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L. Martini (Eds.) Progress in Brain Research, Vol. 182 ISSN: 0079-6123 Copyright 2010 Elsevier B.V. All rights reserved. CHAPTER 14 Hormonal therapy of prostate cancer Fernand Labrie Research Center in Molecular Endocrinology, Oncology and Human Genomics, Laval University and Laval University Hospital Research Center (CRCHUL), Qu�ebec, Canada Abstract: Of all cancers, prostate cancer is the most sensitive to hormones: it is thus very important to take advantage of this unique property and to always use optimal androgen blockade when hormone therapy is the appropriate treatment. A fundamental observation is that the serum testosterone concentration only reflects the amount of testosterone of testicular origin which is released in the blood from which it reaches all tissues. Recent data show, however, that an approximately equal amount of testosterone is made from dehydroepiandrosterone (DHEA) directly in the peripheral tissues, including the prostate, and does not appear in the blood. Consequently, after castration, the 95–97% fall in serum testosterone does not reflect the 40–50% testosterone (testo) and dihydrotestosterone (DHT) made locally in the prostate from DHEA of adrenal origin. In fact, while elimination of testicular androgens by castration alone has never been shown to prolong life in metastatic prostate cancer, combination of castration (surgical or medical with a gonadotropin-releasing hormone (GnRH) agonist) with a pure antiandrogen has been the first treatment shown to prolong life. Most importantly, when applied at the localized stage, the same combined androgen blockade (CAB) can provide long-term control or cure of the disease in more than 90% of cases. Obviously, since prostate cancer usually grows and metastasizes without signs or symptoms, screening with prostate-specific antigen (PSA) is absolutely needed to diagnose prostate cancer at an ‘early’ stage before metastasis occurs and the cancer becomes noncurable. While the role of androgens was believed to have become non-significant in cancer progressing under any form of androgen blockade, recent data have shown increased expression of the androgen receptor (AR) in treatment-resistant disease with a benefit of further androgen blockade. Since the available anti-androgens have low affinity for AR and cannot block androgen action completely, especially in the presence of increased AR levels, it becomes important to discover more potent and purely antagonistic blockers of AR. The data obtained with compounds under development are promising. While waiting for this (these) new anti-androgen(s), combined treatment with castration and a pure anti-androgen (bicalutamide, flutamide or nilutamide) is the only available and the best scientifically based means of treating prostate cancer by hormone therapy at any stage of the disease with the optimal chance of success and even cure in localized disease. Keywords: intracrinology; anti-androgens; androgen blockade; early diagnosis; cure; long-term control Corresponding author. Tel.: (418) 652-0917; Fax: (418) 651-1856; E-mail: [email protected] DOI: 10.1016/S0079-6123(10)82014-X 321 322 Introduction One in eight men will be diagnosed with prostate cancer during their lifetime with 192 280 new cases being predicted in the United States in 2009 (Jemal et al., 2009). Despite the 33% decrease in deaths from prostate cancer in the United States during the 15 years between 1992 and 2007 as estimated by the American Cancer Society (Jemal et al., 2007), prostate cancer remains the second cause of cancer deaths with 27 360 deaths predicted for 2009 in the United States alone (Jemal et al., 2009). Prostate cancer is thus a major medico-social problem comparable to that of breast cancer in women. The main objective of physicians managing patients with cancer is to permanently free them from the disease. It is thus a major progress to see that androgen blockade is now increas ingly recognized as curative, conditional to its use in localized (when it is curable) instead of advanced and metastatic (when it has become non-curable) disease. These news are particu larly timely since more than 95% of patients can now be diagnosed by simple PSA screening and can thus be treated at the localized and only potentially curable stage (Labrie et al., 1996b), thus providing an explanation for the important decrease in prostate cancer deaths observed since 1992 (Jemal et al., 2007). The extremely long delay in recognizing the curative potency of androgen blockade can be explained by two misinterpretations concerning androgen blockade which, unfortunately, are still at the basis of the official guidelines of some uro logical associations distributed to guide the clinical practice of their members. These two common misinterpretations are as follows: 1. Application to localized prostate cancer of observations made in advanced disease which are characteristics specific to metastatic disease and which do not apply to localized disease. As well indicated by Professors Akaza and Namiki (Akaza, 2008; Namiki et al., 2008), the erroneous belief of a temporary efficacy of androgen blockade due to the relatively rapid development of resistance to treatment is a characteristic typical and limited to advanced and metastatic disease. There have never been valid reasons to apply to localized prostate cancer these observations of resistance to treatment which exclusively belong to advanced disease. In fact, contrary to the situation in metastatic prostate cancer, a continuous and very long-term positive response with the high probability of a cure is observed in localized disease (Akaza, 2008; Labrie et al., 2002; Namiki et al., 2008) when optimal or CAB is used. This possibility of cure is however conditional to the start of CAB sufficiently early at time of diagnosis (Labrie et al., 2002). The conclusion that androgen blockade can be curative and does not simply delay progression has been reached in many studies including a meta-analysis of the controlled clinical trials performed as adjuvant hormonal treatment in non-metastatic prostate cancer (Fleshner et al., 2007). The author of this meta analysis has concluded that androgen blockade given as adjuvant to surgery or radiotherapy should be classified as a treatment of curative intent for patients with poor prognosis non-metastatic prostate cancer. It should be mentioned that such positive results could even be observed using a non-optimal androgen blockade, namely monotherapy, while much better results are achieved with CAB without additional negative effects (Akaza, 2008; Akaza et al., 2007; Labrie, 2004; Labrie et al., 2002; Namiki et al., 2008). 