The Journal of International Medical Research 1990; 18 (suppl I): 57 - 68
Clinical Efficacy and Safety of a New Leuprorelin Acetate Depot Formulation in Patients with Advanced Prostatic Cancer A. O'Brienl and M. Hibberd? 'The Meath Hospital, Dublin, Eire; 2Lederle Laboratories, Gosport, UK
A depot preparation of leuprorelin acetate was assessed in 52 patients with advanced prostatic cancer. Patients received 3.75 mg, or occasionally 7.5 mg, leuprorelin acetate depot subcutaneously every 28 ± 3 days for up to 2 years. Following treatment, there was one complete reo mission and 29 partial remissions; in other patients the disease was stable and in five it was progressive, with an estimated median time to progression of 500 days. Significant improvement in performance status, micturition problems and general well-being were reported. Suppression of serum testosterone and luteinizing hormone concentrations was maximal after 28 days and castration levels were maintained for up to 96 weeks. Tumour flare occurred in 15 (29%) patients during the first week of therapy but only one event was serious; sweating and flushing also occurred occasionally during the study. Of all administrations, 97 % were free from any adverse local effect, the remaining events being mild in severity. It is concluded that oncemonthly administration of leuprorelin acetate depot is effective in the management of advanced prostatic cancer and has an acceptable sideeffect profile. Une preparation d'acetate de leuprorelme sous forme retard a ete evaluee chez 52 malades atteints d'un cancer prostatique avance. Les patients ont recu 3,75 mg ou de temps it autre 7,5 mg d'acetate de leuproreline retard tous les 28 ± 3 jours pendant une duree maximale de 2 ans, A I'issue du traitement, on a note une remission complete et 29 remissions partielles; chez d'autres malades, la maladie est restee Present address and address for correspondence: Dr Aidan O'Brien, Department of Urology, The
Beaumont Hospital, Dublin 9, Eire.
© Copyright 1990 by Cambridge Medical Publications Ltd
Downloaded from imr.sagepub.com at UCSF LIBRARY & CKM on April 30, 2015
57
A. O'Brien, M. Hibberd
stable et chez cinq autres elle a progresse avec une duree moyenne de progression estimee a500 jours, On a observe une amelioration significative de la performance, des problemas de nutrition et du bien-etre en general. La diminution des concentrations seriques en hormones lutelnisantes et en testosterone a atteint un taux maximal au bout de 28 jours et les taux de castration se sont maintenus pendant de 96 semaines. La tumeur s'est reveillee chez 15 (29%) des malades durant la premiere semaine du traitement mais la condition ne s'est averee grave que dans un seul cas; des rougeurs et des bouffees de chaleur ont egalement ete deplorees durant I'etude. Sur toutes les administrations, 97% n'ont presente aucun effet secondaire local, et tous les autres effets se sont reveles etre de severite benlgne, On en a conelu que I'administration une fois par mois d'acetate de leuproreline it liberation prolongee etait efficace dans Ie traitement du cancer prostatique avance et que son profil d'effets secondaires etait acceptable. Una terapia a base di leuprorelin acetato, in preparazione 'ritardo', e stata sperimentata su 52 pazienti affetti da cancro prostatico avanzato. I pazienti hanno ricevuto dosi di 3,75 mg, oppure, occasionalmente, di 7,5 mg, di leuprorelin acetato, in preparazione 'ritardo', somministrate per via sottocutanea ogni 28 +/- 3 giorni, per un periodo massimo di 2 anni. AItermine del trattamento, si e verificato un caso di completa remissione e 29 di parziale remissione; in altri pazienti la malattia si e stabilizzata ed in cinque altri e stata progressiva, con una stima del tempo medio di progressione di 500 giorni. Sono stati riscontrati significativi miglioramenti delle condizioni dei pazienti, dei problemi della minzione e del benessere generale. La soppressione delle concentrazioni seriche di testosterone e di ormone luteinizzante ha raggiunto it massimo dopo 28 giorni ed i Ii~elli da castrazione sono rimasti costanti per un periodo massimo di 96 settimane. Un aggravamento tumorale si e verificato in 15 pazienti (29%) nel corso della prima settimana di terapia, tuttavia un solo caso era da considerarsi grave; nel corso dello studio sono stati segnalati, occasional mente, fenomeni di sudorazione e vampate di calore. Di tutti i casi presi in esame, it 97 % non ha presentato alcun effetto negativo localizzato, negli altri casi, tali effetti sono stati di minore entita. Se ne desume che la somministrazione, a cadenza mensile, di leuprorelin acetato, in formulazione a rilascio prolungato, e efficace nella terapia del cancro prostatico in fase avanzata ed e accettabile sotto iI profilo degli effetti collaterali. KEY WORDS: Leuprorelin acetate; sustained release; prostatic cancer.
