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Role of Luteinising Hormone Releasing Hormone (LHRH) Agonists and Hormonal Treatment in the Management of Prostate Cancer
European Urology Supplements
European Urology Supplements 4 (2005) 4–13
Role of Luteinising Hormone Releasing Hormone (LHRH) Agonists and Hormonal Treatment in the Management of Prostate Cancer P. Mongiat-Artus, P. Teillac* Department of Urology, 1, Avenue Claude Vellefaux, 75010 Paris, France
Abstract The use of luteinising hormone releasing hormone (LHRH) agonists has increasingly evolved during the past 10 years. This review paper aims to discuss the role of LHRH agonists in patients with prostate cancer, a leading cause of cancer death in men. To retrieve the most relevant randomised clinical trials (RCTs), a Medline search was performed in the last quarter of 2004. Only fully published studies in English language with at least 25 patients per treatment arm and those frequently cited in review articles were included in the current review. This review does not claim to have included every single study with the selected treatment options, but aimed at including the most important trials performed and fully published with these treatments. The retrieved studies are discussed and put into perspective of the EAU guidelines. Initially, LHRH agonists were part of the treatment strategy for patients with advanced or metastatic disease. Currently, LHRH agonists are increasingly used as a treatment option in a neoadjuvant and/or adjuvant setting for patients with early or localised disease. LHRH analogues are used as adjuvant hormonal therapy after radical prostatectomy, and as neoadjuvant and adjuvant treatment to radiotherapy. Patients with early or localised disease and a low Gleason score may experience clinical benefit from the neoadjuvant addition of LHRH agonists to radiotherapy. In patients with a high Gleason score and positive lymph nodes, adjuvant LHRH agonist treatment is considered standard therapy. In patients with rising prostate specific antigen (PSA) after radical treatment, hormonal therapy is often applied in an intermittent way, but results remain inconclusive. Maximum androgen blockade (MAB), a combination of a LHRH agonist and an antiandrogen, has been applied in advanced prostate cancer. However, due to the increased incidence of side effects and very modest survival benefits, there are few arguments to offer this treatment strategy to patients with prostate cancer. In summary, LHRH agonist therapy is important in the treatment of both early and advanced prostate cancer. Additional studies are needed to further define the optimal use of LHRH agonists within various patient risk groups. # 2005 Elsevier B.V. All rights reserved. Keywords: Prostate cancer; LHRH agonists; Adjuvant therapy; Neoadjuvant therapy; Early prostate cancer; Advanced prostate cancer; Metastatic prostate cancer; Biochemical recurrence; Review
1. Introduction Following Huggins and Hodges observation that prostate cancer (PCa) growth is dependent on the presence of androgens, testosterone suppression or * Corresponding author. Tel. +33 1 4249 96 14; Fax: +33 1 4249 9616. E-mail address: [email protected] (P. Teillac).
deprivation by orchiectomy or oestrogens became the standard treatment for advanced PCa [1]. However, both forms of castration have problems. The irreversibility of orchiectomy limits its use to advanced PCa. Oestrogen treatment is associated with significant cardiovascular morbidity and mortality [2]. Therefore, new ways of non-surgical castration were needed.
1569-9056/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.eursup.2005.04.003
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In 1971, Schally and Guillemin discovered the luteinising hormone releasing hormone (LHRH) which led to the development of LHRH agonists as chemical castration strategy. 1.1. Rational for LHRH agonist therapy The hypothalamus secretes LHRH, also referred to as gonadotropin releasing hormone (GnRH), in a pulsatile pattern. This small peptide has a very short halflife because of peptidase degradation. This is an elegant effect, as it has only to remain active for a short time in the hypophyseal portal circulation. Via this circulation, LHRH travels to the anterior pituitary gland where it binds to the LHRH-receptor and stimulates the synthesis and secretion of both luteinising hormone (LH) and follicle stimulating hormone (FSH). Circulating LH enters the systemic circulation and interacts with receptors on the interstitial Leydig cells of the testis. This interaction activates intracellular mechanisms leading to the synthesis and release of testosterone. More than 90% of this testosterone circulates in the bloodstream bound to the sex hormone binding globulin (SHBG) or to albumin. Only a small percentage (10%) is unbound and through this, available for cellular activation. If the testosterone level increases, testosterone itself regulates the negative feedback loop and inhibits the release of LHRH from the hypothalamus as well as the release of LH from the pituitary. As a result, this decreases the synthesis and release of testosterone from the Leydig cells [3–5]. Testosterone produced by the Leydig cells is transported by the systemic circulation to other organs, including the prostate. In the prostatic cells, testosterone is converted by 5a-reductase into dihydrotestosterone (DHT). DHT has a higher affinity for the intracellular androgen receptor than testosterone. After binding of DHT to the androgen receptor on the cell nucleus, this complex binds to the promotor of the hormone-responsive element, which finally results in protein synthesis of prostate specific antigen (PSA) and growth factors [3–5]. The adrenal glands are a second source of androgens, accounting for approximately 5% of total androgen production. The adrenocorticotropic hormone (ACTH) stimulates the adrenal glands to produce the androgens androstenedione and dehydroepiandrosterone. Both androgens will be converted to testosterone in peripheral tissues and in the prostate gland itself [3–6]. When given for the first time, LHRH agonists induce a transient rise in pituitary LH. Simultaneously, there is a surge in testosterone plasma levels to concentrations far above pre-treatment values (flare phenomenon) [7].
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In the clinical setting this flare can be avoided by shortterm co-treatment with antiandrogens [8]. After an average of 3–4 weeks, LHRH receptors in the pituitary will be down-regulated, resulting in a decline of serum testosterone levels towards the castration level of 50 ng/dL [7,9–11]. Two factors appear to be important in this down-regulation; first, the continuous administration of LHRH agonists as compared to the natural occurring pulsatile pattern and second, the overstimulation of the receptors by maintaining the LHRH agonist blood level constant on >100 pg/mL [12]. 1.2. LHRH agonists applied in different stages of prostate cancer Because of the reversibility of the castration and the favourable side effects profile, LHRH agonists are currently used in both early and advanced disease [13,14]. This article will focus on the literature, defining the use of LHRH agonists in:
Adjuvant therapy to radical prostatectomy Neoadjuvant and adjuvant therapy to radiotherapy Hormonal therapy after biochemical recurrence Hormonal therapy for advanced disease Hormonal therapy for metastatic disease It also briefly reviews their side effect profile.
