Prostate Cancer

Nocturia continued desmopressin’s safety in this group of healthy Norwegians would translate to the ethically diverse US elderly population, with its multiple medical problems. In addition, acceptable sodium levels after 3 days of treatment does not guarantee that the drug is safe after 1 month or 1 year of administration. Several of my patients have presented to the emergency department with confusion and were subsequently found to have sodium levels less than 125 mmol/L after taking stable does of desmopressin for weeks to months. Overall, I believe that desmopressin is a safe and effective drug, and I have had success with this treatment in adult neurogenic bladder patients. However, use of desmopressin in the elderly, even if apparently healthy, should be initiated with considerable caution. Erectile Function The Effects of Phosphodiesterase-5 Inhibitors in Men With “Normal” Erectile Function mean age of 33 years in the sildenafil group (n = 30) and 31 years in the placebo group (n = 30). The International Index of Erectile Function (IIEF) score was 26 or greater at baseline for all subjects in both groups. Patients received sildenafil, 25 mg, or placebo and recorded their posttreatment IIEF score and refractory time to obtaining a second erection. Study results demonstrated no difference in erectile function between the subjects who received sildenafil and those who received placebo. However, the subjects who received sildenafil recorded a lower refractory time than those who received placebo (P < .04). A criticism of this study is that the subjects received only 1 pill, so that outcome measures were made after only 1 trial. Nevertheless, this study suggests that sildenafil will not make a normal man supernormal in terms of his erection but may reduce the refractory time in young men. Whether it is appropriate for a physician to treat a patient with the goal of improving latency time is debatable. References 1. 2. Rochira V, Granata AR, Balestrieri A, et al. Effects of sildenafil on nocturnal penile tumescence and rigidity in normal men: randomized, placebo-controlled, crossover study. J Androl. 2002;23:566-571. Rajfer J. Prescribing PDE5 inhibitors: who is the “normal” man? Rev Urol. 2002;4:197-198. Reviewed by Jacob Rajfer, MD Department of Urology, David Geffen School of Medicine at UCLA; Division of Urology, Harbor-UCLA Medical Center, Los Angeles, CA [Rev Urol. 2004;6(1):44] © 2004 MedReviews, LLC A common belief among the lay population is that oral phosphodiesterase-5 inhibitors will make a “normal” man become “supernormal” regarding his erectile capabilities. Two studies on this topic have been published, both of which have emanated from Italy. In the first study,1 which was reviewed in a previous issue of Reviews in Urology,2 investigators concluded that sildenafil (50 mg) improved erections in normal men. However, the average age of study subjects was 39 years, an age that impotence experts would most likely not equate with “normal” erectile capabilities. Sildenafil Does not Improve Sexual Function in Men Without Erectile Dysfunction but Does Reduce the Postorgasmic Refractory Time Mondaini N, Ponchietti R, Muir GH, et al. Int J Impot Res. 2003;15:225-228. In the second study, by Mondaini and colleagues, the investigators lowered the threshold of normal age to a 44 VOL. 6 NO. 1 2004 REVIEWS IN UROLOGY Prostate Cancer Tissue Microarrays in Prostate Cancer Research Reviewed by Masood A. Khan, MD, Alan W. Partin, MD, PhD The Johns Hopkins Hospital, Baltimore, MD [Rev Urol. 2004;6(1):44-46] © 2004 MedReviews, LLC he high-density tissue microarray (TMA) was developed by Kononen and colleagues1 for the purpose of rapidly analyzing a large number of samples with either in situ or immunohistochemical methods on a single slide. The technique involves taking core tissue biopsies (diameter, 0.6 mm; height, 3-4 mm) from individual “donor" paraffin-embedded tumor blocks and arraying them in a new “recipient" paraffin block (45  20 mm) using a custom-built instrument. Using 0.6-mm