The Journal of International Medical Research 1990; 18(suppl 1): 114 - 125
Leuprorelin Acetate Depot in Advanced Prostatic Cancer: a Phase II Multicentre Trial M. Rizzo" T. Mazzei", E. MinP, R. Bartoletti' and P. Periti" JInstitute ofUrology , University ofFlorence, Italy .. 2Department of Preclinical and Clinical Pharmacology, University of Florence, Italy
The therapeutic efficacy and safety of various doses of leuprorelin acetate depot were determined in an open, multicentre study of patients with locally advanced or metastatic prostatic cancer (stages C, 01 or 02). Patients were randomly assigned to receive 3.75 mg (30 cases), 7.5 mg (eight cases), 15 mg (eight cases) and 30 mg (one patient) leuprorelin acetate depot administered subcutaneously once every 4 weeks. Of the 43 patients evaluable, two (5%) had complete remission, 23 (53%) partial remission and 13 (30%) patients stable disease. No significant differences were observed in response rates in relation to dose, disease stage or previous hormonal therapy. Disappearance or improvement in bone pain and urinary symptoms occurred in 63 % and 79% of cases, respectively. Serum androgen concentrations decreased rapidly and persistently to castration levels, without significant differences for different doses. Treatment was well tolerated with a low incidence of mild side-effects - gynaecomastia (16%), nausea/vomiting (13%) and diarrhoea (2%). It is concluded that 3.75 mg leuprorelin acetate depot given subcutaneously once every 4 weeks is able to produce hormonal effects in all patients, an overall objective response comparable to that obtained using higher doses. On a precede ala determination de Pefflcaeite therapeutlque et de l'Innocuite de diverses doses d'acetate de leuproreline retard dans Ie cadre d'une etude ouverte, multicentrique portant sur des patients atteints du carcinome prostatique metastatique ou avance localement (stade C, 01 ou 02). On a administre aux patients un traitement consistant en acetate de Ieuprorellne retard aux doses de 3,75 mg (30
Address for correspondence: Dr P. Periti, Dipattimento di Fannacologia Preclinica e Clinica, Universita degIi Studi, Viale G.B. Morgagni 65, 50134 Florence, Italy.
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Phase II multicentre trial
cas), 7,5 mg (huit cas), 15 mg (huit cas) et 30 mg (un patient) reparties de facon aleatoire. Ce traitement a ete administre par voie souscutanee une fois toutes les 4 semaines. Sur les 43 malades evalues, on a pu noter une remission complete chez 2 malades (5 %), une remission partielle chez 23 malades (53 %) et une stabilisation de la maladie chez 13 malades (30 %). II n'a pas ete observe de difference significative dans les taux de reponse par rapport a la dose, au stade de la maladie ou a la theraple hormonale precedente. Une disparition ou une amelioration des douleurs osseuses et des symptomes urinaires est survenue dans 63 % et 79 % des casrespectivement. Les concentrations plasmatiques en androgenes ont diminue rapidement et de fa~on persistante jusqu'a des niveaux de castration sans qu'on ait pu noter de difference significative entre les diverses doses administrees, Le traitement a ete bien tolere avec une basse incidence d'effets secondaires benins gynecomastle (16 %), nausees/vomissements (13 %) et diarrhees (2 %). On en a conelu que l'acetate de leuproreline sous forme retard, a une dose de 3,75 mg et administre par injection sous-cutanee une fois toutes les 4 semaines etait capable de produire chute hormonale chez tous les patients, une reponse objective globale chez 58 % et une stabilisation du cancer prostatique chez 30 % des patients. In uno studio aperto multicentrico in pazienti affetti da carcinoma prostatico in stadio avanzato 0 metastatico (C, Dl 0 D2) e stata indagata I'efficacia terapeutica e la tollerabilita di differenti dosi di leuprorelin acetato in formulazione 'ritardo'. I pazienti sono stati assegnati in modo random ai diversi trattamenti che prevedevano dosi di 3.75 mg (30 casi), 7.5 mg (otto casi), 15 mg (otto casi) e 30 mg (uno caso) di leuprorelin acetato somministrate per via sottocutanea una volta ogni 4 settimane. Dei 43 pazienti valutabili, due (5%) presentarono remissione completa, 23 (53%) remissione parziale e 13 (30%) stabilizzazione della malattia. Non sono state riscontrate differenze significative nelle percentuali di risposta rispetto alia diversita delle dosi, degli stadi della malattia e alia eventuale pregressa terapia ormonale. E' stata registrata la ocomparsa 0 comunque la regressione del dolore osseo e dei sintomi urinari rispettivamente nel 63% e nel 79% dei casi. Le concentrazioni seriche di androgeni sono dimunuite rapidamente e stabilmente verso i livelli di castrazione senza differenze significative tra Ie varie dosi impiegate. II trattamento e stato ben tollerato con una bassa incidenza di effetti collaterali di lieve entita: ginecomastia (16%), nausea e vomito (13%), diarrea (2%). In conelusione iI trattamento con leuprorelin acetato 'ritardo' somministrato per via sottecutanea una volta ogni 4 settimane e in grado di produrre effetti sui livelli ormonali in tutti i pazienti con una risposta oggettiva generale nel 58% ed una stabilizzazione della malattia nel 30% dei casi. KEY WORDS: Leuprorelin acetate; depot formulation; prostatic cancer; serum androgen concentrations
l1S
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M. Rizzo, T. Mazzei, E. Mini et al. INTRODUCTION
he androgen dependence of most prostatic cancers has been well established since 1941when Huggins and Hodges showed the effect of castration or oestrogen treatment on serum phosphatases during metastatic disease and initiated the era of hormonal therapy for prostatic cancer. I Bilateral orchidectomy or oestrogen therapy (diethylstilboestrol) has been the most frequently used hormonal treatment, both resulting in temporary remission in most cases.v 3 The negative psychological impact of castration and the relevant and frequent adverse effects of long-term oestrogen therapy, however, have led to a search for alternative ways of inducing androgen suppression by the use of antiandrogens or luteinizing hormone releasing hormone analogues. These analogues, by virtue of their agonistic - antagonistic properties, induce an increase in circulating gonadotrophin concentrations and consequently of serum testosterone at the beginning of treatment, followed by a paradoxical effect due to pituitary inhibition and a decrease in luteinizing hormone and follicle stimulating hormone concentrations to below normal (down-regulation). As a consequence, testicular function is suppressed and serum testosterone concentrations fall to values characteristic of castration.v" Leuprorelin, which is 15 - 50 times more active than endogenous luteinizing hormone releasing hormone, is thus defined as a superagonist analogue of the physiological hypothalamic decapeptide and has been used as a method of inducing chemical castration in metastatic prostatic cancer patients. Leuprorelin has been successfully given on a daily basis by subcutaneous injection7,8 but this type of treatment tends to be unacceptable in the long term, mostly because of poor patient compliance. To overcome this problem, an injectable depot formulation of leuprorelin acetate (TAP-
T
144-SR) has been developed in which the analogue is contained within a biodegradable and biocompatible poly-Ina-lactic acid! glycolic acid) copolymer, which can deliver the drug over a period of approximately 4 weeks. In the multicentre study reported here, the therapeutic efficacy and safety of various doses ofleuprorelin acetate depot given subcutaneously were evaluated in patients with locally advanced or metastatic prostatic cancer. PATIENTS AND METHODS
