Expert Opinion on Optimal Testosterone Control in Prostate Cancer

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1 European Urology Supplements European Urology Supplements 4 (2005) Expert Opinion on Optimal Testosterone Control in Prostate Cancer Alex Zlotta a,1, Frans M.J. Debruyne b, * a Department of Urology, University Clinics of Brussels, Erasme Hospital, Belgium, Route de Lennik 808, 1070 Brussels, Belgium b Academisch ziekenhuis Nijmegen St. Radboud, Geert Grooteplein 10, Postbus 9101, 6500 HB Nijmegen, The Netherlands Abstract There are currently no definitions regarding Optimal testosterone control in Prostate Cancer. Therefore an Expert Consensus Meeting (May , San Antonio, USA) and an expert consultation at a Discussion Forum during the 6 th International Consultation on New Developments in Prostate Cancer and Prostate Diseases (June , Paris, France), have been organised to discuss definitions regarding Optimal testosterone control in Prostate Cancer. The experts attending the Expert Consensus Meeting received background information based on recently published data and the predefined definitions and/or recommendations that needed to be discussed. During this meeting, the experts agreed that the term castration is misleading in case of luteinising hormone releasing hormone (LHRH) agonists, as castration stands for surgical removal of the testes, by bilateral orchiectomy. The experts believe that bilateral orchiectomy should be used as a benchmark for introducing the appropriate testosterone level that needs to be achieved with LHRH agonists. As most patients will achieve and maintain a testosterone level of 20 ng/dl after bilateral orchiectomy, the experts agreed that this level should be used for defining chemical castration. Furthermore, the experts agreed that a testosterone rise from nadir above 50 ng/dl could be considered as clinically relevant and could have implications on treatment. In order to reflect previous agreements with a larger group of experts in the field, questions regarding Optimal testosterone control in Prostate Cancer were asked to the delegates of the Discussion Forum using an interactive voting system. Before the interactive voting session, the currently published data were presented to the audience. Similar to the experts, the delegates also indicated that achieving the lowest testosterone level possible is their main goal of hormone therapy. 64% of the delegates agreed that they would consider a castrate level of below or equal to 20 ng/dl to be optimal. # 2005 Published by Elsevier B.V. Keywords: Prostate cancer; Testosterone; LHRH agonists; Appropriate testosterone suppression; Testosterone rise; Expert consensus meeting; Guidelines; Expert consultation 1. Introduction The importance of achieving and maintaining effective testosterone suppression is well recognised in the treatment of prostate cancer [1,2] and discussed in the * Corresponding author. Present address: Radboud University Nijmegen, Medical Centre Department of Urology 426, Geert Grooteplein 10, Postbus 9101, 6500HB Nijmegen, Netherlands. Tel ; Fax: addresses: azlotta@ulb.ac.be (A. Zlotta), f.debruyne@uro.umcn.nl (Frans M.J. Debruyne). 1 Tel ; Fax: article by Tombal and Berges [3]. As a consequence, achieving low testosterone levels is the main goal of hormone therapy. Historically bilateral orchiectomy was the standard treatment for achieving this goal. However, with the advent of luteinising hormone releasing hormone (LHRH) agonists, which quickly became the preferred method for suppressing testosterone, the post treatment target level was historically set at below 50 ng/dl because of detection limits of old assays. Several authors have challenged this empirically set target level of testosterone and claim the lower the testosterone the better [4]. With the availability of /$ see front matter # 2005 Published by Elsevier B.V. doi: /j.eursup

