Curr Urol Rep DOI 10.1007/s11934-011-0178-0
Androgen Suppression Strategies for Prostate Cancer: Is There an Ideal Approach? Mohamed Ismail & Matthew Ferroni & Leonard G. Gomella
# Springer Science+Business Media, LLC 2011
Abstract Androgen suppression therapy (AST) was first described in 1941 as a treatment of prostate cancer (PCa) and remains the mainstay of therapy in patients with hormone-naïve metastatic disease. It also is used in locally advanced or recurrent disease and in combination with radiation therapy in patients with higher-risk features. Several approaches to AST have been developed as a result of increased understanding of the pathways controlling testosterone production. Increased recognition of the side effects has resulted in strategies to minimize complications associated with AST. Attempts to reduce AST adverse effects include intermittent hormonal therapy and methods to reduce amount of intracellular androgens without reducing the circulating testosterone levels. Keywords Androgen suppression therapy . Hormonal therapy . Prostate cancer . Luteinizing hormone–releasing hormone . LHRH . LHRH agonists . LHRH antagonists . Intermittent hormonal therapy . Antiandrogens
Introduction
deaths in the United States in 2010 [1]. In 1941, Huggins and Hodges recognized that the growth of benign and malignant prostate tissue is regulated by androgens. Since that time, hormone therapy, mainly achieved by androgen suppression therapy (AST), has become commonplace in the management of PCa. AST is achieved by both surgical and medical means, relying primarily on reduction of circulating testosterone levels. The key advantage to medical castration is its reversibility. In the 1980s, Luteinizing hormone–releasing hormone (LHRH) agonists were introduced and soon were followed by the nonsteroidal antiandrogens. Maximal androgen blockade (MAB), sometimes referred to as complete androgen blockade, is a combination of surgical or medical castration and oral antiandrogens (steroidal or nonsteroidal) to block both testicular and nontesticular sources of androgens. Other modalities include LHRH antagonists, antiandrogen monotherapy, 5-α-reductase (5AR) inhibitor combinations, and intermittent hormonal therapy (IHT). This article reviews the indications, strategies, timing, duration, and side effects of AST in the contemporary management of PCa. When available, the optimum approach to AST based on best randomized clinical trial evidence is described.
Prostate cancer (PCa) is the most commonly diagnosed solid tumor in men and the second leading cause of cancer Indications for Androgen Suppression Therapy M. Ismail Department of Urology, Wilmington VA Medical Center, 1601 Kirkwood Highway, Wilmington, DE 19805, USA M. Ferroni : L. G. Gomella (*) Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, 1025 Walnut Street, Suite 1112, Philadelphia, PA 19107, USA e-mail:
[email protected]
AST is universally accepted as the standard of care for advanced (metastatic) PCa. While controversial, AST sometimes is used as monotherapy without documented metastatic disease in settings such as T2/T3 PCa, if the patient’s life expectancy is less than 10 years and there are adverse risk factors such as a prostate-specific antigen (PSA) level above 25 ng/mL or a PSA doubling time (PSADT) less than 12 months [2].
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AST combined with radiation therapy is proven to be beneficial in multiple randomized clinical trials [3–6, 7••]. In high-grade locally advanced tumors, the Radiation Therapy Oncology Group (RTOG), the European Organization for Research and Treatment of Cancer (EORTC), and the TransTasman Radiation Oncology Group (TROG) trials all showed a long-term survival advantage from the addition of AST to the external-beam radiation. A study from Dana-Farber Cancer Institute in men with intermediate- and high-risk PCa treated with external-beam radiation therapy found that AST is beneficial in the patients with no or mild comorbidity [8]. However, no benefit was seen in men with moderate or severe comorbidities. In an analysis of two combined studies, AST was associated with a shorter time to a fatal cardiac event [8]. On the other hand, reviews of the RTOG 86–10 and 85–31 trials found that neither resulted in an increase in cardiac mortality due to addition of AST [9, 10••].Taken together the data suggest that in patients with either highgrade, locally advanced, or node-positive disease, the risk of PCa mortality is high, justifying the routine use of AST with external-beam radiation therapy. In patients with localized disease, comorbidities should be considered in the decision of adding AST. In recurrent PCa after failure of local therapy, AST is an option used at a given level of PSA or PSADT after a period of observation and will be discussed later.
