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Hormone Therapy: Improving Therapy Decisions and Monitoring
european urology supplements 5 (2006) 369–376
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Hormone Therapy: Improving Therapy Decisions and Monitoring Alexandre R. Zlotta a,*, Per-Anders Abrahamsson b, Bertrand Tombal c, Richard Berges d, Frans Debruyne e a
University Clinics of Brussels, Erasme Hospital, Brussels, Belgium Malmo¨ University Hospital, Malmo¨, Sweden c Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium d PAN-Klinik am Neumarkt, Cologne, Germany e Radboud University Medical Center, Nijmegen, The Netherlands b
Article info
Abstract
Keywords: EAU guidelines LHRH agonists Monitoring Prostate cancer Prostate specific antigen Testosterone Treatment decision
Objectives: Due to the increased diagnosis of prostate cancer at earlier stages and the overall increased use of hormone therapy, also in earlier disease stages, many patients will receive long-term hormone therapy. Therefore, the timing of initiating hormone therapy and the type of hormone therapy have become crucial items in the appropriate management of patients with prostate cancer. In addition, as patients receiving longterm hormone therapy are at an increased risk of acute and chronic side effects, the monitoring of these patients deserves attention. The timing and type of hormone therapy and the monitoring of patients receiving hormone therapy are reviewed in this paper. Methods: A literature review was performed in Medline. Results: The prostate specific antigen doubling time (PSA DT) has been evaluated to determine the risk of disease progression in patients having a relapse after radical therapy. Patients with a PSA DT of <12 mo have a high risk for disease progression and should probably receive hormone therapy rapidly. In case of a diagnosis of advanced prostate cancer, there is not yet a consensus on when to start hormone therapy. During an interactive voting session, over 200 urologists indicated that the preferred luteinizing hormone releasing hormone (LHRH) agonist should be able to achieve a castrate level of 20 ng/dl, as well as to maintain these low testosterone levels without inducing acute-on-chronic or breakthrough responses. Eligard1, a novel depot formulation of leuprolide acetate, appears to be the only LHRH agonist currently available able to achieve and maintain serum testosterone levels below the castrate level of 20 ng/dl. Patients receiving long-term hormone therapy should be adequately monitored during follow-up visits. Besides frequent assessment of the PSA level and other recommended assessments, serum testosterone levels should also be determined. In this way, response to therapy can be evaluated, relevant testosterone rises after initial treatment response can be detected, and potential reasons for unexpected PSA rises can be verified, which will improve the monitoring of patients receiving hormone therapy. Conclusions: Measuring testosterone levels before and during therapy initiation might improve hormone therapy decisions and monitoring. Eligard1 is an interesting LHRH agonist because it is able to achieve and maintain testosterone levels below 20 ng/dl. # 2006 Elsevier B.V. All rights reserved.
* Corresponding author. University Clinics of Brussels, Erasme Hospital, Department of Urology, Route de Lennik 808, 1070 Brussels, Belgium. Tel. +32 2 555 36 14; Fax: +32 2 555 36 99. E-mail address: [email protected] (A.R. Zlotta). 1569-9056/$ – see front matter # 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.eursup.2006.01.002
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Introduction
Measuring serum prostate specific antigen (PSA) levels has become the most widely used practice for screening prostate cancer. Over the past 15 yr, this has resulted in a well-recognized stage migration with the majority of patients with prostate cancer currently being diagnosed at a clinically localized stage [1]. Although hormone therapy was originally introduced as a treatment option for patients diagnosed with metastatic prostate cancer, it is currently being increasingly used in earlier stages of prostate cancer, such as for patients with PSA relapse after previous radical therapy and patients diagnosed with advanced prostate cancer [2]. Due to the earlier detection of prostate cancer and the increased use of hormone therapy in earlier disease stages, many patients will receive hormone therapy for a (very) long period. The timing of initiating hormone therapy as well as the type of hormone therapy are therefore crucial in the appropriate management of patients with prostate cancer. In addition, patients receiving long-term hormone therapy are increasingly vulnerable to the long-term side effects of this type of therapy [2]. Therefore, adequate monitoring of patients receiving hormone therapy deserves attention. This will also enable the evaluation of the patient’s response to hormone therapy. In this paper, we will try to answer the following questions: (1) When should we initiate hormone therapy? (2) What type of hormone therapy should be given? (3) How should we monitor patients on hormone therapy?
2.
When to initiate hormone therapy?
Due to the increasing number of relatively young patients diagnosed with localized prostate cancer, a distinction should be made between patients with indolent malignancy (good-risk patients) and patients with a biologically aggressive disease (intermediate-to-high risk patients). PSA doubling time (PSA DT) has been investigated as a prognostic factor to define the risk of prostate cancer progression. However, there is as yet no consensus regarding the most appropriate cut-off point for the PSA DT. D’Amico et al. [3] showed that, in patients with localized or locally advanced prostate cancer who had undergone surgery or radiation therapy, a PSA DT of <3 mo was statistically significantly associated with the time to prostate cancer death. This suggests that a PSA DT of <3 mo after radical therapy is a surrogate end point for
prostate cancer-specific mortality. In another study in patients undergoing surgery for localized prostate cancer, patients with a PSA DT of >10 mo after surgery had a 76% probability of remaining free of metastatic disease for 5 yr after biochemical failure, whereas this was 35% for patients with a PSA DT <10 mo [4]. The Mayo Clinic Prostate Cancer Registry, including patients with localized prostate cancer undergoing prostatectomy, identified a PSA DT of 12 mo after radical therapy as a discriminant factor between patients at low and high risk of disease progression (clinical failure) [5]. In addition, Moul et al. [6] showed that in patients with a PSA relapse after radical prostatectomy, immediate hormone therapy was associated with delayed bone metastasis in those patients with a pathologic Gleason sum >7 or a PSA DT of 12 mo. Although the debate on the cut-off point of PSA DT as a prognostic factor for disease progression remains, it seems that in patients with a PSA relapse after surgery, a PSA DT of 3 mo is the cut-off point for identifying patients at risk of death from prostate cancer. Patients with a PSA DT of >3 mo can remain on active surveillance, including serial PSA level determinations and periodic prostate rebiopsy. Patients with a PSA DT of <12 mo have a high risk for disease progression and should probably receive hormone therapy rapidly. In case of a diagnosis of advanced prostate cancer, there is not yet a consensus on whether hormone therapy should be started immediately after diagnosis or after first appearance of clinical progression [7–10]. Although some studies are supportive for early hormonal therapy in patients with advanced disease, the data are not convincing and consequently, the final answer on the appropriate timing of hormone therapy remains inconclusive [11].
