News and Views from the Literature
Incontinence
REVIEWING THE LITERATURE News and Views From the Literature Prostate Cancer Tumor Markers: An Update on Human Kallikrein 2 Steven R. Potter, MD, Alan W. Partin, MD, PhD The Johns Hopkins Hospital, Baltimore [Rev Urol. 2000;2(4):221-222] T he development and use of prostate-specific antigen (PSA) in the early detection and staging of prostate cancer has revolutionized management of this disease. The limited specificity of PSA at total PSA (tPSA) levels lower than 10 ng/mL, however, leads to increased numbers of unnecessary prostate biopsies, with attendant patient anxiety, cost, and potential morbidity. Human glandular kallikrein 2 (hK2) is a prostate-specific kallikrein (produced by the prostatic epithelium with approximately 80% DNA sequence homology with PSA) that is emerging as a potential adjunct to PSA as a prostate cancer tumor marker.1 In contrast to PSA, hK2 is a potent protease, with more than 20,000 times the activity of the relatively weak protease PSA. In fact, evidence is increasing that hK2 activates and thus regulates PSA. Some key features of hK2 are summarized in Table 1. While PSA production is often decreased in poorly differentiated prostate cancers, hK2 production appears to be increased. This differential production may ultimately be the key to defining the clinical role of hK2. Like PSA, hK2 exists in serum in free (unbound) and complexed (bound) forms. Serum levels of hK2 are much lower than tPSA values in the same patient population, typically ranging from 0% to 10% of PSA levels. These low levels, combined with the molecular similarity of hK2 to PSA, have made reliable assay of hK2 levels relatively difficult. Two groups of investigators have recently tackled the problem of defining the clinical role of hK2 using different techniques, reporting results that raise interest in the potential role of hK2 as a prostate cancer tumor marker. Table 1 Key Features of Human Kallikrein 2 (hK2) • Gene for hK2 is found adjacent to gene for prostatespecific antigen (PSA) on chromosome 19. • Like PSA, hK2 is localized to prostatic epithelium. • Like PSA, hK2 exists in multiple forms in serum as free and complexed hK2. • hK2 is more than 20,000-fold more enzymatically potent than PSA on appropriate substrates. • Unlike PSA, hK2 expression increases as prostate cancers become more undifferentiated. • Monoclonal antibodies have been produced to detect hK2; these antibodies have an acceptably low cross-reactivity with PSA. In Prostatism Patients the Ratio of Human Glandular Kallikrein to Free PSA Improves the Discrimination Between Prostate Cancer and Benign Hyperplasia Within the Diagnostic “Gray Zone” of Total PSA 4 to 10 ng/mL Kwiatkowski MK, Recker F, Piironen T, et al. Urology. 1998;52:360-365. Kwiatkowski and associates studied the role of serum hK2 measurement in prostate cancer detection in men with PSA levels of 4 to 10 ng/mL referred for lower urinary tract symptoms. Of these men, 81 underwent transurethral resection of the prostate and 6 underwent radical prostatectomy. The authors determined PSA, percent free PSA (%fPSA), and hK2 levels. They indirectly measured hK2 levels with an assay that measured both PSA and hK2 by using multiple monoclonal antibodies that blocked PSA measurement. With a cut point set to allow 100% sensitivity, hK2/fPSA had a specificity of 48.2%. With cut points set to provide a sensitivity of 94.4%, hK2/fPSA and %fPSA had specificities of 60% and 28%, respectively. The investigators concluded that hK2/fPSA offered better specificity for the detection of prostate cancer than did the use of tPSA or %fPSA in the range of 4 to 10 ng/mL. This improvement in specificity did not appear to occur at the expense of decreased sensitivity. It should be noted that this study included relatively few men with prostate cancer and that men with hK2 levels lower than 0.05 ng/mL were excluded. FALL 2000 REVIEWS IN UROLOGY 221 Prostate Cancer continued Use of Human Glandular Kallikrein 2 for the Detection of Prostate Cancer: Preliminary Analysis Partin AW, Catalona WJ, Finlay JA, et al. Urology. 1999;54:839-845. Intrigued by the differences in expression and biologic activity of PSA and hK2, Partin and associates characterized the role of hK2 in the detection of prostate cancer using a prototype assay that uses 2 antibodies against total hK2 (thK2). They analyzed 937 archival serum samples from 922 men with PSA levels greater than 2 ng/mL, all with prostate biopsies revealing either cancer (184 men) or benign prostatic tissue (738 men). Of the men studied, 86% had a benign digital rectal examination (DRE). Median age, PSA level, and thK2 levels were similar, while median %fPSA and thK2/fPSA values differed significantly between men with and without prostate cancer. Multivariate logistic regression analysis identified %fPSA as the best predictor of the presence of prostate cancer, followed by thK2/fPSA. The investigators constructed cut points of %fPSA and thK2/PSA that stratified patients into prostate cancer risk groups. In men with benign DRE results and tPSA levels of 2 to 4 ng/mL, the use of both %fPSA and thK2/fPSA identified 40% of all cancers while requiring biopsy in only 16.5% of the men. Combining %fPSA and thK2/fPSA was also useful in men with benign