British Journalof Urology (1990), 66,94-97 01990 British Journal of Urology
0007-1 331/90/0066-0094/$10.00
Comparison of Primary Orchiectomy and Polyoestradiol Phosphate in the Treatment of Advanced Prostatic Cancer R. HAAPIAINEN, S. RANNIKKO, 0. ALFTHAN and the FINNPROSTATE GROUP Second Department of Surgery, Urological Unit, Helsinki University Central Hospital, Helsinki, Finland
Summary-The primary clinical efficacy of orchiectomy and polyoestradiol phosphate (PEP) 160 mg/month i.m. was evaluated by progression and cancer mortality rates in a Finnish multicentre study comprising 200 prostatic cancer patients. After the minimum follow-up time of 2 years there was a significant difference between the groups-orchiectomy delayed progression of the disease more effectively. The follow-up time is rather short for prostatic cancer, but on the basis of this preliminary study the dose of PEP seems to be insufficient in the treatment of advanced prostatic
cancer. Endocrine therapy is effective in retarding prostatic cancer growth in 70 to 80% of cases (Scott et al., 1980). Although it is still uncertain whether endocrine therapy influences overall survival, it is obvious that some patients enjoy a prolonged symptom-free life after endocrine palliation ; a disease-free interval may last some years. In Finland, orchiectomy has traditionally been the treatment of choice ; in the Scandinavian countries PEP has been another common treatment (Jonsson, 1977). Previously, PEP was given at a dosage of 80 mg/month in combination with oral ethinyloestradiol, but during recent years the dose has been doubled and PEP has been used alone in advanced cases. The purpose of the present study was to compare the clinical efficacy of orchiectomy and PEP (160 mg/month)inpatients with advanced prostatic cancer.
pensated cardiac insufficiency, severe liver disease, daily use of acetosalicylic acid (ASA), allergy to ASA and anticoagulant therapy. The patients were randomised into 2 treatment groups, the orchiectomy group comprising 75 patients (mean age 72.6 years) and the other 125 patients (mean age 70.7 years) given PEP (Estradurin) 160 mg/month. The imbalance between the groups was due to the trial design, according to which oestrogen-treated patients were randomised to receive in a double-blind manner either oral ASA (75 mg) or placebo during the first 6 months of oestrogen therapy. The results of the possible inhibitory effect of daily low dose ASA on cardiovascular complications during the high risk early phase of oestrogen therapy have been reported previously (Aro et af., 1989). At the time of diagnosis there were no significant differences between the orchiectomy and oestrogen groups in terms of local extent of tumour (T classification), presence of distant metastases (M Patients and Methods classification) or histological differentiation grade The series comprised 200 patients with prostatic of the malignancy (G classification) (Table 1). The patients were examined 3, 6 and 12 months carcinoma verified histologically and/or cytologiafter the start of treatment and thereafter every 6 cally between January 1985 and March 1987 in 9 months. Apart from regular assessment visits, Finnish hospitals. The exclusion criteria were : previously treated prostatic cancer, history of acute examinations were performed whenever symptoms thromboembolic episode, non-respondent decom- indicated progression. The same criteria were applied to all patients in the evaluation of response Accepted for publication 22 August 1989 to treatment. Progression of disease was evaluated 94
95
ORCHIECTOMY AND POLYOESTRADIOL PHOSPHATE IN PROSTATIC CANCER TREATMENT
Table 1 Extent of Primary Tumour (T classification), Presence of Distant Metastases (M classification) and Differentiation Grade (G classification) in Patients with Prostatic cancer by Treatment Groups Therapy
No. of patients
Orchiectomy 75 Oestrogen 125
To-2 T 3 4 MO MI
GI
G2 G3
7 10
15 30
45 82
68 115
47
66
28 59
15
13
according to the SPCG (Scandinavian Prostatic Cancer Group) criteria (Aro et al., 1989), a modification of the EORTC criteria (Schroeder, 1984). Progression was defined as an increase in prostatic tumour size of more than 25% and/or an increase in the size of metastases of more than 25%, or appearance of new metastases. Progression was not based on changes in prostatic acid phosphatase or performance status only. Statistical analysis of proportions was done using the x2 test and the test for linear trend. Survival analyses were performed by the conventional product limit method and the Cox proportional hazard method. The term “non-progression” indicates disease-free interval. The response criteria used were progression of disease as defined above and cancer death which was registered during the primary therapy form, i.e. the disease was progressing very rapidly and was so aggressive that the patient died during evaluation of the progressive state.
