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Hormonal therapy for prostate cancer: Current topics and future perspectives

2010; Wiley; Volume: 17; Issue: 4 Linguagem: Inglês

10.1111/j.1442-2042.2010.02460.x

1442-2042

Hiroyoshi Suzuki, Shiro Hinotsu, Hideyuki Akaza, Yasuhisa Fujii, Satoru Kawakami, Kazunori Kihara, Koichiro Akakura, Motofumi Suzuki, Tadaichi Kitamura, Yukio Homma, Atsushi Mizokami,

Prostate Cancer Diagnosis and Treatment

Prostate cancer is androgen-dependent, and hormone therapy, which is mainly achieved by androgen deprivation, is one of the main treatment modalities in the clinical management of prostate cancer patients. Dr Charles Brenton Huggins was awarded the 1966 Nobel Prize for Physiology or Medicine for discovering that hormones could be used to control the spread of some cancers in 1940s. This was the first discovery that showed that cancer could be controlled by chemicals. Hormone therapy for prostate cancer has been widely used for more than 6 decades since then, spreading to a variety of modalities, while the principle of the therapy has remained the same. In the 1980s, luteinizing hormone-releasing hormone (LHRH) agonists that reduce testosterone to castrate levels were introduced. Also, non-steroidal anti-androgens in addition to steroidal anti-androgens were developed after the 1980s. Since then, so-called maximum androgen blockade (MAB)/combined androgen blockade (CAB), which is a combination of surgical or medical castration and oral anti-androgens, has been developed. More recently, novel treatment modalities, such as intermittent androgen suppression, non-steroidal anti-androgen monotherapy, alternative anti-androgen therapy for initial MAB/CAB relapsed cases and deferred MAB/CAB have been developed. The present reviews are focused on these treatment modalities as current topics and perspectives of hormone therapy for prostate cancer. Also, Hinotsu et al. introduces a novel risk assessment tool (i.e. the Japanese prostate cancer risk assessment [J-CAPRA]) and Suzuki et al. explains the possibilities of personalized medication of estramustine phosphate by individual single-nucleotide polymorphism analysis. Finally, Mizokami discusses new hormonal therapy for the recurrence of prostate cancer. The answers and opinions follow as Guest Editorials. The International Journal of Urology is inviting submissions in response to any part of this Editorial, including views that oppose this Editorial. You are invited to submit Letters to the Editor by 31 August 2010. Please submit at: http://mc.manuscriptcentral.com/iju. Hiroyoshi Suzuki md Deputy Editor Although many risk-assessment tools for prostate cancer have been published, most of the tools are developed using data from one country after a single modality of treatment. We developed a novel risk-assessment tool for prostate cancer patients undergoing primary androgen deprivation therapy (PADT) in Japan and the USA.1 In 2001, the Japan Study Group of Prostate Cancer (J-CaP Study Group) was organized to gather information about the hormone therapy administered to Japanese prostate cancer patients. J-CaP surveillance is a nationwide longitudinal observational study of the patients starting hormone therapy for prostate cancer for the first time from January 2001 to December 2003. In this program, participants registered individual cases, with entry of information on endocrine therapy via secure server over the Internet. After registration, information on the prognosis of individual registered cases and changes in treatment, if any, were entered periodically. A total of 26 272 cases were registered from 395 institutions in the J-CaP server. Of these cases, 26 170 cases were diagnosed by biopsy as having prostate cancer and began to receive treatment between 1 January 2001 and 31 December 2003. Among these cases, the number of patients who initially received PADT after diagnosis of prostate cancer and for whom detailed information on the endocrine therapy given was available was 19 409. The Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database is a large, community-based registry of prostate cancer patients in the USA, with 11.4% of the patients treated at academic centers.2 Patients are treated according to the participating physicians' usual practice; 2077 (15.1%) were managed with PADT. We developed a collaborative study between the J-CaP database and the CaPSURE database in order to compare patterns of risk and outcomes, and to develop a novel instrument for risk stratification of patients undergoing PADT. Cooperberg et al. introduced a risk-assessment tool for prostate cancer, the prostate cancer risk assessment (CAPRA) score, using the patient's outcome data in the CaPSURE registry.3 