DRE results and PSA levels between 4 and 10 ng/mL with an initial negative biopsy. In this population, a thK2/fPSA ratio greater than 0.18 predicted a subset of men at greater risk for harboring cancer, supporting a strategy of repeated biopsy in these men. In summary, Partin and associates demonstrated the reliability of a direct immunoassay for thK2. Multivariate logistic regression was used to compare the utility of %fPSA and thK2/fPSA in prostate cancer detection. While %fPSA outperformed thK2/fPSA, the information provided by these markers was complementary, allowing the greatest specificity for prostate cancer detection. The use of thK2/fPSA in men with PSA levels of 2 to 4 ng/mL identified 40% of all detectable cancers while sparing biopsy in 83% of men without detectable cancer. The thK2/fPSA ratio also appeared to offer promise in helping counsel men with a prior negative biopsy on the need for subsequent biopsy. Reference 1. Rittenhouse HG, Finlay JA, Mikolajczyk SD, Partin AW. Human kallikrein 2 (hK2) and prostate-specific antigen (PSA): two closely related, but distinct, kallikreins in the prostate. Crit Rev Clin Lab Sci. 1998;35:275-368. 222 REVIEWS IN UROLOGY FALL 2000 Vaccine-Based Immunotherapy for Prostate Cancer Shahrokh F. Shariat, MD, Farshid Sadeghi, MD, Kevin M. Slawin, MD Baylor College of Medicine, Houston [Rev Urol. 2000;2(4):222-227] A fter a long period of smoldering activity in cancer immunotherapy, interest in cancer vaccines has caught fire. This interest is reflected in the logarithmic increase in the number of open clinical trials for the treatment of prostate and other cancers. The renewed enthusiasm has been fanned largely by a more sophisticated understanding of the intricacies of immune system regulation and by the availability of better reagents (recombinant cytokines, dendritic cells, etc) to manipulate the immune response. The concept of active immunotherapy of cancer is based on the theory that tumor cells escape detection and destruction by the host’s immune system through various strategies: deficient tumor antigen processing and presentation, lack of immune costimulation, production of inhibitory factors by tumor cells, and insufficient helper activity from CD4 cells. One method of inducing the immune system to recognize and destroy cancer cells is cancer vaccination. Cancer vaccines attempt to facilitate the presentation of tumor antigens to the immune system; typically, in conjunction with factors that augment immune system activation, generating cellular and humoral antitumor activity. Several distinct approaches to prostate cancer vaccination are currently being investigated. One important factor is the choice of material used as the tumor antigen. Some investigators have used irradiated, intact autologous prostate cancer cells derived from patients’ own tumors or allogeneic prostate cancer cells from previously established prostate cancer cell lines, such as LNCaP and PC-3. Others have used prostate cancer cellular homogenates, which contain a multitude of poorly defined tumor- and non–tumor-specific antigens, or have used more well-defined single antigens; often, prostate-specific proteins, such as PSA, prostatespecific membrane antigen (PSMA), or the cancer-associated mucin MUC-1.1 Another important factor is the method chosen to augment the normally muted immune response to these antigens. Approaches currently being evaluated include the use of dendritic cells, which are highly efficacious in presenting antigens to T cells, and the use of various cytokines, such as tumor necrosis factor, interleukin (IL)-2, IL4, IL-10, IL-12, and granulocyte-macrophage colony-stimulating factor (GM-CSF), to improve the immune system’s response to the desired antigens. Prostate Cancer GM-CSF is a potent inducer of hematopoietic differentiation, stimulating the production of macrophages and dendritic cells from monocyte precursors. In vivo administration of exogenous GM-CSF induces differentiation of bone marrow-derived antigen presenting cell-like macrophages, which are critical for antigen presentation to T cells. In addition, GM-CSF also stimulates the activation of quiescent dendritic cells. In 1997, Simons and associates2 at Johns Hopkins University in Baltimore reported on the feasibility, safety, and bioactivity of a GM-CSF–gene transduced autologous tumor vaccine for patients with metastatic renal cell carcinoma. Although initial clinical responses were limited, this vaccine was shown to induce a specific immune response to tumor cells. Recently, Simons and colleagues reported the results of a small phase I study investigating the feasibility and safety of prostate cancer vaccines using autologous prostate cancer cells similarly engineered to express GM-CSF in patients with metastatic prostate cancer (first review). Prostate cells express tissue-specific proteins, such as PSA and PSMA, which represent a unique potential antigenic target for antitumor immune response targeted specifically to prostate cells. Sanda and coworkers at the University of Michigan have explored the use of a vaccinia viral vector carrying the PSA complementary DNA (cDNA) as a potential vaccination strategy for prostate cancer patients (second review). Since PSA is already present in patients as a “self” protein, it