2. A second extremely common error, not to say generalized, is the use of monotherapy as first treatment, a treatment much inferior to CAB even though a significant rate of cure (33%) can be obtained with monotherapy in localized prostate cancer (Peto and Dalesio, 2003). However, a major limitation of monotherapy (castration alone or an antiandrogen alone) is that 40% of active androgens are left in the prostate under monotherapy (Labrie, 2007; Labrie et al., 2009a; Labrie et al., 1985). These androgens made locally in the prostate continue to stimulate prostate cancer after any 323 treatment limited to castration or an antiandrogen alone, thus permitting continued stimulation of cancer proliferation and metastasis at distance where resistance to treatment always develops and cure becomes impossible (Huggins and Hodges, 1941). prostate cancer is almost always possible with current androgen blockade …’. At the metastatic stage, on the other hand, while monotherapy first used by Huggins and Hodges (1941) has not been shown to prolong survival, a 20% prolongation of prostate cancer-specific survival can be obtained with CAB applied at start of treatment (Bennett et al., 1999; Caubet et al., 1997; Craw ford et al., 1989; Denis et al., 1998; Janknegt et al., 1993; Labrie et al., 1996a; Labrie et al., 1982; Labrie et al., 1985; Prostate Cancer Triallists’ Collaborative Group, 2000). It is important to indicate that since the anti-androgen was generally added at time of progression following castration alone, the above mentioned studies compare early versus late CAB and not placebo versus CAB as generally believed. In localized disease, the simple addition to castration of a pure anti-androgen in order to block the action of the androgens made locally in the prostate increases the potential of cure from 33% observed with monotherapy (Fleshner et al., 2007; Peto and Dalesio, 2003; Prostate Cancer Triallists’ Collaborative Group, 2002) to more than 90% (Labrie, 2007; Labrie et al., 2002) (Fig. 1B). It is very important to read Professor Akaza (2008) saying: ‘cure of A. Metastatic prostate cancer 1. Monotherapy Non-statistically significant effect 0 20 40 60 80 100% 2. Combined androgen blockade * First and only statistically significant treatment 0 20 40 60 80 100% B. Localized prostate cancer 1. Monotherapy * Statistically significant 0 20 40 60 80 100% 80 100% 2. Combined androgen blockade Cure in > 90% 0 20 40 60 Fig. 1. Comparison of the efficacy on prostate cancer-specific survival of monotherapy (castration alone or anti-androgen alone at high dose) (1) and combined androgen blockade (CAB) (castration þ pure anti-androgen) (2) administered in metastatic (A) and localized (B) prostate cancer. A1: No positive study available A2: Bennett et al. (1999), Caubet et al. (1997), Crawford et al. (1989), Denis et al. (1998), Janknegt et al. (1993), Labrie et al. (1985) and Prostate Cancer Triallists’ Collaborative Group (2000) B1: Peto and Dalesio (2003) and Prostate Cancer Triallists’ Collaborative Group (2002) B2: Labrie et al. (2002) The asterisk () indicates that since the anti-androgen was added at time of progression following castration, these studies compare early versus late CAB and not placebo versus CAB. 324 In other words, a greater difference in survival, even at the advanced metastatic stage, should have been obtained if a true comparison between placebo and CAB had been studied. It is, in fact, well recognized that a significant number of positive responses are observed when a pure anti-androgen is added at time of progression in patients who had castration as first treatment (Labrie et al., 1988). These responses observed at time of addition of the anti-androgen decrease the difference between the castration alone and CAB groups. Discovery of the local formation of androgens from DHEA of adrenal origin by the action of the enzymes of intracrinology (Labrie, 1991; Labrie et al., 1989b) has indicated the need to develop CAB (Labrie et al., 1982; Labrie et al., 1985), a treatment which adds to castration (medical or surgical) a pure anti-androgen in order to block the action of the androgens made locally in the prostate from DHEA. In fact, all the enzymes required to make androgens from DHEA are expressed in the prostate (Luu-The et al., 2008; Pelletier, 2008). It is important to mention that recent data indi cate that androgen blockade is important, not only as first line therapy in both localized and meta static diseases, but could also play a role in pros tate cancer which has become resistant to first line androgen blockade (Chen et al., 2004; Scher and Sawyers, 2005; Taplin and Balk, 2004). Two sources of androgens of approximately equal importance are present in men: castration removes only 60% of androgens in the prostate while bicalutamide (Casodex) alone, at the 150 mg daily dose, has an effect similar to castration Intracrinology An important advance in our understanding of the biology and endocrinology of prostate cancer is the observation that humans are unique among animal species in having adrenals that secrete large amounts of the inactive precursor steroids DHEA, and its sulfate DHEA-S, which are converted into active androgens in a large series of peripheral tissues, including the prostate (Fig. 2). Intact – normal GnRH Testosterone Pituitary gland LH ACTH Testosterone Testis DHEA DHT Prostate Adrenal Fig. 2. Schematic illustration of the two sources which provide approximately equal amounts of androgens to the normal prostate and prostate cancer. (1) The testicles secrete testosterone released in the blood stream while (2) the adrenals secrete dehydroepiandrosterone (DHEA) in the circulation, the precursor being converted into testosterone and then into dihydrotestosterone (DHT) in the prostate. The local synthesis of active steroids in per ipheral target tissues has been named intracri nology (Labrie, 1991; Labrie et al., 2004; Labrie et al., 2003; Labrie et al., 1989a). The active androgens made locally exert their action by binding to the prostatic AR without being released in significant amounts in the extracel lular environment or general circulation. Most importantly, the active androgens made in per ipheral tissues are inactivated locally as glucur onides before their elimination through the circulation (Fig. 3). Contrary to the previous belief that the testes are responsible for 95% of total androgen production in men (as could be inferred from the 95–97% decrease in serum testosterone observed after castration) (Fig. 4), it is now well established that the prostate makes the androgens testo and DHT locally in relatively large amounts. Very limited effect of castration on total androgen availability in the prostate While the serum levels of testo are reduced by 97.4% following castration in 69–80-year-old 325 GnRH CRH LH ACTH Adrenal gland Testo Circulation DHEA DHEA Testo 4-Dione E1 ADT–G 3α–diol–G Testis Circulation E2 DHT E2 ADT–G E1S Testo E 2 Circulation A-Dione 3α–Diol–G Peripheral target tissues Circulation DHEA Fig. 3. Schematic representation of the testicular and adrenal sources of sex steroids in men. The adrenal glands – as well as secreting cortisol that decreases CRH secretion, which otherwise stimulates ACTH levels – secrete large amounts of DHEA; this precursor is converted in specific target tissues into androgens and/or estrogens via the process of intracrinology. Only small amounts of these peripherally made sex steroids diffuse into the circulation. The androgens are metabolized into the metabolites ADT and 3a-diol which are then further transformed into the more water-soluble glucuronide derivatives and released into the blood where they can be measured as parameter of total androgenic activity. Approximately 60% of androgens are made in the testicles as testosterone which is distributed in the peripheral tissues by the circulation. ACTH, adrenocorticotropin; CRH, corticotrophin-releasing hormone; DHEA, dehydroepiandrosterone; 4-dione, androstenedione; A-dione, 5a-androstanedione; DHT, dihydrotestosterone; E1, estrone; E1S, estrone sulfate; E2, estradiol; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; testo, testosterone; ADT-G, androsterone