the initial value, a result compara ble to patients treated with higher doses of CPA [ 16], but a significantly minor decline compared to patients treated by orchiectomy. The higher levels in testosterone concentrations in patients treated with CPA are not a sign of inefficacy, as CPA in addition to its antigonadotrophic action shows a strong antiandrogcnic effect on receptors. This antiandrogenic effect may be of value in protecting the cancer from cortical androgens [6]. In the first study CPA at a dose of 100-250 mg/day was used in the treatment of prostatic cancer [17], In later trials, the applied dose was increased to 250 mg/day [14, 18]. Primarily, we used a daily dose of 200 mg CPA in a small preliminary pilot study, but some of the patients complained of severe depressions. Tveter et al. [ 19] also observed severe side effects with 200 mg CPA/day. This is in contrast to the studies of Geller et al. [18] and Pavone-Macaluso et al. [14] in which a daily dose of 250 mg CPA did not increase the relative fre quency and severeness of side effects. As a consequence of our preliminary results, we reduced the dose to 100 mg/day in this trial. In spite of the dose reduction, results comparable to orchiectomy concerning symptom relief, remission, and survival were still found. During treatment, only a few and minor side effects in patients treated with CPA were found, and less patients complained of hot flushes compared to orchiectomized patients. It is concluded that the treatment of prostatic cancer with CPA at a dose of 100 mg/day is an alternative to orchiectomy.
References 1 Huggins C, Hodges CV: Studies on prostatic cancer. Effect of castration, oestrogen and androgen injection on serum phospha tase in metastatic carcinoma of the prostate. Cancer Res 1941; 1: 293-297. 2 Robinson MRG. Hetherington J: The EORTC studies: Is there an optimal endocrine management for Mi prostatic cancer? World J Urol 1986;4:171-175. 3 Schroeder FH, Lock MTW, Chadha RD. Debruyne MJF, Karthaus HFM, De Jong FH, Klijn JGM, Matroos AW, Dc Voogt
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vival patterns between the treatment groups. The me dian time of survival in orchiectomized patients was 15 months (range 3-50 months), and 9 months in those treated with CPA (range 3-38 months). All patients were dying with progressing disease. Most patients in both treatment groups noted a loss in libido and an inability to obtain erections. Almost all orchiectomized patients complained of hot flushes, whereas no patient in the CPA group was hampered by this symptom. Apart from this, no major side effects were reported in both treatment groups.
Ostri/Bonnesen/Nilsson/Frimodt-Mellcr
Treatment of Prostatic Cancer with Cyproterone Acetate versus Orchiectomy
5
6
7
8
9
10
11
12
13 Klein LA: Prostatic carcinoma. N Engl J Med 1979;300:824833. 14 Pavone-Macaluso M, de Voogt HJ, Viggiano G, Barasolo E, Lardennois B, de Pauw M, Sylvester R: Comparison of diethylstilbestol, cyproterone acetate and medroxyprogesterone acetate in the treatment of advanced prostatic cancer: Final analysis of a randomized phase III trial of the EORTC Urological Group. J Urol 1986;136:624-631. 15 Beurton D, Grail J, Davody Ph, Cukier J: Treatment of prostatic cancer with cyproterone acetate as monotherapy; in Murphy PG, Khoury S, Kuss R, Châtelain C, Denis L (eds): Prostate Cancer, Part A. New York, Liss, 1987, pp 369-377. 16 Jacobi GH, Altwein JE, Kurth KH, Basting R, Hohenfellner R: Treatment of advanced prostatic cancer with parenteral cyprote rone acetate: A phase III randomised trial. Br J Urol 1980;52: 208-215. 17 Scott WW, Schirmer HKA: A new oral progestational steroid effective in treating prostatic cancer. Trans Am Ass Genitourin Surg 1966;58:54-60. 18 Geller J, Vazakas G, Fruchtman B, Newman H, Nakao K, Loh A: The effect of cyproterone acetate on advanced carcinoma of the prostate. Surg Gynecol Obstet 1968;127:748-758. 19 Tveter KJ, Otnes B, Hannestad R: Treatment of prostatic carci noma with cyproterone acetate. Scand J Urol Nephrol 1978; 12: 115-118.