Patients Patients with histologically and/or cytologically diagnosed adenocarcinoma of the prostate (stages C, 01 or 02), based on the American Cancer Society classification," were entered into the study. Disease was measurable or evaluable for at least two of the following features: periprostatic lesions; osteoblastic lesions; osteolytic lesions; elevation of serum acid and/or alkaline phosphatase; obstructive uropathy (secondary to disease); pulmonary metastases; hepatic metastases; objective involvement of tissues, e.g. lymph nodes. Patients were accepted in the study if they had a performance status of 3 or less according to the World Health Organization scale; 10 patients with a performance status of 4 were also admitted if this was due exclusively to pain. The patients had been given no previous treatment or had received alternative hormonal therapy (oestrogens, estramustine phosphate or antiandrogens) for more than 1 month, with relapse or resistance to treatment. No patient had undergone orchidectomy. Patients who had previously undergone radiotherapy were only included in the study if evaluable lesions existed in sites that had not been irradiated. The study did not include patients that had brain metastasis, a life expectancy of less than 3months, anotherneoplasm (except skin neoplasms, other than melanoma) or
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Phase II multicentre trial
severe concomitant illness (renal, hepatic, cardiovascular or neuropsychiatric disorders). Patients who were older than 75 years were also excluded, except if their performance status was rated 2 or less. A total of 47 patients with advanced prostatic cancer entered the study (Table I). Metastatic disease was present (two
stage D I and 43 stage D2) and two patients had extensive locally invasive disease extending throughout the prostatic capsule (stage C). Of these 47 patients, 37 (79%) had not previously received hormonal therapy; the remaining patients had received hormonal therapy alone (seven patients) or together with surgery (extracapsularprostat-
Table 1 Characteristics of patients treated with 3.75 - 30 mg leuprorelin acetate depot given subcutaneously once every 4 weeks
Variable No. of patients Treated Evaluable
Group A (3.75 mg)
30 27
Group B (7.5 mg)
8 7
Group C (15 mg)
Group D (30 mg)
8 8
Total
47 43
Age (years) Median Range
68.5 52-86
67 60-82
71.5 53 -79
Performance status Median Range
1 0-3
2 0-3
2 0-4
2
18 1 - 1682
71 1-664
17.5 2-444
10
18 1 - 1682
Disease duration (days) Median Range
61
69 52-86
I
0-4
Previous therapy None Hormonal therapy Surgery Radiotherapy
23 5 4 2
4 4 0 0
6 1 1 1
1 0 0 0
34
Disease stage C Dl D2
2 2 26
0 0 8
0 0 8
0 0 1
2 2 43
30
8
7
26 1 4 0
8 0 0 1
8 2 1 0
Site of disease Prostatel periprostatic tissues Bone Lung Nodes Liver
10
5 3
46 1 0 0 0
43 3 5 1
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M. Rizzo, T. Mazzei, E. Mini et al.
ectomy, two patients), or together with radiotherapy (one patient). Patients' ages ranged between 52 and 86 years (median 69 years) and they had a mean performance status of 1 (range 0 - 4). The median duration of the disease was 18 days (range 1- 1682 days). The majority of patients (91%) were stage D2 before beginning treatment with metastatic disease in bone (92%) and/or soft tissues (98%). Study design and treatment Patients were randomly assigned to receive one of the following doses of leuprorelin acetate depot (Enantone"): 3.75 mg (group A); 7.5 mg (group B); 15 mg (group C); or 30 mg (group D). The drug was supplied in vials containing 3.75, 7.5, 15 or 30 mg lyophilized powder consisting of microspheres ofleuprorelin acetate in poly(o,L-lacticacid/ glycolic acid) copolymer. After the first case had received 30 mg leuprorelin acetate depot, randomization at this dose level was stopped because information from other on-going studies had shown that a dose of 7.5 mg was suffIcient to produce the required hormonal responses.!':" The last cases received the lowest dose following evidence that suggested this dose was sufficient to inhibit completely gonadal steroidogenesis." In all cases, the drug was administered subcutaneously once every 4 weeks until disease progression. Evaluation of disease Before treatment was started the extent of disease was evaluated by blood chemistry, hormone profiles, radionuclide bone scan, liver echo scan, and chest and other X-rays. Blood samples for hormonal studies were taken between 8.00 and 10.00 a.m. and sera were stored at -20"C until ana-
Enantone" is the registered trademark of Takeda Italia Farmaceutici SpA.
lysed. Testosterone and dihydrotestosterone were measured by radioimmunoassay after extraction with diethyl ether; the lowest limit of detection was 0.5 nmol/l for testosterone and 0.05 nmol/l for dihydrotestosterone. Commercial kits were used for determining testosterone (Mallinkrodt). Evaluation of therapeutic response Patients underwent clinical examination, including rectal examination, and determination of haematological and biochemical profiles every week for the first month, monthly for the first 3 months and once every 3 months thereafter. Any X-rays or scans that were positive at the beginning of the therapy were repeated after the first 3 months and every 3 months thereafter. Bone scan was performed every 6 months if negative before treatment. Tumour response to therapy was assessed based on the criteria of the National Prostatic Cancer Project. 15 Complete response was defmed as disappearance of all signs and symptoms of the disease for at least 1 month. Partial response was defmed as: a reduction by more than 50% in the dimension of the prostate or localization of soft tissues or of viscera when present; return to normal acid phosphatase concentrations, if initially elevated; recalcification of one or more of the osteolytic lesions, if present; and disappearance of one or more of the osteoblastic lesions and thickening of mixed localization. Progression was defined as an increase in any previously measurable lesion by more than 25% or the appearance of new lesions. Any increase in acid or alkaline phosphatase alone was not considered to be an indication of progression. Stable disease was classified as any other situation not by complete or partial response or progression. Evaluation of pain and urinary symptoms was carried out at the beginning of treatment and at weekly intervals thereafter for the first month of therapy, monthly until
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Phase II multicentre trial 3 months and then every 3 months. Pain was classified according to its severity and frequency, type of analgesia used and frequency of itsuse. Urinary symptoms (dysuria and retention) were classified as: grade ,I, mild; grade 2, moderate; grade 3, substantial; or grade 4, severe. Subjective responses for urinary symptoms were defmed as: disappearance of pain and urinary pain together with symptoms; improvement, scores being improved for 1month or more; no change; or worse. The date for the first evaluation of efficacy was the end of the third month of therapy. Treatment was interrupted in the first month only in those cases in which severe adverse effects to the drug or early disease progression were observed. Tolerability Side-effects were evaluated at weekly intervals during the first month, monthly for the first 3 months and every 3 months thereafter. The parameters used to quantify tolerability varied in relation to type of side-effect. Gastro-intestinal effects (nausea/vomiting and diarrhoea) were classified as: grade 1, mild; grade 2, moderate; or grade 3, severe. Hot flushes were defined as: grade 1, tolerable; or grade 2, severe. Effects on libido were described as: grade 1, a decrease; or grade 2, a loss. Effects on impotence were classified as: grade 1, impotence; grade 2, partial or complete.