3.
Which type of hormone therapy?
Since Charles Huggins demonstrated in 1941 the responsiveness of prostate cancer to androgen deprivation [12,13], hormone therapy has emerged to become a standard therapy in prostate cancer. Although currently many different types of hormone therapy are available, only a few are recommended by the recently updated EAU guidelines [7,8]. Overall, hormonal therapies can be divided into testosterone-lowering therapies (castration), antiandrogen monotherapy, and combination therapy. Testosterone-lowering therapies comprise bilateral orchiectomy, estrogens, luteinizing hormone releasing hormone (LHRH) agonists and LHRH antagonists. Although bilateral orchiectomy has been the gold
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standard for many years, it is currently not often performed due to its negative psychological effect [14]. Estrogens have fallen out of favor due to the high risk of cardiovascular morbidity and mortality [15]. Currently, LHRH agonists have become the number one choice of hormonal therapy as they combine the good efficacy profile of both orchiectomy and estrogens, without inducing the estrogenrelated cardiovascular side effects and/or physical and psychological discomfort associated with orchiectomy. Although LHRH antagonists seem to have a more desirable mechanism of action compared to LHRH agonists, an open-label multicenter study showed no difference in achieving and maintaining castrate levels of testosterone and reducing PSA levels between both types of treatment [16]. Also, due to the limited number of studies available, LHRH antagonists are not (yet) recommended. In addition, they are also not available in many countries. Antiandrogen treatment includes steroidal (cyproterone acetate) and nonsteroidal antiandrogens (flutamide, nilutamide, bicalutamide). The primary side effects of these drugs include gynecomastia, breast pain, and gastrointestinal problems (nausea, vomiting) [17]. Currently, bicalutamide is the most widely used antiandrogen [18]. With regard to combination therapy, a metaanalysis of 27 randomized trials published by Lancet in 2000 showed that the addition of a steroidal antiandrogen to androgen deprivation (LHRH agonist or orchiectomy) decreased 5-yr survival when compared to androgen deprivation alone, whereas the addition of a nonsteroidal antiandrogen to androgen deprivation increased 5-yr survival by only 2–3% when compared to androgen deprivation alone [19]. It remains debatable whether this small advantage of complete androgen blockade (CAB) with a nonsteroidal antiandrogen and androgen deprivation can be meaningful to the patient, especially because combination therapy goes along with an increased number of side effects [19,20]. As only antiandrogens and LHRH agonists are currently recommended by the EAU guidelines, only these will be discussed below in more detail.
ful waiting. Primary end points were objective progression-free survival and overall survival. After a median follow-up of 5.4 yr, bicalutamide significantly prolonged progression-free survival, decreasing the risk of disease progression by 27% compared to placebo. A subgroup analysis of this study showed the greatest risk reduction of objective progression in node-positive patients [17]. However, both studies only showed advantages for bicalutamide in patients with locally advanced disease, and there was no difference seen in overall survival between bicalutamide and placebo (HR 1.03; 95%CI 0.92, 1.15; p = 0.582). Also, the number of deaths that occurred after receiving bicalutamide (15.5%) was comparable to the patients receiving placebo (15.0%). Based on these data, bicalutamide is not recommended for patients at low risk of disease progression, such as those with localized prostate cancer. A second important study compared 150 mg/d bicalutamide with castration (either medical or surgical) in 1453 patients diagnosed with advanced and/or metastatic disease [22]. The primary end points were time to treatment failure, time to objective progression, and time to death. After a median follow-up of approximately 100 wk, bicalutamide was found to be less effective than castration in patients with metastatic disease. Also regarding time to treatment failure ( p = 0.0001), time to progression ( p = 0.0001), and time to death ( p = 0.02), castration was significantly favored over bicalutamide. These data clearly demonstrate that bicalutamide is inferior to castration in locally advanced/metastatic prostate cancer. Because of these data, the use of antiandrogen monotherapy with bicalutamide should no longer be recommended for patients with prostate cancer. Monotherapy with other antiandrogens such as flutamide and cyproterone acetate were also conducted; however, these were small-scale studies with various end points and therefore no recommendation in terms of monotherapy with these agents can be given [7,8,23–26]. 3.2.
3.1.
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LHRH agonist monotherapy
Antiandrogen monotherapy
The most important study currently published with regard to antiandrogen monotherapy comprises three randomized, placebo-controlled trials that enrolled >8000 patients with localized or locally advanced disease [21]. Patients were randomized to receive 150 mg/d bicalutamide (n = 4052) or placebo (n = 4061) in addition to standard care consisting of radiation therapy, radical prostatectomy, or watch-
LHRH agonist monotherapy has become standard of care for obtaining castration in prostate cancer. However, as there are many different LHRH agonists and formulations available on the market, how can we select the most appropriate LHRH agonist formulation? No studies available directly compare the different LHRH agonists. As demonstrated in a metaanalysis by Seidenfeld et al. [27], indirect compar-
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ison demonstrates no difference in overall survival, although confidence intervals were wider for leuprolide (HR, 1.0994; CI, 0.207–5.835) and buserelin (HR, 1.1315; CI, 0.533–2.404) than for goserelin (HR, 1.1172; CI, 0.898–1.390).