2. LHRH agonists as a treatment option in early disease 2.1. Rationale As a consequence of the introduction of PSA as a marker for PCa, awareness of both patients and physicians has increased. PCa is nowadays often diagnosed at earlier stages, younger ages (<60 years), and in men with lower PSA and testosterone levels [15,16]. Staging of PCa in early disease is not straight forward, as 50% of cancers diagnosed as clinical stage T2 are often found to be pT3 after radical prostatectomy [17]. Conceptually, early PCa can be cured, meaning that patients diagnosed at this stage, can have a 5-year survival rate of 100% [18]. Radical treatment, either radical prostatectomy (and other treatment modalities such as high-intensity focused ultrasound (HIFU)) and/or radiotherapy (external beam radiation therapy (EBRT) and brachytherapy), is the standard therapy for patients with early disease (Fig. 1) [19–21]. Radical prostatectomy can be considered as curative, if surgical margins are negative. However, surgery
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Fig. 1. Treatment strategies are dependent on the possibility of cure, but overall, LHRH agonists play an important role in the treatment of PCa.
may fail in some men because the cancer tissue is incompletely resected, due to clinical under staging before surgery or undetected micrometastatic disease. The addition of hormonal therapy in a neoadjuvant setting will lower the pathological stage and reduce positive margins [22]. However, it should be noted that neoadjuvant hormonal therapy to radical prostatectomy can induce fibrosis and thereby complicate surgery. In addition, pathological evaluation of the Gleason score and subsequently prediction of prognosis appears to be more difficult. As a consequence, neoadjuvant hormonal therapy prior to radical prostatectomy is no longer a recommended treatment strategy [23,24]. After surgery, however, hormonal therapy in an adjuvant setting may be indicated. Growth of locally residual cancer cells or undetected micrometastatic disease can cause progression of disease in some men. Adjuvant hormonal therapy in case of positive lymph nodes, started immediately after radical prostatectomy, will increase patient survival [15,25,26]. Radiation therapy options include EBRT [27,28] and implantation of radioactive seeds (brachytherapy) [29,30]. The purpose of neoadjuvant therapy before radiotherapy is to downsize the tumour and decrease the radiation field. 2.2. Hormone therapy in combination with radical prostatectomy Several studies have already suggested the improvement of local control and survival in patients after receiving adjuvant hormonal therapy following radical prostatectomy. There are a few studies that show a significantly positive effect on cause-specific survival.
Zincke et al. [31] retrospectively reviewed patients with PCa stage pT3b who received adjuvant hormonal therapy. The survival rates, including cause-specific (95% vs. 87% in the control group), systemic progression-free (90% vs. 78% in the control group) and biochemical progression-free survival (67% vs. 23% in the control group), significantly improved at 10 years. The Eastern Cooperative Oncology Group (ECOG) trial 7887 [25,26] also provided information about adjuvant hormonal therapy in patients who were found to have nodal metastases after radical prostatectomy. After a median follow-up of 7.1 years [25], only 15% of the patients treated with adjuvant therapy had died, compared to 35% of patients who received deferred therapy (p = 0.02). Thirty-three percent of patients who received hormonal therapy appeared to have recurrent disease (detectable PSA levels), as compared to 82% of patients in the deferred-therapy group (p < 0.001). Overall survival was significantly better in patients who received immediate hormonal therapy as compared to deferred therapy (Fig. 2). An updated analysis after 10 years [26] confirmed that overall survival (p = 0.025) as well as disease-specific survival (p = 0.001) was statistically significantly better in patients who had received adjuvant hormonal therapy. 2.3. EAU guidelines Overall, according to the EAU guidelines, radical prostatectomy is the standard treatment for patients with a life expectancy of more than 10 years [32]. Immediate androgen deprivation in an adjuvant setting to patients who already received radical prostatectomy
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Fig. 2. Overall survival was significantly better in patients who received immediate hormonal therapy as compared to deferred therapy [25]. Adapted with permission, # 1999 Massachusetts Medical Society. All rights reserved.
for node positive disease, provides a highly significant survival benefit. 2.4. Hormone therapy in combination with radiation therapy Several studies by the Radiation Therapy Oncology Group (RTOG) have investigated the effect of hormonal therapy in combination with radiotherapy, and all found beneficial results. RTOG 8610 [33] found a statistical significance (p < 0.001) in terms of progression-free survival rates between patients (T2–T4) who had received neoadjuvant hormonal therapy (36%), as compared to patients who had only received radiotherapy (15%). After 8 years of follow-up [34], neoadjuvant hormonal therapy showed improved local control, reduced the incidence of distant metastases, improved disease-free survival and decreased causespecific mortality. Patients with low-to-intermediate grade (Gleason score 2–6) had a statistically significant benefit from additional hormonal therapy.
The European Organization for Research on Treatment of Cancer (EORTC 22863) [35] compared radiotherapy alone with the combination of radiotherapy immediately followed by adjuvant hormonal therapy in 415 patients with T1–T4, N0 PCa. After a median follow-up of 45 months, 5-year overall survival, disease-specific survival and disease-free survival improved after adjuvant hormonal deprivation, compared with radiotherapy alone. Long-term follow-up of 66 months [36] confirmed these results (Table 1). Also two RTOG studies (RTOG 85-31 [37,38] and RTOG 92-02 [39]) investigated the additional effect of adjuvant hormonal therapy to radiation therapy. Both studies were able to demonstrate a statistically significant advantage in all endpoints, except 5-year overall survival. However, subgroup analysis showed that overall survival was significantly greater in patients with Gleason score 8–10, receiving adjuvant hormonal therapy.
Table 1 After a mean follow-up of 66 months, survival after radiotherapy alone showed to be lower as compared to radiotherapy combined with a LHRH agonist for 3 years [36]
Deaths PCa deaths 5-year clinical disease-free survival (95% CI) 5-year overall survival (95% CI) 5-year specific survival (95% CI) 5-year biochemical disease-free survival (95% CI) 5-year cumulative incidence of distant metastases (95% CI) 5-year cumulative incidence of locoregional failure (95% CI) #
p < 0.0001. p = 0.0002. ** p = 0.0001. *
Radiotherapy
Radiotherapy plus LHRH agonist
N = 78 N = 42 40% (32–48%) 62% (52–72%) 79% (72–86%) 45% (30–60%) 29.2% (22.7–35.6%) 16.4% (10.8–22.1%)
N = 50 N = 12 74% (67–81%)# 78% (72–84%)* 94% (90–98%)** 76% (69–83%)# 9.8% (5.4–14.2%)# 1.7% (0–3.7%)#