Statistical analysis Statistical analysis was performed using Fisher's exact test and the ie-test. RESULTS Therapeutic response A total of 43 of the 47 (91%) patients treated were evaluable for therapeutic response: 27 patients in group A; seven in group B; eight in group C; and one patient in group D. The responses as a function of disease stage are reported in Table 2. Overall, two (5%) patients experienced complete remission, 23 (53%) partial remission, 13 (30%) stable disease and five (12%) had disease progression. The median duration of complete remission was 14.5 weeks (range 643 weeks), that of partial remission 15 weeks (range 3 - 27 weeks) and that of stable disease was 8 weeks (range 3 - 23 weeks). No significant differences in the response rates in relation to disease stage were observed. When the response was evaluated in relation to previous hormonal therapy there was a lower incidence of objective remission (complete and partial) in 4/9 (44%) patients who had received oestrogens and/or anti-androgens prior to leuprorelin acetate depot, compared with 21/34 (62%)untreated patients; this difference was not statistically significant (Table 3). It was noted that 25 (66%) patients with bone metastases and only six (16%) of
Table 2 Effects of 3.75 - 30 mg leuprorelin acetate depot given subcutaneously once every 4 weeks on prostatic cancer in relation to disease stage No. of patients Response Complete response Partial response Stable disease Progression Total
C 0 1(50%) 1(50%) 0 2
D1
0 1(50%) 1(50%) 0 2
D2 2(5%) 21(55%) 11(28%) 5(12%) 39
Total 2(5%) 23(53%) 13(30%) 5(12%) 43
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M. Rizzo, T. Mazzei, E. Mini et al.
Table 3 Effect of treatment with 3.75 - 30 mg leuprorelin acetate depot given subcutaneously once every 4 weeks in relation to previous hormonal therapy No. of patients Response
Previous hormonal therapy
Complete response Partial response Stable disease Progression Total
1(11%) 3(33%) 4(44%) 1(11%) 9
No previous therapy
Total 2(5%) 23(53%) 13(30%) 5(12%) 43
1(3%) 20(59%) 9(26%) 4(12%) 34
Table 4 Response to 3.75 - 30 mg leuprorelin acetate depot given subcutaneously once every 4 weeks in relation to site of evaluable disease No. of patients
Response Complete response Partial response Stable disease Progression Total
Prostate/periprostatic tissues
Bone
Liver
2(5%) 4(11%) 31(82%) 1(3%) 38
16(42%) 9(24%) 10(26%) 3(8%) 38
0 0 1 0 1
those with disease localization at primary site and/or periprostate tissues responded partially or completely (Table 4). Remission was also attained in all three patients withevaluable pulmonary metastases (Table 4). Increasing the dose of leuprorelin acetate depot to more than 3.75 mg once every 4 weeks did not significantly increase objective response rate (Table 5). Evaluation of the subjective response in the 16 patients with bone pain at the beginning of treatment showed that eight (50%) of these patients experienced complete disappearance of pain, whereas two (13%) patients reported some improvement, in five (31 %) the pain remained unchanged and in one (6%) it worsened (Table 6). Dysuria
Lung 3(100%) 0 0 0 3
and/or urinary retention disappeared in 21 cases (50%), improved in 12 (29%), remained stable in six (14%) and worsened in three (7%) (Table 7). No significant differences in subjective response rates were observed in relation to drug dose (Tables 6 and 7). Previously untreated patients had mean baseline serum testosterone concentrations of 9.10 ± 6.77 nmol/l, which were higher than those observed in patients who had previously received hormonal therapy (1.62 ± 1.63nmol/l) (Fig. I). Following treatment with leuprorelin acetate depot, mean serum testosterone concentrations fell to castration levels after 3 weeks' treatment and were maintained for the complete duration of treatment.
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Phase II multicentre trial
Table 5 Effect of 3.75- 30 mg leuprorelin acetate depot given subcutaneously once every 4 days on response No. of patients Response Complete response Partial response Stable disease Progression Total
3.75 mg
7.5 mg
15 mg
30 mg
0 14(52%) 9(33%) 4(15%) 27
1(14%) 3(43%) 2(29%) 1(14%) 7
1(12.5%) 5(62.5%) 2(25%) 0 8
0 I 0 0 I
Total 2(5%) 23(53%) 13(30%) 5(12%) 43
Table 6 Subjective response to 3.75 - 15 mg leuprorelin acetate depot given subcutaneously once every 4 weeks in patients (n =16) with bone pain No. of patients Dose (mg)
Disappearance
Improvement
No change
Worse
Total
3.75 7.5 15.0 Total
5(45%) 1(33%) 2(100%) 8(50%)
1(9%) 1(33%) 0 2(13%)
4(36%) 1(33%) 0 5(31%)
1(9%) 0 0 1(6%)
II
3 2 16
Table 7 Subjective response to 3.75 - 30 mg leuprorelin acetate depot given subcutaneously once every 4 weeks in patients (n =42) with urinary symptoms No. of patients Dose (mg) 3.75 7.5 15.0 30.0 Total
Disappearance 14(54%) 3(38%) 4(57%) 0 21(50%)
Improvement 7(27%) 2(25%) 2(29%) 1(100%) 12(29%)
No change
Worse
Total
4(15%) 2(25%) 0 0 6(14%)
1(4%) 1(13%) 1(14%) 0 3(7%)
26 8 7 1 42 121
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M. Rizzo, T. Mazzei, E. Mini et al.
18 • 16
~
No hormonal pretreatment Hormonal pretreatment
14
!
12
8
10
.s'"
8
s 2 "
6
"e
- - -0- -
2
2'"
CIl
4 2
0
0
10
40
30
20
50
Time (weeks)
Fig. 1. Mean serum testosterone concentrations as a function of time following administration of a single dose of 3.75 - 30 mg leuprorelin acetate depot given subcutaneously in patients not previously treated with hormone (n = 34) or pretreated with hormones (n = 4).
3 •
No hormonal pretreatment Hormonal pretreatment
- - -0- -
I
It ~
2 -
-0
s
1\ 1\
CIl
I \
~
1\
o
o L......L o
b-o- Q
.., .0 ...
0--
..,'"
....0. ----1
10
_
---
---l_ _---loi'-=-
20 Time (weeks)
_ _ _ _ _ -0 L.-
30
,
40
Fig. 2. Mean serum dihydrotestosterone concentrations as a function of time following administration of a single dose of 3.75 - 30 mg leuprorelin acetate depot in patients not previously treated with hormone (n = 28) or pretreated with hormones (n = 2).
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Phase II multicentre trial
An increase in serum testosterone concentrations was observed on the second day of treatment but concentrations rapidly declined to baseline values by the seventh day. Disease flare-up did not occur at any time. Serum dihydrotestosterone concentrations in both previously untreated patients and those who had previously received hormonal therapy are shown in Fig. 2. Mean dihydrotestosterone concentrations in previously treated patients diminished to castration levels in the third week of treatment, whereas in pretreated patients the baseline concentrations were already equivalent to castration values. Mean serum alkaline phosphatase concentrations in 34 patients did not show any significant variation according to clinical response. On the contrary, in responding patients and those with stable disease, serum prostatic acid phosphatase levels decreased,reachingthe lowestvalues(1.66 ± 85 and 1.33 ± 0.73 lUll, respectively) in the third month of treatment; enzyme concentrations were then maintained at that level for the rest of the observation period. In three patients in progression, stability of initial values occurred at concentrations higher than the norm (6.6 lUll) and then rose abruptly between the first and second months of treatment.
