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Leuprorelin in : a European Update Persad R Journal für Urologie und Urogynäkologie 2002; 9 (Sonderheft Homepage: 3) (Ausgabe für Österreich), 16-26 www.kup.at/urologie Online-Datenbank mit Autoren- und Stichwortsuche

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P.b.b. 02Z031116M, Verlagspostamt: 3002 Purkersdorf, Erscheinungsort: 3003 Gablitz LEUPRORELIN R. Persad ACETATE IN : LEUPRORELIN ACETATE IN PROSTATE A EUROPEAN UPDATE CANCER: A EUROPEAN UPDATE*

Meta-analysis has shown that Summary month depot of 3.75 mg or survival after therapy with an LHRH three-month of 11.25 analogue is equivalent to that after This review provides an update on mg. Both the one-month and three- orchiectomy [6]. Survival rates with leuprorelin acetate, the world’s most month formulations are effective in LHRH analogues appear to be higher widely prescribed depot luteinising delaying tumour progression and in advanced disease, and treatment -releasing hormone ana- alleviating symptoms of locally withdrawals less common, than with logue. Leuprorelin acetate has been advanced and metastatic prostate non-steroidal used as in clinical use in the palliative treat- cancer. Tolerability is generally monotherapy [6]. The current trend ment of prostate cancer for more good, with side-effects reflecting is towards initiating LHRH analogue than 20 years, but advances continue effective suppression. therapy early – as soon as metastatic to be made in terms of convenience Recent studies have investigated the or locally advanced prostate cancer and flexibility of administration, and place of leuprorelin acetate as part of is diagnosed – rather than waiting in the incorporation of leuprorelin continuous or intermittent maximal until the onset of symptoms. A Medical acetate into novel treatment regimens. blockade (MAB) and in Research Council trial in the UK The drug is administered in the form neoadjuvant therapy (ie, to reduce found that, compared with deferred of a depot injection containing the size of the prostate and downsize treatment, immediate androgen leuprorelin acetate microspheres, the tumour before radiotherapy). Addi- suppression reduced progression and and is at least as effective in suppres- tional formulations and presentations complications due to the disease and sing testosterone secretion as orchi- are in development, including a six- delayed the development of meta- ectomy. In patients with prostate month injection, with the aim of static pain [8]. cancer, serum testosterone levels are adding to the clinical flexibility and reduced to castrate levels (= 50 ng/ patient acceptability of this important Leuprorelin acetate as a one-month dl) within 2–3 weeks of the first one- palliative treatment for prostate cancer. depot was first launched in Europe in France in April 1989, and now is Cancer of the prostate is the most suppression, is psychologically well established as the leading LHRH common malignancy in elderly men difficult for patients to accept [4]. analogue. Since the publication of (> 65 years) and the second most Most patients prefer one-month or earlier reviews [7, 9, 10], new studies common cause of death in this age quarterly injections of luteinising have contributed to our understanding group [1]. In recent years, screening hormone-releasing hormone (LHRH) of the role of leuprorelin in prostate programmes using prostate-specific analogues – the current mainstay of cancer. New formulations have also antigen (PSA) levels have increased therapy for locally advanced or been developed to maximise flexi- detection rates for early-stage disease, metastatic prostate cancer [3]. bility and convenience of admini- which is treatable with radical prostat- stration for both doctor and patient. ectomy or radiation therapy [2]. LHRH analogues such as leuprorelin This review aims to provide an up- Many cases remain undiagnosed, acetate, , and to-date summary of the clinical however, until the disease finally work by inhibiting LH profile of an established but still becomes symptomatic, by which production. This in turn suppresses evolving treatment. time it is usually already locally production of testosterone and advanced or metastatic. For these , on which the patients, and for those with recurrent growth of hormone-dependent cancer after radical prostatectomy or cancer cells depends [5]. Androgen radiation, androgen suppression suppression delays clinical progression CHEMISTRY AND PHARMACY using hormonal therapy is now the and palliates symptoms of metastatic standard palliative treatment [2]. disease such as bone pain [6]. LHRH analogues do not cure prostate cancer Natural LHRH was first isolated and The earliest forms of hormonal or prolong median survival (which is identified in 1971 [11]. Leuprorelin therapy used oestrogens, such as about 24 months in metastatic prostate was first synthesised in 1974 by diethylstilboestrol (DES). However, cancer) [7]. They do, however, Takeda Chemical Industries, Japan, because of their cardiovascular improve symptoms in 60–80 % of [12] and is a synthetic non-peptide toxicity, oestrogens are generally no patients. Relapse eventually occurs analogue of naturally occurring longer widely used in prostate despite the sustained suppression of porcine LHRH [13]. It has a longer cancer [3]. Orchiectomy, although testosterone with growth of androgen- half-life than natural LHRH due to its an effective means of androgen independent tumour cells. enhanced binding affinity and increased resistance to peptidase *Nachdruck mit Genehmigung aus: Int J Clin Pract 2002; 56: 389–96 degradation, associated with amino

