The Journal of International Medical Research 1990; 18 (suppl I): 69 - 73
Preliminary Clinical Evaluation of Leuprorelin Acetate Depot Injection in France, in the Management of Prostatic Cancer H. Navratil Urological Service, Gaston Doumergue Centre, Nimes, France
In a preliminary multicentre clinical trial of 3.75 mg leuprorelin acetate depot 18 previously untreated patients with metastatic prostatic cancer were treated with the depot given subcutaneously once every 4 weeks for 28 weeks. Patients also received 100 mg nilutamide taken orally three times a day for the first 14 days of treatment to prevent flare-up. Leuprorelin acetate suppressed the serum testosterone concentration to castration levels; luteinizing hormone levels were also suppressed. The incidence of progressive disease was low and partial reponse occurred in five patients after treatment. No sideeffects were assigned to the flare-up period. It is concluded that leuprorelin acetate depot is a safe and efficacious treatment for metastatic prostatic cancer. Dans Ie cadre d'une etude c1inique multicentrique prelimlnaire portant sur I'acetate de leuproreline retard a une dose de 3,75 mg, on a administre Ie medicament a 18 malades atteints d'un cancer prostatique metastatique non traite au prealable, et ce sous forme d'injection sous-cutanee une fois toutes les quatre semaines pendant 28 semaines. On a egalement prescrit aux malades 100 mg de nilutamide qui a ete ingeree par voie orale trois fois par jour pendant les 14 premiers jours du traitement en vue d'empecher un reveil de la tumeur. L'acetate de leuprerellne a reduit la concentration plasmatique de testosterone jusqu'a des taux de castration; les taux d'hormones lutetnisantes ont egalement ete reduits, L'incidence de progression de la maladie a ete basse et une reponse partielle a ete observee chez cinq patients sous Ie traitement. Aucun effet secondaire n'a ete assode ala periode de reveil
Address for correspondence: Professor H. Navratil, Service d'Urologie, Centre Gaston Doumergue, 5 Rue Hoche, 30006 Nimes Cedex, France. © Copyright 1990 by Cambridge Medical Publications Ltd
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69
H. Navratil
de la tumeur. On en a conclu que I'acetate de Ieuprereline retard etalt un traitement sur et efficace du cancer prostatique metastatique. In uno studio preliminare policentrico della terapia a base di 3,75 mg di leuprorelin acetato, in preparazione "ritardo", a 18 pazienti afTetti da cancro prostatico metastatico, che non erano stati trattati in precedenza, estata somministrata la suddetta dose di farmaco, in preparazione "ritardo" per via sottocutanea, una volta ogni 4 settimane, per 28 settimane. Ai pazienti sono stati somministrati anche 100 mg di nilutamide, per via orale, tre volte al giorno, per i primi 14 giorni di trattamento, al tine di impedire I'aggravamento. I1leuproreJin acetato ha soppresso la concentrazione serica di testosterone a livelli da castrazione; anche i livelli di ormone luteinizzante sono stati soppressi. L'incidenza dei casi di malattia progressiva e stata bassa ed in cinque pazienti si erilevata una risposta parziale, dopo it trattamento. Nessun efTetto collaterale e stato attribuito al periodo di aggravamento. Se ne desume che it leuprorelin acetato, in preparazione "ritardo" costituisce un trattamento sicuro ed efficace per it cancro della prostata metastatico. KEY WORDS: Leuprorelin acetate depot; metastatic prostatic cancer; nilutamide.
INTRODUCTION
euprorelin acetate depot consists of leuprorelin acetate, a potent nonapeptide luteinizing hormone releasing hormone agonist, entrapped in copoly(lactic acid/ glycolic acid).' Leuprorelin acetate has been shown to be effective in the treatment of prostatic cancer.' It produces a fall in plasma luteinizing hormone and testosterone concentrations, after an initial increase, when injected subcutaneously once every 4 weeks. The decrease in testosterone concentrations is the rationale for using leuprorelin acetate depot in the management of metastatic prostatic cancer. This paper reports the initial clinical experience of the use of leuprorelin acetate in a multicentre study carried out in France.
L
PATIENTS AND METHODS
Patients The protocol was approved by the Ethical Committee of Tours, France, and was conducted at three centres beginning in De-
cember 1987 and finishing in March 1989 (Table I). The non-randomized trial was limited to patients between 40 and 80 years of age with histologically diagnosed prostatic cancer and metastasis (stage D), who had not received hormone treatment previously. Patients who had been treated by orchidectomy, those with concurrent malignancy and those with a performance status of more than stage 3 were excluded.'