should be nonimmunogenic. It is possible, however, that once PSA is processed by antigen-presenting cells in the context of the vaccinia virus, it may enter different processing and packaging pathways, unmasking PSA peptide epitopes that can generate a humoral and cellular immune response. Alternatively, vaccinia virus proteins may act as an adjuvant to augment an otherwise weak anti-PSA response. Finally, the characterization of dendritic cells, thought to be the most powerful antigen-presenting cells of the body, has stimulated intense interest as a potential cancer vaccine reagent. Dendritic cells are bone marrow–derived “professional” antigen-presenting cells. They have distinct pathways of differentiation that can be subdivided into myeloidand lymphoid-derived lineages. Dendritic cells are vital for the stimulation of cytotoxic and helper T-cells because of their ability to recognize, phagocytose, and process antigens in the peripheral tissues, which they transport to and present in secondary lymphoid organs. In the clinical setting, a convenient source of myeloid-derived dendritic cells is peripheral blood monocytes, which can be induced to differentiate into dendritic cells using GM-CSF and IL-4. Dendritic cell– based tumor vaccines have produced encouraging early results in various cancers, such as melanoma and renal cell carcinoma. Murphy and colleagues3-6 from Washington University have done extensive preclinical and clinical research on dendritic cell–based immunotherapy of prostate cancer. Moreover, they have studied a prostate cancer vaccine strategy using autologous dendritic cells as a vehicle to present prostate antigens, such as PSMA-derived peptides to T cells (third review). Numerous centers around the country are investigating use of new tumor vaccines to treat patients with prostate cancer and other tumors. Preclinical and early clinical data suggest that tumor vaccine therapies are feasible and safe. Most trials report only mild systemic side effects, such as hypotension, fever, chills, and fatigue; reactions at the vaccination site, such as erythema, swelling, and pruritus; and discomfort during injection. These approaches have shown that a systemic immune response to human prostate cancer can be generated, although clinical importance of the current generation of tumor vaccines remains to be established in phase II and III studies. Induction of Immunity to Prostate Cancer Antigens: Results of a Clinical Trial of Vaccination With Irradiated Autologous Prostate Tumor Cells Engineered to Secrete Granulocyte-Macrophage Colony-Stimulating Factor Using Ex Vivo Gene Transfer Simons JW, Mikhak B, Chang JF, et al. Cancer Res. 1999;59(20):5160-5168. In a small-dose escalation study, Simons and associates evaluated the safety of vaccinating patients who had metastatic prostate cancer with irradiated, autologous prostate cancer cells, modified ex vivo to produce high levels of GM-CSF. Tumor cells were obtained from each patient at surgery and were established in culture. The cells were then genetically modified through transduction with a replication-defective retrovirus containing a cDNA encoding the GM-CSF gene. After expansion and irradiation (to prevent further proliferation), the vaccine cells were reinjected subcutaneously into the patient. Eleven immunocompetent patients with metastatic prostate cancer found incidentally at radical prostatectomy were enrolled. The vaccine was administered subcutaneously into the limbs. Two dose levels of vaccine (1 107 and 5 107 cells) secreting human GM-CSF at 150 to 1500 ng/million cells/24 h were assessed. Vaccination was repeated every 2 weeks until exhaustion of the vaccine supply, yielding between 3 and 6 vaccination cycles. Primary cultures of prostate tumor cells failed to establish for 3 patients, leaving 8 of the 11 patients for evaluation. Further difficulties with in vitro expansion of primary cultures shifted 4 patients from the planned high-dose group (5 107) to the low-dose group (1 107). Thus, the highdose group comprised 3 patients and the low-dose group, 5. continued FALL 2000 REVIEWS IN UROLOGY 223 Prostate Cancer continued In contrast to these difficulties, ex vivo retroviral GM-CSF gene transfer was successful in all 8 patients. No dose-limiting toxicity was observed. Toxicity was limited to injection pain, erythema, swelling, and pruritus at the vaccination site as well as mild, low-grade fever; malaise; and chills. No significant alterations in serum electrolyte, chemistry, and hematologic counts were observed. Vaccine site biopsies revealed the presence of prostate tumor–derived vaccine cells and inflammatory infiltrates composed of antigen presenting cells, such as Langerhans cells and macrophages as well as neutrophils, T cells, and eosinophils. The authors observed a dose response with higher intensity of cellular infiltrates in the high-dose group. T-cell antitumor response was evaluated with serial cutaneous delayed-type hypersensitivity (DTH) reactivity tests to irradiated, untransduced, autologous prostate cell targets. Two patients displayed DTH reactivity before vaccination and 7 patients, after vaccination. Both vaccine and DTH site biopsies displayed massive eosinophil recruitment. Modest numbers of B-cells were also observed in the