Tolerability Tolerability was evaluated in all patients. Side-effects observed were impotence (100%), decrease or disappearance of libido (100%), hot flushes (64%), gynaecomastia (16%), nausea/vomiting (13%) and diarrhoea (2%) (Table 8). Hot flushes were tolerable in the majority of cases (72%). Cases of nausea/vomiting and gynaecomastia were almost always mild. The only case of diarrhoea observed was classified as grade 3. No significant changes in blood chemistry were recorded during therapy. A case of nephrotic syndrome was observed, which led to interruption of therapy. It was difficult, however, to attribute this adverse event to treatment with leuprorelin acetate depot. DISCUSSION
Leuprorelin is a luteinizing hormone releasing hormone agonist useful in the treatment of advanced prostatic cancer, being employed to bring about medical castration.7. 8 Depot formulations of the luteinizing hormone releasing hormone agonist represent, with regards to patient compliance and drug availability, an advantage over daily subcutaneous injections or intranasal administration. The present study, which was aimed at
Table 8 Evaluation of side-effects in leuprorelin acetate depot given subcutaneously Grade Side-effects
No. of patients'
1
2
Impotence Decrease of libido Hot flushes Gynaecomastia Nausea/vomiting Diarrhoea
41/41(100%) 41/41(100%) 30/47(64%) 7/44(16%) 6/47(13%) 1/47(2%)
1 1 21 7
40 40 8
3
o
4
1
o
o
'Number of patients with side-effects/total number of patients evaluable.
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M. Rizzo, T. Mazzei, E. Mini et al. evaluating, as a function of dose, the clinical effects of subcutaneously administered leuprorelin acetate depot in patients with advanced prostatic cancer, showed that an overall objective response was obtained in 58% of patients and a stabilization of disease in 30%. An objective response was observed in 16% of evaluable patients with disease in the prostate and periprostatic tissues, and stabilization in 82% evaluable cases. A higher objective response rate (66%) was observed in patients with bone disease. In the case of patients with pulmonary metastases, all three experienced complete remission and one with liver metastases had stabilization. These results, which were obtained in the few cases with visceral metastases, did not allow evaluation of the efficacy of the drug. Disappearance or improvement in bone pain and urinary symptoms occurred in 63% and 79% of cases, respectively. No significant differences between dose levels were noted in terms of objective or subjective response. These data are in agreement with those previously reported for daily subcutaneous administration of leuprorelin7• 8 for monthly doses of leuprorelin acetate depot ranging from 3.75 to 7.5 mg,Il·16 or for other depot luteinizing hormone releasing hormone agonists (goserelin, triptorelin) at similar dosage." 17 Administration of leuprorelin acetate depot subcutaneously once every 4 weeks was sufficient to suppress rapidly (within 3 weeks) and persistently serum androgen concentrations to castration levels, with no substantial differences being noted for the different drug doses. Treatment with leuprorelin acetate depot was well tolerated in the present study but as a consequence of its primary pharmacological action, most of the evaluable patients experienced a reduction or loss of libido, sexual impotence and hot flushes. Gynaecomastia and other side-effects (nausea/vomiting, diarrhoea) were rare and
not dose-related; treatment never had to be withdrawn due to these side-effects. None of the patients experienced infiltration, granulomas or calcifications at injection site. The hormonal and clinical results, therefore, demonstrate that leuprorelin acetate depot at a dose as low as 3.75 mg was able to ensure medical castration, which is necessary for the treatment of advanced prostatic cancer. ACKNOWLEDGEMENTS
Leuprorelin acetate depot Enantone" was kindly provided by Takeda Italia Farmaceutid SpA. REFERENCES 1. Huggins C, Hodges CV: Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941; 1: 293 - 297. 2. Bahnson RR, Catalona WJ: Current management of prostatic carcinoma. Prim Care 1985; 12: 795
-813. 3. Bailar JC, III, Byar DP, The Veterans Administration Cooperative Urological Research Group: Estrogen treatment for cancer of the prostate. Early results with 3 doses of diethylstilbestrol and placebo. Cancer 1970; 26: 257 - 261. 4. De Sy WA, De Meyer JM, Casselman J, et al: A comparative study of a long-acting luteinizing hormone releasing hormone agonist (decapeptyl) and orchiectomy in the treatment of advanced prostatic cancer. Acta Urol Belg 1986; 54: 221 229. 5. Eisenberger MA, O'Dwyer PJ, Friedman MA: Gonadotropin hormone-releasing hormone analog: a new therapeutic approach for prostatic carcinoma. J Clin Onco11986; 4: 414- 424. 6. Gonzales-Barcena 0, Perez-Sanchez P, BereaDominguez H, et al: Persistent blockade of the pituitary - gonadal axis in patients with prostatic carcinoma during chronic administration of 0Trp-6-LH-RH. Prostate 1986; 9: 207 - 215. 7. Leuprolide Study Group: Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N EnglJ Med 1984; 20: 1281-1286. 8. Crawford ED, Eisenberger MA, McLeod DG,et al: A controlled trial ofleuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989; 32 (suppl1): 419- 424. 9. Frank IN: Urologic and male genital cancer. In: Clinical Oncology (Rubin P, ed.). New York:
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Phase II multicentre trial American Cancer Society, 1983. 10. Zubrod CG, Schneidennan MA, Frei E et at: Appraisal ofmethods for the study of chemotherapy in man: comparative therapeutic trial of nitrogen mustard and triethylene thiophosphoramide. J Chronic Dis 1960; 11: 7 - 33. II. Isurugi K, Niijima T, AkazaH, et at: Treatment of prostatic cancer with TAP-I44-SR, a depot preparation ofLH-RH agonist (leuprolide). Sixth Mediterranean Congress of Chemotherapy, Taormina, 22 - 27 May 1988, pp 1237 - 1241. 12. Max 0, Seely J, Swanson L, et al: Clinical studies of leuprolide depot formulation in metastatic prostatic cancer (abstract). International Symposium on GnRH Analogues in Cancer and Human Reproduction, Geneva. 18 - 21 February 1988,
p80. 13. O'Brien A, Oliver RT, Man AM, et al: A phase II trial of depotleuprorelin acetate (TAP-I44-SR) in patients with advanced prostatic cancer (abstract). Sixth Mediterranean Congress ofChemotherapy, Taormina, 22 -27 May 1988, p 69.
14. Mazzei T, Mini E, Rizzo M, et al: Human pharmacokinetic and pharmacodynamic profiles of leuprorelin acetate depot in prostatic cancer patients. J lnt Med Res 1990; \8(suppll): 42 - 56. IS. SchmidtJD, Scott WW, Gibbons R, et al: Chemotherapy programs of the National Prostatic Cancer Project (NPCP). Cancer 1980; 45: 19461973. 16. Seely MD, Swanson L, Browneller R: Clinical studies ofleuprolide depot formulation in metastatic prostatic cancer (abstract). International Symposium on GnRH Analogues in Cancer and Human Reproduction, Geneva, 18-21 February 1988, p SO. 17. Perren Jl, Clayton RN, Blakledge G, et al: Pharmacokinetic and endocrinological parameters of a slow-release depot preparation of the GnRH analogue lei 118630 (Zoladex) compared with a subcutaneous bolus and continuous subcutaneous infusion of the same in patients with prostatic cancer. CancerChemother Pharmacol 1986; 18: 39-43.