glucuronide; 3a-diol-G, androstane-3a-diol-3 or 17-glucuronide. men (Fig. 4A), the sum of the metabolites of androgens (ADT-G, 3a-diol-3G and 3a-diol 17G), the only accurate and valid parameter of total androgenic activity measurable in the circu lation (Labrie et al., 2006), is only reduced by 58.9% (Fig. 4B), thus indicating that a very impor tant amount (41.1%) of androgens is still present in the prostate after complete elimination of testi cular androgens. Such data are in close agreement with the concentration of intraprostatic DHT that shows that, on average, 39% of DHT is left in the prostate after castration in various studies, namely 45% (Labrie et al., 1985), 51% (Bélanger et al., 1989), 25% (Nishiyama et al., 2004) and 35% (Mostaghel et al., 2007). In another study, it was observed that intraprostatic DHT levels remained at 50% of pre-treatment values after castration (Yoon et al., 2008). The observations based upon the best and vali dated parameters of androgenic activity, where all steroids are measured by the mass spectrometry technology show that ~40% of androgens are made in the prostate in 69–80-year-old men. Since serum DHEA decreases markedly with age starting in the thirties (Labrie et al., 2005), and testicular androgen secretion decreases only slightly, it is most likely that intraprostatic androgens of adrenal origin have an even greater relative and absolute importance at younger ages. The logical conclusion from these data is that castra tion is an insufficient treatment for prostate cancer since, on average, it eliminates only 60% of andro gens in the prostate. Very limited blockade of total androgens achieved with an anti-androgen alone Since an anti-androgen used alone can, like castra tion, show easily detectable effects on serum PSA and also clinically, due to the particularly high sensitivity of prostate cancer to androgen depriva tion, it is important to remember that, at best, administration of an anti-androgen alone can only partially block androgens, thus leaving an important amount of DHT free to stimulate AR and prostate cancer growth and metastasis. In fact, the data obtained from phase III stu dies have shown that daily 150 mg bicalutamide monotherapy provides a survival outcome simi lar, and sometimes inferior, to that observed 326 A. B. C. 5 40 100 30 75 3 ng/ml −97.4% ng/ml 4 −58,9% −61% 20 50 10 25 2 1 0 0 0 Intact Castrated Testosterone Intact Castrated ADT–G + 3α–diol–3G+17G Intact Castrated DHT in prostate Fig. 4. Effect of castration on the concentration of serum testo (A), total androgen pool (sum of serum ADT-G, 3a-diol-3G and 3a-diol-17G) (B) and intraprostatic DHT, the predominant androgen in the prostate (C). Data in C are the average of values published in Bélanger et al. (1989), Labrie et al. (1985), Mostaghel et al. (2007) and Nishiyama et al. (2004). Data are presented as means + SEM (Labrie et al., 2009b). with castration alone in patients with locally advanced (no metastases) disease (Iversen et al., 2001; Iversen et al., 2000; Tyrrell et al., 1998; Wirth et al., 2004). The 50 mg dose of bicalutamide, on the other hand, has been shown to be clearly inferior to castration (Bales and Chodak, 1996). Very unfortunately, the 50 mg daily dose of bicalutamide used alone is the approved dose in the United States, Canada and most other countries. In Japan, the approved dose is 80 mg. Because, as mentioned above, 40–50% of andro gens are left in the prostate following castration (Fig. 4C), two conclusions are obvious. First, when used in association with medical or surgical castration, bicalutamide should be used at the 150 mg daily dose to efficiently block the action of the 40–50% of androgens left in the prostate after castration. On the other hand, monotherapy with a daily dose of 150 mg bicalutamide leaves, like cas tration, about 40–50% of androgens free to con tinue to stimulate the AR, thus indicating the need to simultaneously block the secretion of testicular androgens by a GnRH agonist or orchiectomy. Accordingly, although the use of a non-steroidal anti-androgen alone provides some advantages in terms of secondary effects, especially loss of libido and sexual dysfunction compared to castration, an anti-androgen alone is only a partial therapy of prostate cancer with the high risk of negative con sequences on survival. It is relevant to mention that no PSA progres sion has been observed for up to 7 years in patients with localized or locally advanced pros tate cancer who received CAB with a GnRH ago nist and 250 mg flutamide 3 times daily (Labrie, Cusan, Gomez, Belanger and Candas, 1999). Such results are quite different from the data obtained following monotherapy with bicalutamide at the dose of 150 mg daily (Wirth et al., 2004) where clinical progression already occurred in 8.5% of patients at 5.3 years of follow-up, whereas 14.0% had progressed in the placebo group (p < 0.0001). Although statistically significant, due to the large number of patients (8113 patients), a 5.5% differ ence in disease progression between monotherapy with bicalutamide and placebo is a small effect compared with the data obtained with CAB in 327 patients at a comparable stage of the disease where no (0%) PSA progression occurred before 7 years of treatment (Labrie et al., 2002; Labrie et al., 1999). Although not randomized, this last study per formed in a small number of patients is highly suggestive of the marked superiority of CAB in localized and locally advanced disease compared with monotherapy. In fact, an even greater dif ference was seen in the group of patients chosen for watchful waiting where 29.4% of patients with localized disease progressed with bicaluta mide whereas 44.2% of those with locally advanced disease progressed with bicalutamide (Wirth et al., 2004), thus clearly demonstrating the high risk of watchful waiting and the super iority of CAB where, as mentioned above, no progression occurred in a group of 26 men until 7 years of follow-up (Labrie et al., 2002; Labrie et al., 1999). Clinical effects of monotherapy versus combined androgen blockade as first line therapy in localized disease Monotherapy (GnRH agonist alone, orchiectomy alone or anti-androgen alone) has a significant but far from optimal effect on localized prostate cancer The availability of a safe and highly efficient method of medical castration has generated renewed interest in the treatment of prostate can cer and has stimulated an unprecedented number of clinical trials, which rapidly led to the world wide commercialization of a series of GnRH agonists having equivalent characteristics, mechanisms of action and efficacy. This marked the end of the requirement for surgical castration, a procedure that is psychologically difficult to accept by the majority of men. Most importantly, this was the end of the need to administer high doses of estrogens to achieve medical castration at the expense of serious cardiovascular effects (Peeling, 1989; Robinson and Thomas, 1971; VACURG, 1967). The importance of medical castration achieved with GnRH agonists was well recognized by Jacobi and Wenderoth (1982) who stated: ‘What medical developments have urologists witnessed since orchiectomy and estrogen treatment by Huggins 40 years ago? Gestagens, antiandrogens, adrenal inhibitors, antiprolactins, antiestrogens, cytotoxic agents? In principle, the gain in terms of efficacy and the loss as a result of toxicity have