biopsies. Comparison of prevaccination with postvaccination serum analyses showed an increase in antibody titers to prostate tumor antigens in 3 of the 8 patients. While new antibodies to 3 undefined prostate antigens were identified, no anti-PSA antibodies and no PSA-specific T-cell recognition were detected. Although efficacy is not an end point of phase I studies, it is noteworthy that all 8 patients exhibited disease progression. As noted by the authors, establishing and expanding human prostate cancer cells is technically difficult, limiting dose and number of cycles of autologous tumor vaccines. Use of allogeneic tumor cells, which, in contrast to autologous tumor cells, are not from the patient’s own tumor but are histologically similar human tumor cell lines, may be a practical alternative. In support of this argument, all 3 of the newly identified prostate antigens were also found in LNCaP cells. The Johns Hopkins team, therefore, switched to GMCSF–gene transduced LNCaP and PC-3 for the phase II trial. responsive and received antiandrogen therapy for a median duration of 7 months (range, 2 to 14 months) before inclusion in the study. Antiandrogen therapy was interrupted at the beginning of the study period to allow tumor cells to reexpress PSA, the target for the vaccine therapy. Seven days after each of the patients received the last administration of goserelin depot 3.6 mg, they were given a single intradermal injection of vaccinia-PSA at a dose of 2.65 107 or 2.65 108 plaque-forming units (3 patients per dose level). In all 6 patients, the vaccinia-PSA virus proved safe, with minimal toxicity limited to constitutional symptoms, such as vaccine site erythema and vesicle formation, fever, chills, fatigue, and diarrhea. Induction of humoral immunity to PSA by the vaccine was evaluated with Western blot analysis of anti-PSA antibody in patient sera. Vaccine-related anti-PSA IgG was induced in only 1 patient and anti-PSA IgM, in none. Two patients had detectable anti-PSA IgG and 5 patients had detectable anti-PSA IgM before vaccination. Five of the 6 patients exhibited a PSA level rise in a median time of 1 month (range, 0 to 4 months) after restoration of serum testosterone levels. The interval from androgen restoration to PSA rise was used as a surrogate end point of antitumor activity. The fact that vaccination occurred concurrently with cessation of hormone therapy makes it difficult to determine the effect of either on clinical response. The observation that 2 patients had anti-PSA antibodies before vaccination and that 1 patient seroconverted despite a rapidly rising PSA level questions the clinical effects of a humoral response to prostate cancer. Evaluation of Phase I/II Clinical Trials in Prostate Cancer With Dendritic Cells and PSMA Peptides Tjoa BA, Simmons SJ, Bowes VA, et al. Prostate. 1998;36:39-44. Recombinant Vaccinia-PSA (Prostvac) Can Induce a Prostate-Specific Immune Response in Androgen-Modulated Human Prostate Cancer Infusion of Dendritic Cells Pulsed With HLA-A2-Specific Prostate-Specific Membrane Antigen Peptides: A Phase II Prostate Cancer Vaccine Trial Involving Patients With Hormone-Refractory Metastatic Disease Sanda MG, Smith DC, Charles LG, et al. Urology. 1999;53:260-266. Murphy GP, Tjoa BA, Simmons SJ, et al. Prostate. 1999;38:73-78. Sanda and colleagues administered vaccinia-PSA to 6 patients with biochemical recurrence after radical prostatectomy. The vaccinia virus has an attractive safety profile, having been used for more than 200 years for smallpox immunization. These investigators used the vaccinia virus as a vector for introducing recombinant PSA as a tumor-associated antigen with the goal of enhancing the cellular recognition of prostate cancer cells. All patients were androgen Phase II Prostate Cancer Vaccine Trial: Report of a Study Involving 37 Patients With Disease Recurrence Following Primary Treatment Murphy GP, Tjoa BA, Simmons SJ, et al. Prostate. 1999;39:54-59. continued on page 226 224 REVIEWS IN UROLOGY FALL 2000 Prostate Cancer continued continued from page 224 Follow-up Evaluation of a Phase II Prostate Cancer Vaccine Trial Tjoa BA, Simmons SJ, Elgamal A, et al. Prostate. 1999;40:125-129. Murphy and associates have explored a prostate cancer tumor vaccine approach that employs dendritic cells to present prostate antigens to autologous T cells. This approach requires cultivating peripheral blood mononuclear cells harvested from enrolled patients. The cells are then cultured in the presence of cytokines to induce differentiation of monocytes into antigen-presenting cells. These cells are pulsed with the desired antigen (PSMA) and then given back to the patient intravenously, as a vaccine. The authors have chosen two 9–amino-acid fragments from each end of the PSMA molecule (PSM-P1 and PSM-P2) with a high affinity for the class I human leukocyte antigen (HLA-A0201) molecule. In their initial phase I clinical trial comprising 51 patients with metastatic hormone-refractory prostate cancer, Murphy and coworkers6 demonstrated that the administration of autologous dendritic cells pulsed with HLA-A0201–derived peptides from PSM-P1 and -P2 was safe. Toxicity was limited to transient hypotension. Seven partial responders were observed. On the basis of phase I data, this group expanded its