4. Hormone therapy and optimal testosterone control The goal of hormone treatment is to achieve low testosterone levels. Historically, a castrate testosterone level 50 ng/dl was defined based on methodologic considerations and sensitivity of the old assays [28]. This value has remained the recommended testosterone level to achieve castration for ever since. However, more recent studies measuring serum testosterone levels after surgical castration by means of chemiluminescence reported a mean testosterone value around 20 ng/dl [28–32]. These data suggest that castrate levels should be redefined as 20 ng/dl instead of the conventional 50 ng/dl. Unfortunately, no good data exist that allow analysis of the impact of testosterone levels on clinical outcomes, as the studies comparing LHRH agonist therapy with orchiectomy were underpowered to do so. Nevertheless, general consensus exists [33] that testosterone levels achieved and maintained with LHRH agonist therapy should be equivalent to surgical castration. If one would like to achieve castration, it makes sense then to fight for the lowest level possible and to have it maintained at these low values as long as possible. If one would like to reintroduce testosterone at a certain point, it should be done in a controlled fashion and not in an uncontrolled manner as this might happen in those patients where testosterone levels sometimes are >50 ng/dl when treated with LHRH agonists. 4.1.
Optimal testosterone control in clinical practice
During an interactive voting session at a symposium in Malta, it became clear that few practicing urologists measure testosterone levels during LHRH agonist therapy on a regular basis. However, they would take testosterone levels achieved with a particular LHRH agonist into account in their treatment decisions (Fig. 1A). Around 37% of the attendees indicated that the ability to suppress testosterone is the major driver in deciding which LHRH agonist formulation they would choose (Fig. 1B). Most delegates agreed that the testosterone level achieved after LHRH agonist therapy should be as low as possible (Fig. 2A). When using bilateral
Fig. 1 – (A) Almost 80% of the attendees indicated that the ability to achieve castrate levels of testosterone is an important factor to decide which is the preferred LHRH agonist. (B) The ability to suppress testosterone levels is the most important indicator to choose a specific LHRH agonist formulation.
orchiectomy as a benchmark, it would be desirable to obtain a testosterone level as low as 20 ng/dl (Fig. 2B). The experts also stated that after achieving these low testosterone levels, a rise of testosterone above 50 ng/dl is considered as clinically significant and should have implications for treatment [33]. A difference can be made between an acute-on-chronic response and a breakthrough response [33]. A breakthrough response is defined as the occurrence of one single testosterone increase above 50 ng/dl during the whole treatment period. An acute-on-chronic response is associated with a testosterone increase above 50 ng/dl immediately after administration of the LHRH agonist [33]. Overall, the most optimal LHRH agonist should be able to achieve and maintain castrate testosterone levels 20 ng/dl and to avoid acute-on-chronic as well as breakthrough responses. 4.2.
LHRH agonists and optimal testosterone control
Currently, the ability of achieving optimal control of testosterone is an important differentiator
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4.3.
Fig. 2 – (A) Over 80% of the attendees indicated that achieving ‘‘the lowest possible level of testosterone’’ is the best. (B) Over 80% of the attendees indicated that 20 ng/dl is the preferred castrate testosterone level that needs to be achieved after LHRH agonist therapy.
between the available LHRH agonists. As demonstrated by Oefelein and Cornum [34], when using the 50- and 20-ng/dl definitions of castrate testosterone levels, 5% and 13% of the patients, respectively, failed to achieve these castrate levels. A literature review on LHRH agonists revealed that between 2% and 17% of the patients receiving depot formulations of different LHRH agonists were not able to reach the former castrate level of 50 ng/dl [16,34–37]. Even worse, in 13% to 38% of the patients, LHRH agonists were not able to suppress the serum testosterone level below 20 ng/dl [16,34,35, 38]. Although this should be avoided, both acute-onchronic and breakthrough responses occur frequently during LHRH agonist therapy. The incidence of breakthrough responses ranges between 0% and 12.5% [39–45], whereas acute-on-chronic responses have been reported in about 0% to 10% of the patients [39–41]. It is clear that current LHRH agonist formulations often fail to achieve and to maintain testosterone levels similar to surgical castration.
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Eligard1 and optimal testosterone control
Eligard1 is a new depot formulation of either 7.5 mg or 22.5 mg leuprolide acetate, in a 1- or 3-mo formulation, respectively [46,47]. Eligard1 uses the Atrigel1 drug delivery system, which results in an increase in bioavailability of leuprolide compared to other delivery systems [46–49]. The efficacy and safety of both the 1-mo [46] and the 3-mo formulations [47] have been evaluated in two 6-mo, open-label studies, enrolling, respectively, 120 and 117 men with prostate cancer. With both formulations testosterone levels decreased rapidly. After an initial rise, testosterone levels were 50 ng/dl in 17.6% and 94.1% of the patients at 14 and 28 d after injection of the 1-mo depot formulation [46]. By day 42, all the patients achieved castrate levels 50 ng/dl, which was maintained until the end of the study. At 6 mo, testosterone levels were suppressed to 20 ng/dl in 98% of the patients. The median times to achieve testosterone castrate levels of 50 ng/dl and 20 ng/dl with the 1-mo formulation were 21 and 28 d, respectively [46,48,49]. Results were comparable for the 3-mo depot formulation of Eligard1 [47]. In 20%, 99%, and 100% of the patients, castrate testosterone levels of 50 ng/dl were observed at 14, 28, and 35 d after injection, respectively. At the end of the study, testosterone levels were 20 ng/dl in 94% of the patients. Mean time to achieve testosterone castrate levels 50 ng/dl and 20 ng/dl with the 3-mo formulation were 21 and 28 d, respectively [47–49]. Overall, the mean testosterone levels observed at the end of the studies were <20 ng/dl for the 1- and 3-mo Eligard1 formulations (Fig. 3), respectively [46– 49]. None of the patients receiving the 1-mo Eligard1 formulation experienced an acute-on-chronic or breakthrough response [46]. One patient (0.9%)
Fig. 3 – Both the 1-mo and the 3-mo formulations of Eligard1 are able to achieve testosterone castrate levels far below 20 ng/dl [46,47]. *: Achieved after 6 mo of Eligard1.
