The Journal of International Medical Research 1990; 18 (suppl I): 103 - 113
3.75 and 7.5 mg Leuprorelin Acetate Depot in the Treatment of Advanced Prostatic Cancer: Preliminary Report W. Bischoff and German Leuprorelin Study Group Backnang, FRG
In an on-going, non-comparative, open, multicentre phase III study in Germany, 190 patients with advanced prostatic cancer were treated with 3.75 or 7.5 mg leuprorelin acetate depot given subcutaneously or intramuscularly once monthly, with or without concomitant antiandrogen or cytostatic therapy. The two doses and the different routes of administration did not have any significant effects on serum testosterone, dihydrotestosterone, follicle stimulating hormone and luteinizing hormone concentrations, tumour activity or clinical tolerance. Using either dose, the 'no progression' rate (complete remission plus partial remission plus stable disease) was 88.5% overall and was 88.2% in Tl- T2 disease and 82.5% in T3 - T4 disease after 12 months' treatment. It is concluded that the depot formulation of leuprorelin acetate offers an important alternative in the treatment of advanced prostatic cancer. Patients (190) souffrant d'un cancer prostatique ont He evalues dans Ie cadre d'une etude multicentrique, non comparative de phase III se poursuivant encore a ce jour, lors de laquelle ll leur a ete administre 3,75 ou 7,5 mg d'acetate de Ieuprorellne sous forme retard par injection sous-cutanee ou intramusculaire une fois par mois avec ou sans traitement cytostatique ou antiandrogene concomitant. Les deux posologies et voies d'administration differentes n'ont pas eu d'etTet significatif sur les concentrations plasmatiques en hormones luteinisantes, en hormones de stimulation des follicules, en dihydrotestosterone et en testosterone sur I'activite de la tumeur ou la tolerance clinique. Par I'utilisation de I'une ou de I'autre posologie, Ie taux de 'non-progression' (remission totale, plus remission partielle, plus
Address for correspondence: Prof. Dr med W. Bischoff, Urologe, Ed-Breuningerstrasse 3, 7150 Backnang, FRO. © Copyright 1990 by Cambridge Medical Publications Ltd
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103
W. Bischoff, German Leuprorelin Study Group
stabilisation de la maladie) etait globalement de 88,5 % et de 88,2 % dans une maladie au stade Tl - T2 et de 82,5 % dans une maladie au stade T3 - T4 apres 12 mois de traitement. II en a ete conclu que la formulation d'acetate de leuproreline retard representait une alternative a considerer dans Ie traitement du cancer avance de la prostate. In uno studio ancord in corso, non comparativo, aperto, policentrico, fase III, 190 pazienti con cancro prostatico avanzato sono stati trattati con 3,75 0 7,5 mg di leuprorelin acetato, in preparazione 'ritardo', somministrato per via sottocutanea od intramuscolare, una volta al mese, con 0 senza concomitante terapia antiandrogena 0 citostatica. I due dosaggi e Ie differenti vie di somministrazione non hanno avuto alcun effetto significativo sulle concentrazioni seriche di testosterone, diidrotestosterone, ormone follicolostimolante ed ormone luteinizzante, sull'attivlta tumorale 0 sulla tolleranza clinica. Adottando I'uno o l'altro dosaggio, la percentuale di casi di 'non peggioramento' (completa remissione, pin parziale remissione, pin stabilizzazione della malattia) e risultata pari ad 88,5% complessiva ed e stata di 88,2% negli stadi Tl - T2 e di 82,5% negli stadi T3 - T4, dopo un trattamento di 12 mesi. Si conclude che la formulazione 'ritardo' del leuprorelin acetato costituisce un'importante alternativa nel trattamento del cancro prostatico in fase avanzata.
KEY WORDS:
Leuprorelin acetate depot; hormonal effects; flutamide; prostatic cancer.
INTRODUCTION
T
he choice of procedure for the treatment of prostatic cancer should be based on histological evidence of the cancer and tumour staging. I The aim of hormonal therapy is to prevent the effector hormone from making contact with the target cell or to reduce or prevent the binding of the effector hormone to the intracellular receptor system," Since 1941, when Huggins and Hodges! showed that prostatic cancer was androgen-dependent, various methods of hormonal manipulation have been attempted in patients with metastatic disease to suppress testosterone production and, con-
Enanton" is a registered tradename of Takeda Pharrna GmbH, Stolberg, FRG.
sequently, inhibit androgen-dependent tumour growth:" for example, androgen deprivation has been achieved by the systemic administration of luteinizing hormone releasing hormone analogues such as leuprorelin.' - 8 The aim of the present study was to evaluate the clinical efficacy of 3.75 and 7.5 mg leuprorelin acetate depot (Enanton") given either subcutaneously or intramuscularly once monthly. PATIENTS AND METHODS
Patients A total of 190 patients (mean age ± SD 72 ± 9 years, mean height ± SD 172 ± 6 em, mean body weight ± SD 73 ± 9 kg) with prostatic cancer were included in the study; no patient had previously received specific hormone therapy but transurethral
104 Downloaded from imr.sagepub.com by guest on June 6, 2016
Leuprorelin acetate depot in advanced prostatic cancer
resection had been performed for stage Tl patients. Tumour staging and grading of patients included in the study are summarized in Table 1.
Table 2 Leuprorelin acetate depot dosesand routes of administration in the treatment of patients with prostatic cancer
Treatment Patients received 3.75 or 7.5 mg leuprorelin acetate depot given once monthly subcutaneously or intramuscularly for up to 15 months (Table 2). Some patients received besides leuprorelin acetate other antitumour drugs: 15 patients received concomitant 50 mg cyproterone acetate twice daily; 65 patients received 250 mg flutamide three times daily; and four patients received cytostatic agents (epirubicin or estramustine phosphate).