2 38 A. Zlotta, F.M.J. Debruyne / European Urology Supplements 4 (2005) new detection methods which enable to detect serum testosterone levels below 50 ng/dl [5], discussion arises concerning the appropriate level of testosterone to be achieved and maintained with LHRH agonists. Currently, there is no agreement on the optimal level of testosterone to be achieved. Also it is not clear at what point a rise in testosterone after LHRH agonist therapy becomes relevant. Consequently, it is not surprising that large practice variations exist towards the measurement and interpretation of testosterone levels before (at diagnosis) and/or during hormone therapy (follow-up). In order to discuss these issues, expert opinion was explored at both an Expert Consensus Meeting (May , San Antonio, USA) and a Discussion Forum (June , Paris, France) during the 6 th International Consultation on New Developments in Prostate Cancer and Prostate Diseases. 2. Expert Consensus Meeting Prior to the Expert Consensus Meeting, the experts (list of experts see Appendix A) received background information (see Appendix B) based on currently published data and two forms with pre-defined definitions and/or recommendations that needed to be discussed during the meeting. The purpose of these forms was to upfront prepare individual suggestions for annotating the pre-developed definitions and/or to formulate comments on the different definitions to be discussed. The forms were the basis for the structured debate leading to the proposed definitions and statements. The debate was moderated by F. Debryune Definition of castration? The experts concluded that the term castration is misleading in relation to LHRH agonist therapy. This term originates from the application of bilateral orchiectomy and stands for surgical removal of the testes and can therefore not be applied as such to LHRH agonist therapy Definition of optimal testosterone suppression? The experts concluded that optimal testosterone suppression after LHRH agonist therapy should be seen in comparison to the testosterone levels obtained after orchiectomy. They agreed on the following statement: Using orchiectomy as the benchmark, achieving testosterone levels below/equal to 20 ng/dl after LHRH agonist therapy would be desirable. However, several comments were made complementing this statement: 1. The relationship between testosterone values obtained after treatment and clinical outcomes remains unknown. Unfortunately this has not yet been appropriately addressed in clinical studies. 2. The former assays were not sensitive enough to detect low testosterone levels [5]. The optimal range of mostly used testosterone assays is within normal testosterone levels. 3. There is an important inter-assay and intra-assay variability complicating the interpretation of currently available data. The optimal testosterone suppression discussion was concluded with the following statement: Giving all circumstances being the same, achieving lower testosterone values, is better Testosterone rise after initial suppression? Patients may experience a rise in testosterone levels after initial suppression. This could indicate a treatment failure and may have clinical consequences for the patient. It was debated that unfortunately virtually no data are available on this subject. From previous definition point of view, each testosterone rise above the level of 20 ng/dl may be indicative for a treatment failure. However, in the clinical context of patient management this makes no sense as this would mean that a testosterone rise to 21 ng/dl indicates a therapy failure, while 19 ng/dl is not. Additionally, due to the intra-assay variability, a deviation of about 7% should be accounted for when interpreting testosterone values. Therefore the expert team concluded that a testosterone rise of minimally 10% above previous castrate level can be considered as a real rise. With the absence of good data on defining a clinically significant testosterone rise, the experts agreed, based upon their experience, to the following statement: A rise in testosterone from nadir above 50 ng/dl, is considered to be clinically significant and should have implications for treatment Recommendations for testosterone testing? Although testosterone levels currently are rarely measured in clinical practice, most physicians are aware that the patient s testosterone level is important information to verify the potential reasons of unexpected prostate specific antigen (PSA) rises.