Methods of Androgen Suppression The understanding of the androgen synthesis and regulatory pathways has led to development of a number of treatments collectively known as AST. Testosterone production is regulated by luteinizing hormone (LH) and LHRH (Fig. 1). LHRH, released in the hypothalamus, stimulates the release of LH and follicle-stimulating hormones (FSH) from the pituitary gland. LH, in turn, acts on Leydig cell of the testes to produce testosterone. This accounts for 90% to 95% of testosterone production. The remaining androgens and androgen precursors mostly are produced by the adrenal glands. These androgens are taken up into the cytoplasm of target tissue cell where it either binds to the androgen receptor directly or is converted to 5-α-dihydrotestosterone (DHT), which binds to the androgen receptor with a greater affinity than testosterone. The androgen-receptor complex enters the nucleus of the cell, where it exerts its effects by influencing gene expression. In the case of PCa, these androgens stimulate cellular growth. Surgical Orchiectomy and Estrogens Estrogens can suppress the LHRH/LH axis, causing a primary reduction in circulating testosterone, and can induce other antitumor effects. The use of estrogens generally has been
Fig. 1 Primary regulation of androgen production in males. LHRH Luteinizing hormone–releasing hormone; LH Luteinizing hormone; T testosterone; DHT dihydrotestosterone
abandoned in the United States due to the potential for serious cardiovascular side effects. Orchiectomy remains an effective PCa intervention, resulting in rapid reduction of circulatingtestosterone levels. However, the procedure is irreversible and is not a preferred option in most patients, but has a role in selected patient populations in whom LHRH agonist or antagonist cannot be reliably administered. LHRH Agonists LHRH agonists, first introduced in the 1980s, are the mainstay of AST for PCa. These agents act by binding to the LHRH receptor in the pituitary gland with higher affinity than native LHRH and interfering with the natural pulsatile release of these hormones. The initial response is the release of LH from the anterior pituitary that paradoxically causes a rise in testosterone, known as the “testosterone flare,” that is maximal at about 2 weeks. This is followed by inhibition of LH secretion, resulting in suppression of serum testosterone levels over the following 2 weeks. Several LHRH agonists
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have been commercialized based on substitution of amino acids at various positions on the LHRH decapeptide (Table 1). This greater biological activity of the synthetic LHRH is due to increased resistance to enzymatic degradation and increased receptor affinity. The use of sustained-release formulations, which can be administered monthly or every 3, 4, 6, or 12 months, makes treatment of PCa more convenient. A meta-analysis comparing the effects of orchiectomy to medical castration with LHRH agonists showed no difference in overall survival between the two [11]. Because LHRH agonists initially stimulate LH release, their immediate effect is to induce an increase in testosterone levels known as the “testosterone surge” or “flare.” This biochemical response can result in transient tumor growth and can be accompanied by a worsening in symptoms, known as “clinical flare.” An analysis of nine