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Leuprorelin Acetate Depot in Advanced Prostatic Cancer: a Phase II Multicentre Trial M. Rizzo" T. Mazzei", E. MinP, R. Bartoletti' and P. Periti" JInstitute ofUrology , University ofFlorence, Italy .. 2Department of Preclinical and Clinical Pharmacology, University of Florence, Italy
The therapeutic efficacy and safety of various doses of leuprorelin acetate depot were determined in an open, multicentre study of patients with locally advanced or metastatic prostatic cancer (stages C, 01 or 02). Patients were randomly assigned to receive 3.75 mg (30 cases), 7.5 mg (eight cases), 15 mg (eight cases) and 30 mg (one patient) leuprorelin acetate depot administered subcutaneously once every 4 weeks. Of the 43 patients evaluable, two (5%) had complete remission, 23 (53%) partial remission and 13 (30%) patients stable disease. No significant differences were observed in response rates in relation to dose, disease stage or previous hormonal therapy. Disappearance or improvement in bone pain and urinary symptoms occurred in 63 % and 79% of cases, respectively. Serum androgen concentrations decreased rapidly and persistently to castration levels, without significant differences for different doses. Treatment was well tolerated with a low incidence of mild side-effects - gynaecomastia (16%), nausea/vomiting (13%) and diarrhoea (2%). It is concluded that 3.75 mg leuprorelin acetate depot given subcutaneously once every 4 weeks is able to produce hormonal effects in all patients, an overall objective response comparable to that obtained using higher doses. On a precede ala determination de Pefflcaeite therapeutlque et de l'Innocuite de diverses doses d'acetate de leuproreline retard dans Ie cadre d'une etude ouverte, multicentrique portant sur des patients atteints du carcinome prostatique metastatique ou avance localement (stade C, 01 ou 02). On a administre aux patients un traitement consistant en acetate de Ieuprorellne retard aux doses de 3,75 mg (30
Address for correspondence: Dr P. Periti, Dipattimento di Fannacologia Preclinica e Clinica, Universita degIi Studi, Viale G.B. Morgagni 65, 50134 Florence, Italy.
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Phase II multicentre trial
cas), 7,5 mg (huit cas), 15 mg (huit cas) et 30 mg (un patient) reparties de facon aleatoire. Ce traitement a ete administre par voie souscutanee une fois toutes les 4 semaines. Sur les 43 malades evalues, on a pu noter une remission complete chez 2 malades (5 %), une remission partielle chez 23 malades (53 %) et une stabilisation de la maladie chez 13 malades (30 %). II n'a pas ete observe de difference significative dans les taux de reponse par rapport a la dose, au stade de la maladie ou a la theraple hormonale precedente. Une disparition ou une amelioration des douleurs osseuses et des symptomes urinaires est survenue dans 63 % et 79 % des casrespectivement. Les concentrations plasmatiques en androgenes ont diminue rapidement et de fa~on persistante jusqu'a des niveaux de castration sans qu'on ait pu noter de difference significative entre les diverses doses administrees, Le traitement a ete bien tolere avec une basse incidence d'effets secondaires benins gynecomastle (16 %), nausees/vomissements (13 %) et diarrhees (2 %). On en a conelu que l'acetate de leuproreline sous forme retard, a une dose de 3,75 mg et administre par injection sous-cutanee une fois toutes les 4 semaines etait capable de produire chute hormonale chez tous les patients, une reponse objective globale chez 58 % et une stabilisation du cancer prostatique chez 30 % des patients. In uno studio aperto multicentrico in pazienti affetti da carcinoma prostatico in stadio avanzato 0 metastatico (C, Dl 0 D2) e stata indagata I'efficacia terapeutica e la tollerabilita di differenti dosi di leuprorelin acetato in formulazione 'ritardo'. I pazienti sono stati assegnati in modo random ai diversi trattamenti che prevedevano dosi di 3.75 mg (30 casi), 7.5 mg (otto casi), 15 mg (otto casi) e 30 mg (uno caso) di leuprorelin acetato somministrate per via sottocutanea una volta ogni 4 settimane. Dei 43 pazienti valutabili, due (5%) presentarono remissione completa, 23 (53%) remissione parziale e 13 (30%) stabilizzazione della malattia. Non sono state riscontrate differenze significative nelle percentuali di risposta rispetto alia diversita delle dosi, degli stadi della malattia e alia eventuale pregressa terapia ormonale. E' stata registrata la ocomparsa 0 comunque la regressione del dolore osseo e dei sintomi urinari rispettivamente nel 63% e nel 79% dei casi. Le concentrazioni seriche di androgeni sono dimunuite rapidamente e stabilmente verso i livelli di castrazione senza differenze significative tra Ie varie dosi impiegate. II trattamento e stato ben tollerato con una bassa incidenza di effetti collaterali di lieve entita: ginecomastia (16%), nausea e vomito (13%), diarrea (2%). In conelusione iI trattamento con leuprorelin acetato 'ritardo' somministrato per via sottecutanea una volta ogni 4 settimane e in grado di produrre effetti sui livelli ormonali in tutti i pazienti con una risposta oggettiva generale nel 58% ed una stabilizzazione della malattia nel 30% dei casi. KEY WORDS: Leuprorelin acetate; depot formulation; prostatic cancer; serum androgen concentrations
l1S
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M. Rizzo, T. Mazzei, E. Mini et al. INTRODUCTION
he androgen dependence of most prostatic cancers has been well established since 1941when Huggins and Hodges showed the effect of castration or oestrogen treatment on serum phosphatases during metastatic disease and initiated the era of hormonal therapy for prostatic cancer. I Bilateral orchidectomy or oestrogen therapy (diethylstilboestrol) has been the most frequently used hormonal treatment, both resulting in temporary remission in most cases.v 3 The negative psychological impact of castration and the relevant and frequent adverse effects of long-term oestrogen therapy, however, have led to a search for alternative ways of inducing androgen suppression by the use of antiandrogens or luteinizing hormone releasing hormone analogues. These analogues, by virtue of their agonistic - antagonistic properties, induce an increase in circulating gonadotrophin concentrations and consequently of serum testosterone at the beginning of treatment, followed by a paradoxical effect due to pituitary inhibition and a decrease in luteinizing hormone and follicle stimulating hormone concentrations to below normal (down-regulation). As a consequence, testicular function is suppressed and serum testosterone concentrations fall to values characteristic of castration.v" Leuprorelin, which is 15 - 50 times more active than endogenous luteinizing hormone releasing hormone, is thus defined as a superagonist analogue of the physiological hypothalamic decapeptide and has been used as a method of inducing chemical castration in metastatic prostatic cancer patients. Leuprorelin has been successfully given on a daily basis by subcutaneous injection7,8 but this type of treatment tends to be unacceptable in the long term, mostly because of poor patient compliance. To overcome this problem, an injectable depot formulation of leuprorelin acetate (TAP-
T
144-SR) has been developed in which the analogue is contained within a biodegradable and biocompatible poly-Ina-lactic acid! glycolic acid) copolymer, which can deliver the drug over a period of approximately 4 weeks. In the multicentre study reported here, the therapeutic efficacy and safety of various doses ofleuprorelin acetate depot given subcutaneously were evaluated in patients with locally advanced or metastatic prostatic cancer. PATIENTS AND METHODS