Treatment A suspension of 3.75 mg leuprorelin depot was administered subcutaneously once every 4 weeks for 28 weeks. Patients also received a non-steroidal anti-androgen, 100 mg nilutamide, given orally three times a day for up to 14 days starting on the same day as the injection ofleuprorelin acetate in order to prevent adverse effects of flare-up.
C finical evaluations Needle biopsies of the prostate were performed on entry to the study and all patients
70 Downloaded from imr.sagepub.com at SAGE Publications on June 20, 2016
French experience with leuprorelin acetate
Table 1 Patients entered between December 1987 and July 1988 into a French clinical trial of 3.75 mg leuprorelin acetate depot for the treatment of prostatic cancer
Institution
Centre hospitalier de Nimes Centre hospitalier de Tours Centre hospitalier de Reims
were investigated extensively in order to establish the metastatic status of the disease. Isotopic bone scans or X-rays were evaluated by a radiologist after 16 and 28 weeks. The disappearance of all abnormal changes on a scan or X-rays implied complete remission. Partial remission was classified by a recognizable decrease in activity shown on two successive scans and no development of new lesions. Progressive disease was defined as a detectable increase in the extent of existing lesions or the appearance of a new lesion. For non-scan lesions, complete remission implied the absence of any clinically detectable tumour and partial remission consisted of a decrease of 50% or more in volume of a lesion. Progressive disease was indicated by an increase in the lesion and no change implied a change of less than 50%. The criteria used were those recommended by the National Prostatic Cancer Project." Blood samples were obtained once a week for the first 4 weeks and then at 4week intervals for a total of 28 weeks and serum concentrations of testosterone, luteinizing hormone, follicle stimulating hormone and leuprorelin were assayed. RESULTS
A total of 18 patients entered into the study (Table 1), all of whom were evaluable for objective response. The mean age of the
No. of patients entered
No. of patients ineligible
o
7 6 5
o o
Table 2 Sites of metastasis in prostatic cancer patients before being treated with 3.75 mg leuprorelin acetate depot Site
No. of patients
Bone metastasis Other Brain metastasis SubcIavicular node
16
Table 3 Treatment for prostatic cancer patients prior to 3.75 mg leuprorelin acetate depot Treatment
No previous treatment Pelvic radiotherapy for stage C, 2 years before Surgical treatment of brain metastasis
No. of patients
16
patients was 70.5 years (range 61 - 78 years) and the average weight was 70.6 kg (range 58 - 101 kg). The initial site of metastasis was the bone in 16/18 patients (Table 2). The majority (16/18) of patients had not received any previous treatment (Table 3) and all patients were classified as 0 or 1 on the performance status scale. After 16 weeks, there was no change 71
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H. Navratil
Table 4 Objective reponses (no. of patients) according to National Prostatic Cancer Project criteria after treatment with 3.75 mg leuprorelin acetate depot given subcutaneously once every 4 weeks Duration of treatment
Complete response
Partial response
No change
Progressive disease
16 weeks 28 weeks
o o
6 5
11 10
3
1
Table 5 Mean serum testosterone concentrations (ng/ml) in prostatic cancer patients receiving 3.75 mg leuprorelin acetate depot given subcutaneously once every 4 weeks Week 0 Mean No. of patients
5.01
Week 4 0.38 18
Week 8
Week 12 Week 16 Week 20 Week 24 Week 28
0.24 18
according to National Prostatic Cancer Project criteria in II patients and a partial response in six (Table 4) and after 28 weeks there was no change in 10 patients and a partial response in five. Progressive disease was reported in one patient after 16 weeks and in two after 28 weeks. Serum luteinizing hormone (Table 5) and testosterone (Table 6) concentrations had fallen markedly by 4 weeks and thereafter remained low. Some variation in serum testosterone levels was noted: a patient weighing 100 kg had an upper limit testosterone castration concentration of 0.5 ng/ml. In another, the serum testosterone concentration decreased only slowly, with a non-castrated level at week 4 of 1.4 ng/ml. This patient had a very large prostatic tumour with bilateral urinary tract obstruction. A patient with slight renal insufficiency had a relatively low serum testosterone concentration before treatment of 2.5 ng/rnl, which fell to the castration level at 4 weeks, but thereafter it was difficult to