Table 2 Progression and Cause of Death in Orchiectomised and Oestrogen-treated Patients with Carcinoma of the Prostate No. of patients
Therapy
Orchiectomy 75 Oestrogen 125
Progression
Cancer death
Cardiovascular Other disease reason
16
5 6
1
0
2
4
51
groups overall; orchiectomy was more effective in delaying progression of disease. Some differences were also observed in respect to M categories. Among MO patients (Fig. 2) the difference between the groups was statistically significant (P= 0.009), orchiectomy being more efiective. The same trend was seen among M1 patients (Fig. 3). The effect was seen later, however, and thle difference was not statistically significant (P=0.300).
Discussion This is the first prospective, randomised prostatic cancer study in which PEP 160 mg/month is compared with orchiectomy. The results are surprising,: significantly more progression of disease was olbserved in the oestrogen-treated patients 1001
z
0
2
Results
80
W
During the first 2 years, which is the minimum follow-up time, 16 of 75 orchiectomised patients (21%) showed evidence of progression and another 5 (7%) had such aggressive disease that they died of disseminated prostatic cancer during the evaluation phase. In the oestrogen group, 51 of 125 patients (41%) showed progression and, in addition, 6 patients (5%) died from prostatic carcinoma. One patient in the orchiectomy and 2 in the oestrogen group died from cardiovascular disease. For other reasons 4 oestrogen-treated patients died (1 suicide, 2 pneumonias and 1 uraemia not related to the basic disease). The progression and mortality rates are presented in Table 2. The cumulative non-progression curve (Fig. 1) demonstrates all of the progression events in both treatment groups (1 6 5 orchiectomised and 5 1 6 oestrogen-treated patients). There was a statistically significant difference (P= 0.004) between the
+
+
LI
c3 0
60
i
0
I
z
Mo+ M,
2 40
PROGRESSION
s1
z
-ORCHIECTOMY (n=75)
16
5
---PEP
51
6
2oc
0
CANCER DEATH
(n=125)
(p= 0.004)
I
I
I
I
I
3
6
9
12
15
I
I
18 21
I
24
TIME (months) Fig. 1 Cumulative non-progression curve of patients with prostatic carcinoma treated by oestrogen or orchiectomy.
96
BRITISH JOURNAL OF UROLOGY
of the patients was the same; as was the composition of the study group, and the same criteria were applied in both studies. Thus Tt is not surprising that the percentage of orchiectomised patients who I were progression-free in these 2 studies was very L?. much the same. When the 2 forms of oestrogen therapy: (1) combination of intramuscular polyoestradiol phosphate (PEP) 80 mg monthly and oral ethinyloestradiol (EE) 0.15 mg/day versus (2) PEP 160 mg/ month, were compared with orchiectomy, there was a difference slightly in favour of the combinaMO tion of intramuscular PEP +oral EE in the previous PROGRESSION y & : LR study. In the present study, significantly more -ORCHIECTOMY (n=471 3 3 progression of disease was observed in the group --- PEP (n=66) 22 0 treated with PEP 160 mg monthly. Ip=0.0091 What is the explanation for this? Small, insignificant random variations in the local extent of tumour, histological differentiation grade of malignancy or the presence of metastases do not explain the differences in the clinical efficacy between the 0 oestrogen-treated patients (146 vs 125 patients). 0 3 6 9 12 15 18 21 24 The Cox proportional hazard method is valid for TIME (months) analysis of data and it shows that the effect of Fig. 2 Cumulative non-progression curve of MO patients therapy form is more significant than any other of treated by oestrogenor orchiectomy. the factors mentioned above. The prognostic value of the 2-year analysis in the during the first 2 years of therapy. Among MO patients this difference was clearer and it began to appear after the first 6 months. The same trend was noted among M1 patients, but at a later phase. This may reflect the fact that it is easy to define z progression when metastasis is verified in a patient 0 80 who primarily belonged to the MO category, but $ w progression of disease among M1 patients may U sometimestake longer, and control visits are needed 0 0 to confirm the progression. Even if the minimum U 60 follow-up is only 2 years, the difference in clinical efficacy between the 2 treatment regimes is so clear that it cannot be denied. Further investigation is warranted to find an explanation. 401 M, PROGRESSION c,p$:R Considering the results of our previous investiF -ORCHIECTOMY (n=281 13 2 gation (Haapiainen et al., 1986) and the present 6 study, one of the main observations is that there is no essential difference in progression and survival rates between the orchiectomised patients in this study and those in the earlier study (2-year report). In the previous study, orchiectomy was performed in 131 patients; in the present study 75 0' I I I I I I I J patients underwent the procedure. At the time of 0 3 6 9 12 15 18 21 24 diagnosis there were no significant differences TIME (months) between these 2 series in terms of local extent of tumour, histological differentiation grade of malig- Fig. 3 Cumulative non-progression curve of M1 patients nancv and Dresence of metastases. The mean aee treated by oestrogen or orchiectomy.
