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Primary Treatment of Prostatic Carcinoma with Estramustine Phosphate: Preliminary Report
Vol. 115, February
THE JOURNAL OF UROLOGY
Copyright © 1976 by The Williams & Wilkins Co.
Printed in U.S.A.
PRIMARY TREATMENT OF PROSTATIC CARCINOMA WITH ESTRAMUSTINE PHOSPHATE: PRELIMINARY REPORT TORGNY NILSSON*
AND
GOSTA JONSSON
From the Department of Urology, University of Lund, Lund, Sweden
ABSTRACT
Estramustine phosphate has been used as primary treatment in 38 patients with advanced prostatic carcinoma. Of these 38 patients 36 responded objectively to treatment, regression occurring in 10 patients with soft tissue metastases, 3 with pulmonary metastases and 3 with bony metastases. Primary cytotoxic treatment in patients with far advanced prostatic carcinoma is advocated and a randomized clinical study is suggested. Cytotoxic treatment of prostatic carcinoma has been advocated when conventional hormonal therapy has failed. Preliminary results with aniline mustard, cyclophosphamide and mithramycin were to some extent successful. 1· 3 However, the over-all impression from these initial studies was that the side effects of the compounds were too severe to justify their use, especially when there was bone marrow depression owing to tumor growth. Recently, encouraging results have been obtained with conventional cytotoxic agents, 4 ' 5 as well as with estramustine phosphate (estracyt) 6 • 7 for patients who cease to respond to hormonal therapy. It may be argued that an even better therapeutic result could be obtained with the cytotoxic treatment if it were used primarily. Of the patients with prostatic carcinoma 20 per cent are hormone resistant from the beginning. If such patients could be identified they would be the most suitable for primary cytotoxic treatment. Another kind of patient for whom cytotoxic treatment might be suitable as primary treatment is the patient with widespread aggressive prostatic carcinoma in whom treatment as effective as possible is mandatory from the beginning. It is known that estramustine phosphate has an effect when estrogen is no longer effective, especially on regression of soft tissue metastases and on local shrinking of the prostate itself. We thought that it might be worthwhile to try this kind of cytotoxic therapy as primary treatment in a selected group of high risk patients.
increased mobility and withdrawal of urethral catheter were carefully judged and supported by laboratory findings of increased hemoglobin, decreased serum acid phosphatase activities and decreased creatinine to be considered as objective evidence in judging response to treatment. Regression of metastases was judged by cytological or histological evaluation or by repeated x-rays. To be considered a regression the lesion must have diminished by at least 50 per cent from its original size and have remained stable for 6 months. On the basis of these criteria 36 of 38 patients responded favorably to treatment and ;3 of these had regression of pulmonary metastases, 10 had regression of soft tissue metastases and 3 had regression of bony metastases. The elevated serum acid phosphatase activity was suppressed in 25 of 27 patients, correlating with the clinical results. The clinical course of patients is shown in the figure. Many patients survived for several years. The 2 patients who died within 6 months after treatment was begun died of myocardial infarction and suicide. Side effects of therapy have been minor and all were reversible when the treatment was discontinued (table 2). The most serious side effect was gastrointestinal disturbance, which forced 4 patients to discontinue therapy. The low incidence rate of generalized side effects, estrogenic and cytotoxic, indicates that the effect of the compound is localized.
MATERIAL AND METHODS
Estramustine phosphate was given to 38 patients as primary treatment for advanced prostatic carcinoma. Each patient had a confirmed diagnosis of prostatic carcinoma, proved either cytologically or histologically (table 1). Clinical evaluation placed the patients in the Gleason category 12 to 15. 8 All patients had an expected survival of less than 1 year. Routine clinical evaluations were done, including biochemical survey, bone survey, chest x-ray and an excretory urogram every 6 months. Every patient was followed for at least 6 months before evaluation. Estramustine phosphate was given either intravenously in a dosage of 300 to 450 mg. daily or orally in a dosage of 600 mg. daily. RESULTS
The response to treatment was graded as favorable or non-favorable. For a response to be considered favorable subjective and objective signs of regression had to be present. Relief of pain, weight gain (not counting water retention), Accepted for publication ,June 20, 1975. Read at annual meeting of American Urological Association, Miami Beach, Florida, May 11-15, 1975. * Current address: 1300 University Ave., Madison, Wisconsin 5:3706. 168
DISCUSSIO'.\!