0.16 16
0.15 15
0.17
13
0.20 16
0.14 15
maintain. Adverse events were relatively minor, with three reporting headaches, five hot flushes and one visual side-effects; no patient discontinued treatment because of adverse events. There was no increase in symptoms during the first weeks of treatment and no pain at the site of the injection was reported. DISCUSSION
In this preliminary study in France on the use of 3.75 mg leuprorelin acetate depot administered subcutaneously at 4-week intervals for the treatment of prostatic cancer patient compliance was excellent. Hormone measurements confirmed that the depot preparation was effective in decreasing serum testosterone blood levels and in maintaining low levels, as has been described in other countries.v' Nevertheless, this trial provides more detailed data about particular cases. During the study, there were no consequences ofthe flare-up, which
72 Downloaded from imr.sagepub.com at SAGE Publications on June 20, 2016
French experience with leuprorelin acetate
Table 6 Serum luteinizing hormone releasing hormone concentrations (mIU/ml) in prostatic cancer patients treated with 3.75 mg Ieuprorelin acetate depot given subcutaneously once every 4 weeks
Mean No. of
Week 0
Week 4
Week 8
3.38
0.46 18
0.25 18
Week 12 Week 16 Week 20 Week 24 Week 28 0.26 16
0.23
15
0.24 13
0.33 16
0.26
15
patients frequently occurs. It was avoided by administrating nilutamide for the first 14 days of leuprorelin acetate depot treatment." The results of the present study suggest that leuprorelin acetate may provide an interesting alternative treatment for patients who have refused orchidectomy, other trials having confirmed that luteinizing hormone releasing hormone agonists are as effective as orchidectomy." Until recently, the only developments in the treatment of prostatic cancer have involved radiological techniques, but now the concept of total androgen deprivation for initial treatment of metastatic prostatic cancer isgrowing." Several randomized clinical trials using luteinizing hormone releasing hormone agonists associated with non-steroidal anti-androgens must be performed in order to confirm the good clinical results on overall survival already reported. 10 Another possible advantage of luteinizing hormone releasing hormone agonists is the reversibility of their actions, thus allowing easy testing of the effects of androgen deprivation in all non-metastatic prostatic cancer patients including those who do not, subsequently, respond to treatment.
REFERENCES I.
2.
3. 4.
5.
6.
7.
8.
9.
ACKNOWLEDGEMENTS
The help of the following investigators who participated in this study is sincerely acknowledged: Professor Lanson (Tours) and Professor Lardennois (Reims).
10.
Ogawa Y, YamamotoM, Yashiki T, et al: Anew technique to efficiently trap leuproreline acetate into microcapsules of polylactic acid or copoly (lactic/glycolic) acid. Chem Pharm Bull (Tokyo) 1988; 36: 1095 - 1103. Leuprolide Study Group: Leuprolide versus diethylstilbestrol for metastatic prostate. N Engl J Med 1984; 311: 1281- 1286. ECOG: Criteria: Geneva World Health Organization. Murphy GP, Slack NH: Response criteria for the prostate of the USA National Prostatic Cancer Project. Prostate 1980; 1: 375 - 382. Isurugi K, Nijima T, Akaza H, et al: Treatment of prostatic cancer with TAP-144-SR a depot preparation of LH-RH agonist (leuprolide). Sixth Mediterranean Congress on Chemotherapy, Taormina, 22-27 May 1988, pp 1237-1247. Schilling A: Kinetics of sex hormones after administration of depotleuprolide. Sixth Mediterranean Congress of Chemotherapy, Taormina, 22 May 1988. Khun JM, Billebaud T, Navratil H, et al: Prevention of the transient adverse effects of gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide). N Engl J Med 1989; 321: 413 - 418. Parmar H: Randomized controlled study of orchiectomy versus long-acting D- Trp-6-LHRH microcapsules in advanced prostatic carcinoma. Lancet 1985; ii: 1201 - 1205. Labrie A, Dupont A, Bellanger A, et al: New hormonal therapy in prostatic cancer combined use of a pure antiandrogen and an LHRH agonist. HormRes 1983; 18: 18-27. Crawford ED, Eisenberger MA, McLeod 00, et al: A controlled trial ofleuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989; 32 (suppll): 419 -425.
