Appropriate Castration with Luteinising Hormone Releasing Hormone (LHRH) Agonists: What is the Optimal Level of Testosterone?

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1 European Urology Supplements European Urology Supplements 4 (2005) Appropriate Castration with Luteinising Hormone Releasing Hormone (LHRH) Agonists: What is the Optimal Level of Testosterone? B. Tombal* Service d Urologie, Cliniques universitaire Saint-Luc UCL, Hippokrateslaan 10, 1200 Sint Lambrechts-Woluwe, Brussels, Belgium Abstract Traditionally serum testosterone castration levels were set at a minimum of 50 ng/dl. Achieving and maintaining these castration levels are the main goal of therapy with luteinising hormone releasing hormone (LHRH) agonists. As the optimal castration level remains debated, this paper aims to review published literature challenging the 50 ng/ dl definition, as well as studies evaluating the effects of LHRH agonists on testosterone suppression. A Medline search was performed in the last quarter of Only fully published studies and review articles in English language were included. The threshold of 50 ng/dl has been set arbitrarily, based on the available measuring techniques. As those techniques are developed in the late 1960s and current techniques are more accurate, this article discusses elements for defining an appropriate castration as achieving testosterone levels below 20 ng/dl. Ideally, chemical castration with LHRH agonists should achieve similar testosterone levels as those obtained with orchiectomy (15 ng/dl). As a consequence, using orchiectomy as a benchmark would favour 20 ng/dl over 50 ng/dl as a cut-off point for appropriate castration. LHRH agonists have been thought to achieve an almost 100% of response in the initial therapy. Several studies have shown that when using a more stringent definition of castration, treatment with current LHRH agonists does not achieve this goal. As a consequence, measurement of testosterone should regain attention for evaluating treatment response to LHRH agonists as well as for monitoring breakthroughs and acute-on-chronic responses. # 2005 Elsevier B.V. All rights reserved. Keywords: Prostate cancer; Testosterone; Hormonal escape; Breakthrough response; Acute-on-chronic response; LHRH agonists; Castration level; Review 1. Introduction Since the studies of Nobel Prize s laureate Charles Huggins nearly 60 years ago, it has been known that prostate cancer cells rely on a critical level of androgens to grow and survive. On this basis, androgen withdrawal, whether surgically or medically induced, has been the standard form of systemic therapy for advanced prostate cancer for more than 4 decades. For many years, oral oestrogens have been the sole alternative to surgical castration. Although relatively cheap * Tel ; Fax: address: bertrand.tombal@fymu.ucl.ac.be. and effective, they may lead to fluid retention, congestive heart failure, deep veins thrombosis, pulmonary embolism, myocardial infarction and strokes [1]. Surgical castration with bilateral orchiectomy has been regarded as the standard of castration, until Andrew Schally characterized the structure of the luteinizing hormone releasing hormone (LHRH) [2]. A. Schally investigated ways to manipulate this system, like developing synthetic peptide agonists of LHRH. Following this seminal work, several synthetic LHRH agonists were subsequently developed and tested for clinical use. Long-acting microcapsulated delivery systems for these LHRH agonists were developed that were designed to release a controlled dose of /$ see front matter # 2005 Elsevier B.V. All rights reserved. doi: /j.eursup

2 B. Tombal / European Urology Supplements 4 (2005) the peptide over 1 3 months. These agonists have been tested in several clinical trials and were found to be as effective as diethylstilbestrol (DES) in treating prostate cancer [3]. Like other approaches to lowering serum testosterone, treatment with LHRH agonists causes significant side effects, such as hot flushes, loss of libido and impotence. These agents, however, do not lead to the increased thromboembolic events that are associated with oestrogen therapy [3]. A. Schally received the Nobel Prize in Medicine in 1977 and back from these early eighties, surgical castration has been replaced by medical castration. Therapy with LHRH agonists has