4,
4.
$
" I
ORCHIECTOMY AND POLYOESTRADIOL PHOSPHATE IN PROSTATIC CANCER TREATMENT
previous study (Haapiainen et al., 1986) seemed to be reliable ; the respective difference in clinical efficacy between the treatment groups has been confirmed by later analyses (data to be published later). Even if the combination of PEP and EE delayed cancer progression more effectively than orchiectomy, the risk of early phase cardiovascular side effects was also noticeable in the oestrogen group. There is evidence that cardiovascular side effects of oestrogen therapy are specifically related to the oral route of administration (Stege et al., 1987a). Considering the results of our previous investigation (Haapiainen et al., 1986) and the present study, the main question is whether the monthly dose of 160 mg PEP is sufficient to maintain the serum testosterone level low enough. In the study by Norlen et al. (1987), the steady state plasma concentrations of testosterone were reduced to 45, 25 or 15% of the pre-treatment concentrations in response to PEP 80, 160 and 240 mg every 4 weeks, respectively. No castration levels of testosterone were achieved even with the highest dose of PEP (240 mglmonth); the difference in testosterone levels was smaller for the biologically active testosterone, i.e. the free fraction, than the total testosterone. However, it was concluded that PEP (160 or 240 mg/month) induced a substantial reduction in plasma testosterone values and that it would be sufficient to give a clinically good therapeutic response. When the dose of PEP is raised to 320 mg/month the testosterone level can be suppressed to castration level (Stege et al., 1987a). The combination of intramuscular PEP (80 mg/ month) and oral ethinyloestradiol 0.15 mg/day) does, however, suppress serum testosterone to castration level. This combination reduces testosterone levels more effectively than PEP alone at a dosage of 160 mg every 4 weeks (Stege et al., 1987b). The antitumour activity of oestrogens in prostatic carcinoma is based mainly on the decrease in circulating androgens (Huggins and Hodges, 1941). Since regression of prostatic carcinoma can be achieved clinically without maximal suppression of plasma testosterone levels (Scott etal., 1980), it has been proposed that oestrogens have a kind of cytotoxic effect on the tumour tissue (Susan et al., 1976). However, our present clinical results of PEP monotherapy (160 mg/month) do not support this view. In conclusion, PEP 160 mg/month is clinically insufficient in the treatment of advanced prostatic cancer. The reason may be that the dosage is too
97
low to maintain serum testosterone at a castration level. Olrchiectomy is still an important method for treating patients with locally advanced or metastatic pr,ostaticcarcinoma. It is effective in reducing serum testosterone, which is the main goal of endocrhe therapy in prostatic cancer. It is also inexpensive and does not require frequent hormone determinations. Acceptance of the procedure by the pat:ients is not a problem in northern countries.
Acknowledgements The present study was based on a Finnish multicentre study on prostatic cancer (FINNPROSTATE). We are grateful to M. Ala-Opals, J . Aro, E. Hansson, H. Juusela, J . Permi, M. Ruutu, M. Saarialho, J . Seppanen and J . Viitanen for their valuable cooperation. We are also greatly indebted to Miss Paula Saari for skilful secretarial assistance, Petri Voutilainen, for statistical analysis of the material and Sevastiana Ruusamo, for revising the Engliish manuscript.