73
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Preliminary Clinical Evaluation of Leuprorelin Acetate Depot Injection in France, in the Management of Prostatic Cancer H. Navratil Urological Service, Gaston Doumergue Centre, Nimes, France
In a preliminary multicentre clinical trial of 3.75 mg leuprorelin acetate depot 18 previously untreated patients with metastatic prostatic cancer were treated with the depot given subcutaneously once every 4 weeks for 28 weeks. Patients also received 100 mg nilutamide taken orally three times a day for the first 14 days of treatment to prevent flare-up. Leuprorelin acetate suppressed the serum testosterone concentration to castration levels; luteinizing hormone levels were also suppressed. The incidence of progressive disease was low and partial reponse occurred in five patients after treatment. No sideeffects were assigned to the flare-up period. It is concluded that leuprorelin acetate depot is a safe and efficacious treatment for metastatic prostatic cancer. Dans Ie cadre d'une etude c1inique multicentrique prelimlnaire portant sur I'acetate de leuproreline retard a une dose de 3,75 mg, on a administre Ie medicament a 18 malades atteints d'un cancer prostatique metastatique non traite au prealable, et ce sous forme d'injection sous-cutanee une fois toutes les quatre semaines pendant 28 semaines. On a egalement prescrit aux malades 100 mg de nilutamide qui a ete ingeree par voie orale trois fois par jour pendant les 14 premiers jours du traitement en vue d'empecher un reveil de la tumeur. L'acetate de leuprerellne a reduit la concentration plasmatique de testosterone jusqu'a des taux de castration; les taux d'hormones lutetnisantes ont egalement ete reduits, L'incidence de progression de la maladie a ete basse et une reponse partielle a ete observee chez cinq patients sous Ie traitement. Aucun effet secondaire n'a ete assode ala periode de reveil
Address for correspondence: Professor H. Navratil, Service d'Urologie, Centre Gaston Doumergue, 5 Rue Hoche, 30006 Nimes Cedex, France. © Copyright 1990 by Cambridge Medical Publications Ltd
Downloaded from imr.sagepub.com at SAGE Publications on June 20, 2016
69
H. Navratil
de la tumeur. On en a conclu que I'acetate de Ieuprereline retard etalt un traitement sur et efficace du cancer prostatique metastatique. In uno studio preliminare policentrico della terapia a base di 3,75 mg di leuprorelin acetato, in preparazione "ritardo", a 18 pazienti afTetti da cancro prostatico metastatico, che non erano stati trattati in precedenza, estata somministrata la suddetta dose di farmaco, in preparazione "ritardo" per via sottocutanea, una volta ogni 4 settimane, per 28 settimane. Ai pazienti sono stati somministrati anche 100 mg di nilutamide, per via orale, tre volte al giorno, per i primi 14 giorni di trattamento, al tine di impedire I'aggravamento. I1leuproreJin acetato ha soppresso la concentrazione serica di testosterone a livelli da castrazione; anche i livelli di ormone luteinizzante sono stati soppressi. L'incidenza dei casi di malattia progressiva e stata bassa ed in cinque pazienti si erilevata una risposta parziale, dopo it trattamento. Nessun efTetto collaterale e stato attribuito al periodo di aggravamento. Se ne desume che it leuprorelin acetato, in preparazione "ritardo" costituisce un trattamento sicuro ed efficace per it cancro della prostata metastatico. KEY WORDS: Leuprorelin acetate depot; metastatic prostatic cancer; nilutamide.
INTRODUCTION
euprorelin acetate depot consists of leuprorelin acetate, a potent nonapeptide luteinizing hormone releasing hormone agonist, entrapped in copoly(lactic acid/ glycolic acid).' Leuprorelin acetate has been shown to be effective in the treatment of prostatic cancer.' It produces a fall in plasma luteinizing hormone and testosterone concentrations, after an initial increase, when injected subcutaneously once every 4 weeks. The decrease in testosterone concentrations is the rationale for using leuprorelin acetate depot in the management of metastatic prostatic cancer. This paper reports the initial clinical experience of the use of leuprorelin acetate in a multicentre study carried out in France.
L
PATIENTS AND METHODS
Patients The protocol was approved by the Ethical Committee of Tours, France, and was conducted at three centres beginning in De-
cember 1987 and finishing in March 1989 (Table I). The non-randomized trial was limited to patients between 40 and 80 years of age with histologically diagnosed prostatic cancer and metastasis (stage D), who had not received hormone treatment previously. Patients who had been treated by orchidectomy, those with concurrent malignancy and those with a performance status of more than stage 3 were excluded.'