offered an effective and well tolerated treatment option for men diagnosed with prostate cancer, as discussed by P. Mongiat-Artus, in this supplement [4]. When opting for castration, the goal of physicians is to achieve low testosterone levels. Oefelein et al. [5] postulated the lower the better when trying to achieve castration levels of testosterone. But how low is good enough? What is an appropriate castration level? Currently, many physicians consider the achievement of testosterone levels of less than 50 ng/dl (1.73 nmol/l) as indicative for efficacy of LHRH agonist therapies. But is 50 ng/dl the appropriate cut-off point? This article will discuss in more detail the issues related to the achievement of testosterone castration levels of 50 ng/dl and will evaluate 20 ng/dl (0.7 nmol/l) as a more appropriate cut-off point. 2. Castration levels Serum testosterone is considered to be suppressed if two consecutive (on separate days) values of less than 50 ng/dl occurred. Onset of suppression is considered to be the first day on which these suppressed values occurred [6]. This definition, postulated by Sharifi et al. [6], was applied in many clinical trials. Most physicians consider LHRH agonists efficacious when achieving testosterone levels below 50 ng/dl. The importance of low testosterone levels has been recognised for a long time. In 1977, studies with 0.2 mg DES demonstrated that ineffective androgen suppression therapy results in higher prostate cancer mortality [1,7]. Today appropriate testosterone reduction is still the main goal to treat locally advanced and metastatic prostate cancer. Amazingly, only few authors have challenged the historically set definition of 50 ng/dl, since the availability of newer and more accurate dosing methods Old assay methods The testosterone castrate levels of 50 ng/dl are derived from old assay methods. The double-isotopederivate dilution technique to measure serum testosterone was developed in the late 1960s and early 1970s [8]. However, this technique has been reported to have limitations in accuracy and is no longer used [9]. In 1995, the fully automated immunoassay analyser, using chemiluminescent technology, was approved for clinical use. This technique already permitted more accurate serum testosterone measurements, while also decreasing the waiting time for results [10]. Currently, the sensitivity of the assays used to measure serum testosterone levels are as low as 0.1 ng/ml [11]. Development of these new analytical methods, like chemiluminescent testing, makes it possible to detect serum testosterone levels more accurately and well below 50 ng/dl Orchiectomy as benchmark Oefelein et al. [8] undertook a study to re-evaluate the castrate level achieved with orchiectomy using modern dosing methods (chemiluminescent immunoassay method). A group of 35 patients with advanced prostate cancer underwent bilateral orchiectomy and received no additional hormonal therapies. Thirtythree months after orchiectomy, median total testosterone was decreased to 15 ng/dl (0.5 nmol/l; 95% CI 12 to 17 ng/dl). Additionally, the maximum and minimum testosterone values observed were 30 and less than 10 ng/dl, respectively. Overall, the most important observation of this study is that patients after orchiectomy rarely exceed the testosterone threshold of 20 ng/dl. Consequently, one could postulate that 20 ng/dl is a more appropriate cut-off point for defining castration. When reviewing other studies investigating the safety and efficacy of orchiectomy in prostate cancer patients, similar results were found. Kaisary et al. [12] found that mean serum testosterone decreased by week 4 after orchiectomy to 0.91 nmol/l (26.3 ng/dl) in patients with metastatic disease. Røhl and Beuke [13] reported even lower values. One month after orchiectomy, median serum testosterone decreased towards nmol/l (21.0 ng/dl). Lin et al. [14] compared the time to castration between oral oestrogen and bilateral orchiectomy in 20 patients with metastatic disease. The threshold of castrate serum testosterone was considered to be less than 20 ng/dl. Between 3 and 12 hours (mean hours) after patients underwent orchiectomy, all men managed to achieve this low testosterone level. Vogelzang et al. [15] com-