We tried to apply J-CaP data for the CAPRA score, however it was difficult to calculate the CAPRA score because J-CaP reports the clinical stage using the 1997 tumor–node–metastasis (TNM) system, which does not include T2c, and detailed biopsy data (e.g. percent positive core) are not included in the J-CaP database. Therefore, the data available on patients in the J-CaP and CaPSURE subset (patients in the CaPSURE database undergoing PADT since 2000) were used to build a new model to predict the survival of patients using the Cox proportional hazards regression. The parameter estimates for variables in the model were statistically significant predictors of progression. After the validation analysis, we selected five variables (prostate-specific antigen, Gleason score, T-stage, N-stage and M-stage) and calculated points for each variable to determine the J-CAPRA scores listed in Table 1. From the survival data of each J-CAPRA score, we divided the patients into three categories: low-risk patients (J-CAPRA 0–2), intermediate-risk patients (J-CAPRA 3–7) and high-risk patients (J-CAPRA 8–12). The Kaplan–Meier plots for categorized scores are presented in Figure 1. Progression-free survival. , score 0–2; , score 3–7; , score 8+. Most risk-assessment tools are developed for use at the time of diagnosis excluding those with locally advanced or metastatic disease. We developed this tool from a relatively large number of patients who have advanced disease (42.7% in the J-CaP database, 19.9% in the CaPSURE PADT subset). The J-CAPRA tool covers patients with localized disease, locally advanced disease and advanced disease. Also, no other tool had been validated among Japanese patients. The J-CAPRA score is a novel, validated score for predicting outcomes among patients treated with PADT for all clinical stages. This tool will be helpful for evaluating an international comparison for the outcome of PADT in the future. Recently, the survival benefit of combined androgen blockade as PADT for advanced prostate cancer was clearly demonstrated.4 For this paper Moul discussed the state-of-the-art androgen deprivation therapy for prostate cancer in his editorial comment,5 and pointed out the importance of further clinical investigation in this field. For scientific discussion on the outcome and optimal treatment selection for prostate cancer, this novel risk-assessment tool will play a very important role in evaluating the risks for stratification, not only for the data from Japan but also for the data from Western countries. Shiro Hinotsu md and Hideyuki Akaza md for the Japan Study Group of Prostate Cancer (J-CaP) 1Graduate School of Medicine and Public Health, Kyoto University, Kyoto, and 2Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki Japan [email protected] Androgen deprivation (AD) therapy has been the preferred treatment for advanced prostate cancer for over 60 years. AD therapy generally induces a remission in 80–90% of patients with advanced prostate cancer, and results in a median progression-free survival of 12–33 months. However, most if not all patients eventually develop castration-resistant prostate cancer (CRPC), which is characterized at the cellular level by continued tumor proliferation in the absence of testicular androgen production. To date, the best treatment for CRPC remains elusive. Although serum testosterone levels are reduced by up to 95% by castration, the intraprostatic androgen stimulus is sustained by the conversion of the circulating adrenal androgens into dihydrotestosterone within the prostate cells. The action of these adrenal androgens is blocked by adding an anti-androgen to either surgical or pharmacological castration, a concept known as combined (or maximal) androgen blockade (CAB). Many studies evaluating CAB over AD monotherapy (ADMT) have been reported, with contrasting results. From the recent systematic reviews and meta-analyses, it appears that at a follow up of 5 years, CAB using non-steroidal anti-androgens provides a small survival advantage ( 50% decline in PSA levels) to high-dose bicalutamide (150 mg daily) among 16 patients with CRPC during ADMT.10 Similarly, Scher et al. reported that only one (11%) of nine patients with CRPC during ADMT responded to deferred high-dose bicalutamide (200 mg daily).9 A 23% PSA response rate with a median 4.2-month response duration was also reported with deferred flutamide in symptomatic metastatic patients with CRPC.11 In contrast, four previous Japanese studies reported better results for deferred CAB in patients with CRPC during ADMT. In our previous study, 29 (66%) of 44 patients with CRPC had a PSA response to deferred bicalutamide therapy with a relatively long median response duration of 9.2 