References Aro, J. L,. V., Haapiainen, R. L.,Rannikko, S. etal. (1989). High dose polyoestradiol phosphate with and without acetosalicylic acid vsersus orchiectomy in the treatment of prostatic cancer. Br. J . Urol., 63,512-514. Haapiainen,R.,Rannikko,S. andAlfthan,O. (1 986). Comparison of primary orchiectomy and oestrogen therapy in advanced prostatic cancer. A 2-year follow-up report of a national, prospr:ctive prostatic cancer study. Br. J . Urol.,58, 528-533. Huggins., C. and Hodges, C. V. (1941). Studies on prostatic cancer. I. The effect ofcastration, of estrogen, and of androgen injection on serum acid phosphatases in metastatic carcinoma of the prostate. Cancer Res., 1,293-297. Jonsson, G. (1971). Treatment of prostatic carcinoma with polyestradiolphosphate combined with ethinylestradiol. Scand. J . Urol. Nephrol., 5,97-102. Norlen, B. J., Fritjofsson, A., Gronquist, L. ef 111. (1987). Plasma concentrations of estradiol and testosterone in single-drug polyeatradiol phosphate therapy for prostatic cancer. Eur. Urol., 13, 193-197. Schrwder, F. H. (1984). Treatment response criteria for prostatic cancer. Prostate, 5, 181-191. Scott, Pi. W., Menon, W. and Walsh, P. G . (1980). Hormonal therapy of prostate cancer. Cancer, 45, 192991936, Stege, R.., Carlstrom, K., Collste, L. ef al. (1987a). Single drug polyestradiol phosphate (PEP) therapy in prostatic cancer (CAP). Eur. J . Cancer Clin. Oncol., 23, 1249. Stege, EL., Froiander, N., Carlstrom, K. et Irl. (1987b). Steroid sensitive proteins, growth hormone and somatomedin C in prostatic cancer. Effects of parenteral and oral estrogen therapy. Prostate, 10, 333-338.
The Authors R. Haapiainen, MD, Consultant Surgeon and Assistant Lecturer. S. Rannikko, MD, Senior Consultant in Urology. 0.Alfthan, MD, Professor of Urology. Requests for reprints to: R. Haapiainen, Second Department of Surgery, Helsinki University Central Hospital, Haartmaninkatu 4, SF-00290 Helsinki, Finland.
0007-1 331/90/0066-0094/$10.00
Comparison of Primary Orchiectomy and Polyoestradiol Phosphate in the Treatment of Advanced Prostatic Cancer R. HAAPIAINEN, S. RANNIKKO, 0. ALFTHAN and the FINNPROSTATE GROUP Second Department of Surgery, Urological Unit, Helsinki University Central Hospital, Helsinki, Finland
Summary-The primary clinical efficacy of orchiectomy and polyoestradiol phosphate (PEP) 160 mg/month i.m. was evaluated by progression and cancer mortality rates in a Finnish multicentre study comprising 200 prostatic cancer patients. After the minimum follow-up time of 2 years there was a significant difference between the groups-orchiectomy delayed progression of the disease more effectively. The follow-up time is rather short for prostatic cancer, but on the basis of this preliminary study the dose of PEP seems to be insufficient in the treatment of advanced prostatic
cancer. Endocrine therapy is effective in retarding prostatic cancer growth in 70 to 80% of cases (Scott et al., 1980). Although it is still uncertain whether endocrine therapy influences overall survival, it is obvious that some patients enjoy a prolonged symptom-free life after endocrine palliation ; a disease-free interval may last some years. In Finland, orchiectomy has traditionally been the treatment of choice ; in the Scandinavian countries PEP has been another common treatment (Jonsson, 1977). Previously, PEP was given at a dosage of 80 mg/month in combination with oral ethinyloestradiol, but during recent years the dose has been doubled and PEP has been used alone in advanced cases. The purpose of the present study was to compare the clinical efficacy of orchiectomy and PEP (160 mg/month)inpatients with advanced prostatic cancer.