Dose (mg)
Route of administration
No. of patients
3.75 7.5 7.5
Subcutaneous Subcutaneous Intramuscular
157 (82.8%) 23 (12.1%) 10 (5.3%)
Table 1 Classification of prostatic cancers in190 patients before undergoingtreatment with 3.75 or 7.5 mgleuprorelin acetate depot Classification Grading Gl
G2 G3
G4 Not available Primary tumour Tl T2 T3
T4
No. of patients 21 (11.l%) 95 (50.0%) 69 (36.3%) 1(0.5%) 4 (2.1%) 10 (5.3%) 49 (25;8%) 77 (40.5%) 54 (28.5%)
Lymph node involvement
NO
N4 Not available
80 (42.1%) 19(10.0%) 24 (12.6%) 10 (5.3%) 6(3.1%) 51 (26.8%)
Metastases MO Ml M2/3 Not available
85 (44.7%) 87 (46;8%) 8 (4.2%) 10(5.2%)
Nl
N2 N3
Clinical assessment The presence of prostatic cancer was confirmed histologically and cytologically and the stage of tumour development was assessed according to European Organization for Research and Treatment of Cancer (EORTC) criteria." Metastasis was located and verified by X-rays, computer tomography or scintigraphy. Patients were clinically examined before and at l-month intervals during treatment and case histories were recorded. Consumption of analgesics and side-effects were noted and general condition was assessed by the World Health Organization performance status. The following laboratory tests were performed before, after 1 month's treatment and thereafter every 3 months: white blood cell, red blood cell and platelet counts; serum creatinine, y-glutamyl transpeptidase (y-GT),glutamic oxalo-acetic transaminase, alkaline phosphatase, acid phosphatase, prostatic acid phosphatase, prostate-specific antigen, luteinizing hormone, follicle stimulating hormone, testosterone and dihydrotestosterone. Statistical analysis In keeping with the study design, descriptive methods only were used to analyse the available material. Inductive methods were considered inappropriate. In accordance with the intent to treat principle, all case reports were included in the analysis. 105
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W. Bischoff, German Leuprorelin Study Group RESULTS
Treatment with leuprorelin acetate depot suppressed plasma testosterone dihydrotestosterone, luteinizing hormone and follicle stimulating hormone concentrations after 1 month or less (Table 3). Similarly, in several cases, serum prostatic acid and alkaline phosphatase, and prostate-specific antigenconcentrations were normalizedafter leuprorelin acetate depot, thus reflecting an inhibition of the active tumour process. Analysis of the different treatment subgroups revealed no difference in the effects of 3.75 mg leuprorelin acetate depot given subcutaneously and 7.5 mg leuprorelin acetate given subcutaneously or intramuscularly. There were no major changes in haematological parameters or in serum creatinine, glutamic oxalo-acetic transaminase or y-GT. Tables 4 - 6 summarize the remission rates in patients treated in monotherapy with 3.75 mg leuprorelin acetate depot given subcutaneously and 7.5 mg leuprorelin acetate given intramuscularly or subcutaneously. In view of the relatively small number of patients treated with 7.5 mg leuprorelin acetate depot, it was not possible to distinguish statistically between the different doses and routes of administration. Overall remission rates are shown in Table 7 for those patients that received concomitant treatment with flutamide. The median survival time of the patients was 25.3 months; 21.9 months for patients with stage Tl- T2 disease and 24.7 months for patients with stage T3 - T4 disease. Before treatment bone pain was reported by 23.7% of patients and soft tissue pain by 6.8%. After 1 month's treatment, the incidence of pain fell to 14.9% and 4.2%, respectively. This was associated with a decline in the consumption of analgesics from 17.0% to 5.9% after treatment for 1 month. Hot flushes were the most frequent
side-effect, being reported by 71 (37.3%) patients, and in four (2.1%) patients treatment was discontinued prematurely due to side-effects. Minor side-effects were reported, such as sweating, headache, weakness of the legs, loss of appetite, circulatory problems and difficulties in sleeping and hyperaesthesia of the mamilla. Local skin reactions to subcutaneous or intramuscular injections were pain, pruritus and local hyperthermia, which occurred in four (2.1%) patients included in the follow-up evaluation. There was no evidence of any correlation between the administered dose or the injection method and any systemic or local side-effects. A total of 29 patients died during the study period. There were no deaths due to leuprorelin acetate. The study was prematurely terminated in 34 patients due to: orchidectomy in eight (4.25%) patients, progression of disease in 22 (11.6%) and side-effects in four (2.1%). DISCUSSION
Luteinizing hormone releasing hormone analogues bring about chemical castration, thus making them effective against hormonedependent prostatic cancer. 5•IO, 11 An alternative treatment involves the use of oestrogens but the latter compounds have a higher incidence of cardiovascular side-effects 12 and gynaecomastia. The other alternative is orchidectomy, which can have cosmetic and psychological side-effects, as well as the risks arising from surgery, although the hormonal effects and clinical benefits of chemical and surgical castration are virtually identical." There were no differences reported for the overall clinical efficacy of 3.75 mg compared with 7.5 mg leuprorelin acetate depot given subcutaneously or intramuscularly once monthly (52% compared with 62.2%). No significant kinetic differences were found between the modes of application.
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0
-
-...I
Patient numbers are shown in parentheses.