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2.5. EAU guidelines According to the EAU 2005 guidelines, radiotherapy is the standard treatment in patients with a life expectancy of >10 years and not willing to undergo surgery, and patients unfit for surgery with a life expectancy of 5–10 years and poorly differentiated tumours. In case the patient has a poorly differentiated tumour, 2–3 years of neoadjuvant/adjuvant hormonal therapy to radiotherapy has proven to be better than radiotherapy alone. Overall, patients receiving neoadjuvant hormonal therapy to radiation therapy will have a better local control of the disease [32]. 3. LHRH agonists as a treatment option for patients with a rising PSA 3.1. Rationale About 25–40% of patients who undergo radical prostatectomy or radiotherapy will have biochemical recurrence after a follow-up of about 10 years [40,41]. This is a very common problem facing patients and clinicians. In these patients, initiating hormonal therapy is logical, but the crucial question is when to start? Median time to metastasis in these patients has been established to be 8 years, and median time to death after development of metastases is 5 years [42]. Hormonal therapy can be started at the time the PSA level starts to rise, or when symptoms appear. If hormonal treatment is started when the PSA level increases, the patient will receive hormonal therapy for a relative long period (10 years) and will also be at risk of experiencing adverse events of long-term androgen deprivation [43]. As these patients are relatively young and otherwise healthy, therapy should not only improve their survival but also preserve there quality of life (QoL). Therefore, intermittent hormonal therapy was developed as a treatment strategy in this patient population [44]. 3.2. Intermittent hormonal therapy Intermittent hormonal therapy (IHT) aims at delaying the onset of androgen-independent PCa cells, as well as reducing adverse events and costs. Hormonal therapy is administered until a pre-set PSA nadir is reached (mostly <4 ng/mL) and will be started again when the PSA level starts rising again, or exceeds a pre-set threshold (e.g. between 5 and 20 ng/mL) [45,46]. Kurek et al. [47] reported a prospective study in the specific setting of IHTas a treatment strategy for patients with a rising PSA level. After a median follow-up of 48 months, none of the patients had demonstrated progression to hormone-refractory disease. Recently, other studies evaluating the efficacy of IHT have become
available. The Canadian Trials [48] enrolled 109 men with biochemical failure after irradiation. IHT was interrupted when PSA levels were less than 4 ng/mL and restarted again following 3 sequential increases of PSA above 4 ng/mL and testosterone levels less than 0.5 nmol/L. All patients had improved QoL and 80% of patients had achieved normal testosterone levels 24 weeks after therapy interruption. Prapotnich et al. [49] published a 10-year follow-up study of 233 patients who underwent IHT after previous radiotherapy, radical prostatectomy or HIFU. LHRH agonist therapy was interrupted if PSA decreased below 4 ng/mL but restarted when PSA levels increased above 20 ng/mL, the PSA slope over previous 3 months increased above 5 ng/mL per month, or if recurrence of pain or urinary symptoms appeared. Only 2.5% of patients experienced pain and moderate urinary complications, but these were seen as acceptable by the patient. Also, patients needed 5–6 months to recover normal testosterone levels. In 1999, Hall et al. [11] detected that 6 months after cessation of long-term (25–82 months) LHRH agonists, serum testosterone levels were invariably below the normal range. Recently, Oefelein et al. [50] showed that the median duration of castrated levels of serum testosterone was 5.5 months (3.5–10 months) after 1 injection of a LHRH agonist (3-month depot). The method of redosing LHRH agonists based on testosterone levels appeared efficacious, safe and cost-effective. 3.3. EAU guidelines The EAU 2005 guidelines recommend hormonal therapy to patients with a rising PSA, since a PSA level exceeding 0.2 ng/mL after radical therapy can be associated with residual or recurrent disease [32]. As intermittent hormonal therapy improves the patient’s QoL, and may be as efficacious as continuous hormonal treatment, intermittent hormonal therapy is a recommended treatment option in patients with a rising PSA level.
4. LHRH agonists as a treatment option in advanced disease 4.1. Rationale The traditional definition of ‘‘advanced’’ PCa includes patients with a tumour which has extended beyond the prostatic capsule, but without having nodal or distant metastatic spread [17,51,52]. However, some classifications also put patients with a rising PSA into this group. Advanced disease is often referred to as tumours staged as T3b-T4, N0, M0 or T1–T4, N1, M0 or pT3, N0, M0 or Jewett stage C [52].
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Fig. 3. Subjective responses achieved by LHRH agonists are equal to those achieved by orchiectomy [58]. LUTS: lower urinary tract symptoms.
Debruyne et al. [18] reported that 18% of patients presenting with regional disease, which corresponds to patients with ‘‘advanced disease’’, had a five-year survival rate of 94%. Most cases of advanced PCa are hormone sensitive [53]. Denis [54] reported that androgen deprivation produces a temporary halt in cancer growth in 60% of patients with advanced disease, and the subjective response rate may even reach 80%. As a result, treatment approaches are mostly directed towards suppression of testosterone production (Fig. 1) [46,53]. 4.2. LHRH agonists versus orchiectomy Orchiectomy used to be the standard for patients with advanced disease, until the discovery of LHRH agonists. Both orchiectomy and LHRH agonists have the similar efficacy and safety profile (Fig. 3, Table 2); both therapies have an equal testosterone response, subjective and objective response rates and treatment failure [55–58]. Patients prefer LHRH agonist therapy to orchiectomy due to the psychological distress associated with removal of the testes and the reversibility of the castration [13,14]. 4.3. LHRH agonists are mainstay therapy Several studies [59–63] have demonstrated the efficacy of LHRH agonists in reducing serum testosterone
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Fig. 4. Almost all patients reach serum testosterone castrate levels of 50 ng/dL in about 3-4 weeks after the first LHRH agonist injection [59–63].
below the castrate level of 50 ng/dL (Fig. 4). Most patients (>95%) achieve those castrate levels in about 3–4 weeks after the first LHRH agonist injection. On the contrary, limited data are available whether LHRH agonists decrease testosterone to levels of 20 ng/dL, which is achieved by orchiectomy. A comprehensive review on this subject is provided by Prof. Bertrand Tombal, also in this supplement [64]. PSA levels also decrease 90% of baseline value or into normal range of <4 ng/mL in about 90% of patients [62,63,65]. This decrease of PSA levels, together with an overall survival rate of about 3–4 years [66–69], clearly demonstrates that progression free survival increases if patients received LHRH agonists. LHRH agonists have been shown to improve the patient’s QoL. Pain improved in 40–80% of patients [58,70,71], urinary symptoms improved in about 80% of them [58,70], and performance status improved in about 50% of patients [58,71]. 4.4. Early vs. deferred therapy The next question to be addressed is when to start therapy with LHRH agonists. Most physicians start androgen deprivation therapy at diagnosis, in the hope of prolonging the patient’s survival. Alternatively, starting androgen deprivation therapy when symptoms
Table 2 Objective responses achieved by LHRH agonists are equal to those achieved by bilateral orchiectomy [55,56,58]
LHRH n = 148a Orchiectomy n = 144a LHRH n = 138b Orchiectomy n = 145b LHRH n = 55c Orchiectomy n = 49c a
Kaisary et al. Br J Urol 1991. Vogelzang et al. Urology 1995. c Parmar et al. Br J Urol 1987. b
