Urologic Oncology

REVIEWING THE LITERATURE News and Views from the Literature Overactive Bladder A Comparison of Anticholinergic Therapies in the Treatment of Overactive Bladder Reviewed by Herbert Lepor, MD Department of Urology, New York University School of Medicine, New York, NY [Rev Urol. 2001;3(4):209] © 2001 MedReviews, LLC Prospective Randomized Controlled Trial of Extended-Release Oxybutynin Chloride and Tolterodine Tartate in the Treatment of Overactive Bladder: Results of the OBJECT Study Appell RA, Sand P, Dmochowski R, et al. [Mayo Clin Proc. 2001;76:358–363] O ne of the primary limitations of anticholinergic agents for the treatment of overactive bladder is problematic side effects, primarily dry mouth. In many cases, the therapeutic advantage is overshadowed by the adverse effects of anticholinergic therapy. Two new medications for the treatment of overactive bladder are being marketed on the basis of improved tolerability. Appell and colleagues1 recently reported the results of a prospective randomized double-blind, placebo-controlled trial comparing the tolerability and effectiveness of extended-release oxybutynin chloride (Detrol XL ) versus tolterodine tartate (Detrol ) in the treatment of overactive bladder. A total of 378 men and women were randomized to receive extended-release oxybutynin 10 mg/day versus tolteradine tartate 2 mg b.i.d. The incidences of dry mouth or any other adverse event were not significantly different between the two drug regimens. The discontinuation rates for adverse events were also not significantly different between the two different agents. Both drugs significantly improved the incidence of urge incontinence per week, the total number of incontinent events over the 12-week study interval, and the micturition frequency. Extended-release oxybutynin chloride was significantly more effective than tolterodine tartate in improving the incidence of urge incontinence and decreasing micturition frequency. Both of the new agents evaluated for overactive bladder appear to reduce adverse events relative to historical agents, such as propantheline and immediate-release oxybutynin. The first direct comparison study of these new agents demonstrates a modest, but clinically significant advantage of extended-release oxybutynin. One criticism of the study is that the long-acting formulation of tolterodine tartate was not utilized. At the time the study was designed, this new formulation of tolterodine tartate was not available. A recent comparative study showed statistically but not clinically significant advantages of the extended-release formulation of tolterodine tartate over the immediate-release formulation.2 Both of the agents have side effects and, in many cases, incontinence and micturition frequency are improved but not eliminated. Thus significant opportunities remain to create a pharmacologic agent that will more effectively relieve overactive bladder with fewer adverse events. References 1. TM TM 2. Appell RA, Sand P, Dmochowski R, et al. Prospective randomized controlled trial of extended-release oxybutynin chloride and tolterodine tartate in the treatment of overactive bladder: results of the OBJECT Study. Mayo Clin Proc. 2001;76:358–363. Van Kerrebroeck P, Kreder K, Jonas U, et al. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001; 57:414–421. VOL. 3 NO. 4 2001 REVIEWS IN UROLOGY 209 Urologic Oncology continued Urologic Oncology Biomarkers for Early Detection and Optimized Treatment for Transitional Cell Carcinoma Reviewed by Stephen J. Freedland, MD, Matthew H. T. Bui, MD, PhD, Debby Chao, BS, Allan J. Pantuck, MD, Amnon Zisman, MD, Arie S. Belldegrun, MD, FACS Division of Urologic Oncology, Department of Urology, University of California School of Medicine, Los Angeles, CA [Rev Urol. 2001;3(4):210–212] © 2001 MedReviews, LLC B ladder cancer, which currently ranks as the fourth most common cancer in men and the eighth most common cancer in women,1 represents an important health problem in the United States. An estimated 54,300 new cases of bladder cancer will be diagnosed in the United States in 2001, with an estimated 12,400 cancer deaths.1 Although the diagnostic capabilities of cystoscopy and biopsy provide adequate diagnosis, they are invasive and costly. Since prostate-specific antigen (PSA) has revolutionized the field of urology, there has been much research to identify an equivalent biomarker for bladder cancer. Though many biomarkers have been discovered and tested, none as yet appears to rival PSA. Moreover, the ideal treatment for various stages of bladder cancer remains undetermined. Can we optimize the treatments for local or advanced tumors and thus increase our therapeutic efficacy? Here we review three timely articles that address these important issues. Biomarker Risk Assessment and Bladder Cancer Detection in a Cohort Exposed to Benzidine Hemstreet GP, Yin S, Ma Z, et al. J Natl Cancer Inst. 2001;93:427–436. Individual risk assessment and the early detection of cancer are of paramount importance, especially for patients with known risk factors. For bladder cancer, the clinical utility of available urine markers and cytology studies has been mostly limited to the screening of patients for recurrent disease or early detection in symptomatic patients. Generally, there