months.15 Fujikawa et al. reported a 55% PSA response rate for deferred flutamide therapy in 22 men.13 Similarly, Kojima et al. reported that five (42%) of 12 patients had a PSA response for deferred flutamide or bicalutamide.14 Most recently, Soga et al. reported a 65% PSA response rate of delayed CAB.16 However, it is unlikely that the effects of deferred CAB depend on differences in the races of patients. There is also an American study reporting high response rates of deferred CAB. Fowler et al. reported that the deferred use of flutamide after progression on ADMT produced a PSA response in 66% of CRPC patients.8 To date, it remains unclear why response rates of deferred CAB were so different among these studies. Furthermore, it also remains unclear what prognostic factors predict the response to deferred CAB. Only a few studies have examined the pretreatment variables to predict the response to deferred anti-androgen therapy. There was a study suggesting that the presence or absence of metastases influenced the response. Fowler et al. reported that deferred use of flutamide produced a PSA response in 80% of patients with localized disease, but in 54% with metastatic disease.8 In addition, the duration of the response was longer in patients with localized cancer. However, tumor burden was not associated with the effects of deferred bicalutamide in our previous study;15 neither the presence or absence of metastases, nor the PSA level at any treatment point, was predictive of the response to deferred bicalutamide therapy. In the study, the biopsy Gleason score was the only pretreatment variable predictive of a PSA response, and the PSA doubling time (PSA-DT) during ADMT was the only statistically significant variable of PSA failure-free survival during deferred bicalutamide in a multivariate analysis. Similarly, Shulman et al. examined the pretreatment variables in 36 CRPC patients treated with deferred anti-androgens, reporting that only PSA-DT predicted both the response and the duration of response to therapy.12 Previous studies reported that anti-androgen withdrawal syndrome (AWS) is uncommon after deferred CAB,8,14 suggesting that evaluation for AWS could be omitted after the failure of deferred CAB. Also in our previous study, none of 20 patients who were evaluated for AWS had a PSA decrease of ≥50% after bicalutamide withdrawal.15 However, we recently experienced a case in which profound AWS occurred after the cessation of deferred bicalutamide, which permitted salvage radiotherapy.17 Therefore, we now recommend an evaluation for AWS even after the failure of deferred CAB. Primary hormonal therapy with ADMT followed by deferred use of anti-androgens seems to be a reasonable option for advanced prostate cancer in terms of effects, costs and toxicity. We recommend the addition of anti-androgen in patients relapsing after ADMT before the use of cytotoxic agents like docetaxel. Yasuhisa Fujii md phd, Satoru Kawakami md phd and Kazunori Kihara md phd Department of Urology, Tokyo Medical and Dental University, Tokyo, Japan [email protected] After the 1980s, non-steroidal anti-androgens were developed in addition to steroidal anti-androgens. Since then, so-called maximum androgen blockade (MAB)/combined androgen blockade (CAB) therapy, which is a combination of surgical or medical castration and oral anti-androgens, has been developed. MAB/CAB and combination therapy of either a luteinizing hormone-releasing hormone agonist or orchiectomy with an anti-androgen, is widely used in Japan for treating advanced prostate cancer.18 Oral steroids or non-steroidal anti-androgens competitively block testosterone and/or dihydrotestosterone binding to the androgen receptor. Anti-androgen administration concurrently with medical or surgical castration is referred to as MAB/CAB, which significantly but only slightly improves the survival of patients with advanced prostate cancer. As mentioned above, meta-analyses have shown that a regimen of MAB/CAB with non-steroidal anti-androgens confers a survival benefit for advanced prostate cancer patients.19 However, anti-androgen withdrawal syndrome (AWS), first described by Kelly and Scher in 1993, is a manifestation of a prostate-specific antigen (PSA) decline, with or without subjective or objective symptomatic improvement upon discontinuation of the anti-androgen flutamide.20 A decline in PSA has also been observed after discontinuing non-steroidal anti-androgens (such as bicalutamide and nilutamide) and steroidal anti-androgens. The precise mechanism underlying AWS has not been identified, but mutations in androgen receptors or gene amplification of the androgen receptor might result in an altered response to anti-androgens. Some patients with