never been balanced to a degree which could establish one of the aforementioned drugs as the generally accepted standard treatment to replace estrogens. GnRH analogues may prove to be the first nontoxic medical castration measure applic able for general use in the future’. Major progress achieved by the introduction of medical castration with GnRH agonists Clinical effects observed with monotherapy Medical castration with a GnRH agonist achieved in 1980 in the first prostate cancer patient who received this treatment (Labrie et al., 1980) has been a landmark in the field of prostate cancer. Soon after our observation that administration of the GnRH agonist buserelin led to an almost complete inhibition of serum testosterone and DHT levels within 2 weeks of administration by the intranasal route, a less than optimal route of administration, a detailed comparison of the effect of various doses of the same GnRH agonist was performed comparing the intranasal and subcutaneous routes (Faure et al., 1982). Since prostate cancer is the most sensitive of all cancers to hormone therapy, a positive effect on serum PSA and on the clinical evolution of the cancer can be easily observed with such a sub optimal blockade of androgens. Physicians and their patients should not, however, be satisfied by a sub-optimal positive result obtained with monotherapy, since such an effect is only a fraction of what can be achieved by more complete androgen blockade. In fact, although significant positive results are observed with monotherapy, much bet ter results and even cure of the cancer can be achieved by CAB applied to localized disease. 328 Following the meta-analysis of androgen block ade with monotherapy in localized prostate cancer (Fig. 1B1), Peto stated that ‘prostate cancer is usually treated with surgery or radiation, but a few cancer cells may remain and cause an oftenfatal recurrence. Since the mid-80s, oncologists have increasingly followed up with either surgical removal of the testes, or with newer anti-hormone drugs’ (Peto and Dalesio, 2003). The meta-analy sis which looked at several studies involving 5000 men showed that 74% of patients who received early hormone monotherapy were still alive 10 years later, compared with 62% of those who did not (Arnst, 2003; Peto and Dalesio, 2003) (Fig. 1B1). The conclusion of this meta-analysis on the effect of monotherapy in localized and locally advanced prostate cancer was that the risk of dying from prostate cancer within 10 years decreased by one-third if hormonal treatment was given immediately rather than after the dis ease had progressed (Peto and Dalesio, 2003). Since patients originally on placebo were treated by monotherapy at time of progression, this onethird decrease in the risk of dying from prostate cancer was not the result of the comparison between castration and placebo (or no androgen blockade), but between early and late androgen blockade. It is also very important to consider that these results were obtained with only partial blockade of androgen or monotherapy. These data led Peto to the conclusion that ‘Hormone treatment as a whole works much better than previously thought’. In fact, all clinical trials of androgen blockade have shown prolongation of life or a reduced death rate from prostate cancer in patients with localized or locally advanced disease (Table 1). During 3.7–9.3 years of follow-up, the first six studies have shown reductions in deaths from prostate cancer ranging from 37.5 to 81% (Bolla et al., 1997; Granfors et al., 1998; Hanks et al., 2000; Labrie et al., 1999; Messing et al., 1999; Pilepich et al., 1997). A seventh study provided no data on cancer-specific deaths, but a 45% decrease in overall deaths was reported (D’Amico et al., 2004). Simple addition of a pure anti-androgen to castration (Fig. 1B2) can achieve cure in more than 90% of localized prostate cancers instead of the 33% decrease in deaths obtained by monotherapy (Fig. 1B1). Clinical data With today’s knowledge, monotherapy (castration alone or anti-androgen alone) can achieve only 50–60% of androgen blockade (Fig. 4). As Table 1. Effect of the use of androgen blockade on prostate cancer death rates Study Advantage Median follow-up (years) p EORTC 415 patients RTOG 85-31 276 patients Laval University Screening Trial 21 400 subjects Messing et al. (1999) 98 patients Granfors et al. (1998) 91 patients RTOG 92-02 1554 patients D’Amico et al. (2004) 201 patients 77% decrease in cancer-specific death 3.7 0.01 37.5% decrease in cancer-specific death for Gleason score 8–10 67% decrease in cancer-specific death 4.5 0.03 8 0.0002 81% decrease in cancer-specific death 7.1 0.001 39% decrease in cancer-specific death 9.3 0.06 59% decrease in cancer-specific death for Gleason score 8–10 45% decrease in overall death 5 0.007 4.5 0.04 329 Table 2. Androgen blockade in prostate cancer Combined androgen blockade GnRH agonist alone GnRH antagonist alone Orchiectomy DES Proscar alone Proscar þ castration Cyproterone acetate alone Cyproterone acetate with castration Flutamide alone Ninutamide alone Bicalutamide alone Megace Medroxyprogesterone acetate GnRH agonist, GnRH antagonist or Orchiectomy þ Flutamide or Nilutamide or Bicalutamide (150 mg or more daily) mentioned above, although GnRH agonist ther apy in localized prostate cancer has shown impor tant benefits in terms of survival in localized prostate cancer, the knowledge that 40% of androgens (Fig. 4C) remain in the prostate after castration indicates that superior results should be expected from the use of CAB or the combination of an GnRH agonist with a pure anti-androgen (Table 2). Early data already indicated that the benefit of CAB versus monotherapy is greater for patients with minimal metastatic disease than for those with extensive metastatic disease (Crawford et al., 1989; Denis et al., 1998). The availability of GnRH agonists which are much more acceptable than surgical castration or high doses of estrogens (Labrie et al., 1980) has greatly facilitated or even permitted the development of androgen blockade at the localized stage. It has been of major importance to observe that CAB can achieve long-term control or cure of pros tate cancer in at least 90% of patients with localized or locally advanced disease (Fig. 5) provided that treatment is given continuously, uninterrupted, for at least 7 years (Labrie et al., 2002) (Table 2). The effect of CAB on long-term control or pos sible cure of prostate cancer was evaluated by the absence of biochemical failure or the absence of PSA rise for at least 5 years after cessation of con tinuous treatment (Fig. 5). A total of 57 patients with localized or locally advanced disease received Long-term control or cure (%) Monotherapy or combination 100 11/12 7/8 80 60 40 1/3 3/8 20 0/11 0 0 2 4 6 8 Continuous CAB (years) 10 12 Fig. 5. Effect of duration of treatment of localized prostate cancer with continuous combined androgen blockade (CAB) on the probability of long-term control or ‘cure of the disease’ illustrated by no recurrence of PSA rise for at least 5 years after cessation of CAB. The point at 4.75 years of treatment (33%) refers to the three patients treated with CAB for 3.5–5.0 years and followed for at least 5 years, while the point at 5.75 years refers to the eight patients treated continuously with CAB for 5.0–6.5 years before cessation of treatment. The point at 8.25 years, on the other hand, refers to the eight patients