are four categories of cellular biochemical markers for bladder cancer: proliferation and differentiation 210 VOL. 3 NO. 4 2001 REVIEWS IN UROLOGY markers (Ki-67, proliferating cell nuclear antigen [PCNA], and cytoskeletal actin), specific oncogenes/growth regulators (c-myc, ras, src, epidermal growth factor receptor [EGFR], and transforming growth factor [TGF]-beta), markers of genetic instability and tumor suppressor genes (DNA ploidy, microsatellite instability, p53), and markers for apoptosis and cell senescence (survivin and telomerase activity). The study by Hemstreet and colleagues tests the hypothesis that biomarkers can be utilized for individual patient risk stratification in a cohort of at-risk patients. The study population was composed of 1,788 Chinese male workers with known occupational exposure to the carcinogenic chemical benzidine and 373 age-matched, randomly selected male workers with no known occupational exposure to the agent. An initial urine sample was obtained from all the workers for routine cytology, urinalysis, and a quantitative fluorescence image analysis for biomarker measurements. The biomarkers chosen were the bladder cancer–associated antigen (p300), DNA ploidy, and a cytoskeletal marker associated with differentiation (G-actin). Based on this initial analysis, the workers were stratified into three risk groups. The high-risk group (n = 179) was positive for two or more biomarkers or extremely positive for any one of the biomarkers and/or positive on cytology and/or hematuria; the moderate-risk group (n = 369) was positive for any one biomarker; the low-risk group (n = 1299) was negative for all biomarkers, cytology, and hematuria. Surveillance schedules were determined by the risk group stratification, with the high-risk group being screened every 6 months by biomarker ± cystoscopy, the moderate-risk group being screened annually with biomarkers only, and the low-risk group being screened at the endpoint of the study at 3 years following the initial screening. For workers who developed bladder cancer, tumor risk assessment was based on biomarker profiles collected 6 to 12 months prior to tumor detection. In the exposed group, 28 workers were diagnosed with bladder cancer (incidence rate of 263.3/100,000 people/year), whereas in the non-exposed group, 2 workers were diagnosed (incidence rate of 87.2/100,000 people/year). Based on the tumor risk assessment, 23 (77%) of the 30 bladder cancer cases occurred in men from the high-risk group and 3 (10%) from the moderate-risk group. The two strongest markers for tumor risk assessment were DNA ploidy, with a sensitivity and specificity of 88% and 87%, respectively, and an odds ratio (OR) of 46; and p300, with a sensitivity and specificity of 50% and 98%, respectively, and an OR of 40. Although highly specific, cytology and urinalysis were poor markers for risk assessment, with sensitivities of 20% and 14% and OR of 18 and 19, respectively. Workers with Urologic Oncology positive biomarkers for DNA ploidy or p300 had 20 times higher risk for developing bladder cancer than workers who were negative for both markers. For workers who were positive for both DNA ploidy and p300, the risk increased to 81 times. G-actin was a poor marker for risk assessment. The average interval from a positive biomarker profile or conventional screening test to clinical tumor detection was 33 months for the moderate-risk group, 15 months for the high-risk group, 8 months for positive cytology, and 3 months for hematuria. This prospective study demonstrated that biomarkers could be utilized for bladder cancer risk assessment and stratification. This prospective study demonstrated that biomarkers could be utilized for bladder cancer risk assessment and stratification. Although only 25% of the workers were stratified into the moderate- to high-risk groups, 87% of the bladder cancers arose in these groups. This distribution supports the basis for patient risk stratification and illustrates the usefulness of identifying the phenotypic and genotypic alterations that precede clinical tumor detection. The screening of at-risk patients with such biomarkers could help determine optimal surveillance schedules as well as the necessity for more invasive screening methods. This study focused on several biomarkers with the potential to predict pre-neoplastic states, but many other biomarkers with known expression in carcinogenesis have also been identified. Finding a single biomarker or incorporating combinations of biomarkers that can be used for risk stratification with high sensitivity and specificity when applied to the general population can expand the role of biomarkers beyond the screening and risk stratification of at-risk patients. Methods to Improve Efficacy of Intravesical Mitomycin C: Results of a Randomized Phase III Trial Au JL, Badalament RA, Wientjes MG, et al. J Natl Cancer Inst. 2001;93:597–604. Mitomycin C adjuvant therapy for superficial bladder cancer by intravesical infusion is employed to prevent progression and recurrence in patients at high risk of recurrence by having multiple tumors, recurrent tumors, high-grade tumors associated with urothelial atypia, or carcinoma in situ. Mitomycin C has been previously reported to prevent the development of invasive