progressive disease who have undergone initial MAB/CAB therapy might respond to second- and third-line hormonal therapy. Alternative anti-androgens probably have different functional interactions with the androgen receptor. In 2004, our previous study evaluated 70 patients with prostate cancer who relapsed after primary hormone therapy and we assessed the effect of subsequent hormone therapy.14 We found that subsequent non-steroidal anti-androgen therapies were effective against prostate cancer that relapsed after hormonal therapy, although the clinical characteristics of these patients were relatively heterogeneous. Thus, we organized the Non-steroidal Anti-androgen Sequential Alternation for Prostate Cancer (NASA-PC) study group, consisting of 12 medical institutions in Japan, and re-evaluated the clinical course of patients who were treated with MAB/CAB using a non-steroidal anti-androgen (i.e. bicalutamide or flutamide) followed by another available non-steroidal anti-androgen; we found that this treatment modality conferred a clinical benefit.21 The 232 patients with a PSA level before treatment of 1047 ± 2882 (range 4.4–23 500) ng/mL were analyzed. Of the 232, 175 (75%) achieved complete response (CR), and all reached CR or partial response. Concerning the anti-androgen withdrawal response rate after first-line therapy was discontinued, the PSA decreased significantly (≥50%) in 35 of the 232 (15.1%) patients after discontinuing first-line therapy (5.8 ± 3.8 months). Taken together with previous reports, these findings suggest that we need to pay attention to the usage of steroidal anti-androgens. Also, we and others have reported that second-line steroidal anti-androgens have low treatment effectiveness. With respect to the second-line anti-androgen response, PSA was significantly decreased (≥50%) in 83 of the 232 (35.8%) patients. Also, a partial PSA response (PSA decreases of 0–50%) was observed in 59 of the 232 (25.4%) patients. Thus, 61.2% of patients showed a response to second-line therapy. More than half of the cases that had started second-line therapy at PSA levels 50% but also the cases with PSA decreases from 0 to 50% showed significantly better survival than non-responders. This strongly suggests that the PSA response to alternative anti-androgens is one of the most important predictive factors for cause-specific survival. In the logistic regression model, we found that response to second-line therapy was the most important factor, followed by response to first-line therapy, anti-androgen withdrawal response, and Gleason scores (≤7 vs≥8), indicating the potential predictive value of responsiveness to second-line therapies. We and others reported that a relatively low dose of a non-steroidal anti-androgen is effective for prostate cancer that has relapsed after first-line MAB/CAB therapy. Although the precise mechanisms are unclear, flutamide therapy might select mutant androgen receptors that can be stimulated by this agent but that are inhibited by bicalutamide.22 It has been shown that mutation of the androgen receptor codon 741 in the ligand-binding domain for bicalutamide stimulates LNCaP cell lines; under such circumstances, bicalutamide works as an agonist rather than as an antagonist. Importantly, hydroxyflutamide works as an antagonist for these mutant androgen receptors. Flutamide suppresses adrenal androgens, while bicalutamide does not. Also, bicalutamide suppresses androgen receptor pathways via the protein kinase A pathway more than flutamide. Recently, Terada et al. reported novel molecular findings for alternative anti-androgen therapy, using prostate cancer xenograft model KUCaP-1 harboring the W741C mutant androgen receptor.23 The tumor growth of KUCaP-1 after bicalutamide (BCL) withdrawal was suppressed by flutamide, suggesting that alternative anti-androgen therapy with flutamide is an effective treatment modality for prostate cancer patients with mutant androgen receptors induced by bicalutamide treatment. Combined with the clinical data, this suggests that bicalutamide and flutamide are not completely cross-resistant. These results show that second-line MAB/CAB using alternative anti-androgens can be effective after first-line MAB/CAB using flutamide or bicalutamide. More recently, the 2009 EAU Prostate Cancer Guideline picked up the NASA-PC paper and they recommend alternative anti-androgen therapy to treat prostate cancer relapse after initial MAB/CAB therapy. Scher and colleagues have suggested dividing stage D3 hormone refractory prostate cancer cases into the following categories: (i) hormone-naïve; (ii) androgen-independent but hormone-sensitive; and (iii) hormone-independent cancers.24 NASA-PC data support the conclusion that about 