3 Due to the limited information available on the prognostic value of testosterone testing and the difficulties in understanding the meaning of absolute values, the expert panel decided that no firm recommendations could be made for testing testosterone in clinical practice. However, the expert team felt that more attention should be given to testosterone testing in the future, mainly at diagnosis (for prognosis) and sudden relevant PSA rise (therapy failure). A. Zlotta, F.M.J. Debruyne / European Urology Supplements 4 (2005) Discussion Forum Around 400 of the delegates at the 6 th International Consultation on New Developments in Prostate Cancer and Prostate Diseases, participated in the discussion forum on Optimising testosterone control in Prostate Cancer chaired by A. Zlotta. After an introduction to the meeting by A. Zlotta, B. Tombal presented his view on optimal testosterone control in prostate cancer [6]. After this presentation, the delegates could answer questions related to optimal testosterone control using interactive key-pads enabling display of the voting results to the audience. The votes after each question were closed when more than one hundred delegates had transferred their answers Monitoring testosterone levels To obtain a general picture, the first two questions of the Discussion Forum investigated the testosterone monitor behaviour of the audience (Figs. 1 and 2). Only a quarter of the delegates (29%) indicated that they never measure their patients testosterone level. Half of the respondents (49%) claim to know the testosterone level of a few patients, while only 4 13% of the audience claim to know the testosterone level of, respectively, all or the majority of patients (Fig. 1). Fig. 2. Half of the respondents measure the patient s testosterone level in case of a relevant PSA rise, while only 21% measure the testosterone level at least once during LHRH agonist therapy. A quarter of the respondents (26%) claim they never monitor the patients testosterone levels (Fig. 2). Half of the respondents indicate to measure the patient s testosterone level in case of a relevant and/ or unexpected PSA rise. About a quarter of the respondents (21%) further indicate to measure testosterone at least once during LHRH agonist therapy (Fig. 2) The lowest testosterone level possible Specific questions related to Optimizing hormone therapy in Prostate Cancer investigated the opinion of the delegates concerning the appropriate level of testosterone to be achieved and maintained by their prostate cancer patients. About 80% of all delegates agreed that, when opting for hormone therapy, the main goal of therapy is to achieve the lowest possible level of testosterone (Fig. 3). Two-thirds (64%) of the respondents indicated that they would target to achieve a testosterone level of below or equal to 20 ng/dl instead of the conventional 50 ng/dl threshold (Fig. 4). Fig. 1. About 50% of the delegates monitor the testosterone level of a few patients. Fig. 3. Over 80% of the respondents indicate that the lower the testosterone level the better.

4 40 A. Zlotta, F.M.J. Debruyne / European Urology Supplements 4 (2005) Prof. Kurt Miller, Germany kurt.miller@medizin.fu-berlin.de 5. Prof. Per-Anders Abrahamsson, Sweden per-anders.abrahamsson@skane.se 6. Prof. David Crawford, USA david.crawford@uchsc.edu 7. Dr. Gerald L. Andriole, USA andrioleg@msnotes.wustl.edu 8. Dr. Oliver Sartor, USA osarto@lsuhsc.edu 9. Prof. Laurence Klotz, Canada Laurence.Klotz@sw.ca Fig. 4. Two-thirds of the respondents would replace the conventional castrate level of 50 ng/dl by a testosterone level of 20 ng/dl. 4. Conclusions This is the first report of an attempt to using expert opinions to explore definitions on optimal testosterone suppression with hormone therapy. Limited information exists on the relationship of testosterone values and clinical outcomes. In the absence of this information, the expert team felt that given all treatment circumstances being the same, the treatment achieving and maintaining the lowest testosterone values is the best. Following the discussion of the lower the better, the experts agreed that LHRH agonist therapy should be able to achieve and maintain testosterone levels close to the ones obtained after the gold standard treatment, orchiectomy. Current trials with new and more accurate detection limits revealed that patients are able to achieve and maintain testosterone levels below 20 ng/dl after orchiectomy, instead of below the conventional 50 ng/dl, as assumed and adopted for many years. Similarly to the experts, a large group of delegates at the 6 th International Consultation on New Developments in Prostate Cancer and Prostate Diseases confirmed that achieving the lowest testosterone level possible is their main goal of hormone therapy. 64% of this group agreed that they would consider a castrate level of below or equal to 20 ng/dl to be optimal. Appendix A. List of experts 1. Prof. Frans Debruyne (Chair), the Netherlands f.debruyne@uro.umcn.nl 2. Prof. Claude C. Schulman, Belgium Claude.Schulman@ulb.ac.be 3. Prof. Laurent Boccon-Gibod, France Laurent.Boccon-Gibod@bch.ap-hop-paris.fr Appendix B. Background information reference list 1. Oefelein MG, Resnick MI. Effective testosterone suppression for patients with prostate cancer: is there a best castration? Urology 2003;62(2): Byar DP, Corle DK. Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative Urological Research Group studies. NCI Monogr 1988;7: Jordan WP, Blackard CE, Byar DP. Reconsideration of orchiectomy in the treatment of advanced prostatic carcinoma. South Med J 1977;70: 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): 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): 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): Wheeler MJ, D Souza A, Matadeen J, Croos P. Ciba Corning ACS:180 testosterone assay evaluated. Clin Chem. 1996;42(9): 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):502 8.