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receiving the 3-mo depot formulation experienced a breakthrough response (>50 ng/dl) [47]. However, acute-on-chronic responses were not observed with the 3-mo Eligard1 formulation. It can be concluded that both the 1- and 3-mo Eligard1 formulations do not only achieve, but also maintain, these low testosterone levels.
5.
Monitoring after hormone therapy
Monitoring should be performed in patients receiving long-term hormone therapy, that is, those with metastatic or locally advanced prostate cancer. There are three main objectives of monitoring these patients: (1) to monitor the response to hormone treatment, (2) to ensure compliance with treatment, and (3) to detect potential complications of hormone therapy [8]. The EAU guidelines [8] recommend that follow-up visits should be made every 3–6 mo and should at least include a diseasespecific history, a digital rectal examination, an evaluation of symptoms, and a measurement of the serum PSA level. The PSA level initially measured reflects the extent of metastatic disease before treatment. Response to hormone treatment and rate of disease progression can be assessed by means of decreases in PSA levels, either by evaluating the absolute PSA level at 3 or 6 mo after treatment, the PSA nadir during treatment, or the rate at which the PSA decreases. However, it also should be noted that the PSA level is not always a reliable marker of disease progression because it has been shown that clinical disease progression occurred in 15–34% of patients with normal PSA levels [50,51]. Therefore, a PSA measurement cannot stand alone as a follow-up test [8]. Other recommended assessments at follow-up to detect disease progression include monitoring of creatinine levels, hemoglobin levels, and alkaline phosphatase levels. An optional test for monitoring patients on hormone treatment is the determination of serum testosterone levels [7]. Since the early 1970s, when Andrew Schally introduced LHRH agonists as a new method of castration [52,53], hormonal control in prostate cancer patients receiving LHRH agonists was traditionally monitored by assessing PSA levels. The main reason for this was the easy access to PSA assays compared to older and more difficult testosterone assays that also had a high level of interassay and intra-assay variability and that were also insufficiently sensitive to measure low testosterone levels [28,54]. In addition, the assumption was made that LHRH agonists were equal to surgical castration in
terms of achieving and maintaining low testosterone levels and that all LHRH agonists were comparable in this respect. As a consequence, PSA measurement was accepted as a surrogate to monitor therapy effectiveness and testosterone levels were not measured as a routine measurement. However, increased evidence now indicates that not all LHRH agonists are equally effective in achieving castrate testosterone levels. In addition, improved testosterone assays based on chemiluminescence are currently available, making possible the routine measurement of testosterone levels in daily clinical practice. Therefore, clinical practice should be reevaluated and also include the measurement of testosterone levels. As aggressive prostate cancers may arise in low testosterone environments [55], testosterone levels should be measured prior to any therapy. In addition, we recommend assessing the testosterone level before LHRH agonist treatment initiation and its initial response to LHRH agonist therapy. Furthermore, testosterone assessment during follow-up will be helpful to monitor therapy effectiveness, to detect relevant testosterone rises after initial response, and to verify potential reasons for unexpected PSA rises. It can be concluded that testosterone measurement should become a key point in the pretherapy and during therapy monitoring of patients with prostate cancer.
6.
Conclusions
Hormone therapy has been the treatment of choice for patients with locally advanced and metastatic prostate cancer for more than 50 yr. Because it has always been assumed that castration was equally achieved by orchiectomy or by administration of LHRH agonists, medical therapy has rapidly supplanted surgery, mainly for psychological reasons. Most urologists agree that the testosterone level after LHRH agonist therapy should be as low as possible. However, now that more attention has been given to the testosterone level, it has become clear that most available LHRH agonists do not perform as well as expected. Eligard1 appears to be the only LHRH agonist currently available able to achieve castrate levels below the testosterone level of 20 ng/dl in most patients. Many practicing urologists are aware of the importance of optimal monitoring of patients receiving long-term hormone therapy. In addition to recommended tests during follow-up visits such as PSA assessments, serum testosterone levels should also be determined. This will improve the overall management of patients receiving hormone therapy.