treated continuously for 6.5–9.0 years while the point at 11 years refers to the thirteen patients treated for 10.0–11.7 years with continuous CAB before stopping treatment. All patients were followed for at least 5 years after cessation of continuous CAB or until PSA rise. Only 1 patient has died from prostate cancer while 18 have died from other causes (Labrie et al., 2002). CAB for periods ranging from 1 to 11 years. With a minimum of 5 years of follow-up after cessation of long-term CAB, only two PSA rises occurred among 20 patients with Stage T2–T3 cancer who stopped treatment after continuous CAB for more than 6.5 years, for a non-failure rate of 90% (Fig. 5). On the other hand, for the 11 patients who had received CAB for 3.5–6.5 years, the non-failure rate was only 36%. The serum PSA increased within 1 year in all 11 patients with stage B2/T2 treated with CAB for only 1 year, thus indicating that active cancer remained present after shortterm androgen blockade despite undetectable PSA levels. Most importantly, in all patients who had biochemical failure after stopping CAB, serum PSA rapidly decreased again to undetectable levels when CAB was restarted and PSA remained at such low levels afterward. Of these patients, only one patient had died of prostate cancer at last follow-up (Labrie et al., 2002). 330 With the knowledge of the above-described data, it seems reasonable to suggest that the minimal duration of continuous CAB in localized prostate cancer should be 6 years, thus providing an ~50% probability of long-term control or pos sible cure of the cancer. With longer duration of CAB, the probability increases to about 90% at 8–10 years of treatment. The present data indi cate that possible cure of the disease can be obtained in almost all patients with localized prostate cancer treated continuously with CAB for 7 years or more, thus raising hope for the successful treatment of patients who fail after surgery, radiotherapy or brachytherapy where no or minimally effective alternative therapeutic approach exists. A series of recent studies performed in Japan clearly illustrate the very high efficacy of CAB in localized disease (Akaza, 2008; Akaza et al., 2006; Egawa et al., 2004; Namiki et al., 2008; Ueno et al., 2006). In a prospective study performed in stages C and D prostate cancer patients (Akaza, 2006; Akaza et al., 2004) comparing GnRH agonist monotherapy and CAB (GnRH agonist þ bicalutamide 80 mg/ day), the effect of CAB was more pronounced in patients with C than with D disease. In fact, only 5.8% (3/52) of patients progressed under CAB com pared to 42.6% (20/47) with monotherapy, thus showing a marked superiority of CAB compared to monotherapy, especially in stage C or locally advanced disease. These data strongly support our results showing an even much greater advantage of CAB in stage B disease (Labrie et al., 2002). Based upon the above-summarized data, at least for older men, primary hormone therapy is a valid therapeutic option for localized or locally advanced prostate cancer (Akaza et al., 2006). A similar conclusion was reached in a retrospective study of 447 stage B prostate cancer patients who received androgen blockade alone or radical pros tatectomy combined with androgen blockade. No difference in disease-specific survival was found at 9.2 years, thus indicating the predominant effect of androgen blockade and the absence of effect of prostatectomy in men receiving androgen block ade (Egawa et al., 2004). Data on the current treatment of prostate can cer in Japan show that primary androgen blockade is the treatment chosen for localized and locally advanced prostate cancer in a high proportion of cases. In the survey of the Japanese Urological Association published in 2005, androgen blockade alone was used as primary treatment in 40% of T1 patients and over 50% of T2 patients. Moreover, from the data collected in 2001–2003 by the Japa nese Prostate Cancer Surveillance Group (J-CaP) (Akaza et al., 2004), about 60% of patients who receive androgen blockade receive CAB. In addi tion, about 70% of patients who receive androgen blockade receive hormone therapy as first treat ment. A similar trend is seen in the United States from the Cancer of the Prostate Strategic Urologic Research Endeavour (CaPSURE) (Cooperberg et al., 2003). No resistance or loss or lack of response to CAB exists for the treatment of localized disease Recognition of the absence of development of resistance to androgen blockade in localized pros tate cancer is extremely important. In fact, it is very frequently stated that androgen blockade should not be administered early because resistance to treatment will develop and one might as well wait to use androgen blockade at a later stage of the disease. In fact, deferring treatment is a very ser ious error since it implies that, very often, it will then be too late to achieve an otherwise possible cure. In fact, when the cancer has reached the bones, the resistance to treatment can no more be avoided and cure has become impossible. It should be realized that when prostate cancer is first detected, even by screening, the cancer is not small since its diameter is of the order of 1 cm or more. This is the only appropriate time to start treatment with the very strong hope of a cure. Combined androgen blockade in advanced prostate cancer Although androgen blockade should move to the treatment of localized disease, metastatic disease remains frequent and will always be a therapeutic challenge. Again, it is important to indicate that 331 the observations made with metastatic disease, especially the relatively short duration of response to CAB and the appearance of resistance to treat ment should not be applied to localized disease. The results obtained in a large series of clinical trials in patients with advanced prostate cancer have demonstrated that CAB compared to castra tion alone has the following advantages: (1) more complete and partial responses, (2) improved control of metastatic pain, (3) longer disease-free survival and (4) longer survival. As already men tioned, the combination of a pure anti-androgen (e.g. flutamide, nilutamide or bicalutamide) with a GnRH agonist was the first treatment shown to prolong life in patients with advanced prostate cancer (Bennett et al., 1999; Caubet et al., 1997; Crawford et al., 1989; Denis et al., 1998; Labrie et al., 1982; Labrie et al., 1985; Prostate Cancer Triallists’ Collaborative Group, 2000). Analysis of all the studies performed with flu tamide and nilutamide associated with medical or surgical castration compared with castration plus placebo shows that overall survival is increased by an average of 3–6 months (Bennett et al., 1999; Caubet et al., 1997; Crawford et al., 1989; Denis et al., 1993; Denis et al., 1998; Dijkman et al., 1997; Janknegt et al., 1993; Prostate Cancer Triallists’ Collaborative Group, 2000; Schmitt et al., 2001) (Fig. 6). It is essential not to include the data obtained with cyproterone acetate, a compound showing intrinsic androgenic activity in all in vitro and in vivo assays (Labrie et al., 1987; Luthy et al., 1988; Plante et al., 1988). These preclinical data have translated into a shortened survival when cyproterone acetate was added to castration and compared with cas tration alone in men with metastatic disease (Prostate Cancer Triallists’ Collaborative Group, 2000). Since about 50% of patients in that age group die from causes