5 A. Zlotta, F.M.J. Debruyne / European Urology Supplements 4 (2005) 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): Vogelzang NJ, Chodak GW, Soloway MS, Block NL, Schellhammer PF, Smith JA Jr, et al. Goserelin versus orchiectomy in the treatment of advanced prostate cancer: final results of a randomized trial. Zoladex Prostate Study Group. Urology 1995;46(2): Lin BJ, Chen KK, Chen MT, Chang LS. The time for serum testosterone to reach castrate level after bilateral orchiectomy or oral estrogen in the management of metastatic prostatic cancer. Urology 1994;43(6): Perez-Marreno R, Chu FM, Gleason D, Loizides E, Wachs B, Tyler RC. A six-month, open-label study assessing a new formulation of leuprolide 7.5 mg for suppression of testosterone in patients with prostate cancer. Clin Ther 2002;24(11): Chu FM, Jayson M, Dineen MK, Perez R, Harkaway R, Tyler RC. A clinical study of 22.5 mg. LA-2550: A new subcutaneous depot delivery system for leuprolide acetate for the treatment of prostate cancer. J Urol 2002;168(3): Sartor O, Dineen MK, Perez-Marreno R, Chu FM, Carron GJ, Tyler RC. An eight-month clinical study of LA mg: a new 4-month, subcutaneous delivery system for leuprolide acetate in the treatment of prostate cancer. Urology 2003; 62(2): Kawakami J, Morales A. A comprehensive hormonal evaluation in patients with cancer of the prostate on androgen supression with LHRH agonists. J Urol 2002(Suppl 4);167:288 (abs. 1135). 16. Sarosdy MF, Schellhammer PF, Soloway MS, Vogelzang NJ, Crawford ED, Presti J, et al. Endocrine effects, efficacy and tolerability of a 10.8-mg depot formulation of goserelin acetate administered every 13 weeks to patients with advanced prostate cancer. BJU Int 1999;83(7): Jocham D. Leuprorelin three-month depot in the treatment of advanced and metastatic prostate cancer: long-term follow-up results. Urol Int 1998;60 (Suppl 2): Khan MS, O Brien A. An evaluation of pharmacokinetics and pharmacodynamics of leuprorelin acetate 3M-depot in patients with advanced and metastatic carcinoma of the prostate. Urol Int 1998;60(1): Morote J, Esquena S, Abascal JM, Trilla E, Cecchini L, Ravenos CX, et al. In Press. 20. Zinner NR, Bidair M, Centeno A, Tomera K. Similar frequency of testosterone surge after repeat injections of goserelin (Zoladex) 3.6 mg and 10.8 mg: results of a randomized open-label trial. Urology 2004;64(6): 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] Jordan WP, Blackard CE, Byar DP. Reconsideration of orchiectomy in the treatment of advanced prostatic carcinoma. South Med J 1977; 70: [3] Tombal B, Berges R. How good do current LHRH agonists control testosterone? Can this be improved with Eligard 1? Eur Urol Suppl. 2005;(4):30 6. [4] Oefelein MG, Resnick MI. Effective testosterone suppression for patients with prostate cancer: is there a best castration? Urology 2003;62(2): [5] 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): [6] Tombal B. Appropriate castration with luteinising hormone releasing hormone (LHRH) agonists: what is the optimal level of testosterone? Eur Urol Suppl 2005;4:14 9.