60% of prostate cancer cases that relapse after first-line therapy might be androgen-independent but still hormone-sensitive. In other words, as the non-responders to second-line therapy showed worse survival (i.e. hormone-independent cancer), we need to consider the early introduction of novel treatments, such as docetaxel chemotherapy, for these patients. Figure 2 shows a possible treatment flowchart based on these results. Possible treatment flowchart for initial maximum androgen blockade (MAB)/combined androgen blockade (CAB) failure cases. CR, complete response; NC, no change; PCa, prostate cancer; PD, progressive disease; PR, partial response; PSA, prostate-specific antigen. Hiroyoshi Suzuki md phd Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan [email protected] For the management of advanced prostate cancer, endocrine therapy has been utilized as a principle modality of treatment. Since surgical castration was introduced as one of the most common strategies, endocrine therapy has been considered to continue permanently. Although the initial effect of endocrine therapy is prominent, progression to androgen-independent status often occurs within a few years. Therefore, a variety of attempts have been made to maintain the androgen-dependent status of the tumor as long as possible. Intermittent androgen suppression was proposed to prolong androgen dependency of prostate cancer, and was found to provide potential benefits resulting during the off-treatment period. In general, adenocarcinoma of the prostate shows androgen dependency; the tumor develops and grows in the presence of androgen, and regresses through apoptosis by withdrawal of androgen. However, the regressed tumor progresses after a while, and becomes an androgen-independent tumor. In in vitro and in vivo experiments using androgen-dependent models, androgen dependency can be maintained in the presence of androgen; androgen-dependent cancer cell lines can be serially cultured in the physiological concentration of androgen in the medium, and androgen-dependent xenografts are successfully transplanted into the male hosts. However, long-term withdrawal of androgen causes these cancer cells to become androgen-independent. Withdrawal of androgen could be a trigger for progression to androgen-independent status. Therefore, it is hypothesized that when the androgen-dependent tumor regresses following androgen withdrawal, if androgen is replaced again, the tumor might recover the potency of apoptosis induced by androgen withdrawal, and is expected to maintain androgen dependency for longer. Shionogi carcinoma is an androgen-dependent mouse mammary tumor; surgical castration of a tumor-bearing male mouse results in regression of the tumor through induction of apoptosis. Using the Shionogi model, four or five cycles of tumor regression and regrowth have been obtained by cycles of androgen withdrawal and replacement.25 In a human prostate cancer cell line, LNCaP, which was transplanted into nude mice, serum prostate-specific antigen (PSA) level was maintained in an androgen-dependent manner for a longer period by intermittent androgen suppression, compared with continuous androgen suppression. Development of reversible hormonal agents, such as luteinizing hormone-releasing hormone (LHRH) agonists and anti-androgens, and prevalence of PSA as a reliable and feasible tool for monitoring have made it possible to apply endocrine therapy intermittently. Based on the promising results of investigational research using an androgen-dependent animal model, our group in Vancouver reported 47 cases of prostate cancer treated with intermittent androgen suppression. Thereafter, a number of clinical experiences of intermittent therapy have been published for various stages of prostate cancer by different methods and durations of endocrine therapy. Most of the studies demonstrated promising results and emphasized improved quality of life after intermittent androgen suppression.26 Several randomized comparative clinical trials have been conducted to compare the efficacy between intermittent and continuous androgen suppression (Table 3).27–34 At the present time, while only a few trials have obtained the final results,27 no report has demonstrated a significantly worse time to progression and survival with intermittent androgen suppression than with continuous androgen suppression. On the other hand, most trials have indicated that the benefits of intermittent therapy were fewer adverse effects and increased quality of life. Although intermittent androgen suppression has been classified as an experimental method of treatment, the latest Guidelines on Prostate Cancer by the European Association of Urology indicated that 'intermittent androgen