cores while preserving the histologic information allows as many as 1000 specimens to be arrayed in a single recipient T Prostate Cancer block (single slide) with minimal damage to the original tissue blocks. Up to 200 consecutive tissue sections (4-8 m) can be cut onto individual slides from each block array. Serial sectioning of the blocks allows rapid, parallel analyses of the arrayed tumor punches by several methods, including immunohistochemistry, fluorescence in situ hybridization, and RNA/RNA in situ hybridization. The major advantage of TMA is that analysis of tumors from many different patients with different stages of disease can be performed simultaneously. This not only saves The major advantage of TMA is that analysis of tumors from many different patients with different stages of disease can be performed simultaneously. considerable time but also dramatically reduces expenditure and improves intra-sample testing reliability. However, the major drawback of this technique is that, because of the small punch size, TMAs may not demonstrate tumor heterogeneity, which can commonly be estimated in whole section mounts. Therefore, the choice of the tumor area is pivotal and, in the case of widely heterogeneous tumor, numerous punches may be necessary. The following studies report on the use and limitations of TMAs in prostate cancer research. Tissue Microarray Sampling Strategy for Prostate Cancer Biomarker Analysis Rubin MA, Dunn R, Strawderman M, et al. Am J Surg Pathol. 2002;26:312-319. Because prostate cancer is a heterogeneous tumor, the use of TMAs for clinical biomarker studies may be of limited value. However, in an attempt to overcome this disadvantage, the authors investigated the optimal TMA sampling size needed to accurately identify prostate cancer biomarkers. To this end, prostate cancer proliferation as determined by Ki-67 immunohistochemistry was studied. (Ki-67 is a nuclear protein that is expressed in G1, S, G2, and M phases of the cell cycle but not in the G0 phase [at rest].2) Ten replicate measurements of proliferation using digital image analysis were made on 10 regions of prostate cancer from a standard glass slide. Five matching TMA sample cores were tested from each of the 10 regions in the parallel study. A bootstrap resampling analysis was used to statistically simulate all possible permutations of TMA sample number per region or sample. Statistical analysis compared TMA samples with Ki-67 expression in standard pathology immunohistochemistry slides. The optimal sampling for TMA cores was reached at 3, as fewer samples significantly increased Ki-67 variability and a larger number did not significantly improve accuracy. To validate these results, a prostate cancer outcomes TMA containing 10 replicate tumor samples from 88 cases was constructed. Similar to the initial study, 1 to 10 randomly selected cores were used to evaluate the Ki-67 expression for each case, computing the ninetieth percentile of the expression from all samples used in each model. Using this value, a Cox proportional hazards analysis was performed to determine predictors of time until prostate-specific antigen (PSA) recurrence after radical prostatectomy for clinically localized prostate cancer. Examination of multiple models demonstrated the optimal number of cores to be 4. Using a model with 4 cores, a Cox regression model demonstrated that Ki-67 expression, preoperative PSA, and surgical margin status predicted time to PSA recurrence with hazard ratios of 1.49 (95% confidence interval [CI], 1.01-2.20; P < .05), 2.36 (95% CI, 1.15-4.85; P < .05), and 9.04 (95% CI, 2.42-33.81; P < .01), respectively. Models with 3 cores to determine Ki-67 expression were also found to predict outcome. The authors, therefore, concluded that 3 cores are required to optimally represent Ki-67 expression with respect to the standard tumor slide. Furthermore, 3 to 4 cores provided the optimal predictive value in a prostate cancer outcomes array and should be useful in evaluating other putative prostate cancer biomarkers. Inadequate Formalin Fixation Decreases Reliability of p27 Immunohistochemical Staining: Probing Optimal Fixation Time Using High-Density Tissue Microarrays De Marzo AM, Fedor HH, Gage WR, et al. Hum Pathol. 