study assessing the efficacy of autologous dendritic cells pulsed with PSMA peptides. One hundred seven patients were enrolled in an open-labeled, phase II clinical trial comprising 3 main groups of patients. The first group consisted of 33 men with metastatic hormone-refractory prostate cancer who had participated in the previous phase I study. Another group consisted of 33 patients with hormone-refractory prostate cancer with no previous immunotherapy. The third group was made up of 41 patients with evidence of local recurrence after failure of a primary treatment, including surgery, radiotherapy, brachytherapy, or hormone therapy. All study participants received a total of 6 infusions of dendritic cells pulsed with PSMA-derived peptides at 6-week intervals. In addition, approximately half of the study patients also received a 7-day course of systemic adjuvant therapy in a nonrandomized fashion in the form of subcutaneous injections of 75 g/m2/d of GM-CSF starting on the day of infusion. Clinical response as defined by the National Prostate Cancer Project Criteria—a 50% decrease in PSA level or a significant resolution of lesions on scintigraphy— was evaluated. A panel of immunogenic recall antigens for the evaluation of T-cell immune function as assessed by DTH skin test was used. Patients who were receiving hormonal therapy before enrollment in the study continued the same therapy throughout the trial. Of the 33 patients with advanced prostate cancer who participated in the primary study, 9 (27.3%) displayed par- 226 REVIEWS IN UROLOGY FALL 2000 tial response, 11 (33.3%) exhibited no significant change in disease, and 13 had disease progression. Seven patients died during the study. Four of the 9 partial responders also responded in the phase I study. Four of the remaining 5 partial responders did not receive autologous dendritic cells pulsed with PSM-P1 or -P2 in the phase I study. Immune response as assessed with DTH tests did not add any conclusive information. Of the group of 33 patients with hormone-refractory prostate cancer who had no previous immunotherapy, only 25 were evaluable, 2 (8%) of whom were complete responders and 6 (24%) of whom were partial responders. One patient (4%) showed no significant disease change, and 16 (64%) exhibited disease progression. Of these, 7 died and 2 withdrew from the study. Once again, the level of DTH response was equivalent in the responders to that in the nonresponders. In fact, 6 of the 8 responders exhibited no change and 2 exhibited a decrease in immune reactivity. The third group consisted of patients with locally advanced prostate cancer, all of whom did not respond to primary treatment and 35% of whom also did not respond to secondary treatment. Of 41 subjects who were initially enrolled in the study, 37 subjects were evaluable. One complete (4%) and 10 partial (27%) responders were observed. Eight patients (22%) showed no significant change, and 18 (49%) exhibited disease progression. As in the previous studies, DTH tests did not reveal any significant information. Overall, the response rate of the phase II study groups was 30% (ranging from 27% to 32%). Although a majority of the responders expressed HLA-A2, a high number did not, which should have abrogated correct antigen presentation in this group of patients. The authors hypothesize that the clinical improvement in these patients is caused by the ability of the dendritic cells to capture and present other antigens after being infused into the patients, as well as by the affinity of PSM-P1 and -P2 to other HLA molecules. A follow-up evaluation, with an average of 291 days for the hormone-refractory group with no previous immunotherapy and of 557 days for the recurrent group (follow-up days include a treatment period of 221 days plus a follow-up period), revealed that only 58% of the initial responders were still responsive. Disease progression of the initial responders occurred between 20 and 131 days after the end of the trial. The average response duration was 149 days for the hormone-refractory group and 187 days for the group with recurrence. Responders were found to have a statistically significant decrease in post-study versus prestudy serum PSA when compared with nonresponders, who exhibited an increase in PSA levels. While this approach seems intriguing and promising, these studies are not yet sufficient to allow a reliable determination of the efficacy and appropriate clinical scenario for the use of autologous dendritic cells (pulsed with PSMA Erectile Dysfunction peptides) as a prostate cancer vaccine. Further, well-controlled clinical trials are needed. References 1. Slovin SF, Scher HI. Peptide and carbohydrate vaccines in relapsed prostate cancer: immunogenicity of synthetic vaccines in man—clinical trials at Memorial Sloan-Kettering Cancer Center. Semin Oncol. 1999;26:448-454. 2. Simons JW, Jaffee EM, Weber CE, et al. Bioactivity of autologous irradiated renal cell carcinoma vaccines generated by ex vivo granulocyte-macrophage colony-stimulating factor gene transfer. Cancer Res. 1997;57:1537-1546. 3. Tjoa B, Boynton A, Kenny G, et al. Presentation of prostate tumor antigens by dendritic cells stimulates T-cell proliferation and cytotoxicity. Prostate. 1996; 28:65-69. 