Hormonal therapy of widespread prostatic carcinoma will give satisfactory palliation in the majority of cases. The response is sometimes reported to be dramatic, judged as relief of pain, disappearance of uremia and/or regression of metastases. However, 20 per cent of the patients are hormone-resistant. If cytotoxic treatment were used from the beginning it might be possible to achieve an over-all better result in this high risk category by including this hormone treated group. Estramustine phosphate was tried as primary treatment because it had proved previously effective in the treatment of hormone-resistant prostatic carcinoma with no major side effects. We thought that by using the compound in the primary treatment the blocking effects of the estradiol receptor sites from conventional hormonal therapy could be avoided and that a better response from the estramustine phosphate treatment could be obtained. The preliminary results with estramustine phosphate indicate that the drug was effective in more than 90 per cent of the cases in which it was used and show a regression rate of metastases in 40 per cent. It is worthwhile mentioning that the drug works quickly to retard soft tissue metastases and to
PRIMARY TREATMENT OF PROSTATIC CARCINOMA WITH ESTRAMUSTINE PHOSPHATE TABLE
1. Degree of differentiation and therapy response
Well differentiated tumor Moderately differentiated tumor Poorly differentiated tumor ?
Totals
Total Cases
Favorable Response
2 15 16 5
2 14 16 4
38*
36
Unfavorable Response
2 '
* There were 5 stage III and :3:3 stage IV tumors,
AGE
112 1 1112 2 2112 3 3112 4 4112 5 5112 6 6112 7 71;2 8
YEARS
--~->--<--+-+--+--+--+-f-f-+--1--+---r~r---+-f-.j
50-54
suffered fully developed gynecomastia. Although it is difficult to assess impotency in a series such as this many claimed that they did not experience impotence during therapy. Results obtained from treatment with this drug do not differ qualitatively from those obtained from conventional estrogen treatment, However, we believe that the regression of metastases is more constant and that the response is faster and more reliable with estramustine phosphate treatment than with conventional therapy. The effect of treatment in patients with far advanced carcinoma may be superior to conventional hormone treatment, A carefully designed randomized investigation of the treatment must be carried out in order to prove this REFERENCES
55 -59
2, 3,
4,
65-69
5, 70-74
6, 75-79
7,
>80
Clinical summary of 38 patients treated primarily with estramustine phosphate (R-regression of metastases, t-time of death and - followup),
TABLE
169
2, Side effects in 123 patients treated primarily or secondarily
with estramustine phosphate No, Cases Thrombocytopenia Elevated liver enzymes Gastrointestinal disturbances Throm bophle bi tis Urticaria Total
2 1 8
13
relieve pain, These effects were, of course, especially appreciated by the patient, Estramustine phosphate has a low generalized estrogenic effect, as indicated by the fact that there were only a few complaints of gynecomastia, all patients experienced some soreness of the nipple but none
8,
Druckrey, H, and Raabe. S,: Organspezifische Chemotherapie des Krebs (Prostata-Karzinom), Klin, Wchnschr,, 30: 882, 1952, Flocks. R H, and F,: Combination therapy for prostatic carcinoma, J, Iowa Soc,, 58: 125, 1968, 'IV2yrauch, H, l\!L and Nesbet, J, D,, Use of thio-phosphoramide (thio-TEPA) in treatment of prostate, UroL 81: 185. 1959, Yagoda. A,: Non-hormonal cytotoxic agents in the treatment of prostatic adenocarcinoma, In: American Cancer Society's Proceedings of the National Conference on Urologic Cancer, Cancer, 32: 1131. 1973, Welvaart, K,, Merrin. C, K, Mittelman, A, and Murphy, G, P,: Stage D prostatic carcinoma: survival rate in relapsed patients following new forms of palliation, Urology, 4; 283. 1974, Jonsson, G, and Hogberg, B,: Treatment of advanced prostatic carcinoma with estracyt, A preliminary report, Scand, ,J, UroL NephroL, 5: 103, 1971, Nilsson, T, and Ji:insson, G,: Clinical results with estramustine phosphate (NSC-89199): a comparison of the intravenous and oral preparations, Cancer Chemother, Rep,. 59: 229, 1975, Gleason, D, F., Mellinger. G, T, and The Veterans Administration Cooperative Urological Research Group: Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging, J, UroL, lH: 58, 1974, COMMENT
Since the original obse1·vations by Jonsson and Nilsson oral estramustine phosphate has received favorable clinical trials in patients with stages I and II tumors, The present report affirms the original observations that oral estramustine phosphate has a significantly effective activity-objectively and subjectively-when given to patients as primary treatment for advanced prostatic carcinoma, Previous observations have found this therapy helpful in patients who have had relapses, A randomized trial comparing estramustine phosphate to another agent is well underway by the National Prostatic Cancer Task Force, The drug does not appear to be benefiting patients primarily through an estrogenic effect but rather through its primary cytotoxic action,
Gerald P, Murphy Roswell Park Memorial Institute Buffalo, New York
THE JOURNAL OF UROLOGY
Copyright © 1976 by The Williams & Wilkins Co.