other than prostate cancer, this 3–6-month difference in overall survival trans lates into an average of 6–12 months of life gained when cancer-specific survival is ana lyzed. These additional months, or sometimes years, of life can be obtained by simply adding a pure anti-androgen (flutamide, nilutamide or bicalutamide at a proper dose) to castration. These data demonstrate the particularly high level of sensitivity of prostate cancer to andro gen deprivation, considering that such statisti cally significant benefits on survival are obtained, even at the very advanced stage of metastatic disease. Favours CAB Favours castration PCTCG: nilutamide (n = 1751) PCTCG: flutamide (n = 4803) PCTCG: nilutamide + flutamide (n = 6554) * ** Caubet: NSAA (n = 3732) * Caubet: NSAA (n = 1978) ** Caubet: NSAA (n = 2357) ** Klotz: NSAA (n = 5015) * Debruyne: nilutamide (n = 1191) * Bennett: flutamide (n = 4128) * 0.5 *2p < 0.05; **2p < 0.01 1.0 2.0 Hazard ratio and 95% confidence limits Fig. 6. Summary of meta-analyses comparing combined androgen blockade [combination of medical or surgical castration associated with a pure anti-androgen (NSAA), namely flutamide or nilutamide] versus medical or surgical castration alone. Adapted from Klotz et al., 2001. 332 With the clinical data summarized above, the controversy or uncertainty concerning CAB should be part of history and the addition of a pure anti-androgen at a proper dose should be recognized by all as providing an average advan tage of 3–6 months of life in metastatic disease at a time when no alternative treatment even exists. Further improvement of the hormonal therapy of metastatic disease is very difficult. By far the best and today’s only possibility of improvement for the prostate cancer patient is treatment of localized disease. In fact, in analogy with the treat ment of all other types of cancers, the beneficial effects are much greater when the same treatment is applied at an earlier stage of the disease. In the United States, where three million of all men currently alive are expected to die from pros tate cancer (Statbite, 2004), 6 additional months of life per individual correspond to 1.5 million years overall, whereas 12 additional months correspond to 3 million years. Resistance to treatment in metastatic disease Contrary to the situation in localized disease where resistance to CAB practically does not exist, resistance to hormone therapy is the stan dard observation in metastatic prostate cancer, thus creating a major and unresolved therapeutic challenge. In fact, recent evidence indicates that AR functioning is required for the growth of prostate cancer at all stages, including castra tion-resistant disease (Taplin, 2007). These data show that endocrine therapy-resistant prostatic carcinomas generally display uniformly high AR expression (Ruizeveld de Winter et al., 1994; van der Kwast et al., 1991). In a recent study, a sig nificant increase in AR mRNA levels was observed in the cancerous prostatic cells com pared with the benign tissue biopsies (Levesque et al., 2009). Treatment with flutamide has already been shown to decrease AR expression in prostatic carcinoma tissue (van der Kwast et al., 1996). Even at time of progression in patients with metastatic prostate cancer treated by castration alone, the benefits of additional androgen blockade are illustrated by the observation of a positive response in 30–60% of patients in pro gression by hypophysectomy, adrenalectomy or aminoglutethimide (Drago et al., 1984; Labrie et al., 1985; Maddy et al., 1971; Murray and Pitt, 1985). In a relatively large-scale study of 209 meta static prostate cancer patients showing disease progression after orchiectomy or treatment with high doses of estrogens or a GnRH agonist alone, the addition of flutamide permitted to achieve complete, partial and stable responses in 6.2, 9.6 and 18.7% of cases, respectively, for a total clinical benefit of 34.5%. The mean duration of response was 24 months (Labrie et al., 1988). Contrary to the generalized opinion that patients in relapse after castration have exclu sively ‘androgen-insensitive’ tumors, the abovementioned data suggest that ‘androgen-sensitive’ tumors are present at all stages of prostate can cer in all patients and that maximal androgen blockade should always be administered. Instead of being ‘androgen insensitive’, most of the tumors which continue to grow after castration are androgen sensitive and able to grow in the presence of the ‘low’ level of androgens of adre nal origin left after ‘castration’ (Labrie et al., 1988). ‘Control of their growth requires further androgen blockade’. This affirmation was well supported by already available clinical data and fundamental observations (Labrie and Veilleux, 1986). As evidence for the androgen sensitivity of prostate cancer progressing under androgen blockade, Fowler and Whitmore (1981) have observed a rapid and severe exacerbation of the disease in 33 out of 34 patients in relapse within the first 3 days of testosterone adminis tration, thus clearly showing that at least part of prostate cancer cells remain androgen sensitive even at the advanced stage of progression under androgen blockade (Fowler and Whitmore, 1981). Based upon the above-summarized data, it becomes important to develop more potent but always pure blockers of androgen formation or action, the blockade of AR being the most obvious and therapeutically well-supported target. Positive clinical data have recently been reported with a new anti-androgen (Tran et al., 2009), 333 although the true role of this compound used in relapsing patients where the anti-androgen was apparently stopped at time of administration of the new agent remains to be assessed. Similar uncertainty applies to the 50% (or more) decrease in serum PSA in 28 (67%) of 42 patients observed following administration of abiraterone in patients relapsing under antiandrogen treatment (Attard et al., 2009). Con sidering the well-demonstrated clinical benefits and the important decrease in serum PSA which follow simple cessation of administration of the anti-androgen (Dupont et al., 1993; Kelly et al., 1997), the true clinical benefits of these compounds remain undefined. It is clear, how ever, that a more potent blocker of AR having pure antagonistic activity could play an impor tant role in prostate cancer therapy at all stages of the disease. More potent anti-androgens, the key to more successful treatment of prostate cancer While androgen blockade has been known for a long time to be efficacious as first line therapy at all stages of prostate cancer (Akaza, 2008; Huggins and Hodges, 1941; Janknegt et al., 1993; Labrie et al., 2002; Labrie et al., 1985; Namiki et al., 2008), recent data indicate a continuous role of the AR in treatment-resistant metastatic disease (Chen et al., 2004). While the percentage of objective responses in patients with metastatic prostate cancer is higher and the duration of response is longer when CAB is used (Crawford et al., 1989; Jan knegt et al., 1993; Labrie et al., 1985), progres sion of the disease always occurs if the patients have metastatic disease at start of treatment. Somewhat surprisingly, however, it was found that a large percentage of patients show a posi tive clinical response upon discontinuation of the anti-androgen with a decrease in serum PSA by more than 90% in 47% of patients (Dupont et al., 1993). This paradoxical phenom enon