INTRODUCTION
P
rostatic cancer is a major cause of male cancer deaths. The hormone dependency of prostatic cancer has long been
recognized and has led to the development of several treatment modalities that reduce the levels of circulating androgens which has been shown to be of benefit to the ma-
58 Downloaded from imr.sagepub.com at UCSF LIBRARY & CKM on April 30, 2015
Leuprorelin acetate in advanced prostatic cancer jority of these patients. Orchidectomy and oestrogen therapy are two methods of manipulating testosterone levels 1 - 4 but both are associated with risks; in the case of orchidectomy risks are associated with anaesthesia, morbidity, cardiovascular sideeffects' and mortality. Leuprorelin (In-Leus-des-Gly'" NH 2]gonadotrophin releasing hormone proethylamide, TAP - 144) is one ofa group of compounds - luteinizing hormone releasing hormone (LHRH) analogues - that suppresses gonadotrophin production thereby reducing levels of sex hormones." After an initial stimulatory effect, the continued administration of leuprorelin in men results in a paradoxical suppression of gonadotrophin release and the consequent reduction of serum test -osterone concentrations." - 9 The principal side-effects of LHRH analogue therapy are hot flushes and a transient increase in bone pain ('tumour flare' phenomenon). Tumour flare has been reported after hormonal manipulation using LHRH analogues for the treatment of prostatic cancer patients. 10 A depot preparation of leuprorelin acetate (TAP-l44--SR) has been developed. Animal studies using this micro-encapsulated formulation have demonstrated continuous release of the drug for over 30 days and the effective suppression of testosterone after subcutaneous or intramuscular injection. II It was envisaged that a sustained release formulation would increase patient compliance and provide a more canvenient method-of administration, while reducing the incidence of tumour flare. It was also possible that a different hormone profile would be produced from that seen with daily injections of leuprorelin acetate. The present study was conducted to determine the clinical efficacy and safety of the depot formulation and to establish its ability to maintain the suppression of serum testosterone concentrations. The data reported are those collected for the first 2 years of a long-term study.
PATIENTS AND METHODS
Patients Patients with untreated, histologically confirmed advanced prostatic cancer (local advanced and/or distant disease) and a life expectancy of at least 3 months were enrolled into the study. All patients had measurable disease and had a WHO performance status 12 of 0 - 4. Patients with a history of other malignancies, orchidectomy or hormonal treatment were excluded, as were those with central nervous system involvement, hepatitis B surface antigen positivity, uncontrolled cardiac failure or a serum bilirubin level concentration greater than 20 mmol/l. Informed consent was obtained from all patients prior to enrolment, as well as Ethical Committee approval from each institution.
Treatment Leuprorelin acetate depot was supplied as a micro-encapsulated powder in vials of 3.75 and 7.5 mg. Immediately prior to injection the powder was mixed with 2 ml mannitol diluent to form a uniform suspension, which was then administrated subcutaneously without anaesthetic via a syringe fitted with a 23 gauge needle; the injection site was usually the anterior abdominal wall. Treatments were administered every 28 ± 3 days on an out-patient basis. The dose was increased from 3.75 to 7.5 mg if the patient showed disease progression after 12. weeks of therapy and if serum testosterone was not suppressed to castration levels. Patients who initially achieved satisfactory suppression of serum testosterone concentrations but who subsequently showed significant increasing testosterone levels on two consecutive occasions were treated .with the higher dose at the clinician's discretion.
Patient follow-up Patients were seen on the day after therapy, 59
Downloaded from imr.sagepub.com at UCSF LIBRARY & CKM on April 30, 2015
Downloaded from imr.sagepub.com at UCSF LIBRARY & CKM on April 30, 2015
0\ 0
b
a
Testsrepeated3 monthly after week 16. Performed if appropriate and repeated 3 monthlyunless normal.