5.1
(33)
18
(23) 4.5
4.9
(55)
15
5.0
20
12
(72)
5.7
(95)
19
9
(30)
(71)
(87)
5.3 (113) 4.9
(92)
6.2
17 (127)
6
4.5 (119)
(71)
6.8 (100)
16 (134)
3
2.7 (117)
7.3 (152)
(133)
47 8.9 (108)
360 (159)
0
21 (137)
Testosterone (ng/dl)
Time (month)
Follicle stimulating hormone (lUll)
Dlhydrotestosterone (ng/dl)
0.5
0.5
0.5
(30)
(71)
(87)
0.5 (113)
0.5 (118)
0.7 (117)
4.9 (154)
Luteinizing hormone (lUll)
1.0 (19)
0.8 (42)
1.1 (56)
1.1 (65)
1.2 (62)
2.5 (69)
4.1 (81)
RIA prostatic specific phosphatase (ng/ml)
1
1
1
123 (113) 122 120
(80) (60) (33)
(42)
(80)
138 (152)
136 (156)
2 (110) (97)
130 (156)
9 (100)
2
128 (181)
5.3
5.9
5.8
(34)
(67)
(89)
6.6 (132)
7.0 (134)
6.4 (134)
7.4 (155)
Alkaline Acid phosphatase phosphatase (lUll) (lUll)
36 (140)
RIA prostatespecific antigen (mg/dl)
Table 3 Mean serum hormones, prostatic phosphatase, prostate-specific antigen, and alkaline and acid phosphatase concentrations before and during treatment with 3.75 or 7.5 mg leuprorelin acetate depot given subcutaneously or intramuscularly once a month for 1-15 months
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27 (26.7%) 62 (61.4%) 2 (2.0%) 10 (9.9%)
14 (13.6%)
80 (77.7%)
3 (2.9%)
6 (5.8%)
Partial remission
Stable disease
Progression
Not available
0
3 months (n = 101)
0
1 month (n ::; 103)
Complete remission
Tumour size compared with on admission
7 (7.5%)
1 (l.l%)
45 (48.4%)
39 (41.9%)
I (l.l%)
6 months (n = 93)
7 (9.2%)
2 (2.6%)
32 (42.1%)
:32 (42.1%)
3 (3.9%)
(n::; 76)
9 months
4 (6.6%)
2 (3.3%)
31 (50.8%)
21 (34.4%)
3 (4.9%)
12 months (n = 61)
4 (ll.l%)
2 (5.6%)
18 (50.0%)
12 (33.3%)
0
15 months (n = 36)
Table 4 Assessment of remission in patients with Tl- T21T3- T4prostatic cancers receiving 3.75 or 7.5 mg leuprorelin acetate depot given subcutaneously or intramuscularly once a month for 1 - 15 months
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'0
-
0 1 (2.5%)
Progression
Not available
32 (80.0%)
7 (17.5%)
Partial remission
Stable disease
0
1 month (n = 40)
Complete remission
Tumour size compared with on admission
0 1 (2.6%)
1(2.5%)
22 (57.9%)
14 (36.8%)
1 (2.6%)
6 months (n = 38)
0
26 (66.7%)
12 (30.8%)
0
3 months (n = 39)
0
0
16 (55.2%)
1 (4.0%)
0
16 (64.0%)
7 (28.0%)
1 (4.0%)
2 (6.9%) 11 (37.9%)
i2 months (il = 25)
9 months (n = 29)
1 (6.7%)
0
8 (53.3%)
6 (40.0%)
0
15 months (n = 15)
Table 5 Assessment of remission in patients with Tl - T2 prostatic cancer receiving 3.75 or 7.5 mg leuprorelin acetate given subcutaneously or intramuscularly once a month for 15 months
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7 (11.1%)
Partial remission
3 (4.8%)
5 (7.9%)
Progression
Not available
48 (76.2%)
0
Complete remission
Stable disease
1 month (n =63)
Tumour size compared with on admission
9 (14.5%)
2 (3.2%)
36 (58.1%)
15 (24.2%)
0
3 months (n =62)
6 (10.9%)
1(1.8%)
23 (41.8%)
25 (45.5%)
0
6 months (n =55)
3 (8.3%)
2 (5.6%)
2 (4.3%) 7 (14.9%)
15 (41.7%)
16 (34.0%)
21 (44.7%)
14 (38.9%)
2 (5.6%)
=47)
1 (2.1 %)
(n
12 months (n =36)
9 months
3 (14.2%)
2 (9.5%)
10 (47.6%)
6 (28.6%)
0
15 months (n =21)
Table 6 Assessment of remission in patients with T3 - T4 carcinomas receiving 3.75 or 7.5 mg leuprorelin acetate given subcutaneously or intramuscularly once a month for 1 - 15 months
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1 month
6 (3.8%) 13 (8.3%)
3 (1.9%) 9 (5.6%)
Progression
Not available
10 (6.9%)
5 (3.5%)
64 (44.4%)
92 (58.6%)
Stable disease 126 (78.3%)
3 (2.1%)
6 months (n = 144)
62 (43.1%)
23 (14.3%)
Partial remission
0
3 months (n = 157)
46 (29.3%)
0
(n = 161)
Complete remission
Tumour size compared with on admission
10 (9.0%)
9 (8.1%)
41 (36.9%)
46 (41.4%)
5 (4.5%)
(n =111)
9 months
6 (6.9%)
4 (4.6%)
44 (50.6%)
27 (31.0%)
6 (6.9%)
12 months (n = 87)
5 (11.4%)
2 (4.5%)
21 (47.7%)
16 (36.4%)
0
(n =44)
15 months
Table 7 Assessment of remission in patients receiving 3.75 or 7.5 mg leuprorelin acetate given subcutaneously or intramuscularly once a month for 1-15 months as monotherapy or in combination with 250 mg flutamide given orally three times daily
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W. Bischoff, German Leuprorelin Study Group