3 16 B. Tombal / European Urology Supplements 4 (2005) pared medical castration with goserelin versus orchiectomy in 283 patients with stage D2 prostate cancer. Also in this study, patients who underwent orchiectomy reached castrate levels of 20.0 ng/dl at week 4. If we take a testosterone level below 20 ng/dl as the definition of optimal castration, the question arises whether LHRH agonists administration achieves this goal in the majority of patients. Oefelein et al. [16] addressed this question and enrolled 38 patients with prostate cancer to investigate the failure of achieving this castration level after LHRH agonist therapy. All 38 patients in this study received a 3-month depot LHRH agonist (leuprolide or goserelin) and 750 mg flutamide daily. In a significant number of patients (13%) on androgen suppression therapy, the 20 ng/dl castrate cut-off was not achieved and in about 5% of patients, values below 50 ng/dl were not achieved. These results have been confirmed by several other groups (Fig. 1) Trends towards 20 ng/dl castration levels Most physicians use the testosterone castration threshold of 50 ng/dl in daily clinical practice. Also many studies evaluating the efficacy and safety of several LHRH agonists use this cut-off point for reporting results. With the advent of the modern dosing methods, more recent studies [17 20] recognise the importance of accurately measuring testosterone levels and also report the number of patients below 20 ng/dl testosterone. In some publications, like the 2002 study of Kawakami et al. [20], only reports on efficacy using a 20 ng/dl cut-off are used. This study demonstrated that 17.6% of patients did not reach this castrate level. Fig. 1. The percentage of patients that do not reach testosterone castration levels below 50 ng/dl is negligible. Setting the castration threshold on 20 ng/dl is more reliable, as seen that more patients do not reach this threshold [16 18,29]. 1, 3 M: depot formulation of respectively 1 or 3 months; L: leuprolide. 3. Hormonal escapes Although most patients reach testosterone castration levels after 3 4 weeks, there is always the possibility of a hormonal escape during LHRH agonist therapy. A hormonal escape, which is defined as an increase in serum testosterone after castration levels have been achieved, is an important clinical consideration. Although these testosterone escapes are indications for a therapeutic failure, they are often not recognised by the physician. Also, no clear definition exists regarding hormonal escapes. One can divide hormonal escapes into breakthrough responses and acute-onchronic responses. In order to discriminate between patients having a breakthrough response and patients suffering from an acute-on-chronic response, both will be discussed in more detail below. In its conventional definition serum testosterone is considered suppressed appropriately if its levels decline below 50 ng/dl [6]. As a consequence, both breakthrough and acute-on-chronic responses occur after the patient has reached castrate levels below 50 ng/dl. A breakthrough response is defined as the occurrence of one single testosterone increase above 50 ng/dl, during the whole LHRH agonist treatment period. An acute-on-chronic response, on the other hand, is associated with the administration of the LHRH agonist. In contrast with the flare phenomenon, an acute-on-chronic response is not associated with the first LHRH agonist injection, but only from the second and subsequent injections. Also, this escape needs to be detected at maximally 12 hours following re-injection to be defined as an acute-on-chronic response [6,17] Breakthrough response As seen in Fig. 2, about 7% of patients will experience a breakthrough response during their treatment period with a LHRH agonist. Sarosdy et al. [21] reports a study of 58 patients with advanced or metastatic prostate cancer who received 10.8 mg goserelin every 13 weeks. Only one patient (2%) reported a breakthrough response, at week 8. Unfortunately, the authors did not mention if the response was associated with increased side effects. Long-term follow-up results of Jocham et al. [22] reported the efficacy of a 3-month leuprolide (11.25 mg) depot in 62 patients with advanced prostate cancer. Four patients (6.5%) were identified with a breakthrough response. Two of them had only one increase above 50 ng/dl, but one patient had fluctuating testosterone levels throughout the follow-up. One patient reported increased testosterone levels, accom-

