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Depot Leuprolide in Untreated Stage D2 Prostatic Cancer
Accepted 605
606
SUBTOTAL ANDROGEN SUPPRESSION IN THE TREATMENT OF ADVANCED PROSTATIC CARCINOMA. Michael C. Bishop*, William T.
EVALUATION OF TOTAL VS. PARTIAL ANDROGEN BLOCKADE IN THE TREATMENT OF ADVANCED PROSTATIC CANCER: PRELIMINARY RESULTS OF A MULTICENTER PROSPECTIVE AND RANDOMIZED STUDY. Harald
Lawrence*, John Lemberger*,
Nottingham, England.
(Presentation to be made by Dr. Bishop).
Schulze*,
Orchidectomy usually achieves a remission in advanced prostatic carcinoma. Estrogen therapy is equally effect-
Herne, FRG, and the WESTFAELISCHE PROSTATAKARZINOMSTUDIE. (Presentation to be made by Dr. Schulze) It has been proposed that early treatment of patients
ive but less desirable due to thrombo-embolic complications. A more modern approach is to combine medical orchidectomy by the administration of L.H.R.H. with an anti-androgen agent to give total androgen blockade of testicular and adrenal androgen production. The rationale is that the
response of hormone sensitive tumour cells is quantitative and small concentrations of circulating androgen from extra gonadal sources may be significant. Such regimes are extremely expensive and of doubtful benefit in preventing the inevitable relapse due to hormone unresponsiveness. However, estrogens should not be abandoned particularly as they have the added advantage of direct Carcinostatic action. Furthermore thrombo-embolism may be dose related. It is also conceivable that the beneficial effect on prostatic carcinoma is qualitative such that partial androgen suppression is adequate. This paper examines the effect of lmJ dose estrogen in advanced prostatic cancer. A prospective trial of
medical orchiectomy when combined with a direct acting antiandrogen will result in a more complete form of androgen blockade, thereby increasing response and survival rate when compared to orchiectomy alone. In order to evaluate this statement objectively, we initiated a prospective and randomized study in cooperation with 10 urologic departments. Patients with newly diagnosed, previously untreated advanced prostatic cancer are randomly dis-
tributed to one of the following 4 treatment groups: I. Orchiectomy plus antiandrogen Flutamide (3 x 250 mg p.o./ day); II. Depot-Lil-RH analog Zoladex [ICI 118.630] (3,6 mg s. c. /4 weeks) plus antiandrogen Flutamide; III. Orchiectomy alone; Iv·. Depot-LJt.fill analog Zoladex alone. Treatment modalities in groups I and II are meeting the proposed requirement of a total androgen blockade. Treatment in
5.0 n.mol/L (lower limits of normal range 8.0 n.mol/L).
groups III and IV represent the so-called partial androgen blockade. In the follow-up of patients, the response criteria of the National Prostatic Cancer Project are used. To date 57 patients (pts.) have been included in this study (grp.I, 16 pts.; grp,II, 17 pts.; grp.III, 14 pts.; grp.IV, 10 pts.) with a mean follow-up time of 8.7 months (range 3 to 14 months). In the groups treated by total androgen blockade, 2 deaths (grp.I) and 1 progression (grp.II) have occurred; in the partial androgen blockade groups, 2 deaths (grp.IV) and 2 progressions (grp.III) have occurred. Up to
~hen the levels were poorly suppressed control was short-
now no complete remission has been observed in any group.
Estradurin (Polyestradiol phosphate) 160mg i.m. monthly against subcapsular orchidectomy has been undertaken in 100
patients with advanced carcinoma (T3Ml,T4MO/ML). Symptomatically, 90 per cent of patients in both groups responded although plasma testosterone levels on hormone treatment
were usually above the castrate level (2.0 n.mol/L). Qbjective control was also achieved provided plasma testosterone did not exceed a threshold of approximately
lived but re-established after orchidectomy.
No thrombo-
embolic complications were attributable to this form of estrogen therapy. We conclude that sub-total androgen suppression was adequate and a threshold effect demonstrable.