Patients Patients with histologically and/or cytologically diagnosed adenocarcinoma of the prostate (stages C, 01 or 02), based on the American Cancer Society classification," were entered into the study. Disease was measurable or evaluable for at least two of the following features: periprostatic lesions; osteoblastic lesions; osteolytic lesions; elevation of serum acid and/or alkaline phosphatase; obstructive uropathy (secondary to disease); pulmonary metastases; hepatic metastases; objective involvement of tissues, e.g. lymph nodes. Patients were accepted in the study if they had a performance status of 3 or less according to the World Health Organization scale; 10 patients with a performance status of 4 were also admitted if this was due exclusively to pain. The patients had been given no previous treatment or had received alternative hormonal therapy (oestrogens, estramustine phosphate or antiandrogens) for more than 1 month, with relapse or resistance to treatment. No patient had undergone orchidectomy. Patients who had previously undergone radiotherapy were only included in the study if evaluable lesions existed in sites that had not been irradiated. The study did not include patients that had brain metastasis, a life expectancy of less than 3months, anotherneoplasm (except skin neoplasms, other than melanoma) or
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Phase II multicentre trial
severe concomitant illness (renal, hepatic, cardiovascular or neuropsychiatric disorders). Patients who were older than 75 years were also excluded, except if their performance status was rated 2 or less. A total of 47 patients with advanced prostatic cancer entered the study (Table I). Metastatic disease was present (two
stage D I and 43 stage D2) and two patients had extensive locally invasive disease extending throughout the prostatic capsule (stage C). Of these 47 patients, 37 (79%) had not previously received hormonal therapy; the remaining patients had received hormonal therapy alone (seven patients) or together with surgery (extracapsularprostat-
Table 1 Characteristics of patients treated with 3.75 - 30 mg leuprorelin acetate depot given subcutaneously once every 4 weeks
Variable No. of patients Treated Evaluable
Group A (3.75 mg)
30 27
Group B (7.5 mg)
8 7
Group C (15 mg)
Group D (30 mg)
8 8
Total
47 43
Age (years) Median Range
68.5 52-86
67 60-82
71.5 53 -79
Performance status Median Range
1 0-3
2 0-3
2 0-4
2
18 1 - 1682
71 1-664
17.5 2-444
10
18 1 - 1682
Disease duration (days) Median Range
61
69 52-86
I
0-4
Previous therapy None Hormonal therapy Surgery Radiotherapy
23 5 4 2
4 4 0 0
6 1 1 1
1 0 0 0
34
Disease stage C Dl D2
2 2 26
0 0 8
0 0 8
0 0 1
2 2 43
30
8
7
26 1 4 0
8 0 0 1
8 2 1 0
Site of disease Prostatel periprostatic tissues Bone Lung Nodes Liver
10
5 3
46 1 0 0 0
43 3 5 1
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M. Rizzo, T. Mazzei, E. Mini et al.
ectomy, two patients), or together with radiotherapy (one patient). Patients' ages ranged between 52 and 86 years (median 69 years) and they had a mean performance status of 1 (range 0 - 4). The median duration of the disease was 18 days (range 1- 1682 days). The majority of patients (91%) were stage D2 before beginning treatment with metastatic disease in bone (92%) and/or soft tissues (98%). Study design and treatment Patients were randomly assigned to receive one of the following doses of leuprorelin acetate depot (Enantone"): 3.75 mg (group A); 7.5 mg (group B); 15 mg (group C); or 30 mg (group D). The drug was supplied in vials containing 3.75, 7.5, 15 or 30 mg lyophilized powder consisting of microspheres ofleuprorelin acetate in poly(o,L-lacticacid/ glycolic acid) copolymer. After the first case had received 30 mg leuprorelin acetate depot, randomization at this dose level was stopped because information from other on-going studies had shown that a dose of 7.5 mg was suffIcient to produce the required hormonal responses.!':" The last cases received the lowest dose following evidence that suggested this dose was sufficient to inhibit completely gonadal steroidogenesis." In all cases, the drug was administered subcutaneously once every 4 weeks until disease progression. Evaluation of disease Before treatment was started the extent of disease was evaluated by blood chemistry, hormone profiles, radionuclide bone scan, liver echo scan, and chest and other X-rays. Blood samples for hormonal studies were taken between 8.00 and 10.00 a.m. and sera were stored at -20"C until ana-
Enantone" is the registered trademark of Takeda Italia Farmaceutici SpA.
lysed. Testosterone and dihydrotestosterone were measured by radioimmunoassay after extraction with diethyl ether; the lowest limit of detection was 0.5 nmol/l for testosterone and 0.05 nmol/l for dihydrotestosterone. Commercial kits were used for determining testosterone (Mallinkrodt). Evaluation of therapeutic response Patients underwent clinical examination, including rectal examination, and determination of haematological and biochemical profiles every week for the first month, monthly for the first 3 months and once every 3 months thereafter. Any X-rays or scans that were positive at the beginning of the therapy were repeated after the first 3 months and every 3 months thereafter. Bone scan was performed every 6 months if negative before treatment. Tumour response to therapy was assessed based on the criteria of the National Prostatic Cancer Project. 15 Complete response was defmed as disappearance of all signs and symptoms of the disease for at least 1 month. Partial response was defmed as: a reduction by more than 50% in the dimension of the prostate or localization of soft tissues or of viscera when present; return to normal acid phosphatase concentrations, if initially elevated; recalcification of one or more of the osteolytic lesions, if present; and disappearance of one or more of the osteoblastic lesions and thickening of mixed localization. Progression was defined as an increase in any previously measurable lesion by more than 25% or the appearance of new lesions. Any increase in acid or alkaline phosphatase alone was not considered to be an indication of progression. Stable disease was classified as any other situation not by complete or partial response or progression. Evaluation of pain and urinary symptoms was carried out at the beginning of treatment and at weekly intervals thereafter for the first month of therapy, monthly until
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Phase II multicentre trial 3 months and then every 3 months. Pain was classified according to its severity and frequency, type of analgesia used and frequency of itsuse. Urinary symptoms (dysuria and retention) were classified as: grade ,I, mild; grade 2, moderate; grade 3, substantial; or grade 4, severe. Subjective responses for urinary symptoms were defmed as: disappearance of pain and urinary pain together with symptoms; improvement, scores being improved for 1month or more; no change; or worse. The date for the first evaluation of efficacy was the end of the third month of therapy. Treatment was interrupted in the first month only in those cases in which severe adverse effects to the drug or early disease progression were observed. Tolerability Side-effects were evaluated at weekly intervals during the first month, monthly for the first 3 months and every 3 months thereafter. The parameters used to quantify tolerability varied in relation to type of side-effect. Gastro-intestinal effects (nausea/vomiting and diarrhoea) were classified as: grade 1, mild; grade 2, moderate; or grade 3, severe. Hot flushes were defined as: grade 1, tolerable; or grade 2, severe. Effects on libido were described as: grade 1, a decrease; or grade 2, a loss. Effects on impotence were classified as: grade 1, impotence; grade 2, partial or complete.
