Showing papers in "Reviews in urology in 2008"

Superficial bladder cancer: an update on etiology, molecular development, classification, and natural history.

Abstract: Superficial "non-muscle-invasive" bladder tumors represent a heterogeneous group of cancers, including those that are (1) papillary in nature and limited to the mucosa, (2) high grade and flat and confined to the epithelium, and (3) invasive into the submucosa, or lamina propria. The goal of treatment is 2-fold: (1) to reduce tumor recurrence and the subsequent need for additional therapies and the morbidity associated with these treatments and (2) to prevent tumor progression and the subsequent need for more aggressive therapy. This update reviews important contemporary concepts in the etiology, molecular mechanisms, classification, and natural history of superficial bladder cancer.

Prostate Cancer in Elderly Men

Abstract: Due to increasing life expectancy and the introduction of prostate-specific antigen (PSA) screening, a rising number of elderly men are diagnosed with prostate cancer. Besides PSA serum levels and Gleason score, age is considered to be a key prognostic factor in terms of treatment decisions. In men older than 70 years, treatment without curative intent may deprive the frail patient of years of life. Modern radical prostatectomy techniques are associated with low perioperative morbidity, excellent clinical outcome, and documented long-term disease control. Thus, radical prostatectomy should be considered because local treatment of organ-confined prostate cancer potentially cures disease. The huge extent of PSA screening programs may lead to overdiagnosis of prostate cancer. Not every man who is diagnosed with prostate cancer will develop clinically significant disease. This has led to the concept of expectant management for screen-detected, small-volume, low-grade disease, with the intention of providing therapy for those men with disease progression.

Urogenital tuberculosis: update and review of 8961 cases from the world literature

Abstract: The AIDS epidemic caused unexpected worldwide levels of tuberculosis, even in developed countries where the incidence used to be low. Patients with urogenital tuberculosis in developed countries have fewer specific symptoms and lower rates of delayed diagnoses compared with patients from other countries. As a result, the disease tends to be less serious, with more patients presenting without significant lesions of the upper urinary tract on diagnosis. These data point to a correlation of the timing of diagnosis with the severity of urogenital tuberculosis. A systematic search for urogenital tuberculosis, regardless of symptoms, is warranted for early detection.

Using biopsy to detect prostate cancer.

Abstract: Transrectal ultrasound-guided systemic biopsy is the recommended method in most cases with suspicion of prostate cancer. Transrectal periprostatic injection with a local anesthetic may be offered as effective analgesia; periprostatic nerve block with 1% or 2% lidocaine is the recommended form of pain control. On initial biopsy, a minimum of 10 systemic, laterally directed cores is recommended, with more cores in larger glands. Extended prostate biopsy schemes, which require cores weighted more laterally at the base (lateral horn) and medially to the apex, show better cancer detection rates without increasing adverse events. Transition zone biopsies are not recommended in the first set of biopsies, owing to low detection rates. One set of repeat biopsies is warranted in cases with persistent indication. Saturation biopsy (>/=20 cores) should be reserved for repeat biopsy in patients who have negative results on initial biopsy but who are still strongly suspected to have prostate cancer.

Androgen deprivation therapy.

Abstract: In the past decade, androgen deprivation therapy (ADT) has been increasingly used in earlier stages of prostate cancer, despite the presence of mature data from large-scale randomized trials suggesting no survival advantage from earlier intervention. ADT remains a palliative treatment with minimal effect on survival, with almost all patients dying from prostate cancer having hormone-refractory prostate cancer with castrate levels of testosterone.

Critical Evaluation of Urinary Markers for Bladder Cancer Detection and Monitoring

Abstract: Bladder cancer is currently diagnosed using cystoscopy and cytology in patients with suspicious signs and symptoms. These tests are also used to monitor patients with a history of bladder cancer. The recurrence rate for bladder cancer is high, thus necessitating long-term follow-up. Urine cytology has high specificity but low sensitivity for low-grade bladder tumors. Recently, multiple noninvasive urine-based bladder cancer tests have been developed. Although several markers have been approved by the US Food and Drug Administration for bladder cancer surveillance, only a few are approved for detection of bladder cancer in high-risk patients.

Nutraceuticals in Prostate Disease: The Urologist's Role.