2002;33:756–760. p27Kip1 is a cyclin-dependent kinase inhibitor that is expressed nearly uniformly in the prostate luminal secretory cells.3 It is downregulated in carcinoma and has been proposed as a potential biomarker of which immunohistochemical detection may be useful in predicting prognosis.3-5 The authors had previously noted that, with standard formalin fixation in rapidly processed (same-day) radical prostatectomy specimens, there was often a gradient of p27Kip1 staining in normal prostate epithelium, with more staining near the periphery and less toward the center (unpublished observations). This observation raised the hypothesis that the reliability of staining for p27Kip1 might be reduced in inadequately fixed tissues. This hypothesis VOL. 6 NO. 1 2004 REVIEWS IN UROLOGY 45 Prostate Cancer continued was tested using 2 TMAs containing 564 tissue samples. Results demonstrated that there was a significant increase in the percent of cores that stained strongly for p27Kip1 as fixation time increased from 0 (same-day processing) to 1 or more days (P < .001). The authors, therefore, concluded demonstrate heterogeneity of the tumor because of the small sample size used. References 1. 2. Brief tissue fixation to decrease diagnostic turnaround time might limit the reliability of interpretation of some forms of immunohistochemical staining. 3. 4. 5. that brief tissue fixation to decrease diagnostic turnaround time might limit the reliability of interpretation of some forms of immunohistochemical staining. In addition, and more importantly, TMAs, which assure identical test conditions, provide an excellent platform for the evaluation of the effects of tissue fixation on immunohistochemical staining. Limitations of Tissue Microarrays in the Evaluation of Focal Alterations of bcl-2 and p53 in Whole Mount Derived Prostate Tissues Merseburger AS, Kuczyk MA, Serth J, et al. Oncol Rep. 2003;10:223–228. Several investigators have reported the correlation of p53 and bcl-2 immunoreactivity with postoperative PSA recurrence.6-8 Focal and/or clustered expression is typical for these biomarkers. The purpose of this study was to compare the effectiveness of TMAs to detect p53 and bcl-2 overexpression and their prognostic significance. TMAs of 99 patients, with a mean follow-up of 61 months, contained 760 samples from 241 carcinomas, 431 benign glands, and 88 foci of prostatic intraepithelial neoplasia (PIN). Through the use of TMA technology, overexpression of p53 and bcl-2 was detected in 43.3% and 23.7% of the patients, respectively, compared with 66.0% and 26.9% in the corresponding radical prostatectomy samples. Therefore, although TMA is regarded as a powerful tool to study the multifocal and heterogeneous nature of prostate cancer, the prognostic value of p53 and bcl-2 could not be confirmed using this technology in contrast to radical prostatectomy sections. To this end, TMA is probably more informative and reliable in evaluating the prognostic value of homogeneously expressed biomarkers. In conclusion, TMAs have a great advantage in that numerous tissues can be investigated at the same time, which not only reduces time and cost but also assures identical test conditions for all the samples. However, the limitation of TMAs appears to be their relative inability to 46 VOL. 6 NO. 1 2004 REVIEWS IN UROLOGY 6. 7. 