This review paper discusses the importance of optimal testosterone control in prostate cancer (PCa) and the advantages of the luteinising hormone-releasing hormone (LHRH) agonist Eligard® in this respect.
During an expert meeting in Marbella, Spain, in October 2006, PCa experts discussed optimal testosterone control and the role of Eligard. An interactive voting on these topics was held among the delegates. This paper reports on this meeting.
LHRH agonists should suppress testosterone levels to an extent equivalent to surgical castration. A significant proportion of patients on conventional LHRH agonists do not achieve surgical castration levels. In addition, a significant percentage of patients experience hormonal escape during treatment. Eligard uses a modern delivery system and offers 1-, 3- and 6-mo depot formulations. The Eligard 1-mo, 3-mo, and 6-mo formulations achieve testosterone levels ≤20
Eligard provides optimal testosterone control in PCa patients, that is, achieves castration testosterone levels and is associated with a very low percentage of hormonal escapes. Eligard 6 offers flexibility in follow-up of patients and may help reduce emotional distress.
Keywords: Eligard, Hormone therapy, Leuprolide, Luteinising hormone-releasing hormone agonist, Prostate cancer, Testosterone.
Prostate cancer (PCa) is a major health care problem, being a common cancer in American men . The American Cancer Society (ACS) estimates that, during 2007, about 218,890 new cases of PCa will be diagnosed in the United States. Not only is PCa very common, it is also associated with a high mortality rate, being the second leading cause of cancer death. PCa accounts for about 10% of cancer-related deaths in men . When diagnosed with PCa, the patient and his physician have to choose from a wide range of therapies. Depending on stage and grade of the tumour and patient's life expectancy, treatment can be deferred until symptoms appear (expectant management) or the patient can be treated with radical prostatectomy, radiotherapy, androgen-deprivation therapy, or a combination of these treatments. Androgen-deprivation therapy has been the gold standard systemic therapy for the last 30 yr  and . If historically lowering the testosterone level was achieved by surgical castration or estrogen therapy, now luteinising hormone-releasing hormone (LHRH) agonists have become the standard of care for advanced, metastatic, and recurrent disease . Since the testosterone deprivation is reversible upon treatment interruption, LHRH agonists are also increasingly used in earlier stages of the disease in neoadjuvant or adjuvant setting to radiotherapy or surgery . During an expert meeting in Marbella, Spain, in October 2006, which was attended by around 135 European urologists, experts on PCa discussed the importance of optimal testosterone suppression in patients receiving hormone treatment for PCa and the advantages of the new formulation of leuprolide: Eligard® in terms of optimal testosterone control. The opinion of the delegates on several topics was gathered by means of interactive voting, and the results were commented on by the expert panel. This review paper documents the most relevant topics discussed during the meeting and discusses the results of the interactive voting.
2. Importance of optimal testosterone control
2.1. Defining castration testosterone levels
Since the studies of the Nobel Prize's laureate Charles Huggins nearly 60 yr ago, it has been known that PCa cells rely on critical level of androgens to grow and survive  and . Following castration, testosterone levels are suppressed, and prostate size and prostate specific antigen (PSA) levels decrease. By depriving PCa cells of testosterone, apoptosis is induced and the tumour shrinks. The testosterone level at which apoptosis is triggered is not known. The main goal of castration is thus to achieve and maintain low testosterone levels. But to what level should testosterone be suppressed? Although there are currently no clinical data available to support the concept that a low castration testosterone level is associated with better clinical outcomes, “the lower the better” has been advocated . Historically, castration testosterone levels achieved by orchidectomy were regarded as the reference level. This level was set at below 50
2.2. Castration by surgery or LHRH agonist?
Surgical castration by means of bilateral orchidectomy has for many years been the gold standard of castration until Andrew Schally  characterized the structure of LHRH. His research led to the development of synthetic peptide agonists of LHRH that offered new and more convenient alternatives for suppressing testosterone. Long-acting microcapsulated delivery systems for these LHRH agonists were developed and designed to release a controlled dose of the peptide over 1–3 mo. Although surgery is the most rapid method to achieve castration, LHRH agonists may lead to less psychological distress and are a flexible, reversible, and noninvasive method of castration. In a US study, 147 patients with previously untreated stage D PCa were asked whether they would prefer surgical castration or a monthly injection with the LHRH agonist goserelin . Of these patients, 115 (78%) chose goserelin, whereas only 32 (22%) chose orchidectomy. In the same study, quality of life (QoL), as measured by cancer-specific questionnaires, statistically significantly improved in patients treated with goserelin, whereas there was no change observed in patients treated with orchidectomy . With regard to adverse events (AEs), it appears that no major differences exist between orchidectomy and LHRH agonists concerning the rates of cardiovascular AEs (oedema, chest pain), digestive AEs (appetite change, constipation), musculoskeletal pain, and lethargy . The incidence of hot flushes may be somewhat higher with LHRH agonists compared with orchidectomy . A study performed by Potosky  somewhat contradicts these favourable data for LHRH agonists. A total of 431 men with PCa were treated either with orchidectomy (n