Received: January 15, 1990 Accepted: February 6, 1990 Paul Ostri Dickens alle 48 DK-2860 Soborg (Denmark)
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4
HJ: Metastatic cancer of the prostate managed with buscrclin versus buserelin plus cyproterone acetate. J Urol 1987; 137:912— 918. Kirk D: Trails and tribulations in prostatic cancer. Br J Urol 1987;59:375-379. The Veterans Administration Cooperative Urological Research Group: Treatment and survival of patients with cancer of the prostate. Surg Gynecol Obstet 1967; 124:1011-1017. Labrie F, Dupont A, Belanger A: Complete androgen blockade for the treatment of prostate cancer; in De Vita VT, Helman S, Rosenberg SA (eds): Important Advances in Oncology. Philadel phia, Lippincott, 1985, pp 193-217. Schroeder FH, the European Organization on Research and Treatment of Cancer, Urological Group: Treatment response criteria for prostatic cancer. Prostate 1984;5:181-191. Beland G, Elhilali M, Fraddet Y, Laroche B, Ramsey EW, Ven ner PM, Tewari HD: Total androgen blockade vs. orchiectomy in stage D? prostate cancer; in Murphy PG, Khoury S, Kuss R, Châtelain C, Denis L (eds): Prostate Cancer, Part A. New York, Liss, 1987, pp 391-400. Navratil H: Double-blind study of anandron versus placebo in stage D: prostatic cancer patients receiving buserelin; in Murphy PG, Khoury S, Kuss R, Châtelain C, Denis L (eds): Prostate cancer, Part A. New York, Liss, 1987, pp 401-411. Robinson MRG: Complete androgen blockade: The EORTC experience comparing orchidectomy versus orchidectomy plus cyproterone acetate versus low-dose stilboestrol in the treatment of metastatic carcinoma of the prostate; in Murphy PG, Khoury S, Kuss R, Châtelain C, Denis L (eds): Prostate Cancer, Part A. New York, Liss, 1987, pp 383-390. Slack NH, Brady MF, Murphy GP: Investigators in the National Prostatic Cancer Project: Stable versus partial response in ad vanced prostate cancer. Prostate 1984;5:401-415. Nesbit R, Baum WC: Endocrine control of prostatic carcinoma: Clinical and statistical survey of 1,818 cases. JAMA 1950; 143: 1317-1320.
17!
Urol Int 1991;46:167-171
Treatment of Symptomatic Metastatic Prostatic Cancer with Cyproterone Acetate versus Orchiectomy: A Prospective Randomized Trial Paul Ostri, Tom Bonnesen, Tove Nilsson, Cai Frimodt-Moiler Department of Urology, Gentofte Hospital, University of Copenhagen, Denmark
Key Words. Prostatic cancer • Cyproterone acetate • Orchiectomy • Antiandrogenic treatment
Introduction Prostatic cancer is the second-most common cancer of men in Denmark, with about 1,100 new cases re ported a year. In autopsy materials, the prevalence of latent cancer is about 20% in men aged 50 years, and the prevalence is increasing with age. At the time of diagno sis, most of the patients present advanced diseases with carcinomas extending beyond the boundary of the pros tate. Since the observation of the androgen dependency of the tumor in the early forties [1], the therapy of prostatic cancer has been focused on the suppression of the testic ular androgens. Numerous studies based on this princi ple have shown symptom relief and some regression in about 60-80% of patients, but no improvement in sur vival rates [2-4]. Therefore, in Denmark, the attitude towards the treatment of prostatic cancer has been conservative until
now. Therapy is deferred until symptoms of cancer are detectable. Infravesical obstructions are treated with pal liative transurethral resections, and hormonal therapy is deferred until pain or other symptoms from dissemi nated disease occur. Until recently, the dominant form of endocrine therapy has been estrogens or orchiectomy. None of these treatments is ideal. For some patients, orchiectomy may be psychologically unacceptable, and estrogen therapy is followed by a high incidence of side effects such as cardiovascular complications, fluid reten tion, and gynecomasty [5]. In addition, none of these treatments suppress the adrenal androgens which may be responsible for treatment failure in some patients and for later relapse of the disease [6]. Cyproterone acetate (CPA) is a steroid molecule with antiandrogenic activity due to the competitive inhibi tion of the formation of the dihydrotestosterone-recep tor complex in the cytoplasm in the prostatic cells and elsewhere. In addition, CPA is antigonadotrophic by vir