Normal testosterone levels in men aged 45 years or less range from 360 to 990 ng/dl and from 250 to 750 ng/dl in older men. The average serum testosterone concentration in the present study before therapy was 360 ng/dl, which is similar to the concentration of 370.6 ng/dl reported by Seely et al. II Serum testosterone concentrations fell to 17 ng/dl after 4 weeks and to 15 ng/dl after 6 months' treatment with 7.5 mg leuprorelin acetate depot given intramuscularly, which corresponds to findings of the present study in which testosterone concentrations fell to 21 ng/dl after 4 weeks and 17 ng/dl after 6 months. A similar effect of leuprorelin acetate has also been reported in the case of serum follicle stimulating hormone and luteinizing hormone concentrations." Lower serum testosterone concentrations were achieved after intramuscular injections of 7.5 mg leuprorelin acetate depot given once monthly compared with levels occurring following daily subcutaneous injections of 1 mg leuprorelin." This observation, however, was not clinically relevant since all testosterone concentrations recorded were below the castration level, but it is important to note that if an injection was delayed by 2 weeks or more serum testosterone concentrations increased significant!y .II In the present study, the overall 'no progression' rate (complete remission plus partial remission plus stable disease) was 88.5% and rates for patients with Tl - T2 disease and T2 - T3 disease were 88.2% and 88.5%, respectively, which compare with a rate of 81% reported by Seely et al. 11 using 7.5 mg leuprorelin acetate depot given intramuscularly once monthly and a rate of 86% using 1 mg/day leuprorelin acetate given subcutaneously. I I Crawford? found a rate of 78% in patients treated with leuprorelin acetate depot alone and a rate of 82% in patients treated with leuprorelin acetate depot plus 250 mg flutamide, which was administered during the initial phase of
therapy to reduce the degree offlare-up and pain. The severity and nature of the sideeffects occurring in the present study were similar to those reported in other studies. 6, 8 These figures compare favourably with the 13% incidence reported following the administration of 3 mg/day diethylstilboestrol. 6 Microencapsulated leuprorelin acetate depot was shown to be released constantly into serum for 4 weeks after intramuscular injection. The ease of preparation of the depot suspension and its mode of administration increased the compliance by both the patients and the medical staff, resulting in long-term suppression of serum sex hormone concentrations. Although no curative treatment for advanced prostatic cancer has yet been found," leuprorelin acetate depot offers an important alternative to orchidectomy and is superior to oestrogens for the treatment of advanced prostatic cancer. REFERENCES 1. Becker H: Endokrinologie und antiandrogene Therapie. In: Therapie. des fortgeschrittenen Prostatakarzinoms (Altwein JE; Bartsch G, eds). Frankfurt: Perimed Verlag, 1989; pp 32 - 39. 2. Altwein JE: Das fortgeschritteneProstatakarzinom. In: Therapie des .fortgeschrittenen Prostatakarzinoms (AltweinJE, Bartsch G, eds). Frankfurt: Perimed Verlag, 1989; pp 1 - 26. 3. Huggins C, HodgesCV: Studies on prostatic cancer. I. The effect of castration, of oestrogen and of androgen injection on' serum phosphatase in metastatic carcinoma of the prostate. Cancer Res 1941: 1: 293 - 297. 4. Eisenberger MA, O'Dwyer AJ,Friedman MA: Gonadotropin hormone releasing hormone analogues: a new therapeutic 'approach for prostatic carinorna, J Clin Onco11986; 4: 414 - 424. 5. Leuprolide Study Group: Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N EnglJ Med 1984; 311: 1281-1286. 6. Garnick MB: Leuprorelide versus diethylstilbestrol for previously untreated stage D2 prostate cancer: result of a prospectively randomized trial - an update. In:' New Hormonal Treatments for Prostatic Cancer. . Current'Status and New Developments with Emphasis.on-the LHRH-Analogues (Garnick MR, ed.):Kyoto: TAP'Phannaceuticals, 1985; ppI? ~ 20.
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Leuprorelin acetate depot in advanced prostatic cancer 7. Crawford ED: Der zeitige Konzepte in der Behandlung des fortgeschrittenen Prostatakarzinoms und Zwischenbericht tiber die Phase III Studie Leuprorelin 'plus Placebo versus Leuprorelin pills Flutamid der South Western Oncology Group 8494. In: Therapie des fortgeschrittenen Prostatakarzinoms (Altwein JE, Bartsch G, eds), Frankfurt: Perimed Verlag, 1989;pp46-65. 8. O'BrienA,OliverRID,ManAM,etal: Aphase II trial of depot leuprorelin acetate TAP-I44-SR in patients with advanced prostatic carcinoma. Sixth Mediterranean Congress on Chemotherapy. Taormina. 22-27 May 1988. 9. International Union Against Cancer: TMN Classification of Malignant Tumours, 4th edn (Hernmanek P; Sobin LH, eds). New York:
Springer Verlag, 1987. 10. KriigerH, Dorsan J, Mohring K: Leuprolide (TAP 144 SR) versus Zoladex: a comparison of a hormonal profile of two LHRH depot formulations. International Symposium on GnRH Analogues in Cancer and Human Reproduction. Vol. I, Suppl. 2: Park Ridge: Parthenon, 1988; p lB. II. Seely JH, Swanson U, Brauneller R. et al: Clinical studies of leuprolide, depot formation, in metastatic prostatic cancer. International Symposium on GnRH Analogues in Cancer and Human Reproduction, Vol I, Suppl, 2: Park Ridge: Parthenon 1988; p 1-14. 12. ByarDP: VACURG studies of conservative treatment. Scand J Urol Nephrol 1980; 55 (suppl): 99-102.