Treatment A suspension of 3.75 mg leuprorelin depot was administered subcutaneously once every 4 weeks for 28 weeks. Patients also received a non-steroidal anti-androgen, 100 mg nilutamide, given orally three times a day for up to 14 days starting on the same day as the injection ofleuprorelin acetate in order to prevent adverse effects of flare-up.
C finical evaluations Needle biopsies of the prostate were performed on entry to the study and all patients
70 Downloaded from imr.sagepub.com at SAGE Publications on June 20, 2016
French experience with leuprorelin acetate
Table 1 Patients entered between December 1987 and July 1988 into a French clinical trial of 3.75 mg leuprorelin acetate depot for the treatment of prostatic cancer
Institution
Centre hospitalier de Nimes Centre hospitalier de Tours Centre hospitalier de Reims
were investigated extensively in order to establish the metastatic status of the disease. Isotopic bone scans or X-rays were evaluated by a radiologist after 16 and 28 weeks. The disappearance of all abnormal changes on a scan or X-rays implied complete remission. Partial remission was classified by a recognizable decrease in activity shown on two successive scans and no development of new lesions. Progressive disease was defined as a detectable increase in the extent of existing lesions or the appearance of a new lesion. For non-scan lesions, complete remission implied the absence of any clinically detectable tumour and partial remission consisted of a decrease of 50% or more in volume of a lesion. Progressive disease was indicated by an increase in the lesion and no change implied a change of less than 50%. The criteria used were those recommended by the National Prostatic Cancer Project." Blood samples were obtained once a week for the first 4 weeks and then at 4week intervals for a total of 28 weeks and serum concentrations of testosterone, luteinizing hormone, follicle stimulating hormone and leuprorelin were assayed. RESULTS
A total of 18 patients entered into the study (Table 1), all of whom were evaluable for objective response. The mean age of the
No. of patients entered
No. of patients ineligible
o
7 6 5
o o
Table 2 Sites of metastasis in prostatic cancer patients before being treated with 3.75 mg leuprorelin acetate depot Site
No. of patients
Bone metastasis Other Brain metastasis SubcIavicular node
16
Table 3 Treatment for prostatic cancer patients prior to 3.75 mg leuprorelin acetate depot Treatment
No previous treatment Pelvic radiotherapy for stage C, 2 years before Surgical treatment of brain metastasis
No. of patients
16
patients was 70.5 years (range 61 - 78 years) and the average weight was 70.6 kg (range 58 - 101 kg). The initial site of metastasis was the bone in 16/18 patients (Table 2). The majority (16/18) of patients had not received any previous treatment (Table 3) and all patients were classified as 0 or 1 on the performance status scale. After 16 weeks, there was no change 71
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H. Navratil
Table 4 Objective reponses (no. of patients) according to National Prostatic Cancer Project criteria after treatment with 3.75 mg leuprorelin acetate depot given subcutaneously once every 4 weeks Duration of treatment
Complete response
Partial response
No change
Progressive disease
16 weeks 28 weeks
o o
6 5
11 10
3
1
Table 5 Mean serum testosterone concentrations (ng/ml) in prostatic cancer patients receiving 3.75 mg leuprorelin acetate depot given subcutaneously once every 4 weeks Week 0 Mean No. of patients
5.01
Week 4 0.38 18
Week 8
Week 12 Week 16 Week 20 Week 24 Week 28
0.24 18
according to National Prostatic Cancer Project criteria in II patients and a partial response in six (Table 4) and after 28 weeks there was no change in 10 patients and a partial response in five. Progressive disease was reported in one patient after 16 weeks and in two after 28 weeks. Serum luteinizing hormone (Table 5) and testosterone (Table 6) concentrations had fallen markedly by 4 weeks and thereafter remained low. Some variation in serum testosterone levels was noted: a patient weighing 100 kg had an upper limit testosterone castration concentration of 0.5 ng/ml. In another, the serum testosterone concentration decreased only slowly, with a non-castrated level at week 4 of 1.4 ng/ml. This patient had a very large prostatic tumour with bilateral urinary tract obstruction. A patient with slight renal insufficiency had a relatively low serum testosterone concentration before treatment of 2.5 ng/rnl, which fell to the castration level at 4 weeks, but thereafter it was difficult to