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[43] Fontana D, Mari M, Martinelli A, et al. 3-month formulation of goserelin acetate (‘Zoladex’ 10.8-mg depot) in advanced prostate cancer: results from an Italian, open, multicenter trial. Urol Int 2003;70:316–20. [44] Jocham D. Leuprorelin three-month depot in the treatment of advanced and metastatic prostate cancer: longterm follow-up results. Urol Int 1998;60(suppl 2):18–24. [45] 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;60:33–40. [46] 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;24:1902–14. [47] 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;168:1199–203. [48] Perez-Marrero R, Tyler RC. A subcutaneous delivery system for the extended release of leuprolide acetate for the treatment of prostate cancer. Expert Opin Pharmacother 2004;5:447–57. [49] Sartor O. Eligard: leuprolide acetate in a novel sustainedrelease delivery system. Urology 2003;61(2 suppl 1): 25–31. [50] Dupont A, Cusan L, Gomez JL, Thibealut MM, Tremblay M, Labrie F. Prostate specific antigen and prostatic acid phosphatase for monitoring therapy of carcinoma of the prostate. J Urol 1991;146:1064–7. [51] Fossa SD, Waehre H, Paus E. The prognostic significance of prostate cancer. Br J Cancer 1992;66:181–4. [52] Schally AV, Kastin AJ, Arimura A. Hypothalamic folliclestimulating hormone (FSH) and luteinizing hormone (LH)regulating hormone: structure, physiology, and clinical studies. Fertil Steril 1971;22:703–21. [53] Coy DH, Vilchez-Martinez JA, Coy EJ, Arimura A, Schally AV. A peptide inhibitor of luteinizing hormone-releasing hormone (LH-RH). J Clin Endocrinol Metab 1973;37: 331–3. [54] 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;33:1372–5. [55] Hoffman MA, DeWolf WC, Morgentaler A. Is low serum free testosterone a marker for high grade prostate cancer? J Urol 2000;163:824–7.
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Hormone Therapy: Improving Therapy Decisions and Monitoring Alexandre R. Zlotta a,*, Per-Anders Abrahamsson b, Bertrand Tombal c, Richard Berges d, Frans Debruyne e a
University Clinics of Brussels, Erasme Hospital, Brussels, Belgium Malmo¨ University Hospital, Malmo¨, Sweden c Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium d PAN-Klinik am Neumarkt, Cologne, Germany e Radboud University Medical Center, Nijmegen, The Netherlands b
Article info
Abstract
Keywords: EAU guidelines LHRH agonists Monitoring Prostate cancer Prostate specific antigen Testosterone Treatment decision
Objectives: Due to the increased diagnosis of prostate cancer at earlier stages and the overall increased use of hormone therapy, also in earlier disease stages, many patients will receive long-term hormone therapy. Therefore, the timing of initiating hormone therapy and the type of hormone therapy have become crucial items in the appropriate management of patients with prostate cancer. In addition, as patients receiving longterm hormone therapy are at an increased risk of acute and chronic side effects, the monitoring of these patients deserves attention. The timing and type of hormone therapy and the monitoring of patients receiving hormone therapy are reviewed in this paper. Methods: A literature review was performed in Medline. Results: The prostate specific antigen doubling time (PSA DT) has been evaluated to determine the risk of disease progression in patients having a relapse after radical therapy. Patients with a PSA DT of <12 mo have a high risk for disease progression and should probably receive hormone therapy rapidly. In case of a diagnosis of advanced prostate cancer, there is not yet a consensus on when to start hormone therapy. During an interactive voting session, over 200 urologists indicated that the preferred luteinizing hormone releasing hormone (LHRH) agonist should be able to achieve a castrate level of 20 ng/dl, as well as to maintain these low testosterone levels without inducing acute-on-chronic or breakthrough responses. Eligard1, a novel depot formulation of leuprolide acetate, appears to be the only LHRH agonist currently available able to achieve and maintain serum testosterone levels below the castrate level of 20 ng/dl. Patients receiving long-term hormone therapy should be adequately monitored during follow-up visits. Besides frequent assessment of the PSA level and other recommended assessments, serum testosterone levels should also be determined. In this way, response to therapy can be evaluated, relevant testosterone rises after initial treatment response can be detected, and potential reasons for unexpected PSA rises can be verified, which will improve the monitoring of patients receiving hormone therapy. Conclusions: Measuring testosterone levels before and during therapy initiation might improve hormone therapy decisions and monitoring. Eligard1 is an interesting LHRH agonist because it is able to achieve and maintain testosterone levels below 20 ng/dl. # 2006 Elsevier B.V. All rights reserved.
* Corresponding author. University Clinics of Brussels, Erasme Hospital, Department of Urology, Route de Lennik 808, 1070 Brussels, Belgium. Tel. +32 2 555 36 14; Fax: +32 2 555 36 99. E-mail address: [email protected] (A.R. Zlotta). 1569-9056/$ – see front matter # 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.eursup.2006.01.002
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1.
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Introduction
Measuring serum prostate specific antigen (PSA) levels has become the most widely used practice for screening prostate cancer. Over the past 15 yr, this has resulted in a well-recognized stage migration with the majority of patients with prostate cancer currently being diagnosed at a clinically localized stage [1]. Although hormone therapy was originally introduced as a treatment option for patients diagnosed with metastatic prostate cancer, it is currently being increasingly used in earlier stages of prostate cancer, such as for patients with PSA relapse after previous radical therapy and patients diagnosed with advanced prostate cancer [2]. Due to the earlier detection of prostate cancer and the increased use of hormone therapy in earlier disease stages, many patients will receive hormone therapy for a (very) long period. The timing of initiating hormone therapy as well as the type of hormone therapy are therefore crucial in the appropriate management of patients with prostate cancer. In addition, patients receiving long-term hormone therapy are increasingly vulnerable to the long-term side effects of this type of therapy [2]. Therefore, adequate monitoring of patients receiving hormone therapy deserves attention. This will also enable the evaluation of the patient’s response to hormone therapy. In this paper, we will try to answer the following questions: (1) When should we initiate hormone therapy? (2) What type of hormone therapy should be given? (3) How should we monitor patients on hormone therapy?
2.
When to initiate hormone therapy?