became generally recognized (Collinson et al., 1993; Herrada et al., 1996; Kelly and Scher, 1993; Kelly et al., 1997). A possible explanation of the paradoxical effect of antiandrogen withdrawal is the development of hypersensitivity to androgens (Labrie and Veil leux, 1986; Labrie et al., 1988), or intracellular changes making the anti-androgen act as a par tial androgen agonist. The traditional therapeutic approach for metastatic disease which has become resistant to a specific androgen blockade, usually partial androgen blockade achieved by medical or sur gical castration or an anti-androgen alone, deserves re-evaluation following the observa tions of higher AR levels and/or maintenance of responsiveness to androgens in treatmentresistant cancer (Chen et al., 2004; Harris et al., 2009; McPhaul, 2008; Mostaghel et al., 2009; Mulders and Schalken, 2009; Scher and Sawyers, 2005; Taplin and Balk, 2004). While addition of an anti-androgen was the usual approach in patients showing resistance to monotherapy by castration, the patients who had become resistant to CAB were not consid ered candidates for further hormonal manipula tions and were treated by non-hormonal approaches, specially chemotherapy with no clear success (Eisenberger et al., 1985). In fact, elevated AR expression has been found to lead to resistance to anti-androgen therapy in mouse xenograft prostate cancer models (Chen et al., 2004). In any case, such data indicate that AR blockade could well remain an important ther apeutic target even at the last stage of the dis ease when resistance to various forms of androgen blockade has developed. Although the available anti-androgens fluta mide, bicalutamide and nilutamide have pure AR antagonistic activity and have shown major benefits in prostate cancer therapy (Crawford et al., 1989; Janknegt et al., 1993; Labrie et al., 1985; Prostate Cancer Triallists’ Collaborative Group, 2000), the affinity of all these com pounds for AR is very low (Labrie et al., 1997; Labrie et al., 1999; Luo et al., 1996; Simard et al., 1997) and leaves an estimated 5–10% of DHT free to continue to stimulate AR and prostate cancer growth (Labrie et al., 1987). There is thus the need to discover and develop novel anti-androgens having higher 334 affinity for the human AR in order to take optimal advantage of the well-demonstrated sensitivity of prostate cancer to androgens. Using the structural information on the ligandbinding domain (LBD) of the human AR (Cantin et al., 2007; Pereira de Jesus-Tran et al., 2006), we have synthesized a long series of novel molecules having higher or much higher affinity for the human AR and/or higher anti-androgenic potency in intact cell models than flutamide, bicalutamide or nilutamide, the only presently pure AR antago nists available for therapeutic use in men suffering from prostate cancer. In addition to the increased AR levels, the local and autonomous synthesis of androgens may explain the observation that androgen deprivation in prostate cancer xenograft models demonstrated only transient cell cycle arrest, with little evidence of apoptosis, followed by rapid progression (Agus et al., 1999). Moreover, as mentioned above, cancerous prostate tissue was found to synthesize more DHT than the benign prostatic tissue (Nishiyama et al., 2007). With the above-summarized information, it is reasonable to believe that the drug most urgently needed for prostate cancer is a more potent blocker of AR. With the available weak anti-androgens, only partial androgen blockade can be achieved – true total androgen blockade needs more potent compounds. As mentioned above, the problem with current anti-androgens is their low potency which leaves 5–10% of DHT in the prostate cancer tissue (Fig. 7) free to continue to stimulate cancer growth and metastasis. Moreover, with the available pure but weak anti-androgens (Labrie et al., 1997; Labrie et al., 1999; Luo et al., 1996; Simard et al., 1997), CAB must be continued for many years (six or more), even in localized disease (Fig. 5). With a more potent anti-androgen, complete apoptosis and cell death should be achieved more rapidly, thus greatly facilitating cure of localized disease. The compounds which we have synthesized are designed to impede repositioning of the mobile carboxy-terminal helix 12, which blocks the ligand-dependent transactivation function (AF-2) located in the AR ligand-binding domain (ARLBD). Using Intraprostatic DHT % 100 75 Cancer growth decreases but continues − resistance develops 50 25 0 Intact Monotherapy castration or anti-androgen alone Combined androgen blockade castration + anti-androgen Fig. 7. Comparison of the intraprostatic concentrations of DHT in intact men, in men castrated or receiving an antiandrogen alone (monotherapy) and in men receiving combined androgen blockade (castration þ a pure antiandrogen having relatively low potency, namely flutamide, bicalutamide or nilutamide). crystal structures of the human ARLBD (hARLBD), we first found that H12 could be directly reached from the ligand-binding pocket (LBP) by a chain positioned on the C18 atom of an androgen steroid nucleus. A set of DHTderived molecules bearing various C18 chains were thus synthesized and tested for their capa city to bind to human androgen receptor (hAR) and act as antagonists. Although most of those having very high affinity for hAR were agonists, several very potent antagonists were obtained, confirming the structural importance of the C18 chain. To understand the role of the C18 chain in their agonistic/antagonistic properties, the structure of the hARLBD complexed with one of these agonists, EM-5744, was determined at a 1.65 Å resolution (Cantin et al., 2007). We have identified new interactions involving Gln738, Met742 and His874 that explain both the high affinity of this compound and the inability of its bulky chain to prevent the repositioning of H12. These structural information were helpful to refine the structure of the chains placed on the C18 atom in order to obtain efficient H12-direc ted steroidal anti-androgens. With the aim of designing such new antiandrogens, we decided to make use of earlier 335 structural findings on the human estrogen recep tor (hER), a receptor structurally related to the hAR. The hER is unable to interact with co activator partners when a ligand bearing a welloriented bulky chain is bound to its ligand-bind ing site (Brzozowski et al., 1997). Indeed, as revealed by comparison of the crystal structures of the hER ligand-binding domain (hERLBD) in complex with a natural estrogen [estradiol (E2)] and a potent SERM (selective estrogen receptor modulator, raloxifene), agonist and antagonist molecules bind at the same site within the LBD. However, they exhibit different binding modes, inducing a distinct conformation in the transactivation domain (AF-2) characterized by a different positioning of H12. More precisely, the size and structure of raloxifene prevent the molecule from being completely confined within the steroid-binding cavity. Consequently, its bulky side chain protrudes from the cavity and impedes H12 from adopting the position found in the E2–hERLBD complex structure, a confor mation essential for interaction with transcrip tional co-activators. Concerning hAR, the crystal structures of its LBD (hARLBD) in complex with the natural androgens DHT and testo (Pereira de Jesus-Tran et al., 2006; Sack et al., 2001) have shown that H12 occupies therein