8. Kononen J, Bubendorf L, Kallioniemi A, et al. Tissue microarrays for highthroughput molecular profiling of tumor specimens. Nat Med. 1998;4:844-847. Gerdes J, Lemke H, Baisch H, et al. Cell cycle analysis of a cell proliferationassociated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984;133:1710-1715. Guo Y, Sklar GN, Borkowski A, Kyprianou N. Loss of the cyclin-dependent kinase inhibitor p27(Kip1) protein in human prostate cancer correlates with tumor grade. Clin Cancer Res. 1997;3(12 pt 1):2269-2274. Yang RM, Naitoh J, Murphy M, et al. Low p27 expression predicts poor diseasefree survival in patients with prostate cancer. J Urol. 1998;159:941-945. Cote RJ, Shi Y, Groshen S, et al. Association of p27Kip1 levels with recurrence and survival in patients with stage C prostate carcinoma. J Natl Cancer Inst. 1998;90:916-920. Oxley JD, Winkler MH, Parry K, et al. p53 and bcl-2 immunohistochemistry in preoperative biopsies as predictors of biochemical recurrence after radical prostatectomy. BJU Int. 2002;89:27-32. Cesinaro AM, Migaldi M, Ferrari G, et al. Expression of p53 and bcl-2 in clinically localized prostate cancer before and after neo-adjuvant hormonal therapy. Oncol Res. 2000;12:43-49. Stackhouse GB, Sesterhenn IA, Bauer JJ, et al. p53 and bcl-2 immunohistochemistry in pretreatment prostate needle biopsies to predict recurrence of prostate cancer after radical prostatectomy. J Urol. 1999;162:2040-2045. Vasectomy and Prostate Cancer Reviewed by Masood A. Khan, MD, Alan W. Partin, MD, PhD The Johns Hopkins Hospital, Baltimore, MD [Rev Urol. 2004;6(1):46-47] © 2004 MedReviews, LLC asectomy is the most frequently used form of male contraception in the United States, with approximately 500,000 procedures performed annually.1 However, several case-control and cohort studies conducted over the past decade have demonstrated conflicting results regarding the possible association between vasectomy and prostate cancer risk.2-5 This has raised considerable concern, not only among men undergoing vasectomy but also among urologists performing the procedure. Many urologists now screen for prostate cancer early in men who have had a vasectomy and even discourage vasectomy in men with a strong family history of prostate cancer.6 The following study further investigated the possible association between vasectomy and prostate cancer in New Zealand, which has the highest prevalence of vasectomy in the world.7 V Vasectomy and Risk of Prostate Cancer Cox B, Sneyd MJ, Paul C, et al. JAMA. 2002;287:3110-3115. The authors conducted a national population-based casecontrol study of 923 new cases of prostate cancer among Prostate Cancer men aged 40 to 74 years from the New Zealand Cancer Registry who were on the general electoral roll. The control group (n = 1224) was randomly selected from the general electoral roll and matched in 5-year age groups. The primary study outcome was the relative risk (RR) of prostate cancer for men who had vasectomies compared with controls. Mean ages for the cases and controls were 66 and 65 years, respectively. All cases and controls were contacted via telephone by interviewers who were blinded to the subject group and who collected information regarding previous illnesses, urologic symptoms and surgical procedures, smoking and alcohol consumption, prostate-specific Results demonstrated no association between prostate cancer and vasectomy or time since vasectomy. antigen testing, digital rectal examination, family history of cancer, sociodemographic characteristics, and history of vasectomy. Results demonstrated no association between prostate cancer and vasectomy (RR, 0.92; 95% confidence interval [CI], 0.71-1.14) or time since vasectomy (RR, 0.92; 95% CI, 0.68-1.23 for ≥25 years since vasectomy). Furthermore, adjustment for social class, geographic region, religious affiliation, and family history of prostate cancer did not affect the RRs. The authors concluded that vasectomy does not increase the risk of prostate cancer, even at 25 years post-procedure or longer. Despite the fact that nearly all subjects (97%) were of European descent and, as such, the results may not apply to other ethnic groups, this study provides strong evidence to exclude an association between vasectomy and prostate cancer. To this end, men undergoing vasectomy can be reassured that they will not incur an increased risk of developing prostate cancer. References 1. 2. 3. 4. 5. 6. 