bladder cancer in clinical trials.2 However, patient response to mitomycin C in standard dosage and regimen was shown to be less effective than Bacillus Calmette-Guerin (BCG) in the treatment of superficial bladder cancer.3 Currently, the optimum dosage and treatment regimen for mitomycin C is unknown, and therefore it has been empirically based. Au and colleagues hypothesized that the variable patient response rates to mitomycin C are due to inadequate drug delivery to the tumor. The authors attempted to optimize and enhance drug delivery while at the same time comparing the efficacy and toxicity of this approach. The research design includes a prospective, two-arm, randomized, multi-institutional, phase III trial. Three variables were adjusted: drug concentration, urine pH, and urine production rate. In the standard arm, the drug concentration is 20 mg in 20 mL with no patient instruction to refrain from drinking fluids and no attempt to alkalinize the urine. In the optimized arm, the drug concentration was increased to 40 mg in 20 mL, and patients were told to refrain from drinking 8 hours before the administration of mitomycin C. Furthermore, patients were given 1.3 g of oral sodium bicarbonate the night before, the morning of, and 30 minutes before mitomycin C instillation. All patients received the mitomycin C via a Foley catheter. To evaluate efficacy, patients were followed by cystoscopic and cytologic examinations. Mean follow-up was 11.7 months. Tumor recurrence was based on a positive post-treatment biopsy or a positive cytology. The patient populations in the two treatment arms were comparable with respect to demographics and disease characteristics. The only statistically significant differential toxicity between the two treatment arms was increased dysuria in the optimized protocol. However, this did not affect frequency termination. Kaplan-Meier analyses of recurrence showed that across all patients, the median time of recurrence was 11.3 months in the standard arm versus 29.1 months in the optimized arm (P = .002). In the subgroups, there was statistical improvement in the optimized arm for tumors that were multifocal, Ta, papillary, recurrent, primary, grade I/II, and previously treated intravesically. There was no statistical improvement in tumors that were unifocal, T1, Tis, grade III, or prior diagnosed. Furthermore, the authors found an interesting difference in the recurrence data between Caucasian patients (n = 188) and African American patients (n = 6), in that all of the latter recurred in less than 1 year regardless of which treatment arm was used. It is premature to draw a conclusion, because of the low number of African American patients, but this does warrant further investigation. The reduction in tumor recurrence associated with the VOL. 3 NO. 4 2001 REVIEWS IN UROLOGY 211 Urologic Oncology continued optimized treatment arm relative to the standard treatment arm is impressive. Previous studies that directly compared mitomycin C to BCG did not utilize the optimized protocol. It is reasonable to predict that mitomycin C administration using the optimized regimen may be a suitable alternative to BCG, but direct studies comparing these two agents is needed. Randomized Phase III Trial of High-DoseIntensity Methotrexate, Vinblastine, Doxorubicin, and Cisplatin (MVAC) Chemotherapy and Recombinant Human Granulocyte ColonyStimulating Factor Versus Classic MVAC in Advanced Urothelial Tract Tumors: European Organization for Research and Treatment of Cancer Protocol No. 30924 Sternberg CN, de Mulder PH, Schornagel JH, et al. J Clin Oncol. 2001;19:2638–2646 Although chemotherapy is the treatment of choice for advanced transitional cell carcinoma, the exact agents and dosing schedule are unclear. Currently the “gold standard" is a combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). Recently, however, new studies have suggested that alternate treatments may provide similar results with reduced toxicity.4 In the study by Sternberg and colleagues, the authors compared standard MVAC therapy to a high-dose-intensity MVAC (HD-MVAC) regimen using recombinant granulocyte colony-stimulating factor (G-CSF) to reduce toxicity. Patients with bi-directional measurable disease or those with advanced local disease who had not previously received cytotoxic or biological treatment were eligible for enrollment. Adequate renal and liver function and a World Health Organization performance status ≤ 2 was a requirement for enrollment. Patients were randomized to receive either traditional MVAC every 28 days or HD-MVAC every 14 days. Patients given HD-MVAC were treated with 240 g of G-CSF subcutaneously for 7 consecutive days starting on the fourth day of the MVAC cycle. The study was powered to detect a 50% difference in median overall survival. Between 1993 and 1998, 263 patients from 21 European centers were enrolled in this phase II/III trial. The number of patients in the MVAC (n = 129) and HD-MVAC arm (n = 134) were similar, with no differences in patient clinical characteristics or sites or numbers of metastasis. Nearly half the patients had visceral metastasis and three quarters had undergone prior surgery. Over 80% of patients in both groups had bladder cancer, with the remainder split among renal pelvis, ureter, and