113
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3.75 and 7.5 mg Leuprorelin Acetate Depot in the Treatment of Advanced Prostatic Cancer: Preliminary Report W. Bischoff and German Leuprorelin Study Group Backnang, FRG
In an on-going, non-comparative, open, multicentre phase III study in Germany, 190 patients with advanced prostatic cancer were treated with 3.75 or 7.5 mg leuprorelin acetate depot given subcutaneously or intramuscularly once monthly, with or without concomitant antiandrogen or cytostatic therapy. The two doses and the different routes of administration did not have any significant effects on serum testosterone, dihydrotestosterone, follicle stimulating hormone and luteinizing hormone concentrations, tumour activity or clinical tolerance. Using either dose, the 'no progression' rate (complete remission plus partial remission plus stable disease) was 88.5% overall and was 88.2% in Tl- T2 disease and 82.5% in T3 - T4 disease after 12 months' treatment. It is concluded that the depot formulation of leuprorelin acetate offers an important alternative in the treatment of advanced prostatic cancer. Patients (190) souffrant d'un cancer prostatique ont He evalues dans Ie cadre d'une etude multicentrique, non comparative de phase III se poursuivant encore a ce jour, lors de laquelle ll leur a ete administre 3,75 ou 7,5 mg d'acetate de Ieuprorellne sous forme retard par injection sous-cutanee ou intramusculaire une fois par mois avec ou sans traitement cytostatique ou antiandrogene concomitant. Les deux posologies et voies d'administration differentes n'ont pas eu d'etTet significatif sur les concentrations plasmatiques en hormones luteinisantes, en hormones de stimulation des follicules, en dihydrotestosterone et en testosterone sur I'activite de la tumeur ou la tolerance clinique. Par I'utilisation de I'une ou de I'autre posologie, Ie taux de 'non-progression' (remission totale, plus remission partielle, plus
Address for correspondence: Prof. Dr med W. Bischoff, Urologe, Ed-Breuningerstrasse 3, 7150 Backnang, FRO. © Copyright 1990 by Cambridge Medical Publications Ltd
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103
W. Bischoff, German Leuprorelin Study Group
stabilisation de la maladie) etait globalement de 88,5 % et de 88,2 % dans une maladie au stade Tl - T2 et de 82,5 % dans une maladie au stade T3 - T4 apres 12 mois de traitement. II en a ete conclu que la formulation d'acetate de leuproreline retard representait une alternative a considerer dans Ie traitement du cancer avance de la prostate. In uno studio ancord in corso, non comparativo, aperto, policentrico, fase III, 190 pazienti con cancro prostatico avanzato sono stati trattati con 3,75 0 7,5 mg di leuprorelin acetato, in preparazione 'ritardo', somministrato per via sottocutanea od intramuscolare, una volta al mese, con 0 senza concomitante terapia antiandrogena 0 citostatica. I due dosaggi e Ie differenti vie di somministrazione non hanno avuto alcun effetto significativo sulle concentrazioni seriche di testosterone, diidrotestosterone, ormone follicolostimolante ed ormone luteinizzante, sull'attivlta tumorale 0 sulla tolleranza clinica. Adottando I'uno o l'altro dosaggio, la percentuale di casi di 'non peggioramento' (completa remissione, pin parziale remissione, pin stabilizzazione della malattia) e risultata pari ad 88,5% complessiva ed e stata di 88,2% negli stadi Tl - T2 e di 82,5% negli stadi T3 - T4, dopo un trattamento di 12 mesi. Si conclude che la formulazione 'ritardo' del leuprorelin acetato costituisce un'importante alternativa nel trattamento del cancro prostatico in fase avanzata.
KEY WORDS:
Leuprorelin acetate depot; hormonal effects; flutamide; prostatic cancer.
INTRODUCTION
T
he choice of procedure for the treatment of prostatic cancer should be based on histological evidence of the cancer and tumour staging. I The aim of hormonal therapy is to prevent the effector hormone from making contact with the target cell or to reduce or prevent the binding of the effector hormone to the intracellular receptor system," Since 1941, when Huggins and Hodges! showed that prostatic cancer was androgen-dependent, various methods of hormonal manipulation have been attempted in patients with metastatic disease to suppress testosterone production and, con-
Enanton" is a registered tradename of Takeda Pharrna GmbH, Stolberg, FRG.
sequently, inhibit androgen-dependent tumour growth:" for example, androgen deprivation has been achieved by the systemic administration of luteinizing hormone releasing hormone analogues such as leuprorelin.' - 8 The aim of the present study was to evaluate the clinical efficacy of 3.75 and 7.5 mg leuprorelin acetate depot (Enanton") given either subcutaneously or intramuscularly once monthly. PATIENTS AND METHODS
Patients A total of 190 patients (mean age ± SD 72 ± 9 years, mean height ± SD 172 ± 6 em, mean body weight ± SD 73 ± 9 kg) with prostatic cancer were included in the study; no patient had previously received specific hormone therapy but transurethral
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Leuprorelin acetate depot in advanced prostatic cancer
resection had been performed for stage Tl patients. Tumour staging and grading of patients included in the study are summarized in Table 1.
Table 2 Leuprorelin acetate depot dosesand routes of administration in the treatment of patients with prostatic cancer
Treatment Patients received 3.75 or 7.5 mg leuprorelin acetate depot given once monthly subcutaneously or intramuscularly for up to 15 months (Table 2). Some patients received besides leuprorelin acetate other antitumour drugs: 15 patients received concomitant 50 mg cyproterone acetate twice daily; 65 patients received 250 mg flutamide three times daily; and four patients received cytostatic agents (epirubicin or estramustine phosphate).