Printed in U.S.A.
PRIMARY TREATMENT OF PROSTATIC CARCINOMA WITH ESTRAMUSTINE PHOSPHATE: PRELIMINARY REPORT TORGNY NILSSON*
AND
GOSTA JONSSON
From the Department of Urology, University of Lund, Lund, Sweden
ABSTRACT
Estramustine phosphate has been used as primary treatment in 38 patients with advanced prostatic carcinoma. Of these 38 patients 36 responded objectively to treatment, regression occurring in 10 patients with soft tissue metastases, 3 with pulmonary metastases and 3 with bony metastases. Primary cytotoxic treatment in patients with far advanced prostatic carcinoma is advocated and a randomized clinical study is suggested. Cytotoxic treatment of prostatic carcinoma has been advocated when conventional hormonal therapy has failed. Preliminary results with aniline mustard, cyclophosphamide and mithramycin were to some extent successful. 1· 3 However, the over-all impression from these initial studies was that the side effects of the compounds were too severe to justify their use, especially when there was bone marrow depression owing to tumor growth. Recently, encouraging results have been obtained with conventional cytotoxic agents, 4 ' 5 as well as with estramustine phosphate (estracyt) 6 • 7 for patients who cease to respond to hormonal therapy. It may be argued that an even better therapeutic result could be obtained with the cytotoxic treatment if it were used primarily. Of the patients with prostatic carcinoma 20 per cent are hormone resistant from the beginning. If such patients could be identified they would be the most suitable for primary cytotoxic treatment. Another kind of patient for whom cytotoxic treatment might be suitable as primary treatment is the patient with widespread aggressive prostatic carcinoma in whom treatment as effective as possible is mandatory from the beginning. It is known that estramustine phosphate has an effect when estrogen is no longer effective, especially on regression of soft tissue metastases and on local shrinking of the prostate itself. We thought that it might be worthwhile to try this kind of cytotoxic therapy as primary treatment in a selected group of high risk patients.
increased mobility and withdrawal of urethral catheter were carefully judged and supported by laboratory findings of increased hemoglobin, decreased serum acid phosphatase activities and decreased creatinine to be considered as objective evidence in judging response to treatment. Regression of metastases was judged by cytological or histological evaluation or by repeated x-rays. To be considered a regression the lesion must have diminished by at least 50 per cent from its original size and have remained stable for 6 months. On the basis of these criteria 36 of 38 patients responded favorably to treatment and ;3 of these had regression of pulmonary metastases, 10 had regression of soft tissue metastases and 3 had regression of bony metastases. The elevated serum acid phosphatase activity was suppressed in 25 of 27 patients, correlating with the clinical results. The clinical course of patients is shown in the figure. Many patients survived for several years. The 2 patients who died within 6 months after treatment was begun died of myocardial infarction and suicide. Side effects of therapy have been minor and all were reversible when the treatment was discontinued (table 2). The most serious side effect was gastrointestinal disturbance, which forced 4 patients to discontinue therapy. The low incidence rate of generalized side effects, estrogenic and cytotoxic, indicates that the effect of the compound is localized.
MATERIAL AND METHODS
Estramustine phosphate was given to 38 patients as primary treatment for advanced prostatic carcinoma. Each patient had a confirmed diagnosis of prostatic carcinoma, proved either cytologically or histologically (table 1). Clinical evaluation placed the patients in the Gleason category 12 to 15. 8 All patients had an expected survival of less than 1 year. Routine clinical evaluations were done, including biochemical survey, bone survey, chest x-ray and an excretory urogram every 6 months. Every patient was followed for at least 6 months before evaluation. Estramustine phosphate was given either intravenously in a dosage of 300 to 450 mg. daily or orally in a dosage of 600 mg. daily. RESULTS
The response to treatment was graded as favorable or non-favorable. For a response to be considered favorable subjective and objective signs of regression had to be present. Relief of pain, weight gain (not counting water retention), Accepted for publication ,June 20, 1975. Read at annual meeting of American Urological Association, Miami Beach, Florida, May 11-15, 1975. * Current address: 1300 University Ave., Madison, Wisconsin 5:3706. 168
DISCUSSIO'.\!
