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A Comparison of Leuprolide with Flutamide and Leuprolide in Previously Untreated Patients with Clinical Stage D2 Cancer of the Prostate, Phase III, Intergroup Study-0036
Accepted 609
610
PROGRESSION AND DEATH FOLLOWING LHRH-ANALOGUE MONOTREATMENT IN ADVANCED PROSTATIC CARCINOMA. Gunther H. Jacobi, Ulrich K. Wenderoth*, Hubertus v, Wallenberg* and Massimo Gatto*, Mainz, West- Germany ( Presentation to be made by Dr. Jacobi) Since 1981 we have given the LHRH-analogue Buserelin pernasally (3x400 pg/d) to 153 patients with newly diagnosed advanced prostatic carcinoma. Castrate levels of serum testosterone were achieved after 4 weeks and maintained. This analysis is based on a subgroup of 46 of 101 patients treated up to March 1984 who relapsed after initial objective response ( NPCP criteria J. Mean age was 68 years ( 49 to 82 yrs). Stage: 39 x M1; 4 x N2-4; 3 x T4. Follow up ranged from 30 to 58 months. Average time to progression was 13.6 months (3-45 months). Progression of bone metastases was in 22 ( 48 %) , metastatic bone pain in 10 (22 %) , progression from Mo to Ml in 5 (11 %) , lymphatic involvement in 5 (11 %) , and pulmonary metastases in 4 patients (8 %) the first sign of tumo'r relapse. Under continuation of 13userelin 36 patients received additional treatment: high i. v. dose of DES and/or estramustine phosphate (31 J; irradiation of bone metastases ( 5), and additional i. v. Yttrium radioisotope treatment (9 J. Mean survival is 27 months (3-58 months). 32 patients (70 %) died, 31 of, prostate cancer, one of myocardial infarction. The average time interval from relapse to death was 10.5 months (0 to 30 months). Survival of the 14 patients still ~live ranges from 29 to 58 months, with an average of 41 months. This long term study with progression and death as end point of analysis demonstrates that the commonly reported 60 to 80 % response rates after LHRH-analogue treatment may cause misleading interpretations. Preliminary results of relatively small numbers of patients analyzed after only one or two years of treatment are inadequate in judging the true value of androgen deprivation.
A CCMPARISON OF LEUPROLIDE WITH FWTAMIDE AND LEUPROLIDE IN PREVIOUSLY UNTREATED PATIENTS WITH CLINICAL STAGE D2 CANCER OF THE PROSTATE, PHASE III, INTERGROUP SWDY-0036. E. David Crawford, Denver, CO; D, McLeod, A. Dorr, Washington, CC; J. Spaulding, San Francisco, CA; Ralph Benson, Rochester, MN; *M. Eisenberger, Baltimore, MD; *Brent Blumenstein, Seattle, WA. (Presentation to be made by Dr. Crawford) Complete androgen blockade for the treatment of advanced prostate cancer has been championed by Labrie. He has reported that with canbination therapy both time to progression and survival are superior to historical controls treated with either DES or orchiectomy. In order to test these hypotheses an intergroup trial was instituted comparing Leuprolide alone to the combination of Leuprolide with Flutamide. Eligibility requirements included previously untreated histologically confirmed stage D2 adenocarcinoma of the prostate, measurable bone or soft tissue metastases, performance status (PS) of 3 or better, acceptable renal and hepatic function, no severe cardiac disease, and no prior or concomitant endocrine therapy. Stratification at entry was on the basis of PS and none or minimal versus severe degree of bone metastases. After randomization, patients received either Leuprolide 1 m;i subcutaneously/day or the saire dose of Leuprolide plus Flutamide 250 m;J po tid. Patients were evaluated by the usual paraneters on day 8 , weeks 4 and 12 , and every 12 weeks thereafter. 617 patients were entered into this study between March, 1985 and April, 1986. Ten patients found to have either stage C or Dl disease were deemed not eligible. The median age in the Leuprolide only group was 68.0 years (range 43-98 years), and in the combination arm' 67 years (range 44-98 years). At registration 494 patients were stratified as severe disease, PS 0-2, 39 severe disease, PS-3, and 86 minimal disease, PS--0-2. There was no statistically significant difference in the toxicity between the two arms. There are currently 58 deaths in both arms combined. Time to progression, incidence of flare and projected survivals will be presented.