4. Tjoa B, Erickson S, Barren R III, et al. In vitro propagated dendritic cells from prostate cancer patients as a component of prostate cancer immunotherapy. Prostate. 1995;27:63-69. 5. Tjoa BA, Erickson SJ, Bowes VA, et al. Follow-up evaluation of prostate cancer patients infused with autologous dendritic cells pulsed with PSMA peptides. Prostate. 1997;32:272-278. 6. Murphy G, Tjoa B, Ragde H, et al. Phase I clinical trial: T-cell therapy for prostate cancer using autologous dendritic cells pulsed with HLA-A0201-specific peptides from prostate-specific membrane antigen. Prostate. 1996;29:371-380. They came up with a questionnaire—the International Index of Erectile Function (IIEF)—that consists of 15 questions covering 5 domains of erectile function and is reliable and reproducible.1 It has a high degree of sensitivity and specificity for detecting patients with erectile dysfunction. Although the original IIEF test covers 15 questions and is ideal for use in clinical trials of drugs for treating patients with erectile dysfunction, it is not patient-friendly, particularly if it were used as a diagnostic tool by physicians in clinical practice. This suggested the need for a more abbreviated version of the IIEF that would be easy to administer in the office setting. The authors took it upon themselves to devise an abbreviated 5-item version of the original 15-item test that focused primarily on erectile function and intercourse satisfaction (Table 2). Their data indicated that this abbreviated version was excellent in detecting the presence and severity of erectile dysfunction, thereby supporting its use as a valid diagnostic instrument in the clinical setting. The sensitivity of the test was 0.98, and the specificity was 0.88. Reference Erectile Dysfunction Diagnostic Index and Dysfunction Treatment 1. Rosen RC, Riley A, Wagner G, et al. The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 1997;49:822-830. Testosterone Supplementation in the Aging Male Kim Y-C. Int J Imp Res. 1999;11:343-352. Jacob Rajfer, MD University of California at Los Angeles [Rev Urol. 2000;2(4):227-228] T wo areas with potential clinical impact are discussed: the advantages of a patient-friendly questionnaire for diagnosis of erectile dysfunction, and the diagnosis of and treatment for andropause. Development and Evaluation of an Abridged, 5-Item Version of the International Index of Erectile Function (IIEF-5) as a Diagnostic Tool for Erectile Dysfunction Rosen RC, Cappelleri JC, Smith MD, et al. Int J Imp Res. 1999;11:319-326. Nothing irks an epidemiologist more than using a test that is not reliable and reproducible. Therefore, the group of epidemiologists from the Robert Wood Johnson Medical School set out to identify and validate a questionnaire that could be used by any physician to diagnose erectile dysfunction. Treatment of Endocrinologic Male Sexual Dysfunction Nehra A. Mayo Clin Proc. 2000;75(suppl):S40-S45. Is there such a condition as andropause?1 There is heated debate in the endocrinologic world whether such a condition occurs and whether treatment of this condition should be offered to elderly patients. The major clinical manifestations of andropause—if there is such a condition—are decreased cognition, decrease in muscle mass and strength, osteopenia, and loss of libido. It is accepted that since testosterone levels decline with aging, such effects may be reversed with exogenous testosterone, potentially improving the quality of life of older men. The deleterious side effects of exogenous testosterone, however, must be considered in these elderly men. Although prostate cancer and/or benign prostatic hyperplasia are not induced by exogenous testosterone, the hormone may induce already present cancer cells to begin growing. Yet when prostate-specific antigen is measured, most studies show very little, if any, change during androgen therapy. FALL 2000 REVIEWS IN UROLOGY 227 Erectile Dysfunction continued Table 2 The IIEF-5 Questionnaire Over the past 6 months: 1. How do you rate your confidence that you could get and keep an erection? Very low Low Moderate High Very high 1 2 3 4 5 A few times (much less than half the time) Sometimes (about half the time) Most times (much more than half the time) Almost always/ always 1 2 3 4 5 Almost never/never A few times (much less than half the time) Sometimes (about half the time) Most times (much more than half the time) Almost always/ always 1 2 3 4 5 Extremely difficult Very difficult Difficult Slightly difficult Not difficult 1 2 3 4 5 Almost never/never A few times (much less than half the time) Sometimes (about half the time) Most times (much more than half the time) Almost always/ always 1 2 3 4 5 2. When you had erections with Almost sexual stimulation, how often never/never were your erections hard enough for penetration? 3. During sexual intercourse, how often were you able to maintain your erection after you had penetrated your partner? 4. During sexual intercourse, how difficult was it to maintain your erection to completion of intercourse? 