2.3. Do currently available LHRH agonists achieve and maintain castration levels?
Conventional LHRH agonists currently available on the market include leuprolide, buserelin, goserelin, and triptorelin, each available in depot formulations requiring monthly or 3-monthly injections. In light of the standard definition of ≤50
Effective androgen-deprivation therapy should be able not only to achieve castration testosterone levels but also to maintain these low testosterone levels. During long-term LHRH therapy, hormonal escapes may occur. Injection-related testosterone escapes or mini flares are defined as rises in testosterone levels >50
In conclusion, surgical castration reduces testosterone levels to ≤20
3. Eligard: advantages for optimal testosterone control
3.1. Eligard: an innovative second-generation delivery system
Eligard is a unique extended-release formulation of leuprolide that has been developed with the aim to provide optimal testosterone control, that is, to achieve and maintain castration levels in a larger proportion of patients than that achieved with the conventional formulations of LHRH agonists. Although the molecular structure of the different LHRH agonists is virtually the same, they differ in the delivery system used. Leuprolide, which uses a lyophylised microsphere drug depot delivery system, has been used for many years. Eligard uses a new delivery system: the Atrigel® delivery system, which consists of a biodegradable polymer of D,L-lactide-co-glycolide dissolved in N-methyl-2-pyrolidone . After mixing of the polymer and leuprolide, the formulation is injected subcutaneously as a liquid and forms a solid depot within the body for slowly releasing the drug  and , enabling a continuous and sustained release of leuprolide over the delivery period. Compared with the microsphere depot, this delivery system also provides a release of a 2-fold higher dose of leuprolide and maintenance of testosterone suppression for an additional 14 d . The superior Atrigel delivery system was used not only in 1- and 3-mo Eligard depot formulations but also led to the development of a unique 6-mo Eligard depot formulation (45
3.2. Optimal testosterone control with Eligard
In clinical trials, the 1-, 3- and 6-mo formulations of Eligard effectively suppressed testosterone levels. The mean testosterone levels after 6 mo of treatment with the 1-, and 3-mo formulations were 6.1
3.3. Tolerability of Eligard
Eligard 1, 3, and 6 seem to have a tolerability similar to conventional leuprolide microsphere depot formulations , , , , , , and . Most adverse events were related to testosterone suppression and are typical for LHRH agonists (eg, hot flushes, gynaecomastia, asthenia) (Table 1). Hot flushes were reported most frequently and were mainly mild or moderate in nature (Fig. 5) , , and .
|General LHRH agonists||Eligard|
4. Interactive voting: testosterone monitoring and hormone therapy in clinical practice
An interactive voting session was held during the expert meeting in Marbella. When the delegates were asked if they currently measured testosterone levels before initiating hormone therapy, 37% answered “never,” 35% “in some cases,” and 28% “in most cases/always.” According to the PCa experts, it is important to measure testosterone levels before initiating hormone therapy because this allows monitoring of the efficacy of therapy. The majority of the delegates (75%) considered a testosterone level of ≤20
A total of 94% of delegates more or less fully agreed with the statement “when initiating an LHRH agonist, my goal is to achieve “the lowest possible” level of testosterone” (Fig. 6). In addition, 82% of delegates indicated that the testosterone suppression achieved is important when choosing between LHRH agonist formulations (Fig. 6). The majority of the delegates (66%) also agreed that Eligard 6 offers practical advantages for selected PCa patients.
Although there is no objective evidence that a low castration testosterone level is associated with better clinical outcomes, we can assume that efforts should be made to control testosterone in a method comparable to orchidectomy. LHRH agonists should achieve castration testosterone levels and maintain these levels throughout long-term therapy to avoid variations during treatment. Eligard 1, 3, and 6 formulations achieve and maintain castration testosterone levels equal to orchidectomy. The unique Eligard 6 formulation provides urologists with the liberty in follow-up frequency because they are no longer tied to the 3-monthly injection regime. In addition, this formulation may decrease the psychological burden for the patient.
Conflicts of interests
The first author is a paid consultant for Astellas, AstraZeneca, Ferring, Pfizer, Ipsen, and sanofi-aventis. The second author has nothing to disclose.
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