611
612
INHIBITION OF lilRH-ANALOClJE INIUCED 1ESTOSTERONE SURGE BY BLOCKADE OF ANDROGr RECEPIDRS. Wolfgang Aulitzk/, Julian Frick, Helmut Joos , Walter Hauser , Salzburg, Austria (Presentation to be made by Dr. Aulitzky) The effect of combined antiandrogenic therapy on prostate cancer is still under discussion. It is an open question if the initial testosterone surge causes progression of the disease ("flare up"). The aim of this study was to investigate the initial phase of combined antiandrogenic therapy after 1 week of androgenreceptor blockade by a nonsteroidal anti androgen. 30 pat. suffering from primary prostate cancer stage D2 participated in this study. Group A (n=S) received HOE 766 as solitary treatment (control); Group B (n=9) flutemide + HOE 766; Group C (n=16) fluternide + Decapeptyle. Results: Group A: 2/5 pat. showed flare symptoms. Results of ~ T, AP, PAP were identical to those reported in literature. proup B + C: week 1: (antiandrogen only). We found an increase of LH, FSH, T and a marked decrease of PAP, AP in all pat. Improvement of clinical state but no flare up symptoms were reported. Week 2: (antiandrogen and lilRH-analogue) A surge of ill, FSH, Twas observed. The Tsurge under,Decapeptyle was far less pronounced than under HOE 766. PAP, AP~levels showed a marked increase (pathological range)._Week 4: LH, FSH, T showed a clear decrease in all pat. x reaches castration range in Group C, whereas x T of Group Bis still above castration values. PAP, AP-levels decrease again to pretreatment values (1 exception). Our results indicate that blockade of androgenreceptors prior to combined antiandrogenic therapy results in clinical improvement and inhibits the T-surge under Decapeptyle, but not HOE, 766. Jt does not inhibit the analogue induced surge of PAP, AP and therefore disease flare cannot be excluded. Different behaviour of T, PAP, AP levels may be due to unknown peripheral effects of the two drugs~
ANTI-ANDROGEN (FLUTAMIDE) THERAPY IN MANAGEMENT OF RELAPSING METASTATIC PROSTATIC CARCINOMA. Amir v. Kaisary*, Griffith J. Fellows* and Joseph C. Smith*, Oxford, England. (Presentation to be made by Mr. Kaisary) . Twentyfive patients with metastatic prostatic carcinoma
were treated either by bilateral orchidectomy (18 cases) or sub-cutaneous monthly depot injections of LH-RH analogue Zoladex (7 cases). Following initial respopse, relapses in the form of progression of metastases as evidenced by appropriate investigations occurred after a 3-36 months interval. Flutamide, an anti-androgen was then administered as a sec-
ond line therapy.
It was well tolerated by all patients at
a dose of 250 mg t.d.s. and one patient with chronic renal
failure who received 250 mg b.d. Side effects of Flutamide therapy included: nausea (3 patients), diarrhoea (3 patients), depression (1 patient) and breast tenderness (1 patient).
No patient discontinued treatment on account of side
effects. Eleven patients had symptoms of progressive disease, i.~. increased bone pain and/or anaemia, and none showed response
to Flutamide therapy and to date 8 patients in the sub-group have died. The remaining 14 patients were asymptomatic despite evidence of progressive disease at initiation of Flutamide therapy. Follow up of this sub-group showed regress-
ion of metastases (2 patients), stable disease (4 patients), progression (3 patients) with the rest awaiting evaluation of their metastases.
The results of this study seem to suggest that institution of anti-androgen therapy (Flutamide) as a second line management of metastatic prostatic carcinoma failed to alter the progression of the disease in symptomatic patients. However, in those who had 11 asymptomatic 11 progressive metastatic prostatic carcinoma it seems that this form of therapy might lead to a decrease in the pace of dis~ase progression, stabilisation or even regression of metastases in some cases.