X X X
X X X X
X
X
1 week
X X X
X
2 days
X
X
1 day
X X X X X X X X
X X X
X X
X X X X X
Pretreatment
Laboratory investigations Blood cell count Platelet count Urea/electrolytes Creatinine Acid phosphatase Alkaline phosphatase Liver function tests Urinalysis Luteinizing hormone, follicle stimulating hormone, prolactin Testosterone Leuprorelin acetate
Disease measurement Rectal examination Rectal ultrasound Computerized tomography scan/liver ultrasound scan Bone scan Bone X-ray
Clinical examination X-ray + electrocardiogram Body weight Performance status Symptoms
Study parameter
X X X
X X X X X X X
X
X
X
2 weeks
X X X
X X X X X X X X
X
X X X
X
4 weeks
X X
X X X X
X
X
6 weeks
Duration of treatment
X X X
X X X X X X X X
X
X X X
X
X X X X X X X
X
X' X' X'
X· X' X' X' X' X' X' X'
Xb Xb X
X X
X X X X X
8 weeks· 10 weeks 12 weeks
Table 1 Study flow chart for the clinical assessment of 3.75 and 7.5 mg leuprorelin acetate depot given subcutaneously once every 4 weeks for the treatment of advanced prostatic cancer
~
a
g
::I: S'
~
.?
G
::l.
cS
0
Leuprorelin acetate in advanced prostatic cancer
weekly for the first 2 weeks, every 2 weeks for the first 12 weeks and then at l-month intervals. Clinical response assessments Patients were examined and underwent tests according to Table 1. Any adverse reactions were recorded at each visit.
Table 2 Demographic details of patients (n = 52; mean age 68 years; range 47 - 97 years) with prostaticcancer enrolled to be treated with 3.75 and 7.5 mg leuprorelin acetate depot given subcutaneously every 4 weeks No. of patients
Variable Performance status (WHO classification)
o
20 20
I 2 3 4
Disease stage C D
10 I I 14
4
48
Bone involvement Yes
29
No
14 8 I
Not known Missing Alkaline phosphatase elevated Acid phosphatase elevated Serum creatinine elevated Tumour histology Well differentiated Moderately differentiated Poorly differentiated Other Missing 'Data for one patient missing. "Data for six patients missing. 'Data for three patients missing.
39/51" 36/46b 14/4£)
Clinical Efficacy and Safety of a New Leuprorelin Acetate Depot Formulation in Patients with Advanced Prostatic Cancer A. O'Brienl and M. Hibberd? 'The Meath Hospital, Dublin, Eire; 2Lederle Laboratories, Gosport, UK
A depot preparation of leuprorelin acetate was assessed in 52 patients with advanced prostatic cancer. Patients received 3.75 mg, or occasionally 7.5 mg, leuprorelin acetate depot subcutaneously every 28 ± 3 days for up to 2 years. Following treatment, there was one complete reo mission and 29 partial remissions; in other patients the disease was stable and in five it was progressive, with an estimated median time to progression of 500 days. Significant improvement in performance status, micturition problems and general well-being were reported. Suppression of serum testosterone and luteinizing hormone concentrations was maximal after 28 days and castration levels were maintained for up to 96 weeks. Tumour flare occurred in 15 (29%) patients during the first week of therapy but only one event was serious; sweating and flushing also occurred occasionally during the study. Of all administrations, 97 % were free from any adverse local effect, the remaining events being mild in severity. It is concluded that oncemonthly administration of leuprorelin acetate depot is effective in the management of advanced prostatic cancer and has an acceptable sideeffect profile. Une preparation d'acetate de leuprorelme sous forme retard a ete evaluee chez 52 malades atteints d'un cancer prostatique avance. Les patients ont recu 3,75 mg ou de temps it autre 7,5 mg d'acetate de leuproreline retard tous les 28 ± 3 jours pendant une duree maximale de 2 ans, A I'issue du traitement, on a note une remission complete et 29 remissions partielles; chez d'autres malades, la maladie est restee Present address and address for correspondence: Dr Aidan O'Brien, Department of Urology, The
Beaumont Hospital, Dublin 9, Eire.