studies involving 765 patients reported an average clinical flare of 11% [12]. The main symptoms associated with a clinical flare include bone pain, bladder outlet obstruction, ureteral obstruction, spinal cord compression, and cardiovascular effects. In patients with vertebral metastases and/or urinary obstruction, flare can lead to spinal cord compression or ureteral obstruction. As a result, LHRH agonists as initial monotherapy are contraindicated in such patients. Flare protection therapy, which involves treatment with an antiandrogen at the start of LHRH agonist therapy or for 2 weeks or longer, is recommended [13•]. Flare protection therapy generally is only given with the first dose of LHRH agonist. However, several investigators have reported that transient increases in testosterone can be seen after subsequent injections [14]. Such “microflares,” although insufficient to exacerbate symptoms, have been suggested
Table 1 Commonly used FDA-approved hormonal agents used in androgen suppression therapy for prostate cancer Generic
Trade
LHRH agonists Leuprolide acetate for injectable suspension (gel)
Eligarda
Dose, mg
Goserelin acetate
Lupron Depotb Lupron Depot 3 mo Lupron Depot 4 mo Zoladexc
Triptorelin pamoate implant
Trelstard
7.5 22.5 30 45 7.5 22.5 30 3.6 10.8 3.75
Vantase
11.25 22.5 50
Leuprolide acetate for depot suspension
Route
Dosing interval
SC SC SC SC IM IM IM SC SC IM
24 days 84 days 112 days 182 days 28 days 84 days 112 days 28 days 84 days 28 days
IM IM SC
84 days 180 days 365 days
Histerelin LHRH antagonist Degarelix
Firmagonf
240 80
SC SC
2 divided doses initially, then q 28 days
Nonsteroidal antiandrogens Bicalutamide Flutamide Nilutamide
Casodexc Eulexing Nilandrona
50 125 150
Oral Oral Oral
QD 250 mg TID 300 mg QD for 1 month then 150 mg QD
a
Manufactured by Sanofi-Aventis, Bridgewater, NJ
b
Manufactured by Abbott Laboratories, Abbott Park, IL
c
Manufactured by AstraZeneca, London, England, United Kingdom
d
Manufactured by Watson Pharmaceuticals, Corona, CA
e
Manufactured by Endo Pharmaceuticals, Chadds Ford, PA
f
Manufactured by Ferring Pharmaceuticals, Malmö, Sweden
g
Manufactured by Schering-Plough, Kenilworth, NJ
FDA U.S. Food and Drug Administration; IM intramuscular; LHRH luteinizing hormone–releasing hormone; Q every; QD daily; SC subcutaneously; TID three times daily
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to possibly promote tumor growth and potentially adversely affect survival. LHRH Antagonists LHRH antagonists avoid the transient surge in testosterone that occurs with the use of LHRH agonists. These agents bind to the LHRH receptor in the pituitary gland to produce immediate blockade of LH and FSH secretion. This, in turn, results in faster suppression of serum testosterone levels, free of testosterone surge. The marketing of abarelix, the first LHRH antagonist to be approved by the United States Food and Drug Administration (FDA), was discontinued, mostly due to infrequent but severe allergic reactions. Degarelix (Firmagon, Ferring Pharmaceuticals, Saint-Prex, Switzerland), an LHRH antagonist, is approved in the United States and Europe (Table 1). LHRH antagonists are given by deep subcutaneous injection. The main side effect with degarelix is skin reactions, but it is usually self-limiting. In a phase 3 trial, regimens of degarelix (240/80 mg and 240/ 160 mg) and leuprolide, 7.5 mg, suppressed testosterone in more than 95% of patients over a 1-year treatment period. Both degarelix regimens achieved a more rapid reduction of testosterone and PSA than leuprolide, and neither degarelix dose induced testosterone surge or microsurges [15••]. Currently, degarelix is only available in 1-month formulations, and conversion to longer-lasting LHRH agonists is acceptable. Three additional LHRH antagonists are being investigated for treatment of PCa (teverelix, ozarelix, and cetrorelix). Antiandrogen Monotherapy Three types of nonsteroidal antiandrogens currently are available in the United States: bicalutamide, flutamide, and nilutamide (Table 1). They act by binding to the androgen receptors in target tissues, and hence, inhibiting androgen actions. Bicalutamide (Casodex, AstraZeneca, London, England, United Kingdom), approved