the same position as that observed in the E2–hERLBD structure. Such data suggest that this helix is essential for the function of the AF-2 of hAR and, like in the hER, participates in the interaction with co-acti vators. This has been confirmed by the structure of the liganded hARLBD in complex with a pep tide derived from physiological co-activators (Estebanez-Perpina et al., 2005; He et al., 2004; Hur et al., 2004). Using all the available structural information of the hAR, we then proceeded to molecular model ling studies to find the best position on an andro gen nucleus (here DHT) for introducing a bulky chain able to reach the site normally occupied by H12. Finally, the combined data from molecular modelling and structure/activity relationship stu dies served as a basis for the design and improve ment of the chain structure, with the aim of maximizing the affinity of these steroidal-based compounds for hAR. This rational approach yielded several different DHT-based ligands able to bind hAR with high affinity (many folds over that of DHT). In our in vitro tests, a small sub group proved to be very efficient antagonists of DHT stimulation, thus indicating that the particu lar structure of the bulky chain is of paramount importance for its activity. Hormone therapy is greatly underused in prostate cancer Despite the fact that it is well recognized since 1940s (Huggins and Hodges, 1941) that the stan dard and even the only efficient treatment of metastatic prostate cancer is androgen blockade, a recent survey of 9110 men aged 65 years or older who died from prostate cancer between 1991 and 2000 has surprisingly indicated that 38% of black and 25% of white men in the United States did not receive hormone therapy before dying from prostate cancer (Lu-Yao et al., 2006). If such a large proportion of patients with metastatic prostate cancer do not receive hor mone therapy, one can understand the difficulty to implement CAB instead of the partial and limited blockade obtained with monotherapy (Table 3). This deficient use of androgen block ade in prostate cancer can be contrasted with the respective 93.5 and 98% rates of use of beta blockers after myocardial infarction (National Committee for Quality Assurance, 2003, p. 60) and tamoxifen in estrogen-receptor-positive breast cancer (Buzdar and Macahilig, 2005). This deficiency in the field of prostate cancer may be due to the fact that doctors underesti mate the risks of death from prostate cancer compared to other causes of death. Table 3. Frequent errors related to androgen blockade 1. Monotherapy (GnRH agonist alone, orchiectomy alone or anti-androgen alone) instead of combined androgen blockade 2. Too short duration of treatment 3. Treatment started too late 4. Intermittent treatment 336 Early diagnosis is essential in order to be able to apply the available curative treatments of prostate cancer It is very important to realize that the use of the currently available approaches for the diagnosis and treatment of prostate cancer can virtually eliminate death from this disease. With the cur rent techniques, screening can detect prostate can cer at a clinically localized stage in 99% of cases (Labrie et al., 1996b). Radical prostatectomy, radiotherapy or brachytherapy can be instituted immediately with curative intent following such early diagnosis. Moreover, excellent results can be expected with CAB alone, particularly in older patients where the choice of CAB can be easier. In fact, CAB can also be used alone as primary therapy with excellent results, as shown in important recent studies (Akaza et al., 2006; Egawa et al., 2004; Homma et al., 2004; Labrie et al., 2002; Ueno et al., 2006). Most importantly, CAB must be used immedi ately in patients for whom radical prostatectomy, radiotherapy or brachytherapy fails. As men tioned above, it is often erroneously believed that resistance will develop to androgen blockade in localized disease and that this treatment should therefore be delayed until a later stage of the disease. This belief is incorrect. In fact, the use of CAB to treat localized prostate cancer does not lead to resistance to treatment as long as the can cer is limited to the prostate or to tissue near the prostate at time of starting treatment. However, as mentioned above, if the treatment is deferred, the possibility of cure is very often lost because the cancer has the opportunity to metastasize to the bones where cure is practically impossible. In metastatic disease, the response to androgen blockade is short and resistance to treatment can not be avoided. It should be appreciated that when prostate cancer is first detected, even by screening, the tumor is not small. Immediate treat ment is the only treatment that offers a strong hope of cure. In fact, CAB must be started imme diately at time of diagnosis. While showing the high efficacy of hormonal therapy in localized prostate cancer, the present data clearly indicate that long-term treatment with the best available drugs, somewhat similar to the 5 years of tamoxifen in breast cancer, is required for optimal control of prostate cancer. Great caution should be taken, however, when using serum PSA as surrogate marker. In fact, serum PSA rapidly and easily decreases to undetectable levels under androgen blockade although the cancer remains present for much longer periods of time, usually for many years as demonstrated in our recent study (Labrie et al., 2002). For this reason, inter mittent therapy should not be recommended outside prospective and randomized clinical trials. Conclusion With the present knowledge, it is clear that all available means should be taken to diagnose pros tate cancer early and to use efficient therapy immediately in order to prevent prostate cancer from migrating to the bones when cure or even long-term control of the disease is an exception. It is clear that the only means of preventing prostate cancer from migrating to the bones and becoming incurable is efficient treatment at the localized stage. In fact, since radical prostatectomy, radio therapy and brachytherapy (implantation of radioactive seeds in the prostate) can achieve cure in about 50% of cases, these approaches are all equally valid choices as first treatment of loca lized prostate cancer with a curative intent. Androgen blockade should also be considered as first line treatment of curative intent, especially for elderly men and those having other serious health problems. The most important, however, is to follow closely serum PSA after surgery, radiotherapy and brachytherapy and to start CAB as soon as signs of recurrence of the cancer appear. It is also clear from the data summarized above that CAB alone could well be the most efficient therapy of localized prostate cancer while it has already been recognized as the best therapy for metastatic disease. Clearly, the rational use of the presently avail able diagnostic and therapeutic approaches could decrease prostate cancer death by at least 60% (Labrie et al., 1996b; Labrie et al., 1999). As an example, between 1991 and 1999, the death rate 337 from prostate cancer has decreased by 38% in Quebec City and its metropolitan area (Candas and Labrie, 2000) while the death rate has decreased by 62% in the group of men who have been screened. References Agus, D. B., Cordon-Cardo, C., Fox, W., Drobnjak, M., Koff, A., Golde, D. W., et al. (1999). 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