Abstract: Interest in and use of complementary and alternative therapies, especially nutraceuticals, is high in prostate disease. These therapies have shown potential in benign prostatic hyperplasia (BPH), prostatitis, and prostate cancer. Some have produced results equal to or better than pharmaceuticals currently prescribed for BPH. In category III prostatitis, some nutraceuticals may offer relief to patients who get little from standard therapy. Because it is becoming apparent that inflammation may play a role in the progression of BPH and development of prostate cancer, nutraceuticals, which commonly have anti-inflammatory properties, may play a role. These therapies have also shown potential in prostate cancer treatment and prevention, especially those that also reduce cardiovascular events or risk. Nevertheless, uses of some nutraceuticals in prostate disease have had less desirable consequences, showing lack of efficacy, adulteration, and/or severe side effects or drug interactions. By ensuring that these therapies undergo careful study for effectiveness, quality, and safety, urologists can look forward to adding them to their evidence-based armamentarium for prostate disease.

Current Medical Therapies for Men With Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia: Achievements and Limitations

Abstract: Over the last 20 years, our understanding of the pathophysiology and symptomatology of men with lower urinary tract symptoms (LUTS) has become increasingly more sophisticated. With this increase in sophistication, our utilization of various medical therapies, either alone or in combination, has also increased the understanding of the roles of individual medications, combinations of medications, and the benefits of different types of intervention. The rapid decline of the use of transurethral resection of the prostate (TURP) and other surgical procedures for benign prostatic hyperplasia (BPH) in the 1990s is due in part to the introduction of medical therapy. This article reviews the current state of medical therapy for men with LUTS and highlights its promises and its current limitations.

Prostate Cancer Specificity of PCA3 Gene Testing: Examples from Clinical Practice

Abstract: A specific marker for early prostate cancer would fill an important void. In initial evaluations of the prostate cancer antigen 3 (PCA3) gene vis-a-vis serum prostate-specific antigen (PSA) levels, the gene offers great promise. At the cellular level, PCA3 specificity for cancer is nearly perfect because of the gross overexpression of the gene by cancer cells. As a clinical test for early prostate cancer, heightened specificity is also seen in urine containing prostate cells from men with the disease. PCA3 gene testing holds valuable potential in PSA quandary situations: (1) men with elevated PSA levels but no cancer on initial biopsy; (2) men found to have cancer despite normal levels of PSA; (3) men with PSA elevations associated with varying degrees of prostatitis; and (4) men undergoing active surveillance for presumed microfocal disease.

Overactive bladder: pharmacologic treatments in the neurogenic population.

Abstract: Patients with neurologic disease commonly develop overactive bladder (OAB) symptoms of urgency, frequency, and/or urge incontinence. Although treatment for idiopathic OAB has been extensively studied, therapy for those individuals with neurogenic-mediated OAB has not been thoroughly evaluated. Included in the present article is a description of micturition neurophysiology and a neurourologic evaluation scheme. The pharmacologic treatment options for neurogenic OAB, mainly antimuscarinics and chemical denervation, are reviewed and important studies are discussed. Management of OAB in the neurogenic population is a complex issue with no uniform treatment strategy, and individualized treatment with first-line pharmacologic therapy is often recommended.

Clinical utility of prostate carcinoma molecular diagnostic tests.

Abstract: Instead of relying on serum prostate-specific antigen (PSA) to identify patients for prostate biopsy, new laboratory tests are needed that have improved specificity for prostate carcinoma (CaP), allow accurate classification of clinically insignificant CaPs, allow for detection of clinically significant CaP in patients without elevated serum PSA, and allow for identification of aggressive forms of CaP, which may warrant adjunctive or even molecularly targeted therapy in the future. Over the last several years, high-throughput gene expression profiling and proteinomics have led to the identification of genes and proteins that are specifically overexpressed in CaP. Molecular diagnostic techniques readily translated to the clinical laboratory have been incorporated into the development of new tests based on these novel molecular alterations in CaP. Some of these tests already have well-documented clinical utility, such as in facilitating prostate biopsy decisions, and are routinely available. The current review focuses on the biological, clinical, and laboratory aspects of the most promising of these current and near-future molecular CaP tests.