for use in combination with LHRH agonists at a dose of 50 mg/day, has been the most extensively studied as monotherapy in PCa. Although monotherapy is less effective than LHRH agonists in patients with bone metastases, in randomized trials in men with localized or locally advanced PCa, immediate or adjuvant bicalutamide in addition to standard therapy significantly reduced the risk of clinical progression [16]. While bicalutamide monotherapy (150 mg/day) is approved in several countries, it is not approved as monotherapy in the United States. The main advantage of nonsteroidal antiandrogen monotherapy is that it does not reduce serum testosterone levels and can maintain body composition and quality of life. Steroidal
antiandrogens, such as cyproterone acetate, are not used in the United States but are widely used in Europe and Canada. Progression to castrate-resistant PCa is driven by many factors, including elevated expression of androgen receptors. Development of second-generation antiandrogens, such as MDV3100 (Medivation, Inc., San Francisco, CA), that bind to androgen receptor with more affinity than the existing antiandrogens recently have been reported [17]. These compounds are promising candidates for future use in AST. Maximum Androgen Blockade MAB, which includes a combination of either medical or surgical castration with an antiandrogen, is used but controversial. The rationale for MAB is that while castration prevents testicular androgen synthesis, androgens and androgen precursors of adrenal origin are largely unaffected and may continue to stimulate the growth of cancer cells. A meta-analysis of 27 MAB trials by the Prostate Cancer Collaborative Group reported a positive result with the use of antiandrogens [18]. It also was reported that the magnitude of the 5-year survival benefit appears to be influenced by the antiandrogen used, with nonsteroidal antiandrogens having an advantage over the steroidal compounds. Nanda et al. [19•] found that, in men with localized but high-risk PCa treated with radiation, short-course AST with an LHRH agonist plus an antiandrogen is associated with decreased risk of PCa mortality when compared to LHRH monotherapy. In addition, another trial demonstrated a PSA recurrence benefit in men with unfavorable risk PCa treated with radiation and MAB [20]. 5-α-Reductase Inhibitors The inhibition of 5AR blocks the synthesis of the most powerful intracellular androgen, DHT. Several studies using 5AR inhibitors, such as finasteride (Proscar, Merck & Co., Whitehouse Station, NJ), as monotherapy showed a transient effect on PSA levels, but limited overall efficacy [21, 22]. Additional studies evaluated the tolerability and efficacy of adding 5AR inhibitor and a nonsteroidal antiandrogen in men with advanced PCa [23, 24]. Combined therapy was additive to monotherapy with either drug alone, as assessed by PSA, but a clear long-term benefit based on these studies was not apparent. In most of these studies, sexual potency rates remained relatively high after starting treatment. In patients with recurrent PCA after failed definitive therapies, adding a 5AR inhibitor and antiandrogen may be an effective first-
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line hormonal manipulation. In a phase 1/2 trial evaluating dutasteride (Avodart, GlaxoSmithKline, Research Triangle Park, NC), a durable PSA response was reported in 33% of patients with PSA relapse after definitive therapy [25]. Several studies underway investigate the effect of dual5AR inhibitor dutasteride in recurrent PCa (ie, Avodart after Radical Therapy for Prostate Cancer Study [ARTS], Avodart in Intermittent Androgen Suppression [AVIHT], and, in androgen-independent disease, Therapy Assessed by Rising PSA [TARP]). The outcomes of these studies are pending.