16 J. UROL. UROGYNÄKOL. Sonderheft 3/2002 For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. LEUPRORELIN ACETATE IN PROSTATE CANCER: A EUROPEAN UPDATE acid substitutions at positions 6 and month depot preparation reduced 10 of porcine LHRH. Leuprorelin is the total dose of leuprorelin required 80 times more potent than natural to achieve castrate testosterone LHRH [9]. Sustained occupation of levels to one-eighth of that needed pituitary GnRH receptors by leupro- when injected daily [15]. After injection of the one-month relin results in densensitisation and/ depot formulation of leuprorelin or downregulation of receptors in the A sophisticated manufacturing 3.75 mg, peak serum levels are , thereby suppres- system was developed, yielding a achieved within one hour, followed sing gonadotrophin release and product with predictable controlled- by a rapid fall over the next 24 hours. reducing testosterone release by the release characteristics [16]. The A dose-dependent plateau is main- human testes to castrate levels [13]. three-month depot injection differs tained over at least five weeks, There is also evidence that leupro- from the one-month depot injection representing a constant rate of relin may act directly on cell growth in that during microencapsulation, release of leuprorelin from the co- in human prostatic cancer cells, only D, L-poly-() acts as polymer [15]. Injections can be behaving like a negative growth the vehicle instead of the PLGA co- given at intervals of either four weeks factor [14]. polymer, and the product does not or one month, at the convenience of include gelatin [17]. the patient and the physician. Over Leuprorelin is inactive when given an extended 45 month treatment orally, as it is poorly absorbed from The properties of leuprorelin micro- period of repeated monthly injec- the gastrointestinal mucosa. It there- spheres have been compared with tions, leuprorelin remains at a fore has to be given by injection those of the microcapsule formula- constant therapeutic level and there [15]. Originally, leuprorelin 1 mg tion of triptorelin [18]. Both products is no evidence of accumulation was given by daily injection. How- had similar pharmacological potency following the depot injection [19]. ever, a depot formulation was soon in rats. The leuprorelin depot had developed to enable convenient higher drug content and lower resi- As with the one-month injection, the subcutaneous or intramuscular dual impurities (solvents and metals) three-month injection (11.25 mg), injection at one-month intervals. than the triptorelin depot. Leupro- results in an initial rise in serum Now, there is also the option of a relin microcapsules were smaller, levels of leuprorelin, followed by three-month . and had a slower sedimentation rate continuous linear release. A serum The depot formulation enables after dispersion in the vehicle. These level of about 200–287 pg/ml is leuprorelin to be given less often. differences appear to be a result of maintained over at least three months the methods used to produce the (aequivalent to that achieved with a biodegradable matrices and micro- one-month dose of 3.75 mg after capsules of each product. Leupro- repeated injections) [17]. Following MICROSPHERE TECHNOLOGY relin microspheres range in mean injection, the plateau phase is reached diameter between 10 and 20 mm for at about 7 days, and persists for about the one-month depot and between 117 days. This clearly demonstrates Microsphere technology is what 10 and 30 mm for the three-month that leuprorelin three-month injec- makes it possible to give leuprorelin depot. Clinically, this means that tion will yield sufficient levels of as a depot formulation. Microsphere leuprorelin can be given as a liquid leuprorelin to suppress testosterone technology is also used for depot injection through a fine gauge production for at least the intended formulations of triptorelin, whereas needle using conventional injection three-month treatment period. As buserelin and goserelin are used as a techniques. Leuprorelin does not with the one-month depot injection, solid implant. For the one-month require the concurrent administra- there is no evidence of long-term depot formulation of leuprorelin, a tion of a local anaesthetic or a accumulation with the three-month biodegradable co-polymer compo- special injection technique (as is depot injection [17]. sed of lactic and glycolic acids required for the administration of (PLGA) was chosen as the release- some other LHRH analogue implant Effects on testosterone levels controlling substance. PLGA is used formulations). in surgical sutures and has a known To obtain optimal therapeutic effect safety profile. A co-polymer with a against androgen-dependent tumour molecular weight of 14,000 and a cells, serum testosterone levels must lactic acid/glycolic acid ratio of 75/ be reduced to castrate levels (= 50 25 was found to have the most ng/dl) [20]. This level can be achie- satisfactory releasing properties. ved by a one-month depot injection Clinical studies showed that the one- of 3.75 mg leuprorelin [9] or by a