7. Chacko JA, Zafar MB, McCallum SW, Terris MK. Vasectomy and prostate cancer characteristics of patients referred for prostate biopsy. J Urol. 2002;168(4 pt 1):1408-1411. Rosenberg L, Palmer JR, Zauber AG, et al. Vasectomy and the risk of prostate cancer. Am J Epidemiol. 1990;132:1051-1055. Giovannucci E, Tosteson TD, Speizer FE, et al. A retrospective cohort study of vasectomy and prostate cancer in US men. JAMA. 1993;269:878-882. John EM, Whittemore AS, Wu AH, et al. Vasectomy and prostate cancer: results from a multiethnic case-control study. J Natl Cancer Inst. 1995;87:662-669. Zhu K, Stanford JL, Daling JR, et al. Vasectomy and prostate cancer: a case-control study in a health maintenance organization. Am J Epidemiol. 1996;144:717-722. Sandlow JI, Kreder KJ. A change in practice: current urologic practice in response to reports concerning vasectomy and prostate cancer. Fertil Steril. 1996;66:281-284. Sneyd MJ, Cox B, Paul C, Skegg DC. High prevalence of vasectomy in New Zealand. Contraception. 2001;64:155-159. Endothelin-A Receptor Antagonists and Advanced Prostate Cancer Reviewed by Masood A. Khan, MD, Alan W. Partin, MD, PhD The Johns Hopkins Hospital, Baltimore, MD [Rev Urol. 2004;6(1):47-48] © 2004 MedReviews, LLC he endothelin (ET) family consists of 3 peptides—ET-1, ET-2, and ET-3—each of which is composed of 21 amino acids. ETs are potent paracrine/autocrine factors with diverse activity, including modulation of vasomotor tone, nocioception, hormone production, cell proliferation, apoptosis, and stromal formation in a variety of tissues. These effects are predominantly mediated by the action of ET-1 on 2 G protein–coupled ET receptors: ETA and ETB.1,2 In 1993, ET-1 was shown to be produced by benign prostatic epithelial cells and, subsequently, by prostate cancer cells and to play a role in the pathophysiology of prostate cancer progression.3,4 Within the setting of prostate cancer, there is also an impairment of the ET-1 degradation pathway, resulting in a local increase in the concentration of ET-1.5 Furthermore, the expression of ETA receptors has been shown to be upregulated with prostate cancer tumor stage and grade.6 There are a number of pathways by which the ET-1/ETA axis may promote prostate cancer progression.4,7,8 ET-1 is mitogenic for prostate cancer cell lines in vitro and acts synergistically with other peptide growth factors.7 ET-1 is also a mitogen for osteoblasts, the cell type that is pivotal in the hallmark osteoblastic response of bone to metastatic prostate cancer.4,8 Selective ETA-receptor antagonists have been shown to block the proliferative effects of exogenous ET-1 in both prostate cancer cells and osteoblasts.7,9 This observation has generated a great deal of interest in ETAreceptor antagonists for the management of advanced prostate cancer. The following recently published article reports on this subject. T Effect of Endothelin-A Receptor Blockade With Atrasentan on Tumor Progression in Men With Hormone-Refractory Prostate Cancer: A Randomized, Phase II, PlaceboControlled Trial Carducci MA, Padley RJ, Breul J, et al. J Clin Oncol. 2003;21:679-689. Carducci and colleagues evaluated the efficacy and safety of atrasentan (ABT-627), an endothelin-A receptor antago- VOL. 6 NO. 1 2004 REVIEWS IN UROLOGY 47 Prostate Cancer continued nist, for the treatment of asymptomatic, hormone-refractory prostate adenocarcinoma (HRPCa) in a double-blind, randomized, placebo-controlled clinical trial conducted in the United States and Europe. A total of 288 asymptomatic men with HRPCa and evidence of metastatic disease were recruited into the study. The men were randomly assigned to a once-daily oral dose of one of the following: placebo; atrasentan, 2.5 mg; or atrasentan, 10 mg. The primary end point of the study was time to progression; secondary end points included time to prostate-specific antigen (PSA) The median time to PSA progression for the atrasentan, 10 mg, group was twice that of the placebo group. progression, bone scan changes, and changes in bone and tumor markers. Results demonstrated that, among the 244 evaluable men, the median time to progression was significantly