pensated cardiac insufficiency, severe liver disease, daily use of acetosalicylic acid (ASA), allergy to ASA and anticoagulant therapy. The patients were randomised into 2 treatment groups, the orchiectomy group comprising 75 patients (mean age 72.6 years) and the other 125 patients (mean age 70.7 years) given PEP (Estradurin) 160 mg/month. The imbalance between the groups was due to the trial design, according to which oestrogen-treated patients were randomised to receive in a double-blind manner either oral ASA (75 mg) or placebo during the first 6 months of oestrogen therapy. The results of the possible inhibitory effect of daily low dose ASA on cardiovascular complications during the high risk early phase of oestrogen therapy have been reported previously (Aro et af., 1989). At the time of diagnosis there were no significant differences between the orchiectomy and oestrogen groups in terms of local extent of tumour (T classification), presence of distant metastases (M Patients and Methods classification) or histological differentiation grade The series comprised 200 patients with prostatic of the malignancy (G classification) (Table 1). The patients were examined 3, 6 and 12 months carcinoma verified histologically and/or cytologiafter the start of treatment and thereafter every 6 cally between January 1985 and March 1987 in 9 months. Apart from regular assessment visits, Finnish hospitals. The exclusion criteria were : previously treated prostatic cancer, history of acute examinations were performed whenever symptoms thromboembolic episode, non-respondent decom- indicated progression. The same criteria were applied to all patients in the evaluation of response Accepted for publication 22 August 1989 to treatment. Progression of disease was evaluated 94
95
ORCHIECTOMY AND POLYOESTRADIOL PHOSPHATE IN PROSTATIC CANCER TREATMENT
Table 1 Extent of Primary Tumour (T classification), Presence of Distant Metastases (M classification) and Differentiation Grade (G classification) in Patients with Prostatic cancer by Treatment Groups Therapy
No. of patients
Orchiectomy 75 Oestrogen 125
To-2 T 3 4 MO MI
GI
G2 G3
7 10
15 30
45 82
68 115
47
66
28 59
15
13
according to the SPCG (Scandinavian Prostatic Cancer Group) criteria (Aro et al., 1989), a modification of the EORTC criteria (Schroeder, 1984). Progression was defined as an increase in prostatic tumour size of more than 25% and/or an increase in the size of metastases of more than 25%, or appearance of new metastases. Progression was not based on changes in prostatic acid phosphatase or performance status only. Statistical analysis of proportions was done using the x2 test and the test for linear trend. Survival analyses were performed by the conventional product limit method and the Cox proportional hazard method. The term “non-progression” indicates disease-free interval. The response criteria used were progression of disease as defined above and cancer death which was registered during the primary therapy form, i.e. the disease was progressing very rapidly and was so aggressive that the patient died during evaluation of the progressive state.
Table 2 Progression and Cause of Death in Orchiectomised and Oestrogen-treated Patients with Carcinoma of the Prostate No. of patients
Therapy
Orchiectomy 75 Oestrogen 125
Progression
Cancer death
Cardiovascular Other disease reason
16
5 6
1
0
2
4
51
groups overall; orchiectomy was more effective in delaying progression of disease. Some differences were also observed in respect to M categories. Among MO patients (Fig. 2) the difference between the groups was statistically significant (P= 0.009), orchiectomy being more efiective. The same trend was seen among M1 patients (Fig. 3). The effect was seen later, however, and thle difference was not statistically significant (P=0.300).
Discussion This is the first prospective, randomised prostatic cancer study in which PEP 160 mg/month is compared with orchiectomy. The results are surprising,: significantly more progression of disease was olbserved in the oestrogen-treated patients 1001
z
0
2
Results
80
W
During the first 2 years, which is the minimum follow-up time, 16 of 75 orchiectomised patients (21%) showed evidence of progression and another 5 (7%) had such aggressive disease that they died of disseminated prostatic cancer during the evaluation phase. In the oestrogen group, 51 of 125 patients (41%) showed progression and, in addition, 6 patients (5%) died from prostatic carcinoma. One patient in the orchiectomy and 2 in the oestrogen group died from cardiovascular disease. For other reasons 4 oestrogen-treated patients died (1 suicide, 2 pneumonias and 1 uraemia not related to the basic disease). The progression and mortality rates are presented in Table 2. The cumulative non-progression curve (Fig. 1) demonstrates all of the progression events in both treatment groups (1 6 5 orchiectomised and 5 1 6 oestrogen-treated patients). There was a statistically significant difference (P= 0.004) between the
+
+
LI
c3 0
60
i
0
I
z
Mo+ M,
2 40
PROGRESSION
s1
z
-ORCHIECTOMY (n=75)
16
5
---PEP
51
6
2oc
0
CANCER DEATH
(n=125)
(p= 0.004)
I
I
I
I
I
3
6
9
12
15
I
I
18 21
I
24
TIME (months) Fig. 1 Cumulative non-progression curve of patients with prostatic carcinoma treated by oestrogen or orchiectomy.