Vascular Targeted Photodynamic Therapy for Localized Prostate Cancer

Abstract: Survival for men diagnosed with prostate cancer directly depends on the stage and grade of the disease at diagnosis. Prostate cancer screening has greatly increased the ability to diagnose small and low-grade cancers that are amenable to cure. However, widespread prostate-specific antigen screening exposes many men with low-risk cancers to unnecessary complications associated with treatment for localized disease without any survival advantage. One challenge for urological surgeons is to develop effective treatment options for low-risk disease that are associated with fewer complications. Minimally invasive ablative treatments for localized prostate cancer are under development and may represent a preferred option for men with low-risk disease who want to balance the risks and benefits of treatment. Vascular targeted photodynamic therapy (VTP) is a novel technique that is being developed for treating prostate cancer. Recent advances in photodynamic therapy have led to the development of photosynthesizers that are retained by the vascular system, which provides the opportunity to selectively ablate the prostate with minimal collateral damage to other structures. The rapid clearance of these new agents negates the need to avoid exposure to sunlight for long periods. Presented herein are the rationale and preliminary data for VTP for localized prostate cancer.

Use of a Vacuum-Assisted Device for Fournier's Gangrene: A New Paradigm.

Abstract: Fournier's gangrene is a necrotizing infection of the scrotum or perineum that requires aggressive surgical debridement. Radical debridement of perineal necrotizing fasciitis can leave extensive tissue defects that are difficult to close and often require multiple surgical interventions. Vacuum-assisted closure (VAC) devices have been shown to assist in a more rapid closure of these wounds, but placement of such devices in the perineum can pose significant challenges. We have had success with use of VAC devices and report our techniques for their placement.

Maximizing the treatment of overactive bladder in the elderly.

Abstract: Overactive bladder syndrome affects millions of elderly people in the United States and is equally prevalent in men and women. Its impact on quality of life can be devastating, especially to elderly patients with other medical comorbidities. In order to maximize care, health care providers must be able to make the correct diagnosis and have a working knowledge of available therapies. Data exist supporting the efficacy and safety of nonpharmacologic and pharmacologic therapies.

Shock wave lithotripsy and renal hemorrhage.

Abstract: Although shock wave lithotripsy is a safe and efficacious treatment for nephrolithiasis, the most common acute complication is renal hemorrhage. Shock wave-induced renal hemorrhage is a potentially devastating injury if not promptly recognized and treated appropriately. The authors report a large perirenal hematoma occurring after shock wave lithotripsy and review the causes, prevention, and treatment of shock wave-induced renal hemorrhage.

Bacillus Calmette-Guérin Failures and Beyond: Contemporary Management of Non-Muscle-Invasive Bladder Cancer

Abstract: In the United States, bacillus Calmette-Guerin (BCG) is the treatment most used for superficial bladder cancer. Patients with carcinoma in situ (CIS) treated with intravesical BCG plus interferon have a 60% to 70% chance of a complete and durable response if they were never treated with BCG or if they failed only 1 prior induction or relapsed more than a year from induction. Intravesical gemcitabine is safe, but its usefulness for BCG-refractory patients is unclear. Valrubicin, approved for intravesical treatment of BCG-refractory CIS of the bladder, has efficacy and acceptable toxicity. Cystectomy should be considered in high-risk, non-muscle-invasive cancer, particularly if intravesical therapy failed.

Leydig cell hyperplasia revealed by gynecomastia.

Abstract: Leydig cell tumors are rare and represent 1% to 3% of all tumors of the testis. Leydig cell tumors affect males at any age, but there are 2 peak periods of incidence: between 5 and 10 years and between 25 and 35 years. Their main clinical presentation is a testicular mass associated with endocrinal manifestations that are variable according to age and appearance of the tumor. Our patient, a 17-year-old adolescent, presented with an isolated and painless hypertrophy of the right mammary gland. Clinical examination found gynecomastia and no testicular mass. Hormonal levels and tumor markers were normal. Testicular sonography showed an ovular and homogeneous right intratesticular mass 6 mm in diameter. We treated the patient with an inguinal right orchidectomy. The anatomopathological study found a nodule of Leydig cell hyperplasia. The patient recovered without recurrence at 8-month follow-up. The patient opted for mammoplasty 2 months after his orchidectomy rather than wait for the spontaneous gradual regression of his gynecomastia, which requires at least 1 year. Leydig cell hyperplasia manifests in the adult by signs of hypogonadism, most frequently gynecomastia. Although many teams prefer total orchidectomy because of the diagnostic difficulty associated with malignant forms, simple subcapsular orchidectomy should become the first-line treatment, provided it be subsequently followed by close surveillance, as it preserves maximum fertility, and these tumors usually resolve favorably.