J. UROL. UROGYNÄKOL. Sonderheft 3/2002 17 LEUPRORELIN ACETATE IN PROSTATE CANCER: A EUROPEAN UPDATE

Figure 1. Suppression of plasma Table 1. Major studies of the 1-month and 3-month formulations of leuprorelin testosterone by leuprorelin depot in prostate cancer injection, 3.75 mg one-month or Study n Regimen Duration Objective 11.25 mg three-month injection, (months) response* (%) over nine months [17]. Akaza 81 3.75 or 7.5 mg 3 86 1990 [30] 1-month Bischoff 190 3.75 or 7.5 mg 1–15 88 1990 [36] 1-month O’Brien 48 3.75 or 7.5 mg 3 90 1990 [35] 1-month Navratil 18 3.75 mg 7 83 1990 [32] 1-month Rizzo 43 3.75, 7.5, 15 or 30 mg 12 88 three-month depot injection of 11.25 1990 [31] 1-month mg (Figure 1) [17, 21, 22]. As with Wechsel 80 3.75 mg 9 81 other LHRH analogues, a rise in 1996 [17] 1-month testosterone levels is seen after the Wechsel 157 11.25 mg 9 80 first leuprorelin injection only (see 1996 [17] 1-month below), but castrate levels are *no change, partial response or complete response achieved within 2–4 weeks and maintained for the duration of advanced and metastatic prostate no difference in the effects of s.c. or treatment. cancer. Most studies, however, have i.m. administration [36]. For this been carried out with the one-month reason, the European recommended The effects of leuprorelin in suppres- and three-month depot formulations. dose for one-month depot injection sing testosterone secretion appear to is 3.75 mg administered as a single be aequivalent to those of other widely Monthly injection s.c. or i.m. injection at one-month used LHRH analogues. A study in 64 intervals. After two days, the phar- previously untreated patients with Open label studies of depot injections macokinetic curves after the s.c. and metastatic prostate cancer compared given at intervals of four weeks or i.m. injections are the same. The one-month depot injections of leupro- one month in patients with metastatic only practical difference between the relin, goserelin and triptorelin. Histo- or locally advanced prostate cancer two routes is that s.c. injection in the logy, histochemistry and immuno- (Table 1) [19, 30–36] found that forearm may sometimes be more chemistry showed that the effects of serum testosterone fell to castrate convenient. all three LHRH analogues were levels within the first month and similar to those of castration. All had stayed at this level for the duration of Three-month injection similar effects on testosterone levels, therapy (up to 63 months) [19]. and numbers of progressions and Where reported, bone pain [30, 31, The availability of a choice of deaths were similar in the three 34, 36] and urinary symptoms [30, injection frequencies (one-month or groups, although at 3 and 6 months 31, 34, 35] were reduced, and three-month) offers more individuali- patients treated with leuprorelin performance status improved or sed, patient-orientated treatment [38]. showed significantly lower serum stabilised [33, 35, 37]. The tumour The three-month depot formulation PSA levels than the other two groups marker PSA was markedly decreased of leuprorelin is given by s.c. injection. [23]. [34]. Over follow-up periods of 3–24 The three-month injection reduces months, disease progression was the total number of injections to four Clinical efficacy prevented in up to 95 % of patients per year, and can be timed to coincide [19, 30–36]. with a typical schedule of three- Early studies in metastatic or advan- month or six-month check-ups [38]. ced prostate cancer established the Although doses used for one-month This may reduce the number of efficacy of daily s.c. injection of injection in clinical trials have varied doctor visits required. A reduction in leuprorelin (1–20 mg) [24–29] in from 3.75 to 7.5 mg [33] a dose of the number of injections may also suppressing testosterone levels, 3.75 mg has been demonstrated to reduce stress on patients, who are delaying tumour progression and suppress gonadal testosterone syn- often elderly with multiple illnesses alleviating symptoms of locally thesis to castrate levels [15]. There is [38].