4 B. Tombal / European Urology Supplements 4 (2005) Fig. 2. About 7% of patients receiving LHRH agonists will have a breakthrough response, if the castration level is set at 50 ng/dl [21 23]. 3 M: 3 month depot formulation; G: goserelin; L: leuprolide. panied by local tumour response, this breakthrough response is clearly an indication for a therapeutic failure. Khan et al. [23] also investigated the efficacy of a 3- month depot of leuprolide (11.25 mg) in patients with advanced prostate cancer (n = 24). Before the re-injection, 3 patients (12.5%) reported a breakthrough response defined as a testosterone increase above 50 ng/dl Acute-on-chronic response Fig. 3 shows the percentage of patients with an acute-on-chronic response after re-injection with a LHRH agonist for two different thresholds. A study comparing the 1- and 3-month depot formulations of leuprolide (7.5 mg and 22.5 mg, respectively) enrolled 71 patients with advanced prostate cancer [6]. In the 1-month depot group, 2 patients Fig. 3. If the castration level is set at 50 ng/dl, about 6% of patients will have an acute-on-chronic response [6,21,24]. 1, 3 M: depot formulation of respectively 1 or 3 months; G: goserelin; L: leuprolide. (5.9%) had minor testosterone increases following the second depot injection. One patient had increases towards 53 ng/dl (4 hours after re-injection) and the second patient towards 56 ng/dl (8 hours after re-injection). One patient (2.9%) experienced a testosterone increase after the third depot injection. In the 3- month depot group, no values greater than 50 ng/dl were seen after re-stimulation. Sarosdy et al. [21] reported on the efficacy of the 3-month depot formulation (10.8 mg) of goserelin. Six patients (10%) showed rising testosterone levels of respectively 56, 58, 60, 75, 111 and 192 ng/dl. Zinner et al. [24] compared the 1-month (3.6 mg) and the 3-month (10.8 mg) depot injections of goserelin in 237 patients with advanced prostate cancer. Acute-on-chronic responses occurred in 34 patients (27.0%) of the 1-month goserelin group and in 20 patients (17.7%) of the 3-month goserelin group. The magnitude of the testosterone surge to greater than 18.5 ng/dl ranged from ng/dl in the 1-month goserelin group, and ng/dl in the 3-month goserelin group. However, the testosterone castration range was set at 18.5 ng/dl, which explains the higher number of patients with an acute-on-chronic response as compared to previous studies. 4. Testosterone as a trigger for re-dosing depot LHRH agonists Oefelein et al. [16] found that 5% of patients failed to achieve the castrate level of 50 ng/dl and 13% of patients fail to achieve castrate levels of 20 ng/dl. These findings support the conclusion that the standard dose of depot LHRH agonists may be inadequate in some men. However, it has also been reported that depot LHRH agonists provide an excessive castrate testosterone duration [25]. Consequently, re-dosing of depot LHRH agonists based on serum testosterone has been proposed [26]. Thirty-two men diagnosed with prostate cancer stage T3N or more, received the LHRH agonist leuprolide in a 3-month depot injection. Castration levels were defined as 20 ng/dl or less. The median duration of castration was 6.0 months (range ). As seen in Fig. 4, median serum testosterone values beginning 3 months after the last leuprolide depot injection, and monthly intervals thereafter, remain below the castrate level of 20 ng/dl for up to 7 months. Maximum testosterone values only exceed the 50 ng/dl threshold after 7 months, demonstrating the long acting effect of a 3 month depot leuprolide injection. Recently, health related quality of life (QoL) has been assessed in patients with prostate cancer on