0.16 16
0.15 15
0.17
13
0.20 16
0.14 15
maintain. Adverse events were relatively minor, with three reporting headaches, five hot flushes and one visual side-effects; no patient discontinued treatment because of adverse events. There was no increase in symptoms during the first weeks of treatment and no pain at the site of the injection was reported. DISCUSSION
In this preliminary study in France on the use of 3.75 mg leuprorelin acetate depot administered subcutaneously at 4-week intervals for the treatment of prostatic cancer patient compliance was excellent. Hormone measurements confirmed that the depot preparation was effective in decreasing serum testosterone blood levels and in maintaining low levels, as has been described in other countries.v' Nevertheless, this trial provides more detailed data about particular cases. During the study, there were no consequences ofthe flare-up, which
72 Downloaded from imr.sagepub.com at SAGE Publications on June 20, 2016
French experience with leuprorelin acetate
Table 6 Serum luteinizing hormone releasing hormone concentrations (mIU/ml) in prostatic cancer patients treated with 3.75 mg Ieuprorelin acetate depot given subcutaneously once every 4 weeks
Mean No. of
Week 0
Week 4
Week 8
3.38
0.46 18
0.25 18
Week 12 Week 16 Week 20 Week 24 Week 28 0.26 16
0.23
15
0.24 13
0.33 16
0.26
15
patients frequently occurs. It was avoided by administrating nilutamide for the first 14 days of leuprorelin acetate depot treatment." The results of the present study suggest that leuprorelin acetate may provide an interesting alternative treatment for patients who have refused orchidectomy, other trials having confirmed that luteinizing hormone releasing hormone agonists are as effective as orchidectomy." Until recently, the only developments in the treatment of prostatic cancer have involved radiological techniques, but now the concept of total androgen deprivation for initial treatment of metastatic prostatic cancer isgrowing." Several randomized clinical trials using luteinizing hormone releasing hormone agonists associated with non-steroidal anti-androgens must be performed in order to confirm the good clinical results on overall survival already reported. 10 Another possible advantage of luteinizing hormone releasing hormone agonists is the reversibility of their actions, thus allowing easy testing of the effects of androgen deprivation in all non-metastatic prostatic cancer patients including those who do not, subsequently, respond to treatment.
REFERENCES I.
2.
3. 4.
5.
6.
7.
8.
9.
ACKNOWLEDGEMENTS
The help of the following investigators who participated in this study is sincerely acknowledged: Professor Lanson (Tours) and Professor Lardennois (Reims).
10.
Ogawa Y, YamamotoM, Yashiki T, et al: Anew technique to efficiently trap leuproreline acetate into microcapsules of polylactic acid or copoly (lactic/glycolic) acid. Chem Pharm Bull (Tokyo) 1988; 36: 1095 - 1103. Leuprolide Study Group: Leuprolide versus diethylstilbestrol for metastatic prostate. N Engl J Med 1984; 311: 1281- 1286. ECOG: Criteria: Geneva World Health Organization. Murphy GP, Slack NH: Response criteria for the prostate of the USA National Prostatic Cancer Project. Prostate 1980; 1: 375 - 382. Isurugi K, Nijima T, Akaza H, et al: Treatment of prostatic cancer with TAP-144-SR a depot preparation of LH-RH agonist (leuprolide). Sixth Mediterranean Congress on Chemotherapy, Taormina, 22-27 May 1988, pp 1237-1247. Schilling A: Kinetics of sex hormones after administration of depotleuprolide. Sixth Mediterranean Congress of Chemotherapy, Taormina, 22 May 1988. Khun JM, Billebaud T, Navratil H, et al: Prevention of the transient adverse effects of gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide). N Engl J Med 1989; 321: 413 - 418. Parmar H: Randomized controlled study of orchiectomy versus long-acting D- Trp-6-LHRH microcapsules in advanced prostatic carcinoma. Lancet 1985; ii: 1201 - 1205. Labrie A, Dupont A, Bellanger A, et al: New hormonal therapy in prostatic cancer combined use of a pure antiandrogen and an LHRH agonist. HormRes 1983; 18: 18-27. Crawford ED, Eisenberger MA, McLeod 00, et al: A controlled trial ofleuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989; 32 (suppll): 419 -425.
73
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