© Copyright 1990 by Cambridge Medical Publications Ltd
Downloaded from imr.sagepub.com at UCSF LIBRARY & CKM on April 30, 2015
57
A. O'Brien, M. Hibberd
stable et chez cinq autres elle a progresse avec une duree moyenne de progression estimee a500 jours, On a observe une amelioration significative de la performance, des problemas de nutrition et du bien-etre en general. La diminution des concentrations seriques en hormones lutelnisantes et en testosterone a atteint un taux maximal au bout de 28 jours et les taux de castration se sont maintenus pendant de 96 semaines. La tumeur s'est reveillee chez 15 (29%) des malades durant la premiere semaine du traitement mais la condition ne s'est averee grave que dans un seul cas; des rougeurs et des bouffees de chaleur ont egalement ete deplorees durant I'etude. Sur toutes les administrations, 97% n'ont presente aucun effet secondaire local, et tous les autres effets se sont reveles etre de severite benlgne, On en a conelu que I'administration une fois par mois d'acetate de leuproreline it liberation prolongee etait efficace dans Ie traitement du cancer prostatique avance et que son profil d'effets secondaires etait acceptable. Una terapia a base di leuprorelin acetato, in preparazione 'ritardo', e stata sperimentata su 52 pazienti affetti da cancro prostatico avanzato. I pazienti hanno ricevuto dosi di 3,75 mg, oppure, occasionalmente, di 7,5 mg, di leuprorelin acetato, in preparazione 'ritardo', somministrate per via sottocutanea ogni 28 +/- 3 giorni, per un periodo massimo di 2 anni. AItermine del trattamento, si e verificato un caso di completa remissione e 29 di parziale remissione; in altri pazienti la malattia si e stabilizzata ed in cinque altri e stata progressiva, con una stima del tempo medio di progressione di 500 giorni. Sono stati riscontrati significativi miglioramenti delle condizioni dei pazienti, dei problemi della minzione e del benessere generale. La soppressione delle concentrazioni seriche di testosterone e di ormone luteinizzante ha raggiunto it massimo dopo 28 giorni ed i Ii~elli da castrazione sono rimasti costanti per un periodo massimo di 96 settimane. Un aggravamento tumorale si e verificato in 15 pazienti (29%) nel corso della prima settimana di terapia, tuttavia un solo caso era da considerarsi grave; nel corso dello studio sono stati segnalati, occasional mente, fenomeni di sudorazione e vampate di calore. Di tutti i casi presi in esame, it 97 % non ha presentato alcun effetto negativo localizzato, negli altri casi, tali effetti sono stati di minore entita. Se ne desume che la somministrazione, a cadenza mensile, di leuprorelin acetato, in formulazione a rilascio prolungato, e efficace nella terapia del cancro prostatico in fase avanzata ed e accettabile sotto iI profilo degli effetti collaterali. KEY WORDS: Leuprorelin acetate; sustained release; prostatic cancer.
INTRODUCTION
P
rostatic cancer is a major cause of male cancer deaths. The hormone dependency of prostatic cancer has long been
recognized and has led to the development of several treatment modalities that reduce the levels of circulating androgens which has been shown to be of benefit to the ma-
58 Downloaded from imr.sagepub.com at UCSF LIBRARY & CKM on April 30, 2015
Leuprorelin acetate in advanced prostatic cancer jority of these patients. Orchidectomy and oestrogen therapy are two methods of manipulating testosterone levels 1 - 4 but both are associated with risks; in the case of orchidectomy risks are associated with anaesthesia, morbidity, cardiovascular sideeffects' and mortality. Leuprorelin (In-Leus-des-Gly'" NH 2]gonadotrophin releasing hormone proethylamide, TAP - 144) is one ofa group of compounds - luteinizing hormone releasing hormone (LHRH) analogues - that suppresses gonadotrophin production thereby reducing levels of sex hormones." After an initial stimulatory effect, the continued administration of leuprorelin in men results in a paradoxical suppression of gonadotrophin release and the consequent reduction of serum test -osterone concentrations." - 9 The principal side-effects of LHRH analogue therapy are hot flushes and a transient increase in bone pain ('tumour flare' phenomenon). Tumour flare has been reported after hormonal manipulation using LHRH analogues for the treatment of prostatic cancer patients. 10 A depot preparation of leuprorelin acetate (TAP-l44--SR) has been developed. Animal studies using this micro-encapsulated formulation have demonstrated continuous release of the drug for over 30 days and the effective suppression of testosterone after subcutaneous or intramuscular injection. II It was envisaged that a sustained release formulation would increase patient compliance and provide a more canvenient method-of administration, while reducing the incidence of tumour flare. It was also possible that a different hormone profile would be produced from that seen with daily injections of leuprorelin acetate. The present study was conducted to determine the clinical efficacy and safety of the depot formulation and to establish its ability to maintain the suppression of serum testosterone concentrations. The data reported are those collected for the first 2 years of a long-term study.