256A
610
PROGRESSION AND DEATH FOLLOWING LHRH-ANALOGUE MONOTREATMENT IN ADVANCED PROSTATIC CARCINOMA. Gunther H. Jacobi, Ulrich K. Wenderoth*, Hubertus v, Wallenberg* and Massimo Gatto*, Mainz, West- Germany ( Presentation to be made by Dr. Jacobi) Since 1981 we have given the LHRH-analogue Buserelin pernasally (3x400 pg/d) to 153 patients with newly diagnosed advanced prostatic carcinoma. Castrate levels of serum testosterone were achieved after 4 weeks and maintained. This analysis is based on a subgroup of 46 of 101 patients treated up to March 1984 who relapsed after initial objective response ( NPCP criteria J. Mean age was 68 years ( 49 to 82 yrs). Stage: 39 x M1; 4 x N2-4; 3 x T4. Follow up ranged from 30 to 58 months. Average time to progression was 13.6 months (3-45 months). Progression of bone metastases was in 22 ( 48 %) , metastatic bone pain in 10 (22 %) , progression from Mo to Ml in 5 (11 %) , lymphatic involvement in 5 (11 %) , and pulmonary metastases in 4 patients (8 %) the first sign of tumo'r relapse. Under continuation of 13userelin 36 patients received additional treatment: high i. v. dose of DES and/or estramustine phosphate (31 J; irradiation of bone metastases ( 5), and additional i. v. Yttrium radioisotope treatment (9 J. Mean survival is 27 months (3-58 months). 32 patients (70 %) died, 31 of, prostate cancer, one of myocardial infarction. The average time interval from relapse to death was 10.5 months (0 to 30 months). Survival of the 14 patients still ~live ranges from 29 to 58 months, with an average of 41 months. This long term study with progression and death as end point of analysis demonstrates that the commonly reported 60 to 80 % response rates after LHRH-analogue treatment may cause misleading interpretations. Preliminary results of relatively small numbers of patients analyzed after only one or two years of treatment are inadequate in judging the true value of androgen deprivation.
A CCMPARISON OF LEUPROLIDE WITH FWTAMIDE AND LEUPROLIDE IN PREVIOUSLY UNTREATED PATIENTS WITH CLINICAL STAGE D2 CANCER OF THE PROSTATE, PHASE III, INTERGROUP SWDY-0036. E. David Crawford, Denver, CO; D, McLeod, A. Dorr, Washington, CC; J. Spaulding, San Francisco, CA; Ralph Benson, Rochester, MN; *M. Eisenberger, Baltimore, MD; *Brent Blumenstein, Seattle, WA. (Presentation to be made by Dr. Crawford) Complete androgen blockade for the treatment of advanced prostate cancer has been championed by Labrie. He has reported that with canbination therapy both time to progression and survival are superior to historical controls treated with either DES or orchiectomy. In order to test these hypotheses an intergroup trial was instituted comparing Leuprolide alone to the combination of Leuprolide with Flutamide. Eligibility requirements included previously untreated histologically confirmed stage D2 adenocarcinoma of the prostate, measurable bone or soft tissue metastases, performance status (PS) of 3 or better, acceptable renal and hepatic function, no severe cardiac disease, and no prior or concomitant endocrine therapy. Stratification at entry was on the basis of PS and none or minimal versus severe degree of bone metastases. After randomization, patients received either Leuprolide 1 m;i subcutaneously/day or the saire dose of Leuprolide plus Flutamide 250 m;J po tid. Patients were evaluated by the usual paraneters on day 8 , weeks 4 and 12 , and every 12 weeks thereafter. 617 patients were entered into this study between March, 1985 and April, 1986. Ten patients found to have either stage C or Dl disease were deemed not eligible. The median age in the Leuprolide only group was 68.0 years (range 43-98 years), and in the combination arm' 67 years (range 44-98 years). At registration 494 patients were stratified as severe disease, PS 0-2, 39 severe disease, PS-3, and 86 minimal disease, PS--0-2. There was no statistically significant difference in the toxicity between the two arms. There are currently 58 deaths in both arms combined. Time to progression, incidence of flare and projected survivals will be presented.