Complete response (% of patients)
Partial response (% of patients)
Disease progression (% of patients)
Median overall survival time (years)
0 0 4 4 0 0
71 72 17 21 36 33
11 6 9 10 16 19
2.1 1.9 2.3 2.6 1.3 1.1
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appear (deferred therapy) may be as successful as immediate therapy. The first study that addressed this question was the medical research council (MRC) trial [72]. In 1985, 469 patients with asymptomatic advanced disease were treated immediate after diagnosis, while 465 others received deferred therapy until symptoms appeared. Disease progression was halted much longer in patients who had received immediate therapy. Accordingly, the MRC suggested immediate androgen deprivation was the treatment of choice rather than deferred therapy. However, a significant number of patients in the control group never received androgen suppression before death. Recently, an EORTC study by Schroder et al. [73] also looked atdeferred and immediatehormonaltherapy. This study indicated a 23% trend in favour of early treatment, which was however not statistically significant. Overall, due to the conflicting results between early and deferred hormonal therapy, the patient should be able to make his own decision between the expected advantages of early treatment or the potential advantages in QoL of deferred therapy. 4.5. Maximum androgen blockade Castration in men results in a significant reduction of testosterone levels, but does not eliminate testosterone production from the adrenal glands. As a result, those men still have relatively high levels (<40%) of DHT and 5–10% of testosterone. Therefore, it was believed that maximum androgen blockade (MAB), also referred to as complete androgen blockade (CAB) or combination androgen blockade (CAB) may be beneficial for treating patients with PCa. In this case, LHRH agonists are used to inhibit the testosterone production and the addition of antiandrogens inhibits the effects of adrenal androgens [13,46,53,54]. Since 1982, several randomised trials have shown that MAB significantly prolongs survival compared with controls [74,75]. However, more recent data could not confirm these initial results. The Prostate Cancer Trialists’ Collaborative Group (PCTCG) included data from 22 randomized trials in a meta-analysis [76]. Trends favouring MAB were identified in terms of overall morbidity (56% vs. 58%) and 5-year survival (26.2% vs. 22.8%), but none was statistically significant. The follow-up study in 2000 [77] favoured the use of nilutamide and/or flutamide, but failed again to improve median survival. Recently, the Cochrane Collaboration reviewed MAB as a treatment for patients with advanced PCa [78]. Progression-free survival (OR = 1.38) and cancer-free survival (OR = 1.22) were both improved and overall survival was statistically significant at 5 years. However, adverse events were
more frequent in patients receiving MAB and resulted in withdrawal of therapy in >10% of patients, as compared to only 4% withdrawals of those receiving monotherapy with LHRH agonists. Overall, it is felt that marginal benefits do not outweigh the additional adverse events. Currently, MAB is not a standard treatment for patients with advanced PCa. 4.6. EAU guidelines Overall, the EAU 2005 guidelines recommend hormonal therapy as standard treatment for patients diagnosed with advanced disease. Radical therapy alone or in combination with hormonal therapy is not an option in these patients [32]. 5. LHRH agonists as a treatment option in metastatic disease Patients presenting with metastatic disease can be divided into three groups. The first group comprises patients who show to have lymph-node disease when assessed for radical therapy. The second group of patients has a high level of PSA, no symptoms but asymptomatic bone metastases or metastases in soft tissues. And the third group are those with painful metastases [79]. Debruyne et al. [18] established that 11% of patients diagnosed with PCa, already have metastatic disease. The 5-year survival of these patients is very low (only 31%), meaning that treatment for patients with painful metastases is predominantly a palliative therapy. A general consensus exists to treat them with early rather than deferred therapy [79] and, also here, hormonal therapy is the treatment of choice. As compared to early or advanced disease, patients with metastatic disease may benefit from a combination of LHRH agonists and a steroidal antiandrogen [75,80]. In patients with multiple painful bone lesions, biphosphonates [81], radiotherapy [82] or Strontium 89 [83] are also known as palliative treatments. 5.1. EAU guidelines The EAU 2005 guidelines recommend hormonal therapy as standard treatment for patients diagnosed with metastatic disease [32]. 6. LHRH agonist side-effects The most common side effects of LHRH agonists include hot flushes, decreased libido, anaemia, impotence, asthenia/fatigue/decreased energy, gynaecomastia, tenderness and nausea/vomiting [59,65,70,84–86]. Hot flushes occur in 50–70% and gynaecomastia in
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5–15% of patients. The incidence of impotence and decreased libido varies considerably. In some studies [70] rates up to 80–100% have been reported, while other studies [59,65,84] report only 1–2%. This low level is probably due to underreporting. In general, around 6–15% of patients report being bothered by asthenia/fatigue and 0–13% complain about nausea/ vomiting. Overall, treatment discontinuations, a reliable indicator of adverse events, occurred rarely after LHRH agonist therapy (0–4%, as compared to 4–10% after antiandrogen therapy) [57]. Osteoporosis is an important problem in patients receiving long-term androgen deprivation. Physicians should carefully monitor the development of osteoporosis, and advise the patient to stop smoking and take vitamin D and calcium supplements [87,88]. It is well known that testosterone levels increase during the first week of treatment with LHRH agonists. Therefore, a clinical disease flare may occur in up to 63% of those with advanced disease [18]. Patients might experience a worsening of signs and symptoms of disease. In clinical practice, this flare can be inhibited by administering a non-steroidal antiandrogen such as flutamide, bicalutamide or nilutamide. This antiandrogen is administered for two weeks before and two weeks after the first LHRH agonist injection [8,89,90].
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7. Conclusion The use of LHRH agonists is well documented and forms part of treatment approaches in both early and advanced PCa. Clinical data support, in well defined situations, the use of LHRH agonists as adjuvant treatment to radical prostatectomy, and as neoadjuvant and/or adjuvant treatment to radiotherapy. Highest benefits can be expected in patients with the highest risk of progression. Adjuvant hormonal therapy to radiotherapy is especially beneficial in patients with a high Gleason score (8–10) at biopsy. Several studies evaluated the benefits of intermittent hormonal therapy in patients experiencing biochemical recurrence (rising PSA) after radical therapy. Results of these studies remain inconclusive. LHRH agonist therapy remains the mainstay therapy in patients with advanced and metastatic PCa. Most data from trials support that early administration of LHRH agonists is better than deferring therapy upon manifestation of symptoms or pain in these patients. Although LHRH agonists have a favourable side effect profile, physicians should be attentive for the risk of long term androgen deprivation.