deprivation therapy is at present widely offered to prostate cancer patients in various clinical settings, and its status should no longer be regarded as investigational,' based on the recent clinical data. Intermittent androgen suppression is able to achieve several benefits. Incidence and degree of adverse events of androgen deprivation therapy will be decreased or improved by intermittent androgen suppression. Most of symptoms including sexual dysfunction, hot flush, and fatigue will be recovered during the off-treatment period, and risk of cardiovascular events and osteoporosis may be reduced by intermittent therapy. Several domains of quality of life are improved by stopping androgen deprivation therapy. From an economical point of view, the cost of treatment will be reduced by intermittent therapy, comparing continuous therapy with the same agents. Finally, it might be expected that intermittent androgen suppression will achieve prolonged progression-free and overall survival. When applying intermittent androgen suppression, frequent measurements of serum PSA and testosterone will be required. Although it is not certain whether prostate cancer can be cured by endocrine therapy, the chance of cure might be missed by stopping the therapy. As serum PSA is thought to be a useful marker for monitoring the disease status, there is a risk of developing progression without an elevated level of serum PSA during intermittent therapy. Intermittent androgen suppression was initially used for patients with metastatic or advanced prostate cancer. However, recently there has been a dramatic increase in the number of curative therapies, such as radical prostatectomy and radiotherapy, at the early stage of the disease, probably due to the prevalence of serum PSA measurements. In recent years, a number of patients have developed PSA failure after curative therapy. Some of these patients have been treated with endocrine therapy and may be under control for a long time. Therefore, the adverse effects of endocrine therapy will be serious problems for these patients, and intermittent therapy could be an option for the long-term management of prostate cancer patients without metastasis. A meta-analysis study demonstrated significant factors for progression-free survival of patients treated with intermittent therapy.35 However, good candidates for intermittent therapy are still unknown. Moreover, a number of questions are still to be answered: Which is the appropriate method of endocrine therapy for each patient: LHRH agonist, anti-androgen alone, or combined androgen blockade? At which PSA levels should therapy be terminated and restarted? To resolve these questions, the accumulation of clinical data is crucial. A recent study of a mathematical model of intermittent androgen suppression may be able to suggest the future course of each patient by precise analysis of PSA kinetics.36 This model will be extremely useful for the establishment of order-made therapy of intermittent androgen suppression. Koichiro Akakura md phd Department of Urology, Tokyo Kosei Nenkin Hospital, Tokyo, Japan [email protected] Estramustine phosphate (EMP) is a prodrug that consists of 17β-estradiol bound to nor-nitrogen mustard. This compound was first synthesized in the mid-1960s for the treatment of breast cancer. In the 1970s, EMP was applied to the treatment of prostate cancer as a chemoendocrine agent based on the fact that it specifically accumulates in the prostate. EMP has been marketed in Japan since 1984. Recently, EMP has drawn attention for its synergistic effect when combined with docetaxel.37,38 However, EMP frequently causes a variety of toxicity symptoms, resulting in low drug compliance and its eventual discontinuation. Gastrointestinal toxicity (GIT) is a common adverse effect caused by EMP, and we previously reported that 22.4% of our patients with prostate cancer who had been treated with EMP (280 mg/day) developed grade 3 or 4 GIT.39 Naiki et al. also reported that approximately 30% of their patients who received EMP developed severe GIT resulting in the discontinuation of EMP therapy.40 In 2005, we found that the incidence of GIT during EMP therapy for prostate cancer was significantly associated with the genotypes of single-nucleotide polymorphisms (rs4646903, rs1048943, and rs4646421) in the cytochrome P450 1A1 (CYP1A1) gene (domestic patent no. 4117381, registered on 2 May 2008).41 CYP1A1 is involved in the hydroxylation of 17β-estradiol to 2-hydroxyestradiol, and two functional polymorphisms (rs4646903 and rs1048943) of the CYP1A1 gene are known to influence its enzymatic activity. The risk of GIT was approximately 12 times higher in patients carrying the haplotype set of all the major allelic