I
with advanced prostatic cancer by means of surgical or
These preliminary data fail to demonstrate a superiority of total androgen blockade over partial androgen blockade in the treatment of patients with metastatic cancer of the prostate.
607
608
INTERMITTENT HORMONE THERAPY FOR ADVANCED PROSTATE CANCER. Harry W. Herr, New York, NY (Presentation to be made by Dr. Herr) Diethylstilbestrol (DES) is effective pallia• tion for advanced prostatic carcinoma, but it causes sexual dysfunction and other side effects associated with depression of plasma testosterone (T) that impacts adversely on quality of life (QL) Subjective response to DES and the level of plasma Tis variable. Responses may occur with suppression of plasma T above castrate level. To preserve QL, 46 patients (pts) with symptomatic bone (40 pts) or local (6 pts) prostate cancer were managed since 1979 with an intermittent DES schedule. DES (1-3 mg/day) was given until a subjective response occurred (median 6 weeks) and then withdrawn. DES was restarted when disease-related svmptoms recurred. Symptomatic relapse was seen af~er stopping DES in 9 (20%) pts within 1 mo, in 2(4%) before 3 mos, in 2 (4%) before 6 mos, in 10 (22%) at 12 mos, in 7 (15%) between 1 and 2 years, and 16 (35%) have not relapsed (median 19 mos). Of the 30 pts who required repeat DES, 8 (27%) had DES stopped after achieving and maintaining (median 7 mos) a secondary response. At present, 24 (52%) of the 46 pts remain off DES (median 11 mos). Of the 28 (61%) sexually active pts prior to DES, 25 resumed activity off DES. After withdrawing DES, no pt progressed to paraplegia, pathologic fracture, uremia, acute urinary retention, or other acute severe disease-related event. All relapsing pts had a prompt (within i week) relief of symptoms after DES was restarted, General health, disease and treatment-related QL assessment of pts on continuous or intermittent DES favored the latter, The present data indicate that satisfactory palliation and improved QL can be achieved in selected pts with intermittent DES administration.
DEPOT LEUPROLIDE IN UNTREATED STAGE Dz PROSTATIC CANCER. Assaad M. Mounzer*, Michael D. Clayton*, Larry M. Ojeda, Mary W. Lee*, Roohollah Sharifi, Chicago, IL (Presentation to be made by Dr. Mounzer) 20 patients with metastatic adenocarcinoma of the prostate were entered in a study to receive leuprolide, a GnRH analog in a depot intramuscular formulation, which is designed to release leuprolide uniformly over an extended period of time. The main criteria for entering the study were: l)histologically confirmed prostatic adenocarcinoma with clinically measurable metastases, 2)prestudy testosterone levels of 15Dng/dl or more, 3)no previous hormonal treatment. Patients were followed with complete physical and rectal exam, bone scan, CBC, SMA6, and SMA12 every 3 months. Blood was drawn for testosterone, LH, and leuprolide levels on day 0, day 4, every week for 6 weeks, every 2 wee~s for 24 weeks and every month thereafter. As of 9/30/86 14 patients have been on the study for 24 weeks and 6 for 12 weeks. NPCP criteria were used to assess the response to therapy. Followup results shows partial objective response or stable disease in 14 patients and progression in 6 patients. 14 out of 20 patients had a flare-up of testosterone levels on day 4 but without significant deterioration of clinical symptoms except for one patient who developed hematuria and clot retention. By week 4 all testosterone levels*were < 40ng/ml and remained at castrated levels throughout week 12 and 24, except in 2 patients who each missed one dose of the drug. They had a second flare-up of testosterone levels after the next dose, which subsequently came down to castrated levels. We conclude that depot leuprolide with monthly intramuscular injections of 7.5mg are as efficient as daily subcutaneous doses of regular leuprolide in achieving a medical orchiectomy and in palliating metastatic prostate cancer. *of all 20 patients
~I
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:11
11
11. Ml - -
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255A
606
SUBTOTAL ANDROGEN SUPPRESSION IN THE TREATMENT OF ADVANCED PROSTATIC CARCINOMA. Michael C. Bishop*, William T.