Dose (mg)
Route of administration
No. of patients
3.75 7.5 7.5
Subcutaneous Subcutaneous Intramuscular
157 (82.8%) 23 (12.1%) 10 (5.3%)
Table 1 Classification of prostatic cancers in190 patients before undergoingtreatment with 3.75 or 7.5 mgleuprorelin acetate depot Classification Grading Gl
G2 G3
G4 Not available Primary tumour Tl T2 T3
T4
No. of patients 21 (11.l%) 95 (50.0%) 69 (36.3%) 1(0.5%) 4 (2.1%) 10 (5.3%) 49 (25;8%) 77 (40.5%) 54 (28.5%)
Lymph node involvement
NO
N4 Not available
80 (42.1%) 19(10.0%) 24 (12.6%) 10 (5.3%) 6(3.1%) 51 (26.8%)
Metastases MO Ml M2/3 Not available
85 (44.7%) 87 (46;8%) 8 (4.2%) 10(5.2%)
Nl
N2 N3
Clinical assessment The presence of prostatic cancer was confirmed histologically and cytologically and the stage of tumour development was assessed according to European Organization for Research and Treatment of Cancer (EORTC) criteria." Metastasis was located and verified by X-rays, computer tomography or scintigraphy. Patients were clinically examined before and at l-month intervals during treatment and case histories were recorded. Consumption of analgesics and side-effects were noted and general condition was assessed by the World Health Organization performance status. The following laboratory tests were performed before, after 1 month's treatment and thereafter every 3 months: white blood cell, red blood cell and platelet counts; serum creatinine, y-glutamyl transpeptidase (y-GT),glutamic oxalo-acetic transaminase, alkaline phosphatase, acid phosphatase, prostatic acid phosphatase, prostate-specific antigen, luteinizing hormone, follicle stimulating hormone, testosterone and dihydrotestosterone. Statistical analysis In keeping with the study design, descriptive methods only were used to analyse the available material. Inductive methods were considered inappropriate. In accordance with the intent to treat principle, all case reports were included in the analysis. 105
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W. Bischoff, German Leuprorelin Study Group RESULTS
Treatment with leuprorelin acetate depot suppressed plasma testosterone dihydrotestosterone, luteinizing hormone and follicle stimulating hormone concentrations after 1 month or less (Table 3). Similarly, in several cases, serum prostatic acid and alkaline phosphatase, and prostate-specific antigenconcentrations were normalizedafter leuprorelin acetate depot, thus reflecting an inhibition of the active tumour process. Analysis of the different treatment subgroups revealed no difference in the effects of 3.75 mg leuprorelin acetate depot given subcutaneously and 7.5 mg leuprorelin acetate given subcutaneously or intramuscularly. There were no major changes in haematological parameters or in serum creatinine, glutamic oxalo-acetic transaminase or y-GT. Tables 4 - 6 summarize the remission rates in patients treated in monotherapy with 3.75 mg leuprorelin acetate depot given subcutaneously and 7.5 mg leuprorelin acetate given intramuscularly or subcutaneously. In view of the relatively small number of patients treated with 7.5 mg leuprorelin acetate depot, it was not possible to distinguish statistically between the different doses and routes of administration. Overall remission rates are shown in Table 7 for those patients that received concomitant treatment with flutamide. The median survival time of the patients was 25.3 months; 21.9 months for patients with stage Tl- T2 disease and 24.7 months for patients with stage T3 - T4 disease. Before treatment bone pain was reported by 23.7% of patients and soft tissue pain by 6.8%. After 1 month's treatment, the incidence of pain fell to 14.9% and 4.2%, respectively. This was associated with a decline in the consumption of analgesics from 17.0% to 5.9% after treatment for 1 month. Hot flushes were the most frequent
side-effect, being reported by 71 (37.3%) patients, and in four (2.1%) patients treatment was discontinued prematurely due to side-effects. Minor side-effects were reported, such as sweating, headache, weakness of the legs, loss of appetite, circulatory problems and difficulties in sleeping and hyperaesthesia of the mamilla. Local skin reactions to subcutaneous or intramuscular injections were pain, pruritus and local hyperthermia, which occurred in four (2.1%) patients included in the follow-up evaluation. There was no evidence of any correlation between the administered dose or the injection method and any systemic or local side-effects. A total of 29 patients died during the study period. There were no deaths due to leuprorelin acetate. The study was prematurely terminated in 34 patients due to: orchidectomy in eight (4.25%) patients, progression of disease in 22 (11.6%) and side-effects in four (2.1%). DISCUSSION
Luteinizing hormone releasing hormone analogues bring about chemical castration, thus making them effective against hormonedependent prostatic cancer. 5•IO, 11 An alternative treatment involves the use of oestrogens but the latter compounds have a higher incidence of cardiovascular side-effects 12 and gynaecomastia. The other alternative is orchidectomy, which can have cosmetic and psychological side-effects, as well as the risks arising from surgery, although the hormonal effects and clinical benefits of chemical and surgical castration are virtually identical." There were no differences reported for the overall clinical efficacy of 3.75 mg compared with 7.5 mg leuprorelin acetate depot given subcutaneously or intramuscularly once monthly (52% compared with 62.2%). No significant kinetic differences were found between the modes of application.
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0
-
-...I
Patient numbers are shown in parentheses.