Timing of Androgen Suppression Therapy In patients with clinically localized (T2/T3) PCa not amenable to curative treatments, it appears that there is no difference between immediate and delayed treatment in terms of disease progression or PCa-specific mortality. However, early treatment is of benefit in patients who are symptomatic and who have a PSA level above 25 ng/mL [2]. Boustead and Edwards [26] performed a meta-analysis of seven randomized trials that studied the impact of immediate versus delayed androgen suppression in patients with locally advanced disease. Despite heterogeneity of the studies, there was a clear benefit to early AST for every outcome parameter measured. In contrast to earlier studies, Spiess and colleagues [27] found no benefit with immediate AST versus delayed therapy secondary to biochemical recurrence in patients with positive lymph nodes metastasis after radical prostatectomy (RP). There has been no randomized study to compare delayed versus immediate AST in patients with biochemical failure after definitive therapy. In a retrospective analysis in recurrent PCa after radiation therapy, starting AST when either the PSADT is longer than 7 months or the PSA is less than 15 ng/mL was associated with significantly improved survival (mean survival benefit of 30 months) [28]. A retrospective multicenter review by Moul et al. [29] showed no difference in disease-free survival in patients who received early versus late AST for recurrence after RP. Early AST was associated with delayed clinical metastasis in patients with Gleason score above 7 or PSADT less than 12 months. Level 1 evidence does exist for a survival benefit for early AST used before the development of symptomatic metastasis in M0 disease. Several studies, all positive, have compared early to deferred hormonal therapy in more advanced disease states [30–32]. The United Kingdom Medical Research Council study showed that palliative surgery for bladder outlet or ureteral obstruction was reduced by almost 50% and disease-specific survival
improved with immediate AST [31]. EORTC 30891 showed an 11% survival benefit for early AST in early advanced disease [32].
Duration of Androgen Suppression Therapy: Neoadjuvant and Adjuvant Hormonal Therapy The use of AST before RP does not improve long-term cancer control, and the adjuvant use of hormonal therapy in this setting remains unclear. However, neoadjuvant and adjuvant approaches have proven useful particularly when combined with external-beam radiation therapy. The EORTC conducted two studies that helped define the role of long-term AST with radiation therapy. In the first study, a survival advantage was seen with addition of 3 years of AST to radiation in patients with locally advanced disease compared to radiation alone [3]. The second study compared 6 months to 3 years of AST and found that 3 years was superior to 6 months in patients with locally advanced disease [33••]. Results from RTOG 92–02 showed that patients with high-risk localized PCa who received 3 years of AST had a significant improvement in 10-year survival [34]. Taken together, these studies have established that prolonged androgen suppression combined with radiotherapy as a standard of care for patients with high-risk clinically localized and locally advanced PCa. It is generally accepted that 2 to 3 years of AST results in better outcomes in these high-risk patients, but it is important to mention that no studies have directly compared 1 or 2 years of AST to 3 years of AST. The initial results of Dana-Farber Cancer Institute randomized trial 95–096 demonstrated a significant survival benefit to the addition of 6 months of AST to radiation therapy for men with intermediate-risk disease [35]. The combined treatment of postoperative radiation and 2 years of AST yielded encouraging results for patient with pathologic T3 disease and PSA relapse after RP [36•, 37•]. Table 2 summarizes the use of AST with radiation therapy. At present, there is no role for the use of AST in the patient treated with low-risk PCa and external-beam radiation therapy, but may have a role in gland-volume reduction in combination with brachytherapy.