PATIENTS AND METHODS
Patients Patients with untreated, histologically confirmed advanced prostatic cancer (local advanced and/or distant disease) and a life expectancy of at least 3 months were enrolled into the study. All patients had measurable disease and had a WHO performance status 12 of 0 - 4. Patients with a history of other malignancies, orchidectomy or hormonal treatment were excluded, as were those with central nervous system involvement, hepatitis B surface antigen positivity, uncontrolled cardiac failure or a serum bilirubin level concentration greater than 20 mmol/l. Informed consent was obtained from all patients prior to enrolment, as well as Ethical Committee approval from each institution.
Treatment Leuprorelin acetate depot was supplied as a micro-encapsulated powder in vials of 3.75 and 7.5 mg. Immediately prior to injection the powder was mixed with 2 ml mannitol diluent to form a uniform suspension, which was then administrated subcutaneously without anaesthetic via a syringe fitted with a 23 gauge needle; the injection site was usually the anterior abdominal wall. Treatments were administered every 28 ± 3 days on an out-patient basis. The dose was increased from 3.75 to 7.5 mg if the patient showed disease progression after 12. weeks of therapy and if serum testosterone was not suppressed to castration levels. Patients who initially achieved satisfactory suppression of serum testosterone concentrations but who subsequently showed significant increasing testosterone levels on two consecutive occasions were treated .with the higher dose at the clinician's discretion.
Patient follow-up Patients were seen on the day after therapy, 59
Downloaded from imr.sagepub.com at UCSF LIBRARY & CKM on April 30, 2015
Downloaded from imr.sagepub.com at UCSF LIBRARY & CKM on April 30, 2015
0\ 0
b
a
Testsrepeated3 monthly after week 16. Performed if appropriate and repeated 3 monthlyunless normal.
X X X
X X X X
X
X
1 week
X X X
X
2 days
X
X
1 day
X X X X X X X X
X X X
X X
X X X X X
Pretreatment
Laboratory investigations Blood cell count Platelet count Urea/electrolytes Creatinine Acid phosphatase Alkaline phosphatase Liver function tests Urinalysis Luteinizing hormone, follicle stimulating hormone, prolactin Testosterone Leuprorelin acetate
Disease measurement Rectal examination Rectal ultrasound Computerized tomography scan/liver ultrasound scan Bone scan Bone X-ray
Clinical examination X-ray + electrocardiogram Body weight Performance status Symptoms
Study parameter
X X X
X X X X X X X
X
X
X
2 weeks
X X X
X X X X X X X X
X
X X X
X
4 weeks
X X
X X X X
X
X
6 weeks
Duration of treatment
X X X
X X X X X X X X
X
X X X
X
X X X X X X X
X
X' X' X'
X· X' X' X' X' X' X' X'
Xb Xb X
X X
X X X X X
8 weeks· 10 weeks 12 weeks
Table 1 Study flow chart for the clinical assessment of 3.75 and 7.5 mg leuprorelin acetate depot given subcutaneously once every 4 weeks for the treatment of advanced prostatic cancer
~
a
g
::I: S'
~
.?
G
::l.
cS
0
Leuprorelin acetate in advanced prostatic cancer
weekly for the first 2 weeks, every 2 weeks for the first 12 weeks and then at l-month intervals. Clinical response assessments Patients were examined and underwent tests according to Table 1. Any adverse reactions were recorded at each visit.
Table 2 Demographic details of patients (n = 52; mean age 68 years; range 47 - 97 years) with prostaticcancer enrolled to be treated with 3.75 and 7.5 mg leuprorelin acetate depot given subcutaneously every 4 weeks No. of patients
Variable Performance status (WHO classification)
o
20 20
I 2 3 4
Disease stage C D
10 I I 14
4
48
Bone involvement Yes
29
No
14 8 I
Not known Missing Alkaline phosphatase elevated Acid phosphatase elevated Serum creatinine elevated Tumour histology Well differentiated Moderately differentiated Poorly differentiated Other Missing 'Data for one patient missing. "Data for six patients missing. 'Data for three patients missing.
39/51" 36/46b 14/4£)