5.1
(33)
18
(23) 4.5
4.9
(55)
15
5.0
20
12
(72)
5.7
(95)
19
9
(30)
(71)
(87)
5.3 (113) 4.9
(92)
6.2
17 (127)
6
4.5 (119)
(71)
6.8 (100)
16 (134)
3
2.7 (117)
7.3 (152)
(133)
47 8.9 (108)
360 (159)
0
21 (137)
Testosterone (ng/dl)
Time (month)
Follicle stimulating hormone (lUll)
Dlhydrotestosterone (ng/dl)
0.5
0.5
0.5
(30)
(71)
(87)
0.5 (113)
0.5 (118)
0.7 (117)
4.9 (154)
Luteinizing hormone (lUll)
1.0 (19)
0.8 (42)
1.1 (56)
1.1 (65)
1.2 (62)
2.5 (69)
4.1 (81)
RIA prostatic specific phosphatase (ng/ml)
1
1
1
123 (113) 122 120
(80) (60) (33)
(42)
(80)
138 (152)
136 (156)
2 (110) (97)
130 (156)
9 (100)
2
128 (181)
5.3
5.9
5.8
(34)
(67)
(89)
6.6 (132)
7.0 (134)
6.4 (134)
7.4 (155)
Alkaline Acid phosphatase phosphatase (lUll) (lUll)
36 (140)
RIA prostatespecific antigen (mg/dl)
Table 3 Mean serum hormones, prostatic phosphatase, prostate-specific antigen, and alkaline and acid phosphatase concentrations before and during treatment with 3.75 or 7.5 mg leuprorelin acetate depot given subcutaneously or intramuscularly once a month for 1-15 months
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27 (26.7%) 62 (61.4%) 2 (2.0%) 10 (9.9%)
14 (13.6%)
80 (77.7%)
3 (2.9%)
6 (5.8%)
Partial remission
Stable disease
Progression
Not available
0
3 months (n = 101)
0
1 month (n ::; 103)
Complete remission
Tumour size compared with on admission
7 (7.5%)
1 (l.l%)
45 (48.4%)
39 (41.9%)
I (l.l%)
6 months (n = 93)
7 (9.2%)
2 (2.6%)
32 (42.1%)
:32 (42.1%)
3 (3.9%)
(n::; 76)
9 months
4 (6.6%)
2 (3.3%)
31 (50.8%)
21 (34.4%)
3 (4.9%)
12 months (n = 61)
4 (ll.l%)
2 (5.6%)
18 (50.0%)
12 (33.3%)
0
15 months (n = 36)
Table 4 Assessment of remission in patients with Tl- T21T3- T4prostatic cancers receiving 3.75 or 7.5 mg leuprorelin acetate depot given subcutaneously or intramuscularly once a month for 1 - 15 months
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'0
-
0 1 (2.5%)
Progression
Not available
32 (80.0%)
7 (17.5%)
Partial remission
Stable disease
0
1 month (n = 40)
Complete remission
Tumour size compared with on admission
0 1 (2.6%)
1(2.5%)
22 (57.9%)
14 (36.8%)
1 (2.6%)
6 months (n = 38)
0
26 (66.7%)
12 (30.8%)
0
3 months (n = 39)
0
0
16 (55.2%)
1 (4.0%)
0
16 (64.0%)
7 (28.0%)
1 (4.0%)
2 (6.9%) 11 (37.9%)
i2 months (il = 25)
9 months (n = 29)
1 (6.7%)
0
8 (53.3%)
6 (40.0%)
0
15 months (n = 15)
Table 5 Assessment of remission in patients with Tl - T2 prostatic cancer receiving 3.75 or 7.5 mg leuprorelin acetate given subcutaneously or intramuscularly once a month for 15 months
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7 (11.1%)
Partial remission
3 (4.8%)
5 (7.9%)
Progression
Not available
48 (76.2%)
0
Complete remission
Stable disease
1 month (n =63)
Tumour size compared with on admission
9 (14.5%)
2 (3.2%)
36 (58.1%)
15 (24.2%)
0
3 months (n =62)
6 (10.9%)
1(1.8%)
23 (41.8%)
25 (45.5%)
0
6 months (n =55)
3 (8.3%)
2 (5.6%)
2 (4.3%) 7 (14.9%)
15 (41.7%)
16 (34.0%)
21 (44.7%)
14 (38.9%)
2 (5.6%)
=47)
1 (2.1 %)
(n
12 months (n =36)
9 months
3 (14.2%)
2 (9.5%)
10 (47.6%)
6 (28.6%)
0
15 months (n =21)
Table 6 Assessment of remission in patients with T3 - T4 carcinomas receiving 3.75 or 7.5 mg leuprorelin acetate given subcutaneously or intramuscularly once a month for 1 - 15 months
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1 month
6 (3.8%) 13 (8.3%)
3 (1.9%) 9 (5.6%)
Progression
Not available
10 (6.9%)
5 (3.5%)
64 (44.4%)
92 (58.6%)
Stable disease 126 (78.3%)
3 (2.1%)
6 months (n = 144)
62 (43.1%)
23 (14.3%)
Partial remission
0
3 months (n = 157)
46 (29.3%)
0
(n = 161)
Complete remission
Tumour size compared with on admission
10 (9.0%)
9 (8.1%)
41 (36.9%)
46 (41.4%)
5 (4.5%)
(n =111)
9 months
6 (6.9%)
4 (4.6%)
44 (50.6%)
27 (31.0%)
6 (6.9%)
12 months (n = 87)
5 (11.4%)
2 (4.5%)
21 (47.7%)
16 (36.4%)
0
(n =44)
15 months
Table 7 Assessment of remission in patients receiving 3.75 or 7.5 mg leuprorelin acetate given subcutaneously or intramuscularly once a month for 1-15 months as monotherapy or in combination with 250 mg flutamide given orally three times daily
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W. Bischoff, German Leuprorelin Study Group
Normal testosterone levels in men aged 45 years or less range from 360 to 990 ng/dl and from 250 to 750 ng/dl in older men. The average serum testosterone concentration in the present study before therapy was 360 ng/dl, which is similar to the concentration of 370.6 ng/dl reported by Seely et al. II Serum testosterone concentrations fell to 17 ng/dl after 4 weeks and to 15 ng/dl after 6 months' treatment with 7.5 mg leuprorelin acetate depot given intramuscularly, which corresponds to findings of the present study in which testosterone concentrations fell to 21 ng/dl after 4 weeks and 17 ng/dl after 6 months. A similar effect of leuprorelin acetate has also been reported in the case of serum follicle stimulating hormone and