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[19] Eastham JA, Scardino PT. Radical prostatectomy. In: Walsh PC, Retik AB, Vaughan ED, Wein AJ, editors. Campbell’s Urology. Philadelphia: W.B. Saunders Company; 1998. p. 2547–64. [20] Sandler HM. Optimizing hormone therapy in localized prostate cancer: focus on external beam radiotherapy. J Urol 2004;172:S38–41. [21] Blana A, Walter B, Rogenhofer S, Wieland WF. High-intensity focused ultrasound for the treatment of localized prostate cancer: 5-year experience. Urology 2004;63(2):297–300. [22] Labrie F, Cusan L, Gomez J, Diamond P, Suburu R, Lemay M, et al. Down-staging of early stage prostate cancer before radical prostatectomy: the first randomized trial of neoadjuvant combination therapy with flutamide and a luteinizing hormone –releasing hormone agonist. Urology 1994;44:29–37. [23] Abbas F, Scardino PT. Why neoadjuvant androgen deprivation prior to radical prostatectomy is unnecessary. Urol Clin North Am 1996; 23(4):587–604. [24] Teillac P. Is there a place for neoadjuvant hormonal therapy before radical prostatectomy or radiation therapy in the management of prostate cancer? Prostate Cancer Prostatic Dis 1999;2(S2):S8–S11. [25] Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 1999;341:1781–8. [26] Messing E, Manola J, Sarosdy M, Wilding G, Crawford D, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node positive prostate cancer: results at 10 years of EST 3886. J Urol 2003; 169(Suppl):396 (abs. 1480). [27] Hanks GE, Hanlon AL, Pinover WH, Horwitz EM, Price RA, Schultheiss T. Dose selection for prostate cancer patients based on dose comparison and dose response studies. Int J Radiat Oncol Biol Phys 2000;46(4):823–32. [28] Hanks GE. Conformal radiotherapy for prostate cancer. Ann Med 2000;32(1):57–63. [29] Nag S, Beyer D, Friedland J, Grimm P, Nath R. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999;44(4):789–99. [30] Martinez AA, Pataki I, Edmundson G, Sebastian E, Brabbins D, Gustafson G. Phase II prospective study of the use of conformal high-dose-rate brachytherapy as monotherapy for the treatment of favorable stage prostate cancer: a feasibility report. Int J Radiat Oncol Biol Phys 2001;49(1):61–9. [31] Zincke H, Lau W, Bergstralh E, Blute ML. Role of early adjuvant hormonal therapy after radical prostatectomy for prostate cancer. J Urol 2001;166(6):2208–15. [32] EAU Guidelines for prostate cancer. March 2005. [33] Pilepich MV, Krall JM, Al-Sarraf M, John MJ, Doggett RLS, Sause WT, et al. Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group. Urology 1995;45:616–23. [34] Pilepich MV, Winter K, John MJ, Mesic JB, Sause W, Rubin P, et al. Phase III Radiation Therapy Oncology Group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001;50:1243–52. [35] Bolla M, Gonzalez D, Warde P, Dubois JB, Mirimanoff R-O, Storme G, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997;337:295–300. [36] Bolla M, Collette L, Blank L, Warde P, Dubois JB, Mirimanoff RO, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002; 360:103–8.
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Role of Luteinising Hormone Releasing Hormone (LHRH) Agonists and Hormonal Treatment in the Management of Prostate Cancer P. Mongiat-Artus, P. Teillac* Department of Urology, 1, Avenue Claude Vellefaux, 75010 Paris, France
Abstract The use of luteinising hormone releasing hormone (LHRH) agonists has increasingly evolved during the past 10 years. This review paper aims to discuss the role of LHRH agonists in patients with prostate cancer, a leading cause of cancer death in men. To retrieve the most relevant randomised clinical trials (RCTs), a Medline search was performed in the last quarter of 2004. Only fully published studies in English language with at least 25 patients per treatment arm and those frequently cited in review articles were included in the current review. This review does not claim to have included every single study with the selected treatment options, but aimed at including the most important trials performed and fully published with these treatments. The retrieved studies are discussed and put into perspective of the EAU guidelines. Initially, LHRH agonists were part of the treatment strategy for patients with advanced or metastatic disease. Currently, LHRH agonists are increasingly used as a treatment option in a neoadjuvant and/or adjuvant setting for patients with early or localised disease. LHRH analogues are used as adjuvant hormonal therapy after radical prostatectomy, and as neoadjuvant and adjuvant treatment to radiotherapy. Patients with early or localised disease and a low Gleason score may experience clinical benefit from the neoadjuvant addition of LHRH agonists to radiotherapy. In patients with a high Gleason score and positive lymph nodes, adjuvant LHRH agonist treatment is considered standard therapy. In patients with rising prostate specific antigen (PSA) after radical treatment, hormonal therapy is often applied in an intermittent way, but results remain inconclusive. Maximum androgen blockade (MAB), a combination of a LHRH agonist and an antiandrogen, has been applied in advanced prostate cancer. However, due to the increased incidence of side effects and very modest survival benefits, there are few arguments to offer this treatment strategy to patients with prostate cancer. In summary, LHRH agonist therapy is important in the treatment of both early and advanced prostate cancer. Additional studies are needed to further define the optimal use of LHRH agonists within various patient risk groups. # 2005 Elsevier B.V. All rights reserved. Keywords: Prostate cancer; LHRH agonists; Adjuvant therapy; Neoadjuvant therapy; Early prostate cancer; Advanced prostate cancer; Metastatic prostate cancer; Biochemical recurrence; Review
1. Introduction Following Huggins and Hodges observation that prostate cancer (PCa) growth is dependent on the presence of androgens, testosterone suppression or * Corresponding author. Tel. +33 1 4249 96 14; Fax: +33 1 4249 9616. E-mail address: [email protected] (P. Teillac).
deprivation by orchiectomy or oestrogens became the standard treatment for advanced PCa [1]. However, both forms of castration have problems. The irreversibility of orchiectomy limits its use to advanced PCa. Oestrogen treatment is associated with significant cardiovascular morbidity and mortality [2]. Therefore, new ways of non-surgical castration were needed.
1569-9056/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.eursup.2005.04.003
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In 1971, Schally and Guillemin discovered the luteinising hormone releasing hormone (LHRH) which led to the development of LHRH agonists as chemical castration strategy. 1.1. Rational for LHRH agonist therapy The hypothalamus secretes LHRH, also referred to as gonadotropin releasing hormone (GnRH), in a pulsatile pattern. This small peptide has a very short halflife because of peptidase degradation. This is an elegant effect, as it has only to remain active for a short time in the hypophyseal portal circulation. Via this circulation, LHRH travels to the anterior pituitary gland where it binds to the LHRH-receptor and stimulates the synthesis and secretion of both luteinising hormone (LH) and follicle stimulating hormone (FSH). Circulating LH enters the systemic circulation and interacts with receptors on the interstitial Leydig cells of the testis. This interaction activates intracellular mechanisms leading to the synthesis and release of testosterone. More than 90% of this testosterone circulates in the bloodstream bound to the sex hormone binding globulin (SHBG) or to albumin. Only a small percentage (10%) is unbound and through this, available for cellular activation. If the testosterone level increases, testosterone itself regulates the negative feedback loop and inhibits the release of LHRH from the hypothalamus as well as the release of LH from the pituitary. As a result, this decreases the synthesis and release of testosterone from the Leydig cells [3–5]. Testosterone produced by the Leydig cells is transported by the systemic circulation to other organs, including the prostate. In the prostatic cells, testosterone is converted by 5a-reductase into dihydrotestosterone (DHT). DHT has a higher affinity for the intracellular androgen receptor than testosterone. After binding of DHT to the androgen receptor on the cell nucleus, this complex binds to the promotor of the hormone-responsive element, which finally results in protein synthesis of prostate specific antigen (PSA) and growth factors [3–5]. The adrenal glands are a second source of androgens, accounting for approximately 5% of total androgen production. The adrenocorticotropic hormone (ACTH) stimulates the adrenal glands to produce the androgens androstenedione and dehydroepiandrosterone. Both androgens will be converted to testosterone in peripheral tissues and in the prostate gland itself [3–6]. When given for the first time, LHRH agonists induce a transient rise in pituitary LH. Simultaneously, there is a surge in testosterone plasma levels to concentrations far above pre-treatment values (flare phenomenon) [7].