Due to the increasing number of relatively young patients diagnosed with localized prostate cancer, a distinction should be made between patients with indolent malignancy (good-risk patients) and patients with a biologically aggressive disease (intermediate-to-high risk patients). PSA doubling time (PSA DT) has been investigated as a prognostic factor to define the risk of prostate cancer progression. However, there is as yet no consensus regarding the most appropriate cut-off point for the PSA DT. D’Amico et al. [3] showed that, in patients with localized or locally advanced prostate cancer who had undergone surgery or radiation therapy, a PSA DT of <3 mo was statistically significantly associated with the time to prostate cancer death. This suggests that a PSA DT of <3 mo after radical therapy is a surrogate end point for
prostate cancer-specific mortality. In another study in patients undergoing surgery for localized prostate cancer, patients with a PSA DT of >10 mo after surgery had a 76% probability of remaining free of metastatic disease for 5 yr after biochemical failure, whereas this was 35% for patients with a PSA DT <10 mo [4]. The Mayo Clinic Prostate Cancer Registry, including patients with localized prostate cancer undergoing prostatectomy, identified a PSA DT of 12 mo after radical therapy as a discriminant factor between patients at low and high risk of disease progression (clinical failure) [5]. In addition, Moul et al. [6] showed that in patients with a PSA relapse after radical prostatectomy, immediate hormone therapy was associated with delayed bone metastasis in those patients with a pathologic Gleason sum >7 or a PSA DT of 12 mo. Although the debate on the cut-off point of PSA DT as a prognostic factor for disease progression remains, it seems that in patients with a PSA relapse after surgery, a PSA DT of 3 mo is the cut-off point for identifying patients at risk of death from prostate cancer. Patients with a PSA DT of >3 mo can remain on active surveillance, including serial PSA level determinations and periodic prostate rebiopsy. Patients with a PSA DT of <12 mo have a high risk for disease progression and should probably receive hormone therapy rapidly. In case of a diagnosis of advanced prostate cancer, there is not yet a consensus on whether hormone therapy should be started immediately after diagnosis or after first appearance of clinical progression [7–10]. Although some studies are supportive for early hormonal therapy in patients with advanced disease, the data are not convincing and consequently, the final answer on the appropriate timing of hormone therapy remains inconclusive [11].
3.
Which type of hormone therapy?
Since Charles Huggins demonstrated in 1941 the responsiveness of prostate cancer to androgen deprivation [12,13], hormone therapy has emerged to become a standard therapy in prostate cancer. Although currently many different types of hormone therapy are available, only a few are recommended by the recently updated EAU guidelines [7,8]. Overall, hormonal therapies can be divided into testosterone-lowering therapies (castration), antiandrogen monotherapy, and combination therapy. Testosterone-lowering therapies comprise bilateral orchiectomy, estrogens, luteinizing hormone releasing hormone (LHRH) agonists and LHRH antagonists. Although bilateral orchiectomy has been the gold
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standard for many years, it is currently not often performed due to its negative psychological effect [14]. Estrogens have fallen out of favor due to the high risk of cardiovascular morbidity and mortality [15]. Currently, LHRH agonists have become the number one choice of hormonal therapy as they combine the good efficacy profile of both orchiectomy and estrogens, without inducing the estrogenrelated cardiovascular side effects and/or physical and psychological discomfort associated with orchiectomy. Although LHRH antagonists seem to have a more desirable mechanism of action compared to LHRH agonists, an open-label multicenter study showed no difference in achieving and maintaining castrate levels of testosterone and reducing PSA levels between both types of treatment [16]. Also, due to the limited number of studies available, LHRH antagonists are not (yet) recommended. In addition, they are also not available in many countries. Antiandrogen treatment includes steroidal (cyproterone acetate) and nonsteroidal antiandrogens (flutamide, nilutamide, bicalutamide). The primary side effects of these drugs include gynecomastia, breast pain, and gastrointestinal problems (nausea, vomiting) [17]. Currently, bicalutamide is the most widely used antiandrogen [18]. With regard to combination therapy, a metaanalysis of 27 randomized trials published by Lancet in 2000 showed that the addition of a steroidal antiandrogen to androgen deprivation (LHRH agonist or orchiectomy) decreased 5-yr survival when compared to androgen deprivation alone, whereas the addition of a nonsteroidal antiandrogen to androgen deprivation increased 5-yr survival by only 2–3% when compared to androgen deprivation alone [19]. It remains debatable whether this small advantage of complete androgen blockade (CAB) with a nonsteroidal antiandrogen and androgen deprivation can be meaningful to the patient, especially because combination therapy goes along with an increased number of side effects [19,20]. As only antiandrogens and LHRH agonists are currently recommended by the EAU guidelines, only these will be discussed below in more detail.
ful waiting. Primary end points were objective progression-free survival and overall survival. After a median follow-up of 5.4 yr, bicalutamide significantly prolonged progression-free survival, decreasing the risk of disease progression by 27% compared to placebo. A subgroup analysis of this study showed the greatest risk reduction of objective progression in node-positive patients [17]. However, both studies only showed advantages for bicalutamide in patients with locally advanced disease, and there was no difference seen in overall survival between bicalutamide and placebo (HR 1.03; 95%CI 0.92, 1.15; p = 0.582). Also, the number of deaths that occurred after receiving bicalutamide (15.5%) was comparable to the patients receiving placebo (15.0%). Based on these data, bicalutamide is not recommended for patients at low risk of disease progression, such as those with localized prostate cancer. A second important study compared 150 mg/d bicalutamide with castration (either medical or surgical) in 1453 patients diagnosed with advanced and/or metastatic disease [22]. The primary end points were time to treatment failure, time to objective progression, and time to death. After a median follow-up of approximately 100 wk, bicalutamide was found to be less effective than castration in patients with metastatic disease. Also regarding time to treatment failure ( p = 0.0001), time to progression ( p = 0.0001), and time to death ( p = 0.02), castration was significantly favored over bicalutamide. These data clearly demonstrate that bicalutamide is inferior to castration in locally advanced/metastatic prostate cancer. Because of these data, the use of antiandrogen monotherapy with bicalutamide should no longer be recommended for patients with prostate cancer. Monotherapy with other antiandrogens such as flutamide and cyproterone acetate were also conducted; however, these were small-scale studies with various end points and therefore no recommendation in terms of monotherapy with these agents can be given [7,8,23–26]. 3.2.