Hormonal therapy of widespread prostatic carcinoma will give satisfactory palliation in the majority of cases. The response is sometimes reported to be dramatic, judged as relief of pain, disappearance of uremia and/or regression of metastases. However, 20 per cent of the patients are hormone-resistant. If cytotoxic treatment were used from the beginning it might be possible to achieve an over-all better result in this high risk category by including this hormone treated group. Estramustine phosphate was tried as primary treatment because it had proved previously effective in the treatment of hormone-resistant prostatic carcinoma with no major side effects. We thought that by using the compound in the primary treatment the blocking effects of the estradiol receptor sites from conventional hormonal therapy could be avoided and that a better response from the estramustine phosphate treatment could be obtained. The preliminary results with estramustine phosphate indicate that the drug was effective in more than 90 per cent of the cases in which it was used and show a regression rate of metastases in 40 per cent. It is worthwhile mentioning that the drug works quickly to retard soft tissue metastases and to
PRIMARY TREATMENT OF PROSTATIC CARCINOMA WITH ESTRAMUSTINE PHOSPHATE TABLE
1. Degree of differentiation and therapy response
Well differentiated tumor Moderately differentiated tumor Poorly differentiated tumor ?
Totals
Total Cases
Favorable Response
2 15 16 5
2 14 16 4
38*
36
Unfavorable Response
2 '
* There were 5 stage III and :3:3 stage IV tumors,
AGE
112 1 1112 2 2112 3 3112 4 4112 5 5112 6 6112 7 71;2 8
YEARS
--~->--<--+-+--+--+--+-f-f-+--1--+---r~r---+-f-.j
50-54
suffered fully developed gynecomastia. Although it is difficult to assess impotency in a series such as this many claimed that they did not experience impotence during therapy. Results obtained from treatment with this drug do not differ qualitatively from those obtained from conventional estrogen treatment, However, we believe that the regression of metastases is more constant and that the response is faster and more reliable with estramustine phosphate treatment than with conventional therapy. The effect of treatment in patients with far advanced carcinoma may be superior to conventional hormone treatment, A carefully designed randomized investigation of the treatment must be carried out in order to prove this REFERENCES
55 -59
2, 3,
4,
65-69
5, 70-74
6, 75-79
7,
>80
Clinical summary of 38 patients treated primarily with estramustine phosphate (R-regression of metastases, t-time of death and - followup),
TABLE
169
2, Side effects in 123 patients treated primarily or secondarily
with estramustine phosphate No, Cases Thrombocytopenia Elevated liver enzymes Gastrointestinal disturbances Throm bophle bi tis Urticaria Total
2 1 8
13
relieve pain, These effects were, of course, especially appreciated by the patient, Estramustine phosphate has a low generalized estrogenic effect, as indicated by the fact that there were only a few complaints of gynecomastia, all patients experienced some soreness of the nipple but none
8,
Druckrey, H, and Raabe. S,: Organspezifische Chemotherapie des Krebs (Prostata-Karzinom), Klin, Wchnschr,, 30: 882, 1952, Flocks. R H, and F,: Combination therapy for prostatic carcinoma, J, Iowa Soc,, 58: 125, 1968, 'IV2yrauch, H, l\!L and Nesbet, J, D,, Use of thio-phosphoramide (thio-TEPA) in treatment of prostate, UroL 81: 185. 1959, Yagoda. A,: Non-hormonal cytotoxic agents in the treatment of prostatic adenocarcinoma, In: American Cancer Society's Proceedings of the National Conference on Urologic Cancer, Cancer, 32: 1131. 1973, Welvaart, K,, Merrin. C, K, Mittelman, A, and Murphy, G, P,: Stage D prostatic carcinoma: survival rate in relapsed patients following new forms of palliation, Urology, 4; 283. 1974, Jonsson, G, and Hogberg, B,: Treatment of advanced prostatic carcinoma with estracyt, A preliminary report, Scand, ,J, UroL NephroL, 5: 103, 1971, Nilsson, T, and Ji:insson, G,: Clinical results with estramustine phosphate (NSC-89199): a comparison of the intravenous and oral preparations, Cancer Chemother, Rep,. 59: 229, 1975, Gleason, D, F., Mellinger. G, T, and The Veterans Administration Cooperative Urological Research Group: Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging, J, UroL, lH: 58, 1974, COMMENT
Since the original obse1·vations by Jonsson and Nilsson oral estramustine phosphate has received favorable clinical trials in patients with stages I and II tumors, The present report affirms the original observations that oral estramustine phosphate has a significantly effective activity-objectively and subjectively-when given to patients as primary treatment for advanced prostatic carcinoma, Previous observations have found this therapy helpful in patients who have had relapses, A randomized trial comparing estramustine phosphate to another agent is well underway by the National Prostatic Cancer Task Force, The drug does not appear to be benefiting patients primarily through an estrogenic effect but rather through its primary cytotoxic action,
Gerald P, Murphy Roswell Park Memorial Institute Buffalo, New York