luteinizing hormone concentrations." Lower serum testosterone concentrations were achieved after intramuscular injections of 7.5 mg leuprorelin acetate depot given once monthly compared with levels occurring following daily subcutaneous injections of 1 mg leuprorelin." This observation, however, was not clinically relevant since all testosterone concentrations recorded were below the castration level, but it is important to note that if an injection was delayed by 2 weeks or more serum testosterone concentrations increased significant!y .II In the present study, the overall 'no progression' rate (complete remission plus partial remission plus stable disease) was 88.5% and rates for patients with Tl - T2 disease and T2 - T3 disease were 88.2% and 88.5%, respectively, which compare with a rate of 81% reported by Seely et al. 11 using 7.5 mg leuprorelin acetate depot given intramuscularly once monthly and a rate of 86% using 1 mg/day leuprorelin acetate given subcutaneously. I I Crawford? found a rate of 78% in patients treated with leuprorelin acetate depot alone and a rate of 82% in patients treated with leuprorelin acetate depot plus 250 mg flutamide, which was administered during the initial phase of
therapy to reduce the degree offlare-up and pain. The severity and nature of the sideeffects occurring in the present study were similar to those reported in other studies. 6, 8 These figures compare favourably with the 13% incidence reported following the administration of 3 mg/day diethylstilboestrol. 6 Microencapsulated leuprorelin acetate depot was shown to be released constantly into serum for 4 weeks after intramuscular injection. The ease of preparation of the depot suspension and its mode of administration increased the compliance by both the patients and the medical staff, resulting in long-term suppression of serum sex hormone concentrations. Although no curative treatment for advanced prostatic cancer has yet been found," leuprorelin acetate depot offers an important alternative to orchidectomy and is superior to oestrogens for the treatment of advanced prostatic cancer. REFERENCES 1. Becker H: Endokrinologie und antiandrogene Therapie. In: Therapie. des fortgeschrittenen Prostatakarzinoms (Altwein JE; Bartsch G, eds). Frankfurt: Perimed Verlag, 1989; pp 32 - 39. 2. Altwein JE: Das fortgeschritteneProstatakarzinom. In: Therapie des .fortgeschrittenen Prostatakarzinoms (AltweinJE, Bartsch G, eds). Frankfurt: Perimed Verlag, 1989; pp 1 - 26. 3. Huggins C, HodgesCV: Studies on prostatic cancer. I. The effect of castration, of oestrogen and of androgen injection on' serum phosphatase in metastatic carcinoma of the prostate. Cancer Res 1941: 1: 293 - 297. 4. Eisenberger MA, O'Dwyer AJ,Friedman MA: Gonadotropin hormone releasing hormone analogues: a new therapeutic 'approach for prostatic carinorna, J Clin Onco11986; 4: 414 - 424. 5. Leuprolide Study Group: Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N EnglJ Med 1984; 311: 1281-1286. 6. Garnick MB: Leuprorelide versus diethylstilbestrol for previously untreated stage D2 prostate cancer: result of a prospectively randomized trial - an update. In:' New Hormonal Treatments for Prostatic Cancer. . Current'Status and New Developments with Emphasis.on-the LHRH-Analogues (Garnick MR, ed.):Kyoto: TAP'Phannaceuticals, 1985; ppI? ~ 20.
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Leuprorelin acetate depot in advanced prostatic cancer 7. Crawford ED: Der zeitige Konzepte in der Behandlung des fortgeschrittenen Prostatakarzinoms und Zwischenbericht tiber die Phase III Studie Leuprorelin 'plus Placebo versus Leuprorelin pills Flutamid der South Western Oncology Group 8494. In: Therapie des fortgeschrittenen Prostatakarzinoms (Altwein JE, Bartsch G, eds), Frankfurt: Perimed Verlag, 1989;pp46-65. 8. O'BrienA,OliverRID,ManAM,etal: Aphase II trial of depot leuprorelin acetate TAP-I44-SR in patients with advanced prostatic carcinoma. Sixth Mediterranean Congress on Chemotherapy. Taormina. 22-27 May 1988. 9. International Union Against Cancer: TMN Classification of Malignant Tumours, 4th edn (Hernmanek P; Sobin LH, eds). New York:
Springer Verlag, 1987. 10. KriigerH, Dorsan J, Mohring K: Leuprolide (TAP 144 SR) versus Zoladex: a comparison of a hormonal profile of two LHRH depot formulations. International Symposium on GnRH Analogues in Cancer and Human Reproduction. Vol. I, Suppl. 2: Park Ridge: Parthenon, 1988; p lB. II. Seely JH, Swanson U, Brauneller R. et al: Clinical studies of leuprolide, depot formation, in metastatic prostatic cancer. International Symposium on GnRH Analogues in Cancer and Human Reproduction, Vol I, Suppl, 2: Park Ridge: Parthenon 1988; p 1-14. 12. ByarDP: VACURG studies of conservative treatment. Scand J Urol Nephrol 1980; 55 (suppl): 99-102.
113
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