EVALUATION OF TOTAL VS. PARTIAL ANDROGEN BLOCKADE IN THE TREATMENT OF ADVANCED PROSTATIC CANCER: PRELIMINARY RESULTS OF A MULTICENTER PROSPECTIVE AND RANDOMIZED STUDY. Harald
Lawrence*, John Lemberger*,
Nottingham, England.
(Presentation to be made by Dr. Bishop).
Schulze*,
Orchidectomy usually achieves a remission in advanced prostatic carcinoma. Estrogen therapy is equally effect-
Herne, FRG, and the WESTFAELISCHE PROSTATAKARZINOMSTUDIE. (Presentation to be made by Dr. Schulze) It has been proposed that early treatment of patients
ive but less desirable due to thrombo-embolic complications. A more modern approach is to combine medical orchidectomy by the administration of L.H.R.H. with an anti-androgen agent to give total androgen blockade of testicular and adrenal androgen production. The rationale is that the
response of hormone sensitive tumour cells is quantitative and small concentrations of circulating androgen from extra gonadal sources may be significant. Such regimes are extremely expensive and of doubtful benefit in preventing the inevitable relapse due to hormone unresponsiveness. However, estrogens should not be abandoned particularly as they have the added advantage of direct Carcinostatic action. Furthermore thrombo-embolism may be dose related. It is also conceivable that the beneficial effect on prostatic carcinoma is qualitative such that partial androgen suppression is adequate. This paper examines the effect of lmJ dose estrogen in advanced prostatic cancer. A prospective trial of
medical orchiectomy when combined with a direct acting antiandrogen will result in a more complete form of androgen blockade, thereby increasing response and survival rate when compared to orchiectomy alone. In order to evaluate this statement objectively, we initiated a prospective and randomized study in cooperation with 10 urologic departments. Patients with newly diagnosed, previously untreated advanced prostatic cancer are randomly dis-
tributed to one of the following 4 treatment groups: I. Orchiectomy plus antiandrogen Flutamide (3 x 250 mg p.o./ day); II. Depot-Lil-RH analog Zoladex [ICI 118.630] (3,6 mg s. c. /4 weeks) plus antiandrogen Flutamide; III. Orchiectomy alone; Iv·. Depot-LJt.fill analog Zoladex alone. Treatment modalities in groups I and II are meeting the proposed requirement of a total androgen blockade. Treatment in
5.0 n.mol/L (lower limits of normal range 8.0 n.mol/L).
groups III and IV represent the so-called partial androgen blockade. In the follow-up of patients, the response criteria of the National Prostatic Cancer Project are used. To date 57 patients (pts.) have been included in this study (grp.I, 16 pts.; grp,II, 17 pts.; grp.III, 14 pts.; grp.IV, 10 pts.) with a mean follow-up time of 8.7 months (range 3 to 14 months). In the groups treated by total androgen blockade, 2 deaths (grp.I) and 1 progression (grp.II) have occurred; in the partial androgen blockade groups, 2 deaths (grp.IV) and 2 progressions (grp.III) have occurred. Up to
~hen the levels were poorly suppressed control was short-
now no complete remission has been observed in any group.
Estradurin (Polyestradiol phosphate) 160mg i.m. monthly against subcapsular orchidectomy has been undertaken in 100
patients with advanced carcinoma (T3Ml,T4MO/ML). Symptomatically, 90 per cent of patients in both groups responded although plasma testosterone levels on hormone treatment
were usually above the castrate level (2.0 n.mol/L). Qbjective control was also achieved provided plasma testosterone did not exceed a threshold of approximately
lived but re-established after orchidectomy.
No thrombo-
embolic complications were attributable to this form of estrogen therapy. We conclude that sub-total androgen suppression was adequate and a threshold effect demonstrable.