96
BRITISH JOURNAL OF UROLOGY
of the patients was the same; as was the composition of the study group, and the same criteria were applied in both studies. Thus Tt is not surprising that the percentage of orchiectomised patients who I were progression-free in these 2 studies was very L?. much the same. When the 2 forms of oestrogen therapy: (1) combination of intramuscular polyoestradiol phosphate (PEP) 80 mg monthly and oral ethinyloestradiol (EE) 0.15 mg/day versus (2) PEP 160 mg/ month, were compared with orchiectomy, there was a difference slightly in favour of the combinaMO tion of intramuscular PEP +oral EE in the previous PROGRESSION y & : LR study. In the present study, significantly more -ORCHIECTOMY (n=471 3 3 progression of disease was observed in the group --- PEP (n=66) 22 0 treated with PEP 160 mg monthly. Ip=0.0091 What is the explanation for this? Small, insignificant random variations in the local extent of tumour, histological differentiation grade of malignancy or the presence of metastases do not explain the differences in the clinical efficacy between the 0 oestrogen-treated patients (146 vs 125 patients). 0 3 6 9 12 15 18 21 24 The Cox proportional hazard method is valid for TIME (months) analysis of data and it shows that the effect of Fig. 2 Cumulative non-progression curve of MO patients therapy form is more significant than any other of treated by oestrogenor orchiectomy. the factors mentioned above. The prognostic value of the 2-year analysis in the during the first 2 years of therapy. Among MO patients this difference was clearer and it began to appear after the first 6 months. The same trend was noted among M1 patients, but at a later phase. This may reflect the fact that it is easy to define z progression when metastasis is verified in a patient 0 80 who primarily belonged to the MO category, but $ w progression of disease among M1 patients may U sometimestake longer, and control visits are needed 0 0 to confirm the progression. Even if the minimum U 60 follow-up is only 2 years, the difference in clinical efficacy between the 2 treatment regimes is so clear that it cannot be denied. Further investigation is warranted to find an explanation. 401 M, PROGRESSION c,p$:R Considering the results of our previous investiF -ORCHIECTOMY (n=281 13 2 gation (Haapiainen et al., 1986) and the present 6 study, one of the main observations is that there is no essential difference in progression and survival rates between the orchiectomised patients in this study and those in the earlier study (2-year report). In the previous study, orchiectomy was performed in 131 patients; in the present study 75 0' I I I I I I I J patients underwent the procedure. At the time of 0 3 6 9 12 15 18 21 24 diagnosis there were no significant differences TIME (months) between these 2 series in terms of local extent of tumour, histological differentiation grade of malig- Fig. 3 Cumulative non-progression curve of M1 patients nancv and Dresence of metastases. The mean aee treated by oestrogen or orchiectomy.
4,
4.