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In the clinical setting this flare can be avoided by shortterm co-treatment with antiandrogens [8]. After an average of 3–4 weeks, LHRH receptors in the pituitary will be down-regulated, resulting in a decline of serum testosterone levels towards the castration level of 50 ng/dL [7,9–11]. Two factors appear to be important in this down-regulation; first, the continuous administration of LHRH agonists as compared to the natural occurring pulsatile pattern and second, the overstimulation of the receptors by maintaining the LHRH agonist blood level constant on >100 pg/mL [12]. 1.2. LHRH agonists applied in different stages of prostate cancer Because of the reversibility of the castration and the favourable side effects profile, LHRH agonists are currently used in both early and advanced disease [13,14]. This article will focus on the literature, defining the use of LHRH agonists in:
Adjuvant therapy to radical prostatectomy Neoadjuvant and adjuvant therapy to radiotherapy Hormonal therapy after biochemical recurrence Hormonal therapy for advanced disease Hormonal therapy for metastatic disease It also briefly reviews their side effect profile.
2. LHRH agonists as a treatment option in early disease 2.1. Rationale As a consequence of the introduction of PSA as a marker for PCa, awareness of both patients and physicians has increased. PCa is nowadays often diagnosed at earlier stages, younger ages (<60 years), and in men with lower PSA and testosterone levels [15,16]. Staging of PCa in early disease is not straight forward, as 50% of cancers diagnosed as clinical stage T2 are often found to be pT3 after radical prostatectomy [17]. Conceptually, early PCa can be cured, meaning that patients diagnosed at this stage, can have a 5-year survival rate of 100% [18]. Radical treatment, either radical prostatectomy (and other treatment modalities such as high-intensity focused ultrasound (HIFU)) and/or radiotherapy (external beam radiation therapy (EBRT) and brachytherapy), is the standard therapy for patients with early disease (Fig. 1) [19–21]. Radical prostatectomy can be considered as curative, if surgical margins are negative. However, surgery
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Fig. 1. Treatment strategies are dependent on the possibility of cure, but overall, LHRH agonists play an important role in the treatment of PCa.
may fail in some men because the cancer tissue is incompletely resected, due to clinical under staging before surgery or undetected micrometastatic disease. The addition of hormonal therapy in a neoadjuvant setting will lower the pathological stage and reduce positive margins [22]. However, it should be noted that neoadjuvant hormonal therapy to radical prostatectomy can induce fibrosis and thereby complicate surgery. In addition, pathological evaluation of the Gleason score and subsequently prediction of prognosis appears to be more difficult. As a consequence, neoadjuvant hormonal therapy prior to radical prostatectomy is no longer a recommended treatment strategy [23,24]. After surgery, however, hormonal therapy in an adjuvant setting may be indicated. Growth of locally residual cancer cells or undetected micrometastatic disease can cause progression of disease in some men. Adjuvant hormonal therapy in case of positive lymph nodes, started immediately after radical prostatectomy, will increase patient survival [15,25,26]. Radiation therapy options include EBRT [27,28] and implantation of radioactive seeds (brachytherapy) [29,30]. The purpose of neoadjuvant therapy before radiotherapy is to downsize the tumour and decrease the radiation field. 2.2. Hormone therapy in combination with radical prostatectomy Several studies have already suggested the improvement of local control and survival in patients after receiving adjuvant hormonal therapy following radical prostatectomy. There are a few studies that show a significantly positive effect on cause-specific survival.
Zincke et al. [31] retrospectively reviewed patients with PCa stage pT3b who received adjuvant hormonal therapy. The survival rates, including cause-specific (95% vs. 87% in the control group), systemic progression-free (90% vs. 78% in the control group) and biochemical progression-free survival (67% vs. 23% in the control group), significantly improved at 10 years. The Eastern Cooperative Oncology Group (ECOG) trial 7887 [25,26] also provided information about adjuvant hormonal therapy in patients who were found to have nodal metastases after radical prostatectomy. After a median follow-up of 7.1 years [25], only 15% of the patients treated with adjuvant therapy had died, compared to 35% of patients who received deferred therapy (p = 0.02). Thirty-three percent of patients who received hormonal therapy appeared to have recurrent disease (detectable PSA levels), as compared to 82% of patients in the deferred-therapy group (p < 0.001). Overall survival was significantly better in patients who received immediate hormonal therapy as compared to deferred therapy (Fig. 2). An updated analysis after 10 years [26] confirmed that overall survival (p = 0.025) as well as disease-specific survival (p = 0.001) was statistically significantly better in patients who had received adjuvant hormonal therapy. 2.3. EAU guidelines Overall, according to the EAU guidelines, radical prostatectomy is the standard treatment for patients with a life expectancy of more than 10 years [32]. Immediate androgen deprivation in an adjuvant setting to patients who already received radical prostatectomy
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Fig. 2. Overall survival was significantly better in patients who received immediate hormonal therapy as compared to deferred therapy [25]. Adapted with permission, # 1999 Massachusetts Medical Society. All rights reserved.
for node positive disease, provides a highly significant survival benefit. 2.4. Hormone therapy in combination with radiation therapy Several studies by the Radiation Therapy Oncology Group (RTOG) have investigated the effect of hormonal therapy in combination with radiotherapy, and all found beneficial results. RTOG 8610 [33] found a statistical significance (p < 0.001) in terms of progression-free survival rates between patients (T2–T4) who had received neoadjuvant hormonal therapy (36%), as compared to patients who had only received radiotherapy (15%). After 8 years of follow-up [34], neoadjuvant hormonal therapy showed improved local control, reduced the incidence of distant metastases, improved disease-free survival and decreased causespecific mortality. Patients with low-to-intermediate grade (Gleason score 2–6) had a statistically significant benefit from additional hormonal therapy.
The European Organization for Research on Treatment of Cancer (EORTC 22863) [35] compared radiotherapy alone with the combination of radiotherapy immediately followed by adjuvant hormonal therapy in 415 patients with T1–T4, N0 PCa. After a median follow-up of 45 months, 5-year overall survival, disease-specific survival and disease-free survival improved after adjuvant hormonal deprivation, compared with radiotherapy alone. Long-term follow-up of 66 months [36] confirmed these results (Table 1). Also two RTOG studies (RTOG 85-31 [37,38] and RTOG 92-02 [39]) investigated the additional effect of adjuvant hormonal therapy to radiation therapy. Both studies were able to demonstrate a statistically significant advantage in all endpoints, except 5-year overall survival. However, subgroup analysis showed that overall survival was significantly greater in patients with Gleason score 8–10, receiving adjuvant hormonal therapy.