Statistical analysis Statistical analysis was performed using Fisher's exact test and the ie-test. RESULTS Therapeutic response A total of 43 of the 47 (91%) patients treated were evaluable for therapeutic response: 27 patients in group A; seven in group B; eight in group C; and one patient in group D. The responses as a function of disease stage are reported in Table 2. Overall, two (5%) patients experienced complete remission, 23 (53%) partial remission, 13 (30%) stable disease and five (12%) had disease progression. The median duration of complete remission was 14.5 weeks (range 643 weeks), that of partial remission 15 weeks (range 3 - 27 weeks) and that of stable disease was 8 weeks (range 3 - 23 weeks). No significant differences in the response rates in relation to disease stage were observed. When the response was evaluated in relation to previous hormonal therapy there was a lower incidence of objective remission (complete and partial) in 4/9 (44%) patients who had received oestrogens and/or anti-androgens prior to leuprorelin acetate depot, compared with 21/34 (62%)untreated patients; this difference was not statistically significant (Table 3). It was noted that 25 (66%) patients with bone metastases and only six (16%) of
Table 2 Effects of 3.75 - 30 mg leuprorelin acetate depot given subcutaneously once every 4 weeks on prostatic cancer in relation to disease stage No. of patients Response Complete response Partial response Stable disease Progression Total
C 0 1(50%) 1(50%) 0 2
D1
0 1(50%) 1(50%) 0 2
D2 2(5%) 21(55%) 11(28%) 5(12%) 39
Total 2(5%) 23(53%) 13(30%) 5(12%) 43
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M. Rizzo, T. Mazzei, E. Mini et al.
Table 3 Effect of treatment with 3.75 - 30 mg leuprorelin acetate depot given subcutaneously once every 4 weeks in relation to previous hormonal therapy No. of patients Response
Previous hormonal therapy
Complete response Partial response Stable disease Progression Total
1(11%) 3(33%) 4(44%) 1(11%) 9
No previous therapy
Total 2(5%) 23(53%) 13(30%) 5(12%) 43
1(3%) 20(59%) 9(26%) 4(12%) 34
Table 4 Response to 3.75 - 30 mg leuprorelin acetate depot given subcutaneously once every 4 weeks in relation to site of evaluable disease No. of patients
Response Complete response Partial response Stable disease Progression Total
Prostate/periprostatic tissues
Bone
Liver
2(5%) 4(11%) 31(82%) 1(3%) 38
16(42%) 9(24%) 10(26%) 3(8%) 38
0 0 1 0 1
those with disease localization at primary site and/or periprostate tissues responded partially or completely (Table 4). Remission was also attained in all three patients withevaluable pulmonary metastases (Table 4). Increasing the dose of leuprorelin acetate depot to more than 3.75 mg once every 4 weeks did not significantly increase objective response rate (Table 5). Evaluation of the subjective response in the 16 patients with bone pain at the beginning of treatment showed that eight (50%) of these patients experienced complete disappearance of pain, whereas two (13%) patients reported some improvement, in five (31 %) the pain remained unchanged and in one (6%) it worsened (Table 6). Dysuria
Lung 3(100%) 0 0 0 3
and/or urinary retention disappeared in 21 cases (50%), improved in 12 (29%), remained stable in six (14%) and worsened in three (7%) (Table 7). No significant differences in subjective response rates were observed in relation to drug dose (Tables 6 and 7). Previously untreated patients had mean baseline serum testosterone concentrations of 9.10 ± 6.77 nmol/l, which were higher than those observed in patients who had previously received hormonal therapy (1.62 ± 1.63nmol/l) (Fig. I). Following treatment with leuprorelin acetate depot, mean serum testosterone concentrations fell to castration levels after 3 weeks' treatment and were maintained for the complete duration of treatment.
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Phase II multicentre trial
Table 5 Effect of 3.75- 30 mg leuprorelin acetate depot given subcutaneously once every 4 days on response No. of patients Response Complete response Partial response Stable disease Progression Total
3.75 mg
7.5 mg
15 mg
30 mg
0 14(52%) 9(33%) 4(15%) 27
1(14%) 3(43%) 2(29%) 1(14%) 7
1(12.5%) 5(62.5%) 2(25%) 0 8
0 I 0 0 I
Total 2(5%) 23(53%) 13(30%) 5(12%) 43
Table 6 Subjective response to 3.75 - 15 mg leuprorelin acetate depot given subcutaneously once every 4 weeks in patients (n =16) with bone pain No. of patients Dose (mg)
Disappearance
Improvement
No change
Worse
Total
3.75 7.5 15.0 Total
5(45%) 1(33%) 2(100%) 8(50%)
1(9%) 1(33%) 0 2(13%)
4(36%) 1(33%) 0 5(31%)
1(9%) 0 0 1(6%)
II
3 2 16
Table 7 Subjective response to 3.75 - 30 mg leuprorelin acetate depot given subcutaneously once every 4 weeks in patients (n =42) with urinary symptoms No. of patients Dose (mg) 3.75 7.5 15.0 30.0 Total
Disappearance 14(54%) 3(38%) 4(57%) 0 21(50%)
Improvement 7(27%) 2(25%) 2(29%) 1(100%) 12(29%)
No change
Worse
Total
4(15%) 2(25%) 0 0 6(14%)
1(4%) 1(13%) 1(14%) 0 3(7%)
26 8 7 1 42 121
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M. Rizzo, T. Mazzei, E. Mini et al.
18 • 16
~
No hormonal pretreatment Hormonal pretreatment
14
!
12
8
10
.s'"
8
s 2 "
6
"e
- - -0- -
2
2'"
CIl
4 2
0
0
10
40
30
20
50
Time (weeks)
Fig. 1. Mean serum testosterone concentrations as a function of time following administration of a single dose of 3.75 - 30 mg leuprorelin acetate depot given subcutaneously in patients not previously treated with hormone (n = 34) or pretreated with hormones (n = 4).
3 •
No hormonal pretreatment Hormonal pretreatment
- - -0- -
I
It ~
2 -
-0
s
1\ 1\
CIl
I \
~
1\
o
o L......L o
b-o- Q
.., .0 ...
0--
..,'"
....0. ----1
10
_
---
---l_ _---loi'-=-
20 Time (weeks)
_ _ _ _ _ -0 L.-
30
,
40
Fig. 2. Mean serum dihydrotestosterone concentrations as a function of time following administration of a single dose of 3.75 - 30 mg leuprorelin acetate depot in patients not previously treated with hormone (n = 28) or pretreated with hormones (n = 2).
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Phase II multicentre trial
An increase in serum testosterone concentrations was observed on the second day of treatment but concentrations rapidly declined to baseline values by the seventh day. Disease flare-up did not occur at any time. Serum dihydrotestosterone concentrations in both previously untreated patients and those who had previously received hormonal therapy are shown in Fig. 2. Mean dihydrotestosterone concentrations in previously treated patients diminished to castration levels in the third week of treatment, whereas in pretreated patients the baseline concentrations were already equivalent to castration values. Mean serum alkaline phosphatase concentrations in 34 patients did not show any significant variation according to clinical response. On the contrary, in responding patients and those with stable disease, serum prostatic acid phosphatase levels decreased,reachingthe lowestvalues(1.66 ± 85 and 1.33 ± 0.73 lUll, respectively) in the third month of treatment; enzyme concentrations were then maintained at that level for the rest of the observation period. In three patients in progression, stability of initial values occurred at concentrations higher than the norm (6.6 lUll) and then rose abruptly between the first and second months of treatment.