urethral cancer, with one patient having cancer in the prostatic ducts. There were no differences in overall survival or time to 212 VOL. 3 NO. 4 2001 REVIEWS IN UROLOGY progression between the two treatment groups. Median survival for the HD-MVAC group was 15.5 months compared to 14.1 months for the MVAC group (P = .121). However, patients treated with HD-MVAC had a longer progression-free survival (9.1 months) than patients treated with MVAC alone (8.2 months, P = .037). Moreover, patients treated with HD-MVAC had a higher complete (25% vs. 11%, P = .006) and overall response rate (72% vs. 58%, P = .016). That better response rates did not translate into improved survival highlights the importance of using survival as the most important clinical endpoint in trials of systemic therapies for cancer patients. Despite delivering higher doses of chemotherapy, the HD-MVAC arm was associated with less toxicity. Patients in the HD-MVAC arm had significantly less white blood cell Despite delivering higher doses of chemotherapy, the high-dose-intensity MVAC arm was associated with less toxicity. toxicity (P < .001), and there was a marked reduction in the incidence of neutropenic fever (10% vs. 26%, P < .001). Patients on the HD-MVAC arm also had less mucositis (P = .034). There were no differences in the incidence of treatment-related mortality, with 4% in the MVAC arm and 3% in the HD-MVAC arm. The fact that HD-MVAC was associated with reduced morbidity and increased response rates is noteworthy. Thus, the addition of G-CSF resulted in the ability to give more chemotherapy with reduced toxicity, suggesting that its routine use in standard MVAC regimens may further reduce toxicity. Unfortunately, this did not translate into a survival advantage. Given that this study was designed to detect a 50% difference in overall survival, it remains to be seen whether a larger study with more power to detect a smaller improvement in overall survival would prove statistical significance. However, the difference in median survival between the two arms (15.5 vs. 14.1 months) argues that the benefit of HD-MVAC over MVAC in terms of survival is minimal at best. Thus, the search for an effective therapeutic combination that provides survival benefit over that of standard MVAC continues. References 1. 2. 3 4. Greenlee RT, Hill-Harmon MB, Murray T, et al. Cancer statistics, 2001. CA Cancer J Clin. 2001;51:15–36. Huland H, Otto U, Droese M, et al. Long-term mitomycin C instillation after transurethral resection of superficial bladder carcinoma: influence on recurrence, progression, and survival. J Urol. 1984;132:27–29. Lamm DL, Blumenstein BA, Crawford ED, et al. Randomized intergroup comparison of bacillus Calmette-Guerin immunotherapy and mitomycin C chemotherapy prophylaxis in superficial transitional cell carcinoma of the bladder. Urol Oncol. 1995;1:119–121. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;17:3068–3077. Infertility Infertility Men Undergoing ICSI: Y We Do What We Do Jacob Rajfer, MD Division of Urology, Harbor-UCLA Medical Center, Los Angeles, CA [Rev Urol. 2001;3(4):213] © 2001 MedReviews, LLC Absence of Deletion in Azoospermia (DAZ) Genes in Spermatozoa of Infertile Men with Somatic DAZ Deletions de Vries JW, Repping S, Oates R, et al. Fert Steril 2001;75:476–479 M en with severe oligospermia and/or nonobstructive azoospermia (NOA) require intracytoplasmic sperm injection (ICSI) and in vitro fertilization if they are going to achieve paternity. However, one of the questions that remains unanswered is whether the “genetic" defect that supposedly caused the oligospermia and/or NOA is going to be passed on to the sons of these couples. There is evidence to suggest that deletions in the Y chromosome, which are de novo occurrences, are one of the major factors responsible for this spermatogenic defect. Recent data suggest that this deletion may be passed from father to son, but there has been no information regarding the probability of this event occurring. To help determine the likelihood that such a genetic abnormality may be passed from father to son with ICSI, de Vries et al collected sperm from seven men with either oligospermia or NOA and a deletion in the Y chromosome as seen in their peripheral cells and examined the sperm for this deletion. Using fluorescence in situ hybridization, it was found that all the sperm from these seven men carried the same deletion. This suggests that Y deletions are expressed in the Y sperm of men with this abnormality and that the probability of passing this from father to son is extremely high. These data suggest that all men undergoing ICSI as a result of oligospermia and/or NOA should be tested for the Y deletion and that genetic counseling should be part of the work-up of the couple with this finding. Forthcoming Ar ticles REVIEWS “The Future of Bladder Control" Matthew O. Fraser, PhD, John P. Lavelle, MB, FRCSI, Michael S. Sacks, PhD, Michael B. Chancellor, MD “Laparoscopic Prostatectomy: Where Do We Stand?" Mesut Remzi, MD, Bob Djavan, MD, PhD “Interstitial Cystitis: Characterization and Management of an Enigmatic Urologic Syndrome” J. Curtis Nickel, MD, FRCSC MEETING REVIEW “7th Annual NYU Department of Urology Postgraduate Course" Herbert Lepor, MD VOL. 3 NO. 4 2001 REVIEWS IN UROLOGY 213