combinations (T allele of rs4646903, A allele of rs1048943, and G allele of rs4646421) compared with others (odds ratio [OR], 11.86; 95% confidence interval [CI], 3.61–39.02). Since then, with the approval of the Ethics Committee of the University of Tokyo and our affiliated hospitals, we have begun collecting DNA samples from patients with newly diagnosed prostate cancer and performing a genotyping assay of these three polymorphisms to assess the future risk of GIT in response to EMP treatment. From November 2005 to November 2007, a total of 355 genomic DNA samples were collected from Japanese patients with prostate cancer. Of these, 222 men (62.5%) were diagnosed as having a low risk of EMP-induced GIT based on the results of their gene analysis. A total of 36 patients (17 with stages D1 or D2, 9 with stage C, and 10 with stage D3) were treated with EMP (280 mg/day), but only 7 of these patients (19.4%) developed GIT. Previously, we treated 55 patients with prostate cancer using EMP (280 mg/day) but without the CYP1A1 gene analysis, and the incidence of GIT in that series was 40.0% (22 out of 55 patients). We compared the incidence of GIT with the CYP1A1 gene analysis with that in our previous study and estimated the odds ratio using a logistic regression analysis. The effect of performing the CYP1A1 gene analysis prior to EMP therapy was 0.36 (95%CI, 0.127–0.936; P = 0.036) in a univariate analysis and 0.21 (95%CI, 0.21; P = 0.006) in a multivariate analysis, respectively (Table 4). To date, 15 of 36 patients are continuing to receive EMP therapy and have not experienced PSA failure or severe side-effects, whereas the remaining 21 patients have stopped EMP therapy because of reasons unrelated to EMP use (PSA failure in 4 patients, death from prostate cancer in 4 patients, patients' will in 2 patients and death from colon cancer in 1 patient), and because of reasons related to EMP use (hepatic dysfunction in 3 patients, GIT in 2 patients, lower limb edema in 2 patients, hot flush in 1 patient, bloody sputum in 1 patient and pulmonary embolism in 1 patient). We believe that the screening of CYP1A1 gene polymorphisms prior to initiating EMP therapy is useful for selecting patients with a low risk of GIT; however the efficacy of this screening test should be confirmed in a large-scale, prospective, multicenter study. Recently, we observed an increase in white blood cell count during EMP therapy. This phenomenon was first reported by Daponte et al. in 1983.42 This physiological response to an anticancer agent is quite unusual; however, it had not previously attracted our attention. Only the number of neutrophils increased significantly during EMP therapy and decreased to the baseline level after the cessation of treatment. The mechanism of leukocytosis and possible benefits for patients in docetaxel plus EMP chemotherapy requires further investigation. Nowadays a number of agents are being marketed in the urological field, including tyrosine kinase inhibitor for renal cell carcinoma, 5α-reductase inhibitor for benign prostatic hyperplasia, and anti-microtubule agent for prostate cancer. These agents show variable profiles for efficacy and adverse events. Single-nucleotide polymorphism analysis may be useful for predicting efficacy and risk of side-effects, leading to personalized medication for each patient. Motofumi Suzuki md phd, Tadaichi Kitamura md phd and Yukio Homma md phd Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan [email protected] Prostate cancer (PCa) is the most common malignancy and the second leading cause of cancer-related death of men in the USA. As advanced PCa is initially dependent upon androgens, androgen-deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LH-RH) agonist and anti-androgen (bicalutamide or flutamide) is the first choice for advanced PCa. Unfortunately, after an initial response to ADT, PCa eventually does not respond to ADT and progresses into what is termed an androgen-insensitive state against LH-RH agonist and anti-androgen. Multiple molecular mechanisms that could account for the development of resistance to ADT have been proposed that typically invoke the androgen receptor (AR) as a key mediator in the progression of PCa.43 Moreover, alterations of AR itself, which are either absent or at low frequency in the original androgen-dependent state, result in an androgen-hypersensitive situation where stimulation of PCa growth occurs at castrate levels of androgens. Therefore, in addition to its normal ligands, testosterone (T) and dihydrotestosterone (DHT), both androstenediol, a precursor of T, can activate the AR and stimulate the proliferation of LNCaP cells that have a mutated AR.44 T and the more active androgen DHT are important