Downloaded by: Stockholm University Library 130.237.165.40 - 11/26/2018 10:09:21 PM
Abstract. During a 2-year period, 37 patients with symptomatic metastatic prostatic cancer were included in a prospective randomized phase-III trial. Nineteen patients were randomized to subcapsular orchiectomy, and 18 to cyproterone acetate (CPA) treatment with a dose of 50 mg b.i.d. The median age of the patients was 74 years (range 48-88 years), with no differences between the treatment groups. At 3, 6, and 12 months after initiation of the therapy and then every 6 months, patients were clinically and biochemically examined, and isotope scans and X-rays were performed. All patients were followed until death. Relief from symptoms was found following 3 months of treatment in 70.6% (95% confidence limits = 44.0-89.7%) of the patients treated with CPA, and in 83.3% (95% confidence limits = 58.6-96.4%) of the orchiectomized patients. The median time to relapse was 9 months in the CPA group, and 11 months in the orchiectomy group (p > 0.05). The median survival time was 13 months, with no differences between the groups. The treatment of advanced prostatic cancer with CPA is found to be a valuable alternative to orchiectomy.
168
Patients and Methods A prospective randomized controlled open study on patients with prostatic cancer was conducted from June 1982 to January 1984. Included in the study were patients with histologically verified adenocarcinomas, demonstrable métastasés (T |-T 4, Nx, M|) and symptoms of disseminated disease i.e. pain from métastasés, or locally advanced disease causing an obstruction of the upper urinary tract. Métastasés were demonstrated with isotope bone scanning and X-ray examinations, and ureteral obstructions with intravenous urography and l3lI-Hippuran diuresis renography (patients with obstructive uropathy due to infravesical obstruction were primarily treated with an indwelling catheter or transurethral resection of the prostate). Excluded from the study were patients with other malignancies, other rapidly progressing fatal illnesses, or with hépatologie dysfunc tion not based on prostatic cancer. Forty-one patients entered the study. None of them had pre viously received any systemic antiandrogenic treatment, and the expected survival time based on general health condition was at least 3 months. Following informed consent, 20 patients were randomized to subcapsular orchiectomy, and 21 to CPA treatment at a dose of 50 mg b.i.d. Once enrolled in the study, 4 patients were later excluded. One patient in the CPA group died before treatment was initiated, and 3 patients (2 in the CPA group and 1 in the orchiec tomy group) due to protocol violation. The median age of the patients was 74 years (range: 48-88 years), and there was no difference between the two treatment groups (median age in the orchiectomy group: 74.5, range 62-88 years; in the CPA group: 71, range 48-79 years). The clinical assessment of the therapeutic effect on the basis of symptoms and objective findings was made on entry to the study, following 3 and 6 months of treatment, and thereafter at intervals of 6 months. All patients were followed until the time of death. The following investigations were performed at each control: radioisotope bone scan (and if the interpretation of the bone scan was uncertain X-ray examinations), measurements of prostatic acid phosphatase (PAP), Hgb, creatinine, electrolyte concentrations, se rum testosterone, FSH, LH, and liver function tests. Intravenous urography was performed prior to treatment. If obstructive uropa thy was found, additional renographies were performed before treat ment and at the following controls. The patients were physically examined at each control. Perfor mance status, pain, and the use of analgesics were assessed, and side effects of treatment were recorded. The study was undertaken in accordance with the Helsinki declaration of 1975. Informed consent was obtained from all pa tients.