3.1.
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LHRH agonist monotherapy
Antiandrogen monotherapy
The most important study currently published with regard to antiandrogen monotherapy comprises three randomized, placebo-controlled trials that enrolled >8000 patients with localized or locally advanced disease [21]. Patients were randomized to receive 150 mg/d bicalutamide (n = 4052) or placebo (n = 4061) in addition to standard care consisting of radiation therapy, radical prostatectomy, or watch-
LHRH agonist monotherapy has become standard of care for obtaining castration in prostate cancer. However, as there are many different LHRH agonists and formulations available on the market, how can we select the most appropriate LHRH agonist formulation? No studies available directly compare the different LHRH agonists. As demonstrated in a metaanalysis by Seidenfeld et al. [27], indirect compar-
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ison demonstrates no difference in overall survival, although confidence intervals were wider for leuprolide (HR, 1.0994; CI, 0.207–5.835) and buserelin (HR, 1.1315; CI, 0.533–2.404) than for goserelin (HR, 1.1172; CI, 0.898–1.390).
4. Hormone therapy and optimal testosterone control The goal of hormone treatment is to achieve low testosterone levels. Historically, a castrate testosterone level 50 ng/dl was defined based on methodologic considerations and sensitivity of the old assays [28]. This value has remained the recommended testosterone level to achieve castration for ever since. However, more recent studies measuring serum testosterone levels after surgical castration by means of chemiluminescence reported a mean testosterone value around 20 ng/dl [28–32]. These data suggest that castrate levels should be redefined as 20 ng/dl instead of the conventional 50 ng/dl. Unfortunately, no good data exist that allow analysis of the impact of testosterone levels on clinical outcomes, as the studies comparing LHRH agonist therapy with orchiectomy were underpowered to do so. Nevertheless, general consensus exists [33] that testosterone levels achieved and maintained with LHRH agonist therapy should be equivalent to surgical castration. If one would like to achieve castration, it makes sense then to fight for the lowest level possible and to have it maintained at these low values as long as possible. If one would like to reintroduce testosterone at a certain point, it should be done in a controlled fashion and not in an uncontrolled manner as this might happen in those patients where testosterone levels sometimes are >50 ng/dl when treated with LHRH agonists. 4.1.
Optimal testosterone control in clinical practice
During an interactive voting session at a symposium in Malta, it became clear that few practicing urologists measure testosterone levels during LHRH agonist therapy on a regular basis. However, they would take testosterone levels achieved with a particular LHRH agonist into account in their treatment decisions (Fig. 1A). Around 37% of the attendees indicated that the ability to suppress testosterone is the major driver in deciding which LHRH agonist formulation they would choose (Fig. 1B). Most delegates agreed that the testosterone level achieved after LHRH agonist therapy should be as low as possible (Fig. 2A). When using bilateral
Fig. 1 – (A) Almost 80% of the attendees indicated that the ability to achieve castrate levels of testosterone is an important factor to decide which is the preferred LHRH agonist. (B) The ability to suppress testosterone levels is the most important indicator to choose a specific LHRH agonist formulation.
orchiectomy as a benchmark, it would be desirable to obtain a testosterone level as low as 20 ng/dl (Fig. 2B). The experts also stated that after achieving these low testosterone levels, a rise of testosterone above 50 ng/dl is considered as clinically significant and should have implications for treatment [33]. A difference can be made between an acute-on-chronic response and a breakthrough response [33]. A breakthrough response is defined as the occurrence of one single testosterone increase above 50 ng/dl during the whole treatment period. An acute-on-chronic response is associated with a testosterone increase above 50 ng/dl immediately after administration of the LHRH agonist [33]. Overall, the most optimal LHRH agonist should be able to achieve and maintain castrate testosterone levels 20 ng/dl and to avoid acute-on-chronic as well as breakthrough responses. 4.2.
LHRH agonists and optimal testosterone control
Currently, the ability of achieving optimal control of testosterone is an important differentiator
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4.3.
Fig. 2 – (A) Over 80% of the attendees indicated that achieving ‘‘the lowest possible level of testosterone’’ is the best. (B) Over 80% of the attendees indicated that 20 ng/dl is the preferred castrate testosterone level that needs to be achieved after LHRH agonist therapy.
between the available LHRH agonists. As demonstrated by Oefelein and Cornum [34], when using the 50- and 20-ng/dl definitions of castrate testosterone levels, 5% and 13% of the patients, respectively, failed to achieve these castrate levels. A literature review on LHRH agonists revealed that between 2% and 17% of the patients receiving depot formulations of different LHRH agonists were not able to reach the former castrate level of 50 ng/dl [16,34–37]. Even worse, in 13% to 38% of the patients, LHRH agonists were not able to suppress the serum testosterone level below 20 ng/dl [16,34,35, 38]. Although this should be avoided, both acute-onchronic and breakthrough responses occur frequently during LHRH agonist therapy. The incidence of breakthrough responses ranges between 0% and 12.5% [39–45], whereas acute-on-chronic responses have been reported in about 0% to 10% of the patients [39–41]. It is clear that current LHRH agonist formulations often fail to achieve and to maintain testosterone levels similar to surgical castration.