5. When you attempted sexual intercourse, how often was it satisfactory for you? IIEF, International Index of Erectile Function. Adapted with permission from Rosen RC et al. Int J Imp Res. 1999.1 Another consideration in elderly men is the alteration in the lipid profiles of men taking testosterone. In fact, current evidence suggests that exogenous testosterone may raise high-density lipoprotein and lower low-density lipoprotein cholesterol levels; both actions are believed to be beneficial to the cardiovascular system. Counteracting this is the potential for increasing the hematocrit to polycythemic levels, particularly in men who have sleep apnea, another condition that may be exacerbated by testosterone. And what is the best way to provide exogenous testosterone? There is no unanimity of opinion concerning injections versus skin patches, but this may become moot when a skin gel of testosterone becomes available later this year. The compound is rubbed on the skin and dries quickly, obviating the need for patches and protection of clothing. 228 REVIEWS IN UROLOGY FALL 2000 There is also very little dermatitis, which is commonly seen with the patches, associated with the gel. It is apparent that many men will experience symptoms of aging that are believed to be due to a decrease in serum testosterone levels. Thus, andropause may be diagnosed in some older men who complain of erectile dysfunction. Reference 1. Testosterone Replacement in Elderly Men [symposium]. Mayo Clin Proc. 2000; 75(suppl). Incontinence Incontinence First-Line Therapy for Stress Incontinence Michael B. Chancellor, MD University of Pittsburgh School of Medicine [Rev Urol. 2001;2(4):229-230] T wo excellent articles from Europe focus on first-line therapy for patients with stress urinary incontinence. Although many papers have debated the merits of pelvic floor exercise, functional electrical stimulation, and estrogen, few studies have been conducted using strict scientific methodology, which would allow unbiased judgment. The 2 studies selected for review are appropriately designed so that definitive conclusions related to the management of stress incontinence can be made. Just for fun, please answer the following questions before reading the review. 1. Which of the following is the best first-line treatment for stress urinary incontinence? A. Pelvic floor exercise B. Functional electrical stimulation C. Vaginal cone 2. Can estrogen replacement decrease or prevent stress urinary incontinence? A. Yes B. No Single Blind, Randomised Controlled Trial of Pelvic Floor Exercises, Electrical Stimulation, Vaginal Cones, and No Treatment in Management of Genuine Stress Incontinence in Women Bo K, Talseth T, Holme I. BMJ. 1999;318:487-493. What is the best first-line treatment for stress urinary incontinence among pelvic floor exercise, functional electrical stimulation, and vaginal cone? This is a very controversial area of therapy. Many articles in the literature attest that 1 of the 3 is best, but most studies do not compare the modalities in a scientifically valid fashion. If you assemble a urol- ogist, urogynecologist, and physical therapist to discuss the matter, you are likely to get strong and different opinions from each. This important paper answers the question. In Europe, the management of stress incontinence has gradually shifted from surgical interventions to conservative therapies, including pelvic floor exercise, electrical stimulation, and placement of vaginal cones. While pelvic floor exercise has been proved effective for treating genuine stress incontinence, findings from clinical studies evaluating electrical stimulation and vaginal cones have been inconclusive. Further, no comparative study of the 3 modalities has been conducted. Bo and associates from the Norwegian Centre for Physiotherapy Research, the Norwegian University of Sport and Physical Education, and the National Hospital of Norway, Oslo, conducted a multicenter, single-blind, randomized study to compare the effectiveness of these conservative therapies for genuine stress incontinence. The 107 women enrolled in the trial were randomized to 1 of 4 groups: pelvic floor exercises (n = 25); electrical stimulation (n = 25); vaginal cone (n = 27); or no treatment (control) (n = 30). The primary outcomes were subjective patient perception of improvement and results of a pad test with standardized bladder volume. Secondary outcomes included the number of involuntary leakage episodes over 3 days; results from the 24-hour pad test; leakage index score, obtained from patient reports of frequency of urinary leakage during such activities as coughing, sneezing, laughing, and physical exertion before and after treatment; and social activity index (the level of patient participation in social activities). There have been studies of conservative therapy for stress incontinence in which most patients reported some improvement with noninvasive therapy. In the trial reported by Bo and associates, all patients in treatment groups experienced improvement, whereas patients in the control group generally did not. Only women in the pelvic floor exercise group achieved significant improvement, compared with the those in the control group (P < .01). Improvement in the pelvic floor exercise group correlated with increased strength of pelvic floor muscles (P = .03). No change in pelvic muscle strength was observed between women in the electrical stimulation group or those in the vaginal cone group. Women in the pelvic floor exercise group also experienced improvement in the pad test with standardized