Hypercalcemic States Associated With Nephrolithiasis

Abstract: Although kidney stone formation due to hypercalcemic states is rare, it is important for urologists to understand the pathophysiology of these conditions, methods of diagnosis, and treatments. This should foster a quicker diagnosis and institution of appropriate therapy. The latter typically leads to the attenuation of kidney stone activity. Moreover, these patients have a systemic disease, and therapy has other health benefits.

Concomitant medications and possible side effects of antimuscarinic agents.

Abstract: Antimuscarinic agents are the treatment of choice for overactive bladder syndrome; clinical experience and the literature support their efficacy, tolerability, and safety. The most common side effects experienced include dry mouth and constipation. Many commonly prescribed drugs have anticholinergic effects that could increase the anticholinergic “load” or “burden” in patients with overactive bladder, potentially increasing the frequency and severity of side effects. In addition, the adverse events associated with antimuscarinics may be more pronounced in the elderly, especially those taking multiple medications. Knowledge regarding the potential side effects associated with antimuscarinics is important so that patients can be advised and effectively treated.

Managing bone loss and bone metastases in prostate cancer patients: a focus on bisphosphonate therapy.

Abstract: Androgen deprivation therapy (ADT) and bone metastases are the most important risk factors for developing skeletal complications (eg, bone loss, pathologic fractures) in prostate cancer (PC) patients with locally advanced and metastatic disease. Bisphosphonates, which inhibit excessive osteoclast activity caused by ADT and bone metastases, have proven to be safe and effective in preventing skeletal complications and presently are the standard of care in patients with metastatic disease. Bisphosphonates should be considered for use in all PC patients with locally advanced disease initiating ADT for an intended duration of at least 1 year, especially those with a low baseline bone mineral density.

Impact of phosphodiesterase type 5 inhibitors on endothelial function.

Abstract: It is now known that endothelial health is essential for normal erectile function, and changes in endothelial integrity or function may lead to erectile dysfunction (ED) Because phosphodiesterase type 5 (PDE-5) inhibitors have been shown to improve endothelial function, many investigators have questioned whether PDE-5 inhibition will lead to improvement in erectile function Data from the studies reviewed in this article show that therapy with PDE-5 inhibitors results in improvement in flow-mediated dilation, nocturnal penile tumescence and rigidity, and carotid artery intima-media thickness as well as higher scores on the Sexual Health Inventory for Men, International Index of Erectile Function, Erection Function Domain, and other instruments Further research is needed to determine whether long-term PDE-5 inhibition can reverse ED and whether use of these agents will decrease cardiovascular morbidity in high-risk populations

Management of localized prostate cancer and an incidental ureteral duplication with upper pole ectopic ureter inserting into the prostatic urethra.

Abstract: Ectopic ureters are rare congenital malformations of the renal system that most commonly present in females. It is extremely rare to encounter an ectopic ureter in an older man undergoing radical prostatectomy. We report herein a case of a 66-year-old man with prostate cancer and a complete duplication of the left renal collecting system, with an upper pole ectopic ureter and associated normal functioning renal parenchyma entering into the prostatic urethra. This anomaly was incidentally discovered on preoperative magnetic resonance imaging of the prostate. Open radical retropubic prostatectomy and a left ureteroureterostomy were performed.

Renewing intimacy: advances in treating erectile dysfunction postprostatectomy.

Abstract: Erectile dysfunction following prostatectomy is almost universal Herbert Lepor, MD, Professor and Martin Spatz Chairperson of Urology and Professor of Pharmacology at New York University School of Medicine and cofounder of Reviews in Urology; Andrew McCullough, MD, Director of the Sexual Health and Male Fertility and Microsurgery Programs at New York University School of Medicine; and Jason D Engel, MD, Vice Chairman of Urology and Director of Urologic Robotic Surgery at George Washington University Hospital, discuss treatment options for erectile dysfunction postprostatectomy

The QT Interval and Selection of Alpha-Blockers for Benign Prostatic Hyperplasia.