Table 1. Numbers of patients with different symptoms during treatment At entry
Improvements after 3 months
6 months
12 months
CPA Alive Pain Positive bone scan Urostasis
19 19 18 6
17 12 1 2
11 8 1 1
8 6 0 0
Orchiectomy Alive Pain Positive bone scan Urostasis
18 18 17 8
18 15 4 4
14 13 4 4
11 8 3 3
Statistics In the text, populations are described by medians and ranges. Comparative statistical analysis included the Fisher exact test, the Mann-Whitney rank sum test, and Wilcoxon’s matched-pair signedrank test, p < 0.05 was considered the level of significance.
Results The patients’ symptoms at entry and at the following controls in the first year are shown in table 1, demon strating that all were complaining of pain from the can cer, and that all but 1 patient in both groups were found to have métastasés on bone scans. There were no differences in the palliative effect of the two treatments. Following 3 months of treatment, 70.6% (95% confidence limits = 44.0-89.7%) of the patients alive in the CPA group and 83.3% (95% confi dence limits = 58.6-96.4%) of those in the orchiectomy group were found to have a marked reduction in pain and an increase in performance rate. No differences in the duration of the palliation were found between the treatment groups. In the orchiectomy group, the median time to relapse/progression was 9 months (range 3-24 months) versus 11 months in the CPA group (range 3-36 months). During treatment, partial remission (EORTC) was found in only 2 patients treated with orchiectomy and in 1 treated with CPA. No patients in either treatment group fulfilled the criteria for complete remission [7] at any control.
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tue of progestional activity, thereby affecting the hypothalamo-pituitary axis. The present prospective randomized study was per formed to analyze and compare the effects of CPA treat ment and orchiectomy in patients with symptomatic dis seminated prostatic carcinomas.
Ostri/Bonnesen/Nilsson/Frimodt-Mellcr
Treatment of Prostatic Cancer with Cyproterone Acetate versus Orchiectomy
Time after treatment, months
Fig. 1. PAP concentrations (median values) in patients treated with CPA (o) or orchiectomy (■) Fig. 2. Concentrations (median values) of FSH (■, •) and LH (□, o) in patients treated with CPA (•, o) or orchiectomy (■, □).
Fig. 3. Serum testosterone concentrations (median values) in patients treated with CPA (o) or orchiectomy (■). Fig. 4. Survival following treatment, d = All patients; ■ = orchiec tomy group; o = CPA group.
Regression on bone scans (i.e. a reduction in hot spot > 50%) was found in a few patients only (table 1), and no significant differences were found between the groups. A complete normalization of bone scans at 12 months was found in 2 patients treated by orchiectomy. Impaired renal function and stasis of the upper uri nary tract due to obstruction from the cancer were found in 14 patients at entry (table 1). Following 3 months of treatment, normalizations in serum creatinine levels and renographies were observed in approximately 50% in both treatment groups; again, no significant differences were found between the groups. The changes of PAP during treatment are shown in figure 1. In both treatment groups, a significant decline in concentration was found at the 3-month control, fol lowed by a slow but insignificant rise in the following 9 months. There were no differences in PAP concentra tions between the treatment groups at any time.