$
" I
ORCHIECTOMY AND POLYOESTRADIOL PHOSPHATE IN PROSTATIC CANCER TREATMENT
previous study (Haapiainen et al., 1986) seemed to be reliable ; the respective difference in clinical efficacy between the treatment groups has been confirmed by later analyses (data to be published later). Even if the combination of PEP and EE delayed cancer progression more effectively than orchiectomy, the risk of early phase cardiovascular side effects was also noticeable in the oestrogen group. There is evidence that cardiovascular side effects of oestrogen therapy are specifically related to the oral route of administration (Stege et al., 1987a). Considering the results of our previous investigation (Haapiainen et al., 1986) and the present study, the main question is whether the monthly dose of 160 mg PEP is sufficient to maintain the serum testosterone level low enough. In the study by Norlen et al. (1987), the steady state plasma concentrations of testosterone were reduced to 45, 25 or 15% of the pre-treatment concentrations in response to PEP 80, 160 and 240 mg every 4 weeks, respectively. No castration levels of testosterone were achieved even with the highest dose of PEP (240 mglmonth); the difference in testosterone levels was smaller for the biologically active testosterone, i.e. the free fraction, than the total testosterone. However, it was concluded that PEP (160 or 240 mg/month) induced a substantial reduction in plasma testosterone values and that it would be sufficient to give a clinically good therapeutic response. When the dose of PEP is raised to 320 mg/month the testosterone level can be suppressed to castration level (Stege et al., 1987a). The combination of intramuscular PEP (80 mg/ month) and oral ethinyloestradiol 0.15 mg/day) does, however, suppress serum testosterone to castration level. This combination reduces testosterone levels more effectively than PEP alone at a dosage of 160 mg every 4 weeks (Stege et al., 1987b). The antitumour activity of oestrogens in prostatic carcinoma is based mainly on the decrease in circulating androgens (Huggins and Hodges, 1941). Since regression of prostatic carcinoma can be achieved clinically without maximal suppression of plasma testosterone levels (Scott etal., 1980), it has been proposed that oestrogens have a kind of cytotoxic effect on the tumour tissue (Susan et al., 1976). However, our present clinical results of PEP monotherapy (160 mg/month) do not support this view. In conclusion, PEP 160 mg/month is clinically insufficient in the treatment of advanced prostatic cancer. The reason may be that the dosage is too
97
low to maintain serum testosterone at a castration level. Olrchiectomy is still an important method for treating patients with locally advanced or metastatic pr,ostaticcarcinoma. It is effective in reducing serum testosterone, which is the main goal of endocrhe therapy in prostatic cancer. It is also inexpensive and does not require frequent hormone determinations. Acceptance of the procedure by the pat:ients is not a problem in northern countries.
Acknowledgements The present study was based on a Finnish multicentre study on prostatic cancer (FINNPROSTATE). We are grateful to M. Ala-Opals, J . Aro, E. Hansson, H. Juusela, J . Permi, M. Ruutu, M. Saarialho, J . Seppanen and J . Viitanen for their valuable cooperation. We are also greatly indebted to Miss Paula Saari for skilful secretarial assistance, Petri Voutilainen, for statistical analysis of the material and Sevastiana Ruusamo, for revising the Engliish manuscript.
References Aro, J. L,. V., Haapiainen, R. L.,Rannikko, S. etal. (1989). High dose polyoestradiol phosphate with and without acetosalicylic acid vsersus orchiectomy in the treatment of prostatic cancer. Br. J . Urol., 63,512-514. Haapiainen,R.,Rannikko,S. andAlfthan,O. (1 986). Comparison of primary orchiectomy and oestrogen therapy in advanced prostatic cancer. A 2-year follow-up report of a national, prospr:ctive prostatic cancer study. Br. J . Urol.,58, 528-533. Huggins., C. and Hodges, C. V. (1941). Studies on prostatic cancer. I. The effect ofcastration, of estrogen, and of androgen injection on serum acid phosphatases in metastatic carcinoma of the prostate. Cancer Res., 1,293-297. Jonsson, G. (1971). Treatment of prostatic carcinoma with polyestradiolphosphate combined with ethinylestradiol. Scand. J . Urol. Nephrol., 5,97-102. Norlen, B. J., Fritjofsson, A., Gronquist, L. ef 111. (1987). Plasma concentrations of estradiol and testosterone in single-drug polyeatradiol phosphate therapy for prostatic cancer. Eur. Urol., 13, 193-197. Schrwder, F. H. (1984). Treatment response criteria for prostatic cancer. Prostate, 5, 181-191. Scott, Pi. W., Menon, W. and Walsh, P. G . (1980). Hormonal therapy of prostate cancer. Cancer, 45, 192991936, Stege, R.., Carlstrom, K., Collste, L. ef al. (1987a). Single drug polyestradiol phosphate (PEP) therapy in prostatic cancer (CAP). Eur. J . Cancer Clin. Oncol., 23, 1249. Stege, EL., Froiander, N., Carlstrom, K. et Irl. (1987b). Steroid sensitive proteins, growth hormone and somatomedin C in prostatic cancer. Effects of parenteral and oral estrogen therapy. Prostate, 10, 333-338.
The Authors R. Haapiainen, MD, Consultant Surgeon and Assistant Lecturer. S. Rannikko, MD, Senior Consultant in Urology. 0.Alfthan, MD, Professor of Urology. Requests for reprints to: R. Haapiainen, Second Department of Surgery, Helsinki University Central Hospital, Haartmaninkatu 4, SF-00290 Helsinki, Finland.