Table 1 After a mean follow-up of 66 months, survival after radiotherapy alone showed to be lower as compared to radiotherapy combined with a LHRH agonist for 3 years [36]
Deaths PCa deaths 5-year clinical disease-free survival (95% CI) 5-year overall survival (95% CI) 5-year specific survival (95% CI) 5-year biochemical disease-free survival (95% CI) 5-year cumulative incidence of distant metastases (95% CI) 5-year cumulative incidence of locoregional failure (95% CI) #
p < 0.0001. p = 0.0002. ** p = 0.0001. *
Radiotherapy
Radiotherapy plus LHRH agonist
N = 78 N = 42 40% (32–48%) 62% (52–72%) 79% (72–86%) 45% (30–60%) 29.2% (22.7–35.6%) 16.4% (10.8–22.1%)
N = 50 N = 12 74% (67–81%)# 78% (72–84%)* 94% (90–98%)** 76% (69–83%)# 9.8% (5.4–14.2%)# 1.7% (0–3.7%)#
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2.5. EAU guidelines According to the EAU 2005 guidelines, radiotherapy is the standard treatment in patients with a life expectancy of >10 years and not willing to undergo surgery, and patients unfit for surgery with a life expectancy of 5–10 years and poorly differentiated tumours. In case the patient has a poorly differentiated tumour, 2–3 years of neoadjuvant/adjuvant hormonal therapy to radiotherapy has proven to be better than radiotherapy alone. Overall, patients receiving neoadjuvant hormonal therapy to radiation therapy will have a better local control of the disease [32]. 3. LHRH agonists as a treatment option for patients with a rising PSA 3.1. Rationale About 25–40% of patients who undergo radical prostatectomy or radiotherapy will have biochemical recurrence after a follow-up of about 10 years [40,41]. This is a very common problem facing patients and clinicians. In these patients, initiating hormonal therapy is logical, but the crucial question is when to start? Median time to metastasis in these patients has been established to be 8 years, and median time to death after development of metastases is 5 years [42]. Hormonal therapy can be started at the time the PSA level starts to rise, or when symptoms appear. If hormonal treatment is started when the PSA level increases, the patient will receive hormonal therapy for a relative long period (10 years) and will also be at risk of experiencing adverse events of long-term androgen deprivation [43]. As these patients are relatively young and otherwise healthy, therapy should not only improve their survival but also preserve there quality of life (QoL). Therefore, intermittent hormonal therapy was developed as a treatment strategy in this patient population [44]. 3.2. Intermittent hormonal therapy Intermittent hormonal therapy (IHT) aims at delaying the onset of androgen-independent PCa cells, as well as reducing adverse events and costs. Hormonal therapy is administered until a pre-set PSA nadir is reached (mostly <4 ng/mL) and will be started again when the PSA level starts rising again, or exceeds a pre-set threshold (e.g. between 5 and 20 ng/mL) [45,46]. Kurek et al. [47] reported a prospective study in the specific setting of IHTas a treatment strategy for patients with a rising PSA level. After a median follow-up of 48 months, none of the patients had demonstrated progression to hormone-refractory disease. Recently, other studies evaluating the efficacy of IHT have become
available. The Canadian Trials [48] enrolled 109 men with biochemical failure after irradiation. IHT was interrupted when PSA levels were less than 4 ng/mL and restarted again following 3 sequential increases of PSA above 4 ng/mL and testosterone levels less than 0.5 nmol/L. All patients had improved QoL and 80% of patients had achieved normal testosterone levels 24 weeks after therapy interruption. Prapotnich et al. [49] published a 10-year follow-up study of 233 patients who underwent IHT after previous radiotherapy, radical prostatectomy or HIFU. LHRH agonist therapy was interrupted if PSA decreased below 4 ng/mL but restarted when PSA levels increased above 20 ng/mL, the PSA slope over previous 3 months increased above 5 ng/mL per month, or if recurrence of pain or urinary symptoms appeared. Only 2.5% of patients experienced pain and moderate urinary complications, but these were seen as acceptable by the patient. Also, patients needed 5–6 months to recover normal testosterone levels. In 1999, Hall et al. [11] detected that 6 months after cessation of long-term (25–82 months) LHRH agonists, serum testosterone levels were invariably below the normal range. Recently, Oefelein et al. [50] showed that the median duration of castrated levels of serum testosterone was 5.5 months (3.5–10 months) after 1 injection of a LHRH agonist (3-month depot). The method of redosing LHRH agonists based on testosterone levels appeared efficacious, safe and cost-effective. 3.3. EAU guidelines The EAU 2005 guidelines recommend hormonal therapy to patients with a rising PSA, since a PSA level exceeding 0.2 ng/mL after radical therapy can be associated with residual or recurrent disease [32]. As intermittent hormonal therapy improves the patient’s QoL, and may be as efficacious as continuous hormonal treatment, intermittent hormonal therapy is a recommended treatment option in patients with a rising PSA level.
4. LHRH agonists as a treatment option in advanced disease 4.1. Rationale The traditional definition of ‘‘advanced’’ PCa includes patients with a tumour which has extended beyond the prostatic capsule, but without having nodal or distant metastatic spread [17,51,52]. However, some classifications also put patients with a rising PSA into this group. Advanced disease is often referred to as tumours staged as T3b-T4, N0, M0 or T1–T4, N1, M0 or pT3, N0, M0 or Jewett stage C [52].
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Fig. 3. Subjective responses achieved by LHRH agonists are equal to those achieved by orchiectomy [58]. LUTS: lower urinary tract symptoms.
Debruyne et al. [18] reported that 18% of patients presenting with regional disease, which corresponds to patients with ‘‘advanced disease’’, had a five-year survival rate of 94%. Most cases of advanced PCa are hormone sensitive [53]. Denis [54] reported that androgen deprivation produces a temporary halt in cancer growth in 60% of patients with advanced disease, and the subjective response rate may even reach 80%. As a result, treatment approaches are mostly directed towards suppression of testosterone production (Fig. 1) [46,53]. 4.2. LHRH agonists versus orchiectomy Orchiectomy used to be the standard for patients with advanced disease, until the discovery of LHRH agonists. Both orchiectomy and LHRH agonists have the similar efficacy and safety profile (Fig. 3, Table 2); both therapies have an equal testosterone response, subjective and objective response rates and treatment failure [55–58]. Patients prefer LHRH agonist therapy to orchiectomy due to the psychological distress associated with removal of the testes and the reversibility of the castration [13,14]. 4.3. LHRH agonists are mainstay therapy Several studies [59–63] have demonstrated the efficacy of LHRH agonists in reducing serum testosterone
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Fig. 4. Almost all patients reach serum testosterone castrate levels of 50 ng/dL in about 3-4 weeks after the first LHRH agonist injection [59–63].