I
with advanced prostatic cancer by means of surgical or
These preliminary data fail to demonstrate a superiority of total androgen blockade over partial androgen blockade in the treatment of patients with metastatic cancer of the prostate.
607
608
INTERMITTENT HORMONE THERAPY FOR ADVANCED PROSTATE CANCER. Harry W. Herr, New York, NY (Presentation to be made by Dr. Herr) Diethylstilbestrol (DES) is effective pallia• tion for advanced prostatic carcinoma, but it causes sexual dysfunction and other side effects associated with depression of plasma testosterone (T) that impacts adversely on quality of life (QL) Subjective response to DES and the level of plasma Tis variable. Responses may occur with suppression of plasma T above castrate level. To preserve QL, 46 patients (pts) with symptomatic bone (40 pts) or local (6 pts) prostate cancer were managed since 1979 with an intermittent DES schedule. DES (1-3 mg/day) was given until a subjective response occurred (median 6 weeks) and then withdrawn. DES was restarted when disease-related svmptoms recurred. Symptomatic relapse was seen af~er stopping DES in 9 (20%) pts within 1 mo, in 2(4%) before 3 mos, in 2 (4%) before 6 mos, in 10 (22%) at 12 mos, in 7 (15%) between 1 and 2 years, and 16 (35%) have not relapsed (median 19 mos). Of the 30 pts who required repeat DES, 8 (27%) had DES stopped after achieving and maintaining (median 7 mos) a secondary response. At present, 24 (52%) of the 46 pts remain off DES (median 11 mos). Of the 28 (61%) sexually active pts prior to DES, 25 resumed activity off DES. After withdrawing DES, no pt progressed to paraplegia, pathologic fracture, uremia, acute urinary retention, or other acute severe disease-related event. All relapsing pts had a prompt (within i week) relief of symptoms after DES was restarted, General health, disease and treatment-related QL assessment of pts on continuous or intermittent DES favored the latter, The present data indicate that satisfactory palliation and improved QL can be achieved in selected pts with intermittent DES administration.
DEPOT LEUPROLIDE IN UNTREATED STAGE Dz PROSTATIC CANCER. Assaad M. Mounzer*, Michael D. Clayton*, Larry M. Ojeda, Mary W. Lee*, Roohollah Sharifi, Chicago, IL (Presentation to be made by Dr. Mounzer) 20 patients with metastatic adenocarcinoma of the prostate were entered in a study to receive leuprolide, a GnRH analog in a depot intramuscular formulation, which is designed to release leuprolide uniformly over an extended period of time. The main criteria for entering the study were: l)histologically confirmed prostatic adenocarcinoma with clinically measurable metastases, 2)prestudy testosterone levels of 15Dng/dl or more, 3)no previous hormonal treatment. Patients were followed with complete physical and rectal exam, bone scan, CBC, SMA6, and SMA12 every 3 months. Blood was drawn for testosterone, LH, and leuprolide levels on day 0, day 4, every week for 6 weeks, every 2 wee~s for 24 weeks and every month thereafter. As of 9/30/86 14 patients have been on the study for 24 weeks and 6 for 12 weeks. NPCP criteria were used to assess the response to therapy. Followup results shows partial objective response or stable disease in 14 patients and progression in 6 patients. 14 out of 20 patients had a flare-up of testosterone levels on day 4 but without significant deterioration of clinical symptoms except for one patient who developed hematuria and clot retention. By week 4 all testosterone levels*were < 40ng/ml and remained at castrated levels throughout week 12 and 24, except in 2 patients who each missed one dose of the drug. They had a second flare-up of testosterone levels after the next dose, which subsequently came down to castrated levels. We conclude that depot leuprolide with monthly intramuscular injections of 7.5mg are as efficient as daily subcutaneous doses of regular leuprolide in achieving a medical orchiectomy and in palliating metastatic prostate cancer. *of all 20 patients
~I
:J!
~Ir
:11
11
11. Ml - -
t
255A