Significant rises in FSH and LH levels (fig. 2) and a decrease in serum testosterone (fig. 3; p < 0.001) were seen in the orchiectomized patients. In the patients treated with CPA, a decrease in serum testosterone con centrations was found, but the decline was significantly lower compared to the orchiectomy group. No signifi cant changes were seen in FSH and LH concentrations in the CPA group. At entry the median serum creatinine concentrations were 0.110 mmol/1 (range 0.043-0.558 mmol/1) in the orchiectomized group, and 0.105 mmol/1 (range 0.0780.186 mmol/1) in patients treated with CPA. During treatment, there was a slight, insignificant increase in the concentration to 0.129 mmol/1 in the orchiectomy group at the 12-month control, and an insignificant decrease to 0.082 mmol/1 in the CPA group. All patients were followed until death. The survival is shown in figure 4. There were no differences in the sur-
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Treatment time, months
169
170
Discussion Mortality and the duration of survival in patients with advanced metastatic prostatic cancer have not sig nificantly improved since the introduction of hormonal therapy. Labrie et al. [6] claimed that total androgen blockade resulted in better survival, but so far, no ran domized study has been able to prove this statement [810], The median arrival time in our study was 13 months, with no difference between the treatment groups. This survival time is shorter than that found in previous stud ies [2, 8, 11], but only in the present study, exclusively patients with symptomatic metastatic cancers were in cluded. When the prostatic cancer is disseminated, the chances of prolonging life are minimal, and the strategy of therapy must be aimed at relieving the symptoms with minimal side effects. In the present study, subjective improvement was found in 77.1% of the patients, with no significant dif ference between the treatment groups. This is in accor dance with the palliative response rates found in patients treated with orchiectomy [12, 13], estrogens [14], or other ways of androgen deprivation including patients treated with ‘complete androgen blockage’ [8, 10], The median duration of the improvement was 10 months, and again no difference was found between patients treated with orchiectomy or CPA. A significant reduction in PAP was measured in both treatment groups, and a high correlation was found between relief from symptoms and decline in PAP con centrations. Relapse was correlation with but not pre ceded by a rise in PAP. Only in a few patients was remis sion of bone metastases detectable, and again, there was no difference between the two groups. None of the patients fulfilled the EORTC criteria for complete remis
sion, and only 2 patients treated by orchiectomy and 1 treated with CPA fulfilled the criteria for partial remis sion. This remission rate is lower than those found in earlier studies [2, 14, 15], but the patients in this study probably presented more advanced disease before treat ment, as only patients with symptomatic cancers were included. During CPA treatment, serum testosteione decreased to about one third of the initial value, a result compara ble to patients treated with higher doses of CPA [ 16], but a significantly minor decline compared to patients treated by orchiectomy. The higher levels in testosterone concentrations in patients treated with CPA are not a sign of inefficacy, as CPA in addition to its antigonadotrophic action shows a strong antiandrogcnic effect on receptors. This antiandrogenic effect may be of value in protecting the cancer from cortical androgens [6]. In the first study CPA at a dose of 100-250 mg/day was used in the treatment of prostatic cancer [17], In later trials, the applied dose was increased to 250 mg/day [14, 18]. Primarily, we used a daily dose of 200 mg CPA in a small preliminary pilot study, but some of the patients complained of severe depressions. Tveter et al. [ 19] also observed severe side effects with 200 mg CPA/day. This is in contrast to the studies of Geller et al. [18] and Pavone-Macaluso et al. [14] in which a daily dose of 250 mg CPA did not increase the relative fre quency and severeness of side effects. As a consequence of our preliminary results, we reduced the dose to 100 mg/day in this trial. In spite of the dose reduction, results comparable to orchiectomy concerning symptom relief, remission, and survival were still found. During treatment, only a few and minor side effects in patients treated with CPA were found, and less patients complained of hot flushes compared to orchiectomized patients. It is concluded that the treatment of prostatic cancer with CPA at a dose of 100 mg/day is an alternative to orchiectomy.
References 1 Huggins C, Hodges CV: Studies on prostatic cancer. Effect of castration, oestrogen and androgen injection on serum phospha tase in metastatic carcinoma of the prostate. Cancer Res 1941; 1: 293-297. 2 Robinson MRG. Hetherington J: The EORTC studies: Is there an optimal endocrine management for Mi prostatic cancer? World J Urol 1986;4:171-175. 3 Schroeder FH, Lock MTW, Chadha RD. Debruyne MJF, Karthaus HFM, De Jong FH, Klijn JGM, Matroos AW, Dc Voogt
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vival patterns between the treatment groups. The me dian time of survival in orchiectomized patients was 15 months (range 3-50 months), and 9 months in those treated with CPA (range 3-38 months). All patients were dying with progressing disease. Most patients in both treatment groups noted a loss in libido and an inability to obtain erections. Almost all orchiectomized patients complained of hot flushes, whereas no patient in the CPA group was hampered by this symptom. Apart from this, no major side effects were reported in both treatment groups.