Duration of Androgen Suppression Therapy: Recurrent and Metastatic Disease Currently, the standard of care is the use of continuous AST (CAST) for metastatic and recurrent PCa after local treatment failure. The concept of IHT was introduced with the aim of prolonging the time to androgen independence and reversing the side effects of AST during the off periods
Curr Urol Rep Table 2 Duration of androgen suppression therapy with radiation Study
Intervention
Result
Bolla et al. (EORTC 22863) [3] Pilepich et al. (RTOG-85-31) [4] Horwitz et al. (RTOG-92-02) [34] D’Amico et al. [35] Choo et al. [36•]
LHRH day 1 of RT × 3 yrs LHRH beginning last wk of RT and continued 4 months of MAB w/wo additional 24 months MAB 6 months MAB beginning 2 months prior to RT Salvage RT and 2-year AST for PSA relapse after RRP
Choo et al. [37•]
Postoperative RT and 2-year AST for pT3 and/or positive margins post RRP
Increase OS with AST in locally advanced disease Increase OS with AST (GS 8–10) Increase OS with prolonged AST (GS 8–10) Increase OS with AST (GS 7–10) OS 93.2% at 5 and 7 years. RFR 91.5% at 5 years and 78.6% at 7 years OS 96% at 5 years and 93.1% at 7 years. RFR 94.4% at 5 years and 86.3% at 7 years
AST androgen suppression therapy; EORTC European Organization for Research and Treatment of Cancer; GS Gleason Score; LHRH luteinizing hormone—releasing hormone; MAB maximal androgen blockade; OS overall survival; PFS progression-free survival; PSA prostate-specific antigen; RFR recurrence-free relapse; RRP radical retropubic prostatectomy; RT radiation therapy; RTOG Radiation Therapy Oncology Group
of treatment. IHT alternates androgen suppression with treatment cessation, allowing hormonal recovery between treatment periods. Treatment is continued until PSA reaches a nadir and then discontinued, allowing serum testosterone to increase to normal levels; once PSA rises to a predetermined level, treatment is initiated. Clinical studies have shown that IHT improved QOL and reversed sexual dysfunction with no apparent adverse impact on survival [38]. Studies thus far have used different regimens relative to durations of therapy, PSA nadirs, and the PSA threshold to restart therapy. One meta-analysis of 10 phase 2 studies involved 1,446 patients [39]. Patients spent a 39% of time off treatment. Initial PSA, PSA nadir, type of treatment used, and PSA threshold for restarting therapy were important in predicting outcome. Of the 1,446 patients, 181 (12%) developed androgen independence during a maximum follow-up of 197 months. It was noted that patients with a period of remission of over 2 years survived longer and developed androgen independence later than these with remissions of less than 2 years. In those patients who rapidly achieve a good PSA nadir, it is safe to curtail treatment to less than 4 months. In the presence of metastases, treatment should continue for at least 8 months. Restarting therapy at PSA levels approaching 15 ng/mL was associated with improved survival in patient with metastasis. A number of phase 3 trials are underway comparing IHT with CAST, eight of which have published some results [40••]. Although there is general consistency in the PSA levels designated for AST discontinuation (ie, PSA ≤4 ng/mL), the criteria for resuming therapy were less uniform, with levels of 10 ng/mL or more or 20 ng/mL or more reported. Lower thresholds were used in recurrent PCa after failed definitive therapy. In three studies, there was no significant difference in median time to tumor progression (TTP). Equivalence also has been shown for cancer-specific deaths and progression-free survival (PFS).
In contrast, IHT was superior to CAST in one study with respect to 3-year progression and mean estimated PFS. These studies suggest a better tolerability profile and quality of life when IHT is compared to CAST. Crook et al. [41] suggest that men with local or biochemical failure after radiotherapy would benefit from IHT. It was noted by de Leval et al. [42] that IHT also was superior to CAST in patients with poorly differentiated cancers or those without clinically apparent metastasis. Poor candidates for IHT have been described as those with initial bulky tumors, numerous lymph node or bony metastasis, PSADT less than 9 months, and initial serum PSA above 100 ng/mL or severe bone pain [43]. Gleave et al. [44] suggest that patients who fail to achieve a PSA nadir of less than 4 ng/mL after 6 months of therapy and most men with metastatic disease should not be offered IHT, whereas those with positive lymph nodes who are sexually active or intolerant of AST side effects make good candidates. Based on available evidence, IHT is a generally accepted treatment option in men with locally advanced disease, node positive, or recurrent disease after curative therapy, with the understanding that there are many trials still in progress.
Testosterone Levels and Prostate Cancer Outcomes The degree of serum testosterone suppression necessary in PCa currently is a highly debated topic. It is considered to be a critical factor for therapy outcomes in regards to the efficacy of AST for PCa because inadequate testosterone suppression can be one mechanism of disease progression. The issue of testosterone levels is further complicated by the recent consensus statement indicating that the various testosterone assays available are in need of better validation and standardization [45]. Ideally, the testosterone level in systemic AST should match the testosterone level resulting from surgical castration
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(typically