below the castrate level of 50 ng/dL (Fig. 4). Most patients (>95%) achieve those castrate levels in about 3–4 weeks after the first LHRH agonist injection. On the contrary, limited data are available whether LHRH agonists decrease testosterone to levels of 20 ng/dL, which is achieved by orchiectomy. A comprehensive review on this subject is provided by Prof. Bertrand Tombal, also in this supplement [64]. PSA levels also decrease 90% of baseline value or into normal range of <4 ng/mL in about 90% of patients [62,63,65]. This decrease of PSA levels, together with an overall survival rate of about 3–4 years [66–69], clearly demonstrates that progression free survival increases if patients received LHRH agonists. LHRH agonists have been shown to improve the patient’s QoL. Pain improved in 40–80% of patients [58,70,71], urinary symptoms improved in about 80% of them [58,70], and performance status improved in about 50% of patients [58,71]. 4.4. Early vs. deferred therapy The next question to be addressed is when to start therapy with LHRH agonists. Most physicians start androgen deprivation therapy at diagnosis, in the hope of prolonging the patient’s survival. Alternatively, starting androgen deprivation therapy when symptoms
Table 2 Objective responses achieved by LHRH agonists are equal to those achieved by bilateral orchiectomy [55,56,58]
LHRH n = 148a Orchiectomy n = 144a LHRH n = 138b Orchiectomy n = 145b LHRH n = 55c Orchiectomy n = 49c a
Kaisary et al. Br J Urol 1991. Vogelzang et al. Urology 1995. c Parmar et al. Br J Urol 1987. b
Complete response (% of patients)
Partial response (% of patients)
Disease progression (% of patients)
Median overall survival time (years)
0 0 4 4 0 0
71 72 17 21 36 33
11 6 9 10 16 19
2.1 1.9 2.3 2.6 1.3 1.1
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appear (deferred therapy) may be as successful as immediate therapy. The first study that addressed this question was the medical research council (MRC) trial [72]. In 1985, 469 patients with asymptomatic advanced disease were treated immediate after diagnosis, while 465 others received deferred therapy until symptoms appeared. Disease progression was halted much longer in patients who had received immediate therapy. Accordingly, the MRC suggested immediate androgen deprivation was the treatment of choice rather than deferred therapy. However, a significant number of patients in the control group never received androgen suppression before death. Recently, an EORTC study by Schroder et al. [73] also looked atdeferred and immediatehormonaltherapy. This study indicated a 23% trend in favour of early treatment, which was however not statistically significant. Overall, due to the conflicting results between early and deferred hormonal therapy, the patient should be able to make his own decision between the expected advantages of early treatment or the potential advantages in QoL of deferred therapy. 4.5. Maximum androgen blockade Castration in men results in a significant reduction of testosterone levels, but does not eliminate testosterone production from the adrenal glands. As a result, those men still have relatively high levels (<40%) of DHT and 5–10% of testosterone. Therefore, it was believed that maximum androgen blockade (MAB), also referred to as complete androgen blockade (CAB) or combination androgen blockade (CAB) may be beneficial for treating patients with PCa. In this case, LHRH agonists are used to inhibit the testosterone production and the addition of antiandrogens inhibits the effects of adrenal androgens [13,46,53,54]. Since 1982, several randomised trials have shown that MAB significantly prolongs survival compared with controls [74,75]. However, more recent data could not confirm these initial results. The Prostate Cancer Trialists’ Collaborative Group (PCTCG) included data from 22 randomized trials in a meta-analysis [76]. Trends favouring MAB were identified in terms of overall morbidity (56% vs. 58%) and 5-year survival (26.2% vs. 22.8%), but none was statistically significant. The follow-up study in 2000 [77] favoured the use of nilutamide and/or flutamide, but failed again to improve median survival. Recently, the Cochrane Collaboration reviewed MAB as a treatment for patients with advanced PCa [78]. Progression-free survival (OR = 1.38) and cancer-free survival (OR = 1.22) were both improved and overall survival was statistically significant at 5 years. However, adverse events were
more frequent in patients receiving MAB and resulted in withdrawal of therapy in >10% of patients, as compared to only 4% withdrawals of those receiving monotherapy with LHRH agonists. Overall, it is felt that marginal benefits do not outweigh the additional adverse events. Currently, MAB is not a standard treatment for patients with advanced PCa. 4.6. EAU guidelines Overall, the EAU 2005 guidelines recommend hormonal therapy as standard treatment for patients diagnosed with advanced disease. Radical therapy alone or in combination with hormonal therapy is not an option in these patients [32]. 5. LHRH agonists as a treatment option in metastatic disease Patients presenting with metastatic disease can be divided into three groups. The first group comprises patients who show to have lymph-node disease when assessed for radical therapy. The second group of patients has a high level of PSA, no symptoms but asymptomatic bone metastases or metastases in soft tissues. And the third group are those with painful metastases [79]. Debruyne et al. [18] established that 11% of patients diagnosed with PCa, already have metastatic disease. The 5-year survival of these patients is very low (only 31%), meaning that treatment for patients with painful metastases is predominantly a palliative therapy. A general consensus exists to treat them with early rather than deferred therapy [79] and, also here, hormonal therapy is the treatment of choice. As compared to early or advanced disease, patients with metastatic disease may benefit from a combination of LHRH agonists and a steroidal antiandrogen [75,80]. In patients with multiple painful bone lesions, biphosphonates [81], radiotherapy [82] or Strontium 89 [83] are also known as palliative treatments. 5.1. EAU guidelines The EAU 2005 guidelines recommend hormonal therapy as standard treatment for patients diagnosed with metastatic disease [32]. 6. LHRH agonist side-effects The most common side effects of LHRH agonists include hot flushes, decreased libido, anaemia, impotence, asthenia/fatigue/decreased energy, gynaecomastia, tenderness and nausea/vomiting [59,65,70,84–86]. Hot flushes occur in 50–70% and gynaecomastia in
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5–15% of patients. The incidence of impotence and decreased libido varies considerably. In some studies [70] rates up to 80–100% have been reported, while other studies [59,65,84] report only 1–2%. This low level is probably due to underreporting. In general, around 6–15% of patients report being bothered by asthenia/fatigue and 0–13% complain about nausea/ vomiting. Overall, treatment discontinuations, a reliable indicator of adverse events, occurred rarely after LHRH agonist therapy (0–4%, as compared to 4–10% after antiandrogen therapy) [57]. Osteoporosis is an important problem in patients receiving long-term androgen deprivation. Physicians should carefully monitor the development of osteoporosis, and advise the patient to stop smoking and take vitamin D and calcium supplements [87,88]. It is well known that testosterone levels increase during the first week of treatment with LHRH agonists. Therefore, a clinical disease flare may occur in up to 63% of those with advanced disease [18]. Patients might experience a worsening of signs and symptoms of disease. In clinical practice, this flare can be inhibited by administering a non-steroidal antiandrogen such as flutamide, bicalutamide or nilutamide. This antiandrogen is administered for two weeks before and two weeks after the first LHRH agonist injection [8,89,90].
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7. Conclusion The use of LHRH agonists is well documented and forms part of treatment approaches in both early and advanced PCa. Clinical data support, in well defined situations, the use of LHRH agonists as adjuvant treatment to radical prostatectomy, and as neoadjuvant and/or adjuvant treatment to radiotherapy. Highest benefits can be expected in patients with the highest risk of progression. Adjuvant hormonal therapy to radiotherapy is especially beneficial in patients with a high Gleason score (8–10) at biopsy. Several studies evaluated the benefits of intermittent hormonal therapy in patients experiencing biochemical recurrence (rising PSA) after radical therapy. Results of these studies remain inconclusive. LHRH agonist therapy remains the mainstay therapy in patients with advanced and metastatic PCa. Most data from trials support that early administration of LHRH agonists is better than deferring therapy upon manifestation of symptoms or pain in these patients. Although LHRH agonists have a favourable side effect profile, physicians should be attentive for the risk of long term androgen deprivation.
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