18 J. UROL. UROGYNÄKOL. Sonderheft 3/2002 LEUPRORELIN ACETATE IN PROSTATE CANCER: A EUROPEAN UPDATE

either the one-month 3.75 mg formu- was 3.1 years, with a median time to Figure 2. Best response during the lation (n = 80) or the three-month tumour progression of 2.8 years [38]. course of a nine-month study 11.25 mg formulation (n = 157). The comparing leuprorelin depot, 3.75 two formulations of leuprorelin were Comparison with other LHRH mg one-month and 11.25 mg similar in terms of clinical response analogues three-month injections. and tolerability. Comparing one- month with three-month injections Few studies have compared different (Figure 2), complete remission occur- LHRH analogues. A meta-analysis red in 5.0 % versus 5.7 % of patients, suggests there is little or no clinical partial remission in 36.3 % versus difference between leuprorelin, 33.8 % and stabilisation in 40.0 % goserelin and buserelin in terms of versus 40.8 % (ie, efficacy was clinical response [6] though different comparable). The two formulations formulations may differ in their produced virtually identical endocrine acceptability to patients [40]. Although effects, with a pronounced fall in both leuproprelin and triptorelin testosterone and gonadotrophin make use of microcapsule techno- serum levels and a marked reduction logy, goserelin is administered in the in PSA levels (Figure 3). After nine form of an implant rather than an months of treatment, PSA was norma- injection. Anecdotally, patients have lised (< or = 4 ng/ml) in 65.2 % of been reported to prefer leuprorelin patients receiving one-month injec- injection to goserelin implants, tions and 66.1 % of those receiving because of the smaller gauge of three-month injections [17]. needle required [40].

Thirty-seven patients entered a long- One open-label randomised study term follow-up study, in which they has compared one-month s.c. injec- In a randomised open-label compara- received treatment with the three- tion with leuprorelin 3.75 mg with tive study of the efficacy, safety and month formulation for up to 43 triptorelin 3.75 mg. Both treatments tolerability of leuprorelin one-month months (Figure 4) [38]. Suppression were equally effective in reducing and three-month depot in patients of serum testosterone to castrate serum testosterone to castrate levels with advanced prostatic cancer a levels was maintained throughout over a six-month period, although single three-month dose of 11.25 mg the study. The nature and severity of plasma testosterone fell more rapidly has been shown to be therapeutically adverse events was similar to that with leuprorelin [41]. aequivalent to a one-month dose of observed previously. This follow-up 3.75 mg injected three times (Table study also provided prospective data Comparison with DES 1, Figure 1) [17, 21, 39]. This study on median survival time for 63 included 237 patients with locally patients receiving three-month DES (3 mg daily) and leuprorelin advanced or metastatic prostate treatment only. The median survival (1 mg daily s.c. injection) have been cancer, treated for nine months with time from the beginning of treatment shown to be equally effective in

Figure 3. Effect of leuprorelin depot injection, 3.75 mg Figure 4. Median plasma concentrations of testosterone with one-month or 11.25 mg three-month, on PSA levels over three-month leuprorelin depot injection, 11.25 mg over nine months [17]. 43 months [38].