factors in PCa progression. These hormones are still present in PCa tissue after ADT. Specifically, when PCa patients are treated with ADT, serum T and DHT decreases to less than one-tenth of pretreatment levels. However, T and DHT in PCa tissue are still present at 20–40% of pre-treatment values.44 T and DHT in PCa tissue after medical or surgical castration are synthesized locally in the prostate from dehydroepiandrosterone (DHEA) of adrenal origin.45 The metabolism from DHEA to DHT in peripheral target tissues depends upon the level of expression of various steroidogenic enzymes in the specific cell types of these tissues. Adrenal DHEA is converted to T by 17β-hydroxysteroid dehydrogenase (17β-HSD) and 3β-HSD. T is then converted to DHT by 5α-steroid reductase (SRD5A) in the prostate. Currently, two types of 3β-HSD, fifteen types of 17β-HSDs and three types of SRD5A have been identified and localized in various peripheral tissues, including the prostate, with specific expression patterns in each tissue.46,47 Fung et al. have observed increased expression of AKR1C3 (aldo-keto reductase 1C3) (type 5 17β-HSD) in PCa tissue while Stanbrough et al. confirmed that ADT-resistant PCa and bone marrow metastases expressed increased levels of multiple genes responsible for androgen metabolism (type 2 3 β-hydroxysteroid dehydrogenase (HSD3B2), AKR1C3, SRD5A1, aldo-keto reductase 1C2 (AKR1C2), aldo-keto reductase 1C1 (AKR1C1) and UDP-glucuronosyltransferase 2B15 (UGT2B15).48,49 These studies provide support for the concept that PCa tissues can perform local biosynthesis of T and DHT resulting in activation of the AR. Recently, we demonstrated that T and DHT synthesized from DHEA in stromal-cells activated AR in PCa epithelial cells in a paracrine fashion and stimulated PCa proliferation. Thus, adrenal androgen DHEA contribute to the development of ADT resistance in PCa.50 Therefore, alternative anti-androgen therapy (which is described in another section) is an alternative strategy to extend the period when normal ADT (first-line hormonal therapy) is effective. Recently, a second generation of anti-androgens, MDV3100 and RD162, with 10 times more affinity to AR than bicalutamide, were developed. These drugs not only block DHT binding to AR but also reduce the efficiency of its nuclear translocation. In a phase I/II trial using MDV3100, 22 out of 30 castration-resistant PCa (CRPC) had a sustained decline in PSA for at least 12 weeks.51 If these second-generation anti-androgens are clinically available without severe adverse effects, they will be useful as another alternative anti-androgen therapy. As DHT is synthesized in prostate cancer tissue as described above, the SRD5A inhibitor is also a candidate to inhibit progression after alternative anti-androgen therapy. SRD5A inhibitor, dutasteride represses DHT synthesis and inhibits AR activity in LNCaP cells cocultured with stromal cells in vitro. Indeed, Shah reported a phase II study using 3.5-mg dutasteride for CRPC. Of the 25 men, 14 had disease progression by 2 months, nine had stable disease, two had a partial response and none had a complete response. Now, the Therapy Assessed by Rising PSA (TARP) study is ongoing to investigate dutasteride in combination with bicalutamide to prevent or delay disease progression in patients with castration-resistant prostate cancer (CRPC) after initial androgen deprivation therapy. As the source of DHEA is derived from the adrenal gland, a new DHEA synthesis inhibitor, abiraterone, in place of ketoconazole, may be effective for CRPC. Abiraterone inhibits Cytochrome 17 (CYP17), which is associated with DHEA synthesis from cholesterol in the adrenal gland. A decline in PSA of 50% was observed in 28 (67%) of 42 phase II patients, and declines of 90% were observed in eight (19%) of 42 patients with CRPC. Now a randomized phase III study comparing abiraterone plus prednisone versus prednisone plus placebo in CRPC patients who have previously received docetaxel is progressing.52 In conclusion, we may obtain new hormone therapeutic drugs for recurrent prostate cancer several years from now (Fig. 3). It is necessary to evaluate whether we should use them in combination simultaneously, or whether we should use them sequentially. New hormonal therapies for recurrence of prostate cancer. 17β-HSD, 17β-hydroxysteroid dehydrogenase; AR, androgen receptor; CMA, chlormadinone acetate; CYP17, cytochrome 17; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; LHRH, luteinizing hormone-releasing hormone; SRD5A, 5α-steroid reductase; T, testosterone. Atsushi Mizokami md phd Department of Integrative Cancer Therapy and Urology, Kanazawa UniversityGraduate School of Medical Sciences, Ishikawa, Japan [email protected]