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Eligard1 and optimal testosterone control
Eligard1 is a new depot formulation of either 7.5 mg or 22.5 mg leuprolide acetate, in a 1- or 3-mo formulation, respectively [46,47]. Eligard1 uses the Atrigel1 drug delivery system, which results in an increase in bioavailability of leuprolide compared to other delivery systems [46–49]. The efficacy and safety of both the 1-mo [46] and the 3-mo formulations [47] have been evaluated in two 6-mo, open-label studies, enrolling, respectively, 120 and 117 men with prostate cancer. With both formulations testosterone levels decreased rapidly. After an initial rise, testosterone levels were 50 ng/dl in 17.6% and 94.1% of the patients at 14 and 28 d after injection of the 1-mo depot formulation [46]. By day 42, all the patients achieved castrate levels 50 ng/dl, which was maintained until the end of the study. At 6 mo, testosterone levels were suppressed to 20 ng/dl in 98% of the patients. The median times to achieve testosterone castrate levels of 50 ng/dl and 20 ng/dl with the 1-mo formulation were 21 and 28 d, respectively [46,48,49]. Results were comparable for the 3-mo depot formulation of Eligard1 [47]. In 20%, 99%, and 100% of the patients, castrate testosterone levels of 50 ng/dl were observed at 14, 28, and 35 d after injection, respectively. At the end of the study, testosterone levels were 20 ng/dl in 94% of the patients. Mean time to achieve testosterone castrate levels 50 ng/dl and 20 ng/dl with the 3-mo formulation were 21 and 28 d, respectively [47–49]. Overall, the mean testosterone levels observed at the end of the studies were <20 ng/dl for the 1- and 3-mo Eligard1 formulations (Fig. 3), respectively [46– 49]. None of the patients receiving the 1-mo Eligard1 formulation experienced an acute-on-chronic or breakthrough response [46]. One patient (0.9%)
Fig. 3 – Both the 1-mo and the 3-mo formulations of Eligard1 are able to achieve testosterone castrate levels far below 20 ng/dl [46,47]. *: Achieved after 6 mo of Eligard1.
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receiving the 3-mo depot formulation experienced a breakthrough response (>50 ng/dl) [47]. However, acute-on-chronic responses were not observed with the 3-mo Eligard1 formulation. It can be concluded that both the 1- and 3-mo Eligard1 formulations do not only achieve, but also maintain, these low testosterone levels.
5.
Monitoring after hormone therapy
Monitoring should be performed in patients receiving long-term hormone therapy, that is, those with metastatic or locally advanced prostate cancer. There are three main objectives of monitoring these patients: (1) to monitor the response to hormone treatment, (2) to ensure compliance with treatment, and (3) to detect potential complications of hormone therapy [8]. The EAU guidelines [8] recommend that follow-up visits should be made every 3–6 mo and should at least include a diseasespecific history, a digital rectal examination, an evaluation of symptoms, and a measurement of the serum PSA level. The PSA level initially measured reflects the extent of metastatic disease before treatment. Response to hormone treatment and rate of disease progression can be assessed by means of decreases in PSA levels, either by evaluating the absolute PSA level at 3 or 6 mo after treatment, the PSA nadir during treatment, or the rate at which the PSA decreases. However, it also should be noted that the PSA level is not always a reliable marker of disease progression because it has been shown that clinical disease progression occurred in 15–34% of patients with normal PSA levels [50,51]. Therefore, a PSA measurement cannot stand alone as a follow-up test [8]. Other recommended assessments at follow-up to detect disease progression include monitoring of creatinine levels, hemoglobin levels, and alkaline phosphatase levels. An optional test for monitoring patients on hormone treatment is the determination of serum testosterone levels [7]. Since the early 1970s, when Andrew Schally introduced LHRH agonists as a new method of castration [52,53], hormonal control in prostate cancer patients receiving LHRH agonists was traditionally monitored by assessing PSA levels. The main reason for this was the easy access to PSA assays compared to older and more difficult testosterone assays that also had a high level of interassay and intra-assay variability and that were also insufficiently sensitive to measure low testosterone levels [28,54]. In addition, the assumption was made that LHRH agonists were equal to surgical castration in
terms of achieving and maintaining low testosterone levels and that all LHRH agonists were comparable in this respect. As a consequence, PSA measurement was accepted as a surrogate to monitor therapy effectiveness and testosterone levels were not measured as a routine measurement. However, increased evidence now indicates that not all LHRH agonists are equally effective in achieving castrate testosterone levels. In addition, improved testosterone assays based on chemiluminescence are currently available, making possible the routine measurement of testosterone levels in daily clinical practice. Therefore, clinical practice should be reevaluated and also include the measurement of testosterone levels. As aggressive prostate cancers may arise in low testosterone environments [55], testosterone levels should be measured prior to any therapy. In addition, we recommend assessing the testosterone level before LHRH agonist treatment initiation and its initial response to LHRH agonist therapy. Furthermore, testosterone assessment during follow-up will be helpful to monitor therapy effectiveness, to detect relevant testosterone rises after initial response, and to verify potential reasons for unexpected PSA rises. It can be concluded that testosterone measurement should become a key point in the pretherapy and during therapy monitoring of patients with prostate cancer.
6.
Conclusions
Hormone therapy has been the treatment of choice for patients with locally advanced and metastatic prostate cancer for more than 50 yr. Because it has always been assumed that castration was equally achieved by orchiectomy or by administration of LHRH agonists, medical therapy has rapidly supplanted surgery, mainly for psychological reasons. Most urologists agree that the testosterone level after LHRH agonist therapy should be as low as possible. However, now that more attention has been given to the testosterone level, it has become clear that most available LHRH agonists do not perform as well as expected. Eligard1 appears to be the only LHRH agonist currently available able to achieve castrate levels below the testosterone level of 20 ng/dl in most patients. Many practicing urologists are aware of the importance of optimal monitoring of patients receiving long-term hormone therapy. In addition to recommended tests during follow-up visits such as PSA assessments, serum testosterone levels should also be determined. This will improve the overall management of patients receiving hormone therapy.
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