Ostri/Bonnesen/Nilsson/Frimodt-Mellcr
Treatment of Prostatic Cancer with Cyproterone Acetate versus Orchiectomy
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13 Klein LA: Prostatic carcinoma. N Engl J Med 1979;300:824833. 14 Pavone-Macaluso M, de Voogt HJ, Viggiano G, Barasolo E, Lardennois B, de Pauw M, Sylvester R: Comparison of diethylstilbestol, cyproterone acetate and medroxyprogesterone acetate in the treatment of advanced prostatic cancer: Final analysis of a randomized phase III trial of the EORTC Urological Group. J Urol 1986;136:624-631. 15 Beurton D, Grail J, Davody Ph, Cukier J: Treatment of prostatic cancer with cyproterone acetate as monotherapy; in Murphy PG, Khoury S, Kuss R, Châtelain C, Denis L (eds): Prostate Cancer, Part A. New York, Liss, 1987, pp 369-377. 16 Jacobi GH, Altwein JE, Kurth KH, Basting R, Hohenfellner R: Treatment of advanced prostatic cancer with parenteral cyprote rone acetate: A phase III randomised trial. Br J Urol 1980;52: 208-215. 17 Scott WW, Schirmer HKA: A new oral progestational steroid effective in treating prostatic cancer. Trans Am Ass Genitourin Surg 1966;58:54-60. 18 Geller J, Vazakas G, Fruchtman B, Newman H, Nakao K, Loh A: The effect of cyproterone acetate on advanced carcinoma of the prostate. Surg Gynecol Obstet 1968;127:748-758. 19 Tveter KJ, Otnes B, Hannestad R: Treatment of prostatic carci noma with cyproterone acetate. Scand J Urol Nephrol 1978; 12: 115-118.
Received: January 15, 1990 Accepted: February 6, 1990 Paul Ostri Dickens alle 48 DK-2860 Soborg (Denmark)
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HJ: Metastatic cancer of the prostate managed with buscrclin versus buserelin plus cyproterone acetate. J Urol 1987; 137:912— 918. Kirk D: Trails and tribulations in prostatic cancer. Br J Urol 1987;59:375-379. The Veterans Administration Cooperative Urological Research Group: Treatment and survival of patients with cancer of the prostate. Surg Gynecol Obstet 1967; 124:1011-1017. Labrie F, Dupont A, Belanger A: Complete androgen blockade for the treatment of prostate cancer; in De Vita VT, Helman S, Rosenberg SA (eds): Important Advances in Oncology. Philadel phia, Lippincott, 1985, pp 193-217. Schroeder FH, the European Organization on Research and Treatment of Cancer, Urological Group: Treatment response criteria for prostatic cancer. Prostate 1984;5:181-191. Beland G, Elhilali M, Fraddet Y, Laroche B, Ramsey EW, Ven ner PM, Tewari HD: Total androgen blockade vs. orchiectomy in stage D? prostate cancer; in Murphy PG, Khoury S, Kuss R, Châtelain C, Denis L (eds): Prostate Cancer, Part A. New York, Liss, 1987, pp 391-400. Navratil H: Double-blind study of anandron versus placebo in stage D: prostatic cancer patients receiving buserelin; in Murphy PG, Khoury S, Kuss R, Châtelain C, Denis L (eds): Prostate cancer, Part A. New York, Liss, 1987, pp 401-411. Robinson MRG: Complete androgen blockade: The EORTC experience comparing orchidectomy versus orchidectomy plus cyproterone acetate versus low-dose stilboestrol in the treatment of metastatic carcinoma of the prostate; in Murphy PG, Khoury S, Kuss R, Châtelain C, Denis L (eds): Prostate Cancer, Part A. New York, Liss, 1987, pp 383-390. Slack NH, Brady MF, Murphy GP: Investigators in the National Prostatic Cancer Project: Stable versus partial response in ad vanced prostate cancer. Prostate 1984;5:401-415. Nesbit R, Baum WC: Endocrine control of prostatic carcinoma: Clinical and statistical survey of 1,818 cases. JAMA 1950; 143: 1317-1320.
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