611
612
INHIBITION OF lilRH-ANALOClJE INIUCED 1ESTOSTERONE SURGE BY BLOCKADE OF ANDROGr RECEPIDRS. Wolfgang Aulitzk/, Julian Frick, Helmut Joos , Walter Hauser , Salzburg, Austria (Presentation to be made by Dr. Aulitzky) The effect of combined antiandrogenic therapy on prostate cancer is still under discussion. It is an open question if the initial testosterone surge causes progression of the disease ("flare up"). The aim of this study was to investigate the initial phase of combined antiandrogenic therapy after 1 week of androgenreceptor blockade by a nonsteroidal anti androgen. 30 pat. suffering from primary prostate cancer stage D2 participated in this study. Group A (n=S) received HOE 766 as solitary treatment (control); Group B (n=9) flutemide + HOE 766; Group C (n=16) fluternide + Decapeptyle. Results: Group A: 2/5 pat. showed flare symptoms. Results of ~ T, AP, PAP were identical to those reported in literature. proup B + C: week 1: (antiandrogen only). We found an increase of LH, FSH, T and a marked decrease of PAP, AP in all pat. Improvement of clinical state but no flare up symptoms were reported. Week 2: (antiandrogen and lilRH-analogue) A surge of ill, FSH, Twas observed. The Tsurge under,Decapeptyle was far less pronounced than under HOE 766. PAP, AP~levels showed a marked increase (pathological range)._Week 4: LH, FSH, T showed a clear decrease in all pat. x reaches castration range in Group C, whereas x T of Group Bis still above castration values. PAP, AP-levels decrease again to pretreatment values (1 exception). Our results indicate that blockade of androgenreceptors prior to combined antiandrogenic therapy results in clinical improvement and inhibits the T-surge under Decapeptyle, but not HOE, 766. Jt does not inhibit the analogue induced surge of PAP, AP and therefore disease flare cannot be excluded. Different behaviour of T, PAP, AP levels may be due to unknown peripheral effects of the two drugs~
ANTI-ANDROGEN (FLUTAMIDE) THERAPY IN MANAGEMENT OF RELAPSING METASTATIC PROSTATIC CARCINOMA. Amir v. Kaisary*, Griffith J. Fellows* and Joseph C. Smith*, Oxford, England. (Presentation to be made by Mr. Kaisary) . Twentyfive patients with metastatic prostatic carcinoma
were treated either by bilateral orchidectomy (18 cases) or sub-cutaneous monthly depot injections of LH-RH analogue Zoladex (7 cases). Following initial respopse, relapses in the form of progression of metastases as evidenced by appropriate investigations occurred after a 3-36 months interval. Flutamide, an anti-androgen was then administered as a sec-
ond line therapy.
It was well tolerated by all patients at
a dose of 250 mg t.d.s. and one patient with chronic renal
failure who received 250 mg b.d. Side effects of Flutamide therapy included: nausea (3 patients), diarrhoea (3 patients), depression (1 patient) and breast tenderness (1 patient).
No patient discontinued treatment on account of side
effects. Eleven patients had symptoms of progressive disease, i.~. increased bone pain and/or anaemia, and none showed response
to Flutamide therapy and to date 8 patients in the sub-group have died. The remaining 14 patients were asymptomatic despite evidence of progressive disease at initiation of Flutamide therapy. Follow up of this sub-group showed regress-
ion of metastases (2 patients), stable disease (4 patients), progression (3 patients) with the rest awaiting evaluation of their metastases.
The results of this study seem to suggest that institution of anti-androgen therapy (Flutamide) as a second line management of metastatic prostatic carcinoma failed to alter the progression of the disease in symptomatic patients. However, in those who had 11 asymptomatic 11 progressive metastatic prostatic carcinoma it seems that this form of therapy might lead to a decrease in the pace of dis~ase progression, stabilisation or even regression of metastases in some cases.
256A