J. UROL. UROGYNÄKOL. Sonderheft 3/2002 19 LEUPRORELIN ACETATE IN PROSTATE CANCER: A EUROPEAN UPDATE

reducing serum testosterone below seen largely in M0 patients. The data from trials in 8275 men with castrate levels in patients with meta- authors conclude that the data metastatic or locally advanced static prostate cancer [42, 43]. Objec- “provide consistent support for the prostate cancer indicated that tive and subjective responses, and benefits of immediate treatment”. survival was increased by 2–3 % by survival and duration of response the addition of an to an were comparable [42, 43]. However, A further study by the Eastern LHRH analogue or orchiectomy [48]. leuprorelin was better tolerated [42, Cooperative Oncology Group However, the range of uncertainty 43] leading to fewer treatment with- (ECOG) was conducted in 98 patients regarding the true size of the benefit drawals than with DES [43]. Fewer who had undergone radical prostat- ranged from 0 % to about 5 %. adverse cardiovascular events occur- ectomy and had pelvic lymph node red with leuprorelin than with DES metastases (D1) [47]. Compared with Nevertheless, some studies using [42]. In a crossover study, patients deferred therapy, immediate anti- leuprorelin as a daily injection reported that their general health and androgen therapy improved survival alongside antiandrogens indicate social life were better with leupro- and reduced the risk of recurrence beneficial effects of MAB on progres- relin than with DES [44]. [47]. sion and survival [49–53] The largest of these was a double-blind rando- Deferred versus immediate therapy Other data also support immediate mised comparative study in 603 men treatment versus deferred treatment with metastatic prostate cancer [51– Whether hormonal therapy should in advanced disease [45, 46], inclu- 53]. Patients who received leupro- be initiated immediately or deferred ding Study 30846 of the European relin and had longer in patients who suffer biochemical Organisation for Research and progression-free survival than those relapse following radiotherapy or Treatment of Cancer (EORTC) [46]. who received leuprorelin alone (16.5 surgery for the primary tumour This prospective randomised study vs 13.9 months; p = 0.039). The me- remains a topic for debate. The included 412 patients with positive dian length of survival was also potential to prolong survival and lymph nodes who did not undergo a greater in patients who received delay the development of clinical previously planned radical prostat- MAB (35.6 vs 28.3 months; p = 0.035). symptoms are arguments for early ectomy, but were instead randomised The differences between the treat- treatment. Several studies have now to immediate or deferred hormone ments were particularly evident for shown that early hormonal treatment therapy. Early data from 84 patients men with minimal metastatic disease can delay the time to progression indicate that time to distant meta- (vertebrae only) and good perfor- and reduce the rate of cancer-related stases was prolonged by immediate mance status [51–53]. complications such as urinary therapy. obstruction and bone fractures [45, However, a randomised multicentre 46]. Leuprorelin in maximal androgen study [54] in 241 men, in which blockade (MAB) leuprorelin was compared with leupro- For example, a large study by the UK relin plus flutamide in advanced Medical Research Council in 938 LHRH analogues such as leuprorelin prostate cancer found no significant patients with locally advanced or block only testicular testosterone. differences in time to progression or asymptomatic metastatic prostate They have no effect on the 10 % of survival. The authors concluded that cancer compared immediate treat- testosterone produced by the adrenal the benefits of MAB in this study ment (orchiectomy or LHRH analogue) glands. Thus, even with maximally were “at best marginal”. and the same treatment deferred effective doses of LHRH analogues, until an indication occurred [8]. Pro- some testosterone will remain, which A further 160-week randomised, gression from M0 to M1 disease and could have a stimulatory effect on multicentre, open-label trial in 813 development of metastatic pain hormone-sensitive prostatic cancer patients assessed the efficacy and occurred more rapidly in deferred cells. MAB has been developed in an tolerability of two antiandrogens, patients, and transurethral resection attempt to reduce residual testosterone and flutamide, each for local progression was more likely from the adrenal glands, combining combined with one-month depot to be performed in deferred patients. an LHRH analogue with an antiandro- preparations of leuprorelin or gosere- Pathological fracture, spinal cord gen such as flutamide, or lin, in patients with stage D2 prostate compression, ureteric obstruction bicalutamide, or cancer. The percentages of patients and development of extraskeletal [48]. whose tumours progressed or who metastases were twice as common in died during the study were similar deferred patients. Significantly more The usefulness of MAB is contro- for goserelin plus antiandrogen and patients died from prostate cancer in versial and may vary among patient leuprorelin plus antiandrogen thera- the deferred arm; the difference was groups. A recent meta-analysis of pies [55]. There was no long-term