5 18 B. Tombal / European Urology Supplements 4 (2005) These data have significant implications. The design and interpretation of clinical trials of LHRH agonists in a neoadjuvant or adjuvant treatment must consider the time-course of testosterone recovery. An option here is that testosterone levels should be measured during the study as well as prostate specific antigen (PSA) levels. 5. Conclusion Fig. 4. Median serum testosterone level remains below 20 ng/dl for up to 6 months, after the administration of a 3-month depot LHRH agonist [26]. LHRH agonist therapy, who were re-dosed based on serum testosterone values [27]. Patients received a 3-month depot LHRH agonist (goserelin) to achieve testosterone castration levels below 20 ng/dl. If testosterone increased above this threshold, goserelin was re-administered and a new cycle was repeated. The median duration of castrate testosterone levels was 5.5 months (mean 6 months, range ). However, the most important observation was that the patient s assessed health related QoL was improved in the short term and the cost of care was decreased by 50% with no loss in the patient s satisfaction. Hall et al. [28] also reported these prolonged results after cessation of therapy. Patients in this study group had received LHRH agonist therapy for 24 months or longer, until therapy was stopped. Twelve months after cessation, 28.6% of patients still had castrate levels below 50 ng/dl. Median testosterone level for all patients remained in the castrate range at 6 months (44.0 ng/dl) and at 9 months (44.5 ng/dl). The importance of effective androgen suppression therapy is well recognised because ineffective testosterone suppression may result in increased prostate cancer mortality. The availability of new and more accurate assay methods has enabled to detect serum testosterone levels below the threshold of 20 ng/dl. This has triggered the question whether achieving testosterone levels below 50 ng/dl corresponds to optimal castration. If one uses the castration level obtained with orchiectomy as benchmark, 20 ng/dl is a better cutoff point for defining appropriate castration and treatment response. Recent publications have shown that several patients treated with current LHRH agonist formulations do not achieve appropriate castration levels, show breakthroughs and acute-on-chronic responses, particularly if one uses the more stringent definition of 20 ng/dl. Physicians today are not routinely evaluating the testosterone level when initiating and evaluating therapy. The measurement of testosterone should become part of clinical practice when evaluating the effects of hormonal therapy. References [1] Byar DP, Corle DK. Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative Urological Research Group studies. NCI Monogr 1988;7: [2] Schally AV, Kastin AJ, Arimura A. Hypothalamic FSH and LHregulating hormone. Structure, physiology and clinical studies. Fertil Steril 1971;22: [3] The Leuprolide Study Group. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Engl J Med 1984;311: [4] Mongiat-Artus P, Teillac P. Role of luteinising hormone releasing hormone (LHRH) agonists in the management of prostate cancer. Eur Urol Suppl 2005;4(5):4 13. [5] Oefelein MG, Resnick MI. Effective testosterone suppression for patients with prostate cancer: is there a best castration? Urology 2003;62(2): [6] Sharifi R, Browneller R, Leuprolide Study Group. Serum testosterone suppression and potential for agonistic stimulation during chronic treatment with monthly and 3-month depot formulations of leuprolide acetate for advanced prostate cancer. J Urol 2002;168(3): [7] Jordan WP, Blackard CE, Byar DP. Reconsideration of orchiectomy in the treatment of advanced prostatic carcinoma. South Med J 1977; 70: [8] Oefelein MG, Feng A, Scolieri MJ, Ricchiutti D, Resnick MI. Reassessment of the definition of castrate levels of testosterone: implications for clinical decision making. Urology 2000;56(6): [9] Wilke TJ, Utley DJ. Total testosterone, free-androgen index, calculated free testosterone, and free testosterone by analog RIA compared in hirsute women and in otherwise-normal women with altered binding of sex-hormone-binding globulin. Clin Chem 1987;33(8): [10] Wheeler MJ, D Souza A, Matadeen J, Croos P. Ciba Corning ACS:180 testosterone assay evaluated. Clin Chem 1996;42(9): [11] Zherdev AV, Byzova NA, Izumrudov VA, Dzantiev BB. Rapid polyelectrolyte-based immunofiltration technique for testosterone detection in serum samples. Analyst 2003;128(10): [12] Kaisary AV, Tyrrell CJ, Peeling WB, Griffiths K. Comparison of LHRH analogue (Zoladex) with orchiectomy in patients with metastatic prostatic carcinoma. Br J Urol 1991;67(5): [13] Rohl HF, Beuke HP. Effect of orchidectomy on serum concentrations of testosterone and dihydrotestosterone in patients with prostatic cancer. Scand J Urol Nephrol 1992;26(1):11 4.

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