Abstract: The QT interval is the electrocardiographic manifestation of ventricular depolarization and repolarization. Drug-induced long QT syndrome is characterized by acquired, corrected QT (QTc) interval prolongation that is associated with increased risk of torsade de pointes. Every physician must recognize if the drugs he or she prescribes prolongs the QTc interval, especially if the drug is prescribed for a chronic condition in older patients who are on polypharmacy. The evolution of alpha-blockers for the treatment of benign prostatic hyperplasia has allowed the development of drugs that are easier to administer and better tolerated. Because alpha-blockers generally have equivalent efficacy, this class of drugs is typically differentiated by safety and side effects. Studies suggest that alpha-blockers may vary in regard to their effect on the QT interval, and, therefore, on their predisposition to cause potentially life-threatening ventricular arrhythmias.

Chronic prostatitis/chronic pelvic pain syndrome: finding a way forward in the United kingdom: report from the first United kingdom symposium on chronic prostatitis, january 30, 2008, london, United kingdom.

Abstract: Chronic prostatitis or chronic pelvic pain syndrome (CP/CPPS) is a painful, prevalent, and economically important condition. Despite recent advances it remains the least understood of the 3 prostate-related conditions (the other 2 being benign prostatic hyperplasia and prostate cancer). Over the last 2 decades the majority of research in the field has come from North America (the United States and Canada) and, more recently, some areas in Asia and Europe. The level of awareness among health-care professionals and the public mirrors the research activity. In contrast, there is a dearth of CP/CPPS research in the United Kingdom, few specialists with an interest in the condition, and a lack of awareness among doctors and the public alike. This interactive symposium sought to address these issues by bringing together experts in various disciplines. This article highlights some of the findings from that meeting.

The multidisciplinary approach to defining the urologic chronic pelvic pain syndromes: report from a national institutes of health workshop, december 13-14, 2007, Baltimore, MD.

Abstract: Interstitial cystitis and chronic prostatitis remain clinical enigmas, partly because the conditions are so ill-defined, partly because they overlap so much with each other and other local and systemic pain syndromes, and partly because our management strategies are rather poor. Recently, the condition traditionally identified as interstitial cystitis has become known as interstitial cystitis/painful bladder syndrome (IC/PBS), painful bladder syndrome, and/or bladder pain syndrome, whereas chronic nonbacterial prostatitis syndromes have become known as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) or simply chronic pelvic pain syndrome. The overall purpose of the National Institutes of Health (NIH) Urologic Chronic Pelvic Pain Workshop was to begin to redefine these 2 major urologic pelvic pain syndromes in the context of the other major syndromes with which they are commonly associated (eg, fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome). The specific aims of the workshop were to discuss disease definitions and diagnostic protocols of these major chronic pelvic pain disorders, discuss the interrelationships among these disorders, and identify common symptomatology and diagnostic assessment to ensure complete evaluation of all relevant comorbidities. Finally, it was hoped that the workshop would lead to development of a diagnostic algorithm that could be tested in a “pilot” study. The participants included a planning committee, a designated advisory panel, and interested researchers, clinicians, patients, and other stakeholders. The following is a brief synopsis of the discussion.

Is behavioral therapy plus antimuscarinic better than drug alone to treat overactive bladder

Abstract: Urinary incontinence affects more than 10 million Americans and accounts for billions of dollars annually in societal costs. Antimuscarinics and behavioral treatments are both safe and effective first-line treatments for urge incontinence. Most patients do not achieve complete continence with either therapy alone. Adding behavioral training to pharmacologic treatment is an appealing approach to improving outcomes and to possible discontinuation of drug therapy. Evidence for the efficacy of combination therapy over either treatment alone is scarce and inconclusive. Here we review 3 new journal articles that examine this controversy from different perspectives.

Single nucleotide polymorphisms and prostate cancer susceptibility.