20 J. UROL. UROGYNÄKOL. Sonderheft 3/2002 LEUPRORELIN ACETATE IN PROSTATE CANCER: A EUROPEAN UPDATE difference between flutamide and observation period of 48 months, the the influence on survival of neoadju- bicalutamide in terms of survival, mean cumulative treatment-free vant treatment given before surgery, quality of life or subjective response period was 27 months. During the and further data are required before [56]. treatment-free intervals, patients definite conclusions can be drawn reported a decline in side-effects, on the role of this treatment [82]. Leuprorelin in intermittent MAB improvement in their general well- being and an increase in libido, With regard to radiotherapy, neoadju- Continuous androgen ablation produ- which was correlated with a return vant hormonal therapy is used for ces hormonal independence of some to normal serum testosterone levels. decreasing the size of prostatic tumour cells; these then become tumours and optimising the geometry dominant in the tumour and lead to However, phase II studies should be of the target volume. This allows the progression. It is argued that inter- regarded mainly as a demonstration volume of normal tissues exposed to mittent MAB will delay occurrence of the feasibility of the approach. high radiation doses to be reduced, of hormone resistance. It could also Several phase III studies are currently thus limiting the morbidity caused by preserve quality of life while off comparing tumour progression, safety treatment. It might also allow safe therapy and re-increase bone mineral and quality of life with intermittent delivery of higher radiation doses to content [57], allowing libido and or continuous MAB in patients with restricted tissue areas [83]. This potency to return [3]. Studies in metastatic prostate cancer [58, 68]. approach may result in an improve- animal models suggest that, when ment in the therapeutic ratio. In androgen suppression is cycled, Adjuvant and neoadjuvant therapy patients with localised prostate there appears to be recovery of cancer, down-sizing of the prostate apoptosis and subsequent slower Traditionally, the use of LHRH with leuprorelin treatment has been progression to an androgen-indepen- analogues has been confined to shown to reduce the volume of dent state [58]. However, inter- palliative therapy for locally bladder and rectum receiving high mittent MAB is at present still an advanced or metastatic prostate radiation doses [80, 84]. However, experimental therapy. cancer. However, they may also be as with surgery, follow-up studies are used to enhance the efficacy of needed to determine whether neo- Several phase II and III clinical trials surgical or radiological ablation of adjuvant therapy before radiotherapy of intermittent MAB in clinically the prostate. Adjuvant LHRH has any effect on long-term outcome. localised or metastatic prostate analogues have been shown to cancer have recently been reported improve both local control and Safety and tolerability [57–67]. Typically, MAB was given survival after radiotherapy [69, 70]. for lead-in treatment intervals of In one five-year follow-up study, LHRH analogues are, in general, well about 6–9 months. Off-treatment patients with clinically localised tolerated, with withdrawal rates in intervals were of variable length, prostate cancer with poor prognostic clinical studies of only 0–4 %, com- using PSA levels as a surrogate marker features who received short-term pared with 4–10 % for non-steroidal of disease reactivation [58]. These hormonal treatment in addition to antiandrogens [6]. A progressive phase II–III studies have demon- radiotherapy were more likely to decrease in bone density occurs with strated that repeat responses to show no biochemical evidence of increasing duration of androgen androgen deprivation are possible, disease than those who received deprivation therapy [84], although with off-treatment intervals of radiotherapy without short-term there is evidence that LHRH agonists varying length. Several suggest that adjuvant treatment [71]. There was lead to less treatment-induced bone quality of life is improved during off- also a trend towards better distant demineralisation than orchiectomy treatment intervals [67]. metastasis-free survival in patients [85, 86]. Pamidronate has been shown treated with short-term adjuvant to prevent bone loss in the hip and For example, an open, non-rando- . lumbar spine in men receiving treat- mised, prospective pilot study was ment with leuprorelin for prostate conducted in 44 patients with early Recently, there have been studies of cancer [87]. prostate cancer and rising PSA after the use of neoadjuvant treatment transurethral resection of the prostate with LHRH analogues to reduce the Clinical trials on leuprorelin indicate or radical prostatectomy [63]. Leupro- size of the prostate and downsize the good tolerability for both the one- relin (one-month depot) and cypro- tumour before radiotherapy or surgery. month [19, 31–36] and three-month terone were used to achieve MAB for Leuprorelin has been used in a depot injection [17, 21, 39]. The nine-month cycles, interspersed with number of such studies, usually tolerability of the one-month and variable treatment-free intervals alongside antiandrogens [72–84]. So three-month formulations is similar determined by serum PSA. Over an far, there are no conclusive data on (Table 2) [17, 21, 39]: 87.5 % of