Tolerability Tolerability was evaluated in all patients. Side-effects observed were impotence (100%), decrease or disappearance of libido (100%), hot flushes (64%), gynaecomastia (16%), nausea/vomiting (13%) and diarrhoea (2%) (Table 8). Hot flushes were tolerable in the majority of cases (72%). Cases of nausea/vomiting and gynaecomastia were almost always mild. The only case of diarrhoea observed was classified as grade 3. No significant changes in blood chemistry were recorded during therapy. A case of nephrotic syndrome was observed, which led to interruption of therapy. It was difficult, however, to attribute this adverse event to treatment with leuprorelin acetate depot. DISCUSSION
Leuprorelin is a luteinizing hormone releasing hormone agonist useful in the treatment of advanced prostatic cancer, being employed to bring about medical castration.7. 8 Depot formulations of the luteinizing hormone releasing hormone agonist represent, with regards to patient compliance and drug availability, an advantage over daily subcutaneous injections or intranasal administration. The present study, which was aimed at
Table 8 Evaluation of side-effects in leuprorelin acetate depot given subcutaneously Grade Side-effects
No. of patients'
1
2
Impotence Decrease of libido Hot flushes Gynaecomastia Nausea/vomiting Diarrhoea
41/41(100%) 41/41(100%) 30/47(64%) 7/44(16%) 6/47(13%) 1/47(2%)
1 1 21 7
40 40 8
3
o
4
1
o
o
'Number of patients with side-effects/total number of patients evaluable.
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M. Rizzo, T. Mazzei, E. Mini et al. evaluating, as a function of dose, the clinical effects of subcutaneously administered leuprorelin acetate depot in patients with advanced prostatic cancer, showed that an overall objective response was obtained in 58% of patients and a stabilization of disease in 30%. An objective response was observed in 16% of evaluable patients with disease in the prostate and periprostatic tissues, and stabilization in 82% evaluable cases. A higher objective response rate (66%) was observed in patients with bone disease. In the case of patients with pulmonary metastases, all three experienced complete remission and one with liver metastases had stabilization. These results, which were obtained in the few cases with visceral metastases, did not allow evaluation of the efficacy of the drug. Disappearance or improvement in bone pain and urinary symptoms occurred in 63% and 79% of cases, respectively. No significant differences between dose levels were noted in terms of objective or subjective response. These data are in agreement with those previously reported for daily subcutaneous administration of leuprorelin7• 8 for monthly doses of leuprorelin acetate depot ranging from 3.75 to 7.5 mg,Il·16 or for other depot luteinizing hormone releasing hormone agonists (goserelin, triptorelin) at similar dosage." 17 Administration of leuprorelin acetate depot subcutaneously once every 4 weeks was sufficient to suppress rapidly (within 3 weeks) and persistently serum androgen concentrations to castration levels, with no substantial differences being noted for the different drug doses. Treatment with leuprorelin acetate depot was well tolerated in the present study but as a consequence of its primary pharmacological action, most of the evaluable patients experienced a reduction or loss of libido, sexual impotence and hot flushes. Gynaecomastia and other side-effects (nausea/vomiting, diarrhoea) were rare and
not dose-related; treatment never had to be withdrawn due to these side-effects. None of the patients experienced infiltration, granulomas or calcifications at injection site. The hormonal and clinical results, therefore, demonstrate that leuprorelin acetate depot at a dose as low as 3.75 mg was able to ensure medical castration, which is necessary for the treatment of advanced prostatic cancer. ACKNOWLEDGEMENTS
Leuprorelin acetate depot Enantone" was kindly provided by Takeda Italia Farmaceutid SpA. REFERENCES 1. Huggins C, Hodges CV: Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941; 1: 293 - 297. 2. Bahnson RR, Catalona WJ: Current management of prostatic carcinoma. Prim Care 1985; 12: 795
-813. 3. Bailar JC, III, Byar DP, The Veterans Administration Cooperative Urological Research Group: Estrogen treatment for cancer of the prostate. Early results with 3 doses of diethylstilbestrol and placebo. Cancer 1970; 26: 257 - 261. 4. De Sy WA, De Meyer JM, Casselman J, et al: A comparative study of a long-acting luteinizing hormone releasing hormone agonist (decapeptyl) and orchiectomy in the treatment of advanced prostatic cancer. Acta Urol Belg 1986; 54: 221 229. 5. Eisenberger MA, O'Dwyer PJ, Friedman MA: Gonadotropin hormone-releasing hormone analog: a new therapeutic approach for prostatic carcinoma. J Clin Onco11986; 4: 414- 424. 6. Gonzales-Barcena 0, Perez-Sanchez P, BereaDominguez H, et al: Persistent blockade of the pituitary - gonadal axis in patients with prostatic carcinoma during chronic administration of 0Trp-6-LH-RH. Prostate 1986; 9: 207 - 215. 7. Leuprolide Study Group: Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N EnglJ Med 1984; 20: 1281-1286. 8. Crawford ED, Eisenberger MA, McLeod DG,et al: A controlled trial ofleuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989; 32 (suppl1): 419- 424. 9. Frank IN: Urologic and male genital cancer. In: Clinical Oncology (Rubin P, ed.). New York:
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Phase II multicentre trial American Cancer Society, 1983. 10. Zubrod CG, Schneidennan MA, Frei E et at: Appraisal ofmethods for the study of chemotherapy in man: comparative therapeutic trial of nitrogen mustard and triethylene thiophosphoramide. J Chronic Dis 1960; 11: 7 - 33. II. Isurugi K, Niijima T, AkazaH, et at: Treatment of prostatic cancer with TAP-I44-SR, a depot preparation ofLH-RH agonist (leuprolide). Sixth Mediterranean Congress of Chemotherapy, Taormina, 22 - 27 May 1988, pp 1237 - 1241. 12. Max 0, Seely J, Swanson L, et al: Clinical studies of leuprolide depot formulation in metastatic prostatic cancer (abstract). International Symposium on GnRH Analogues in Cancer and Human Reproduction, Geneva. 18 - 21 February 1988,
p80. 13. O'Brien A, Oliver RT, Man AM, et al: A phase II trial of depotleuprorelin acetate (TAP-I44-SR) in patients with advanced prostatic cancer (abstract). Sixth Mediterranean Congress ofChemotherapy, Taormina, 22 -27 May 1988, p 69.
14. Mazzei T, Mini E, Rizzo M, et al: Human pharmacokinetic and pharmacodynamic profiles of leuprorelin acetate depot in prostatic cancer patients. J lnt Med Res 1990; \8(suppll): 42 - 56. IS. SchmidtJD, Scott WW, Gibbons R, et al: Chemotherapy programs of the National Prostatic Cancer Project (NPCP). Cancer 1980; 45: 19461973. 16. Seely MD, Swanson L, Browneller R: Clinical studies ofleuprolide depot formulation in metastatic prostatic cancer (abstract). International Symposium on GnRH Analogues in Cancer and Human Reproduction, Geneva, 18-21 February 1988, p SO. 17. Perren Jl, Clayton RN, Blakledge G, et al: Pharmacokinetic and endocrinological parameters of a slow-release depot preparation of the GnRH analogue lei 118630 (Zoladex) compared with a subcutaneous bolus and continuous subcutaneous infusion of the same in patients with prostatic cancer. CancerChemother Pharmacol 1986; 18: 39-43.
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