prolonged in the atrasentan, 10 mg, group compared with the placebo group (196 vs 129 days; P < .03). Furthermore, the median time to PSA progression for the atrasentan, 10 mg, group was twice that of the placebo group (155 vs 71 days; P < .003). Men who received placebo continued to have significant increases from baseline in serum lactate dehydrogenase (LDH), a marker of disease burden, whereas elevations in LDH were uniformly attenuated by atrasentan (P < .01). Adverse events occurred in 16% to 34% of the men who received atrasentan, 10 mg. These events were usually mild to moderate in severity and included dyspnea, headache, rhinitis, and peripheral edema. Although this study demonstrated that atrasentan, with favorable tolerability, delays progression of HRPCa, it failed to investigate the agent’s influence on survival. This important issue needs to be addressed in future phase III protocols. In addition, the investigators reported that quality of life was neither adversely affected nor improved by atrasentan. The wide use of atrasentan for the management of advanced prostate cancer awaits further clinical trials and results of survival and quality-of-life studies. References 1. 2. 3. 4. 5. Wu-Wong JR. Endothelin receptor antagonists: past, present and future. Curr Opin Cardiovasc Pulmon Renal Invest Drugs. 1999;1:345-351. Masaki T. The endothelin family: an overview. J Cardiovasc Pharmacol. 2000; 35(4 suppl 2):S3-S5. Langenstroer P, Tang R, Shapiro E, et al. Endothelin-1 in the human prostate: tissue levels, source of production and isometric tension studies. J Urol. 1993; 150(2 pt 1):495-499. Nelson JB, Hedican SP, George DJ, et al. Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat Med. 1995;1:944-949. Usmani BA, Shen R, Janeczko M, et al. Methylation of the neutral endopeptidase gene promoter in human prostate cancers. Clin Cancer Res. 2000;6:1664-1670. 48 VOL. 6 NO. 1 2004 REVIEWS IN UROLOGY 6. 7. 8. 9. Gohji K, Kitazawa S, Tamada H, et al. Expression of endothelin receptor A associated with prostate cancer progression. J Urol. 2001;165:1033-1036. Nelson JB, Chan-Tack K, Hedican SP, et al. Endothelin-1 production and decreased endothelin B receptor expression in advanced prostate cancer. Cancer Res. 1996;56:663-668. Takuwa Y, Masaki T, Yamashita K. The effects of the endothelin family peptides on cultured osteoblastic cells from rat calvariae. Biochem Biophys Res Commun. 1990;170:998-1005. Nelson JB, Nguyen SH, Wu-Wong JR, et al. New bone formation in an osteoblastic tumor model is increased by endothelin-1 overexpression and decreased by endothelin A receptor blockade. Urology. 1999;53:1063-1069. Incontinence Incontinence After Childbirth Reviewed by Yongtae Kim, MD, Michael B. Chancellor, MD Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA [Rev Urol. 2004;6(1):48-49] © 2004 MedReviews, LLC Urinary Incontinence After Vaginal Delivery or Cesarean Section Rortveit G, Daltveit AK, Hannestad YS, Hunskaar S, for the Norwegian EPINCONT Study. N Engl J Med. 2003;348:900-907. t is widely accepted that traumatic childbirth is a major cause of pelvic floor damage and stress urinary incontinence. Yet, the actual data to support or refute this are not well characterized. In this noteworthy study, Rortveit and colleagues, from Norway, address this important issue. The investigators studied whether women who deliver by cesarean section have an increased risk of urinary incontinence compared with nulliparous women and whether women who deliver vaginally have an even higher risk. A total of 15,307 women in a community-based cohort were evaluated. Women were included if they answered questions related to urinary incontinence; were younger than 65 years; and had no deliveries, cesarean sections only, or vaginal deliveries only. The prevalence of any incontinence was 10.1% in the nulliparous women, 15.9% in those who had cesarean sections only, and 21.0% in those who had vaginal delivery only. Compared with nulliparous women, those who had cesarean sections had an adjusted odds ratio (OR) for any I