Abstract: According to twin studies, heritable factors account for a substantial fraction of prostate cancer risk.1 Until recently, linkage studies were primarily used to identify gene mutations that cosegregate in prostate cancer families. A notable example is the HPC1 gene on chromosome 1q24-25.2 Unfortunately, such gene mutations account for a small minority of familial prostate cancer cases, so investigation has continued for more prevalent genetic variants. The development of genome-wide association studies has facilitated the search for more common genetic variants. Indeed, numerous single nucleotide polymorphisms (SNPs) have recently been identified that might play an aggregate role in prostate cancer susceptibility. Two articles from the literature highlight these exciting new developments in the field of prostate cancer genetics.

Best of the 2008 AUA Annual Meeting: Highlights from the 2008 Annual Meeting of the American Urological Association, May 17-22, 2008, Orlando, FL.

Abstract: A record number of submissions led to the acceptance of 1965 abstracts for the 2007 annual meeting of the American Urological Association (AUA), up from 1725 last year. The meeting, held in Anaheim, CA, attracted nearly 8800 urologists and other health care professionals, 54% of them from outside the United States. Press, exhibitors, family, guests, and staff pushed total attendance to just over 15,000. The editors of Reviews in Urology have culled the enormous volume of information from this premier source and present here the findings most relevant to the practicing urologist. Additional highlights will be published in the next issue of Reviews in Urology.

New treatments for castration-resistant prostate cancer: highlights from the 44th annual meeting of the american society of clinical oncology, may 30-june 3, 2008, chicago, IL.