J. UROL. UROGYNÄKOL. Sonderheft 3/2002 21 LEUPRORELIN ACETATE IN PROSTATE CANCER: A EUROPEAN UPDATE

Table 2. Side-effects experienced by patients receiving leuprorelin depot A six-month formulation is in develop- injection, 3.75 mg one-month or 11.25 mg three-month, over nine months ment. A change in the current six- [17] month depot formulation is required to extend the release of leuprorelin Side-effect 3.75 mg 1-month 11.25 mg 3-month from the microcapsules beyond three (% patients) (n = 80) (n = 157) months. The biodegradable polymer Hot flushes 60.0 47.8 technology has been changed to Increased sweating 42.5 36.3 achieve a six-month release of leupro- Decreased libido 28.8 23.6 relin, using recognised excipients. Atrophy of testicles 30.0 21.0 Pharmacokinetic studies in dogs Impotence 23.8 22.3 have confirmed the release profile of Skeletal pain 12.5 14.0 leuprorelin over a six-month period, Muscle weakness 15.0 10.8 and patient studies are now planned. Urinary tract infection 16.3 8.9 Fatigue 10.0 12.1 A 12-month leuprorelin implant as a Nocturia 10.0 11.5 titan capsule has been approved in Anorexia 7.5 11.5 the US: a slow-release device that Dysuria 10.0 8.3 delivers leuprorelin continuously for up to one year. It is surgically placed under the of the upper inner patients receiving one-month depot derate and withdrawal rates have arm, and an osmotic device inside injections and 83.4 % of those recei- been low. Local reactions at the the implant releases the drug at a ving three-month depot injections injection site occur in only about 3 % constant rate. In a two-year open- assessed their medication as “well of patients [35, 36]. In a study label trial involving 107 men, the tolerated” or “very well tolerated” comparing leuprorelin plus flutamide implant maintained castrate levels of [17]. with leuprorelin as a single agent, serum testosterone for one year [91]. the only side-effect more common in However, patient acceptance of the As with other LHRH analogues, first the combination group was diarrhoea, 12-month implant has been poor, administration of leuprorelin is almost certainly due to flutamide because the capsule has to be associated with an initial transient [51, 52]. removed by surgery after one year. elevation in testosterone levels, which may lead to an exacerbation of sym- ptoms in 10–30 % of patients [35, 42, 88, 89]. This “flare” subsides on continuation of therapy. Administra- NEW TREATMENT MODALITIES CONCLUSION tion of an antiandrogen is commonly used to reduce the risk of tumour flare [32, 52]. New formulations of leuprorelin are Today, LHRH analogues are the main- in development, and recent research stay of the treatment for locally Most of the other side-effects of suggests ways in which further flexi- advanced and metastatic prostate leuprorelin are related to its thera- bility may be added to an already cancer, and are usually preferred to peutic effects in reducing serum very adaptable administration orchiectomy or oestrogens. The testosterone, and include hot flushes, schedule. The injection system for efficacy of all the available LHRH increased sweating, decreased leuprorelin allows selected patients analogues in suppressing serum libido, atrophy of testicles and impo- to learn and practise self-injection, testosterone to castrate levels appears tence [17]. Gynaecomastia has been depending on local country product to be similar, but leuprorelin has the reported occasionally. Other adverse presentations [89]. This may lead to advantage being administered by events reported infrequently include increased independence for patients, depot injection rather than implant, peripheral oedema, fatigue, nausea, offering them extra choices, and may with the option of one-month or , arthralgia, dizziness, also involve them more in their own three-month administration. , paraesthesia, visual treatment. However, given that disturbances, weight changes and patients with prostate cancer are Unlike implants, leuprorelin one- irritation at the injection site. likely to see a doctor for regular month or three-month injection can check-ups, the number of patients usually be given by either a physician Most adverse reactions observed in wishing to self-inject is likely to be or other member of the healthcare clinical trials have been mild to mo- limited. team, depending on local product

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