bladder volume (P = .02), reduced episodes of leakage over 3 days (P < .01), and improvement in both the social activity index (P < .01) and the leakage index (P < .01). Pelvic floor exercises also resulted in objective cure (2 g or less of leakage in the pad test with standardized bladder volume) in significantly more women (n = 11; P < .02) than did the other therapies (7, electrical stimulation; 2, vaginal cone; 2, con- FALL 2000 REVIEWS IN UROLOGY 229 Incontinence continued trol). Similarly, significantly more women in the pelvic exercise group reported subjective cure (n = 14, P < .001), compared with 3 in the electrical stimulation group, 2 in the vaginal cone group, and 1 in the control group. None of the women in the pelvic floor exercise group experienced any adverse effects of therapy. Two women who received electrical stimulation reported tenderness and bleeding or discomfort, while 8 indicated they had motivation problems and difficulties using the stimulator. Fourteen patients in the vaginal cone group also had difficulties with motivation and/or the device; additionally, 1 experienced abdominal pain, vaginitis developed in 2; and 1 reported bleeding. What is the take-home message in this article? It appears that the best first-line treatment for patients with stress urinary incontinence among pelvic floor exercise, functional electrical stimulation, and vaginal cone is also the least expensive: pelvic floor exercise. The Effect of Oestrogen Supplementation on Post-Menopausal Urinary Stress Incontinence: A Double-Blind Placebo-Controlled Trial Jackson S, Shepherd A, Brookes S, Abrams P. Br J Obstet Gynaecol. 1999;106:711-718. This study addresses the question of whether estrogen replacement can decrease or prevent stress urinary incontinence. The rationale is certainly logical. It is well known that there is an increasing prevalence of urinary incontinence with age and menopause. Therefore, it is logical to postulate that hormone replacement therapy (HRT) may have a therapeutic role in postmenopausal incontinence. The first report of estrogen replacement was published more than 50 years ago and, since then, several hundred papers on this topic have appeared in the literature. The majority of these reported studies have been small and uncontrolled; most have suggested that HRT is beneficial. A placebo-controlled study is essential to establish the treatment-related advantage of estrogen replacement. The purpose of this study by Jackson and associates from the Southmead Hospital, Bristol, UK, was to investigate the effect of HRT on postmenopausal urinary stress incontinence. This double-blind, placebo-controlled, randomized trial was conducted at a teaching hospital associated with Bristol University. The population comprised postmenopausal women with genuine stress incontinence who were not receiving HRT. The women were randomized to 6 months of therapy with estradiol valerate, 2 mg daily, or to placebo. Assessment, both before treatment and on study completion, was done with the SF-36 health status questionnaire, the Bristol Female Lower Urinary Tract Symptoms questionnaire, a 1-week urinary diary, 1-hour perineal pad 230 REVIEWS IN UROLOGY FALL 2000 test, cystometry, and urethral profilometry. Sixty-seven women were randomized to receive estrogen or placebo. Mean age was 63 years. Five women did not have repeat assessment; 3 of the 5 were receiving estrogen. Six women receiving estradiol had breakthrough bleeding during the 6 months; they received additional monthly progestogen. There was no significant effect of estrogen over placebo for any subjective or objective clinical outcome. This trial is one of the largest controlled studies of the effect of estrogen replacement on stress incontinence; it also has the longest duration of treatment. After 6 months of estrogen therapy, no improvement in postmenopausal stress incontinence was demonstrated. Apart from a slight increase in functional urethral length, HRT has only minimal effect on subjective or objective lower urinary tract function. These results are consistent with another well-done controlled trial evaluating the effect of estrogen replacement on stress incontinence.1 Eighty-three postmenopausal women, 70% of whom had either genuine or mixed incontinence, were treated with either 0.625 mg conjugated equine estrogen or placebo. While the study was reported as being double-blind, the women treated with estrogen received medroxyprogesterone acetate for 10 days each month and would therefore have experienced withdrawal bleeding if they had not had hysterectomies. The treatment lasted 3 months. During that time, no significant advantage over placebo was found concerning the number of incontinence episodes, objective fluid loss, frequency of micturition, quality-of-life measures, or subjective improvement. What is the take-home message? The next time a postmenopausal woman with incontinence or a medical colleague asks you if estrogens improve urinary incontinence, the answer is, unfortunately, no. Reference 1. Fantl JA, Bump RC, Robinson D, et al. Efficacy of estrogen supplementation in the treatment of urinary incontinence. Obstet Gynecol. 1996;88:745-749. Based on the studies reviewed, the correct answers to the 2 questions are 1: A. Pelvic floor exercise; 2. B. No.