Abstract: Most of us were taught in medical school that prostate cancer was exquisitely dependent on circulating androgens and that castration, whether surgical or medical, resulted in significant decrease in tumor mass, associated pain in the setting of metastatic disease, and reduction in acid phosphates and prostate-specific antigen (PSA). However, we were told, the cancer would inevitably adapt to the androgen- deprived milieu and progress. Socalled androgen-independent (androgenresistant) prostate cancer (now more often referred to as castration-resistant prostate cancer [CRPC]) was the reason that prostate cancer represents the second most common cause of cancer mortality. We should have questioned this concept more vigorously. Certainly there were clues that the role of androgens in prostate cancer was not “all or none.” We know, for example, that once a man had progressed to the socalled androgen-independent state, cessation of castration (made possible with diethylstilbestrol but more completely with the advent of luteinizing hormone-releasing hormone agonists) most often resulted in more rapid tumor progression. Even before this we had learned from pioneering studies by Willett Whitmore at Memorial Sloan- Kettering Cancer Center that giving testosterone to men previously castrated in an attempt to improve cytotoxic chemotherapeutic response was disastrous, with severe exacerbation of the tumor and patient death. Recently many of these concepts have been disproved. There is evidence to suggest that although castration removes the gonadal testosterone in prostate cancer, androgens originating from other sources, including the adrenal gland and, intriguingly, the prostate cancer itself, may continue to act as a ligand and result in androgen receptor signaling. Recent studies have demonstrated high levels of androgens in CRPC tumor, with ongoing androgen receptor stimulation. This intracrine effect results in the tumor being better able to survive and progress in the castrate setting. Two companies are conducting clinical trials of agents that affect the intratumor androgen effect, and salient findings were presented at the 44th Annual Meeting of the American Society of Clinical Oncology held in Chicago, IL. Cougar Biotechnology (Los Angeles, CA) is developing abiraterone. This novel molecule affects CRPC by targeting an enzyme that catalyzes 2 key steroid reactions involving 17α-hydroxylase and C(17,20)- lyase—critical enzymes in the testosterone synthesis pathway. This is the same target of ketoconazole. De Bono and associates1 described a phase I/II investigation with abiraterone in chemotherapy-naive CRPC patients and a phase II trial in men who progressed while receiving docetaxel. In the phase I study, daily oral doses of 250 to 2000 mg abiraterone were well tolerated. Toxicity owing to increased mineralocorticoid production (hypertension, hypokalemia, fluid retention) was corrected by use of eplerenone or low-dose corticosteroids. A dose of 1000 mg was selected for the phase II component. Among 44 men who had not received chemotherapy (70% of whom had bone metastases), more than 60% had PSA reduction of greater than 50%. Among 21 of these patients who had measurable disease, partial response was seen in 12. The median time to PSA progression was 252 days. Among 28 men who had received docetaxel, 40% had a nadir PSA value less than 50% of baseline. Eighteen had evaluable metastases, and 4 had a partial response. Time to PSA progression was 167 days. In both groups there was symptomatic improvement, reduction in analgesic requirements, and decrease in circulating tumor cells. This latter finding may offer a unique marker for response in CRPC, as was described by Attard and colleagues.2 The fact that ketoconazole targets the same enzyme as abiraterone stimulated an investigation of the efficacy of the latter in patients who had received the antifungal agent. In a phase I trial, Ryan and colleagues3 compared men with CRPC who did and did not receive ketoconazole with abiraterone at daily doses of 250 to 1000 mg. At the time of the presentation data from 33 men were available; 55% had a more than 50% PSA decrease. Among the 14 men who had not received ketoconazole, 61% responded, as compared with 53% of those who had been treated with ketoconazole. Importantly, of the 15 men who discontinued ketoconazole owing to progression as opposed to toxicity, 7 had a more than 50% PSA nadir. The investigators concluded that despite similar targets, a significant number of patients previously treated with ketoconazole will respond to abiraterone. Medivation (San Francisco, CA) is developing MDV3100. This agent is a novel small molecule that acts as an androgen receptor blocker. It was specifically selected to avoid the resistance seen in conventional antiandrogens (flutamide, bicalutamide). It blocks nuclear translocation. Scher and colleagues4 reported the first experience with MDV3100 in men. In this phase I/II dose-escalation study, MDV3100 was administered orally daily beginning with a 30-mg dose in men with progressive CRPC. Scher and colleagues reported on 39 patients treated in this ongoing trial. The agent was well tolerated, with no significant adverse events. In the lowest-dose cohort, 3 of 3 patients had PSA declines between 44% and 87% with follow-up of more than 19 weeks. In the 60-mg cohort, PSA decreased between 74% and 96% in the 3 men with follow-up of 14 or more weeks. No patents demonstrated progression either clinically or with imaging. Additional patients are receiving 150 mg and 240 mg daily. The investigators conclude that MDV3100 resulted in significant PSA reduction in a high proportion of patients and was well tolerated. These two agents are certainly promising. Other molecules are in development to address CRPC, also targeting intratumor androgen activity. Tokai Pharmaceuticals (Cambridge, MA) is developing TOK-001. This molecule, like abiraterone, inhibits the cytochrome P450c17 step in androgen synthesis. Moreover, it is a potent blocker of the androgen receptor and has actually decreased the amount of androgen receptor. Thus, this agent potentially inhibits 3 critical pathways for androgen activity in CRPC. TOK-001 is anticipated to enter clinical trials in 2009. Despite considerable effort by researchers and the pharmaceutical industry, we have seen little real progress in the management of CRPC. Our reassessment of the ongoing role of androgens after castration has resulted in the development of several intriguing molecules, which we hope will result in new approaches to treating this difficult disease. Main Points There is evidence to suggest that although castration removes the gonadal testosterone in prostate cancer, androgens originating from other sources, including the adrenal gland and, intriguingly, the prostate cancer itself, may continue to act as a ligand and result in androgen receptor signaling. Two companies are conducting clinical trials of agents that affect the intratumor androgen effect: Cougar Biotechnology is developing abiraterone, and Medivation is developing MDV3100. In a phase I/II study of abiraterone, daily oral doses of 250 to 2000 mg were well tolerated; a dose of 1000 mg was selected for the phase II component. Among 44 men who had not received chemotherapy (70% of whom had bone metastases), more than 60% had a reduction in prostate-specific antigen (PSA) of more than 50%. In a phase II study of abiraterone among 28 men who had received docetaxel, 40% had a nadir PSA value less than 50% of baseline. In a phase I/II dose-escalation study, MDV3100 was administered orally daily beginning with a 30-mg dose in men with progressive castration-resistant prostate cancer. In 39 patients treated in this ongoing trial, the agent was well tolerated, with no significant adverse events. In the lowest-dose cohort, 3 of 3 patients had PSA declines between 44% and 87% with follow-up of more than 19 weeks. In the 60-mg cohort, PSA decreased between 74% and 96% in the 3 men with follow-up of 14 or more weeks. No patients demonstrated progression either clinically or with imaging.