CME

CME - The Role, Timing, and Clinical Utility of Hormone Therapy in Prostate Cancer

Learning Objectives

At the conclusion of this activity, participants should be able to:

  • identify patients who could benefit from hormone therapy, 
  • list current hormone therapies available for the treatment of biochemical recurrence as well as advanced and metastatic prostate cancer,
  • discuss the importance of achieving balance among disease control, toxicity minimization, and treatment tolerance,
  • explain the role of monotherapy and combination hormone therapy for advanced prostate cancer, and
  • identify factors influencing the controversies of timing, institution of alternative therapies, and continuous versus intermittent administration of treatment for patients with advanced prostate cancer, castrate-resistant prostate cancer, and biochemical recurrence 

Target Audience

This activity is designed for urologists and other health care professionals interested in or involved with the management of patients with prostate cancer. 

Faculty

Pamela I. Ellsworth, MD (Program Chair)

Associate Professor of Surgery, Division of Urology, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA 

Fred Saad, MD, FRCS

Professor and Chairman of Urology, Director of Urologic Oncology, University of Montreal Endowed Chair in Prostate Cancer, University of Montreal Faculty of Medicine, Montreal, Canada 

Presented by the Warren Alpert Medical School of Brown University, Office of Continuing Medical Education. This activity is supported by an educational grant from Abbott Laboratories. 

Faculty Disclosures

In accordance with the disclosure policy of the Warren Alpert Medical School of Brown University as well as standards set forth by the Accreditation Council for Continuing Medical Education, all speakers and individuals in a position to control the content of a CME activity are required to disclose relevant financial relationships with commercial interests (within the past 12 months). Disclosures of this activity’s speakers and planning committee have been reviewed and all identified conflicts of interest, if applicable, have been resolved. 

Pamela I. Ellsworth, MD, has indicated that she is a consultant/advisory board member for Allergan, Inc., Astellas Pharma US, Inc., and Pfizer Inc. She is a speaker for Allergan, Inc. and Pfizer Inc. 

Fred Saad, MD, FRCS, has indicated that he has received grant/research support from and has served as a consultant/advisory board member for Abbott, Amgen, Astellas Pharma US, Inc., Janssen, Millennium Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, and Sanofi Aventis. 

Activity Staff Disclosures

The planners, reviewers, editors, staff, or other members at Health and Wellness Education Partners and the Alpert Medical School CME Office who control content have no relevant financial relationships to disclose.

Accreditation Statement

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Warren Alpert Medical School of Brown University and Health and Wellness Education Partners. The Warren Alpert Medical School is accredited by the ACCME to provide continuing medical education for physicians. 

Credit Designation Statement

The Warren Alpert Medical School designates this enduring material for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Method of Participation/CME Credit

  • There are no prerequisites or fees for participating in and receiving credit for this activity.
  • Review the learning objectives, faculty information, and CME information.
  • Complete the CME activity.
  • Complete the post-test and activity evaluation at the conclusion of the activity. A minimum score of 80% is required to receive a CME credit certificate. Click here
  • A CME credit certificate will be emailed to you within 4 weeks. 

Program Release: May 29, 2012

Program Expiration: May 31, 2013

Estimated time to complete: 60 minutes

There are no prerequisites for participation. 

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This enduring material is produced for educational purposes only. Content is provided by faculty who have been selected because of recognized expertise in their field. The opinions and recommendations expressed by the faculty whose input is included in this activity are their own. The use of the Warren Alpert Medical School of Brown University name implies oversight and review by the CME Office of educational content, format, design, and approach. Participants have the professional responsibility to review the complete prescribing information of specific drugs or combination of drugs including indications, contraindications, warnings, and adverse effects before administering pharmacologic therapy to patients. The Warren Alpert School of Medicine of Brown University assumes no liability for the information herein.

Contact Information

If you have questions about this CME activity, please contact the Warren Alpert Medical School Office of Continuing Medical Education at 1-401-863-3337 or .

INTRODUCTION

Prostate cancer is the second-leading cause of cancer death in men in the United States, accounting for 28,170 deaths annually [1]. It accounts for approximately 29% of new cancer cases and an estimated 9% of cancer-related deaths in men [1]; most prostate cancer-related deaths are caused by advanced disease. However, with earlier diagnosis and the development of new treatment options for early and advanced disease, there has been a gradual but steady decline in prostate cancer mortality [2,3].

With earlier detection and treatment for disease at all stages, including advanced disease, the age-adjusted incidence of stage IV prostate cancer has been declining [4]. However, with more men living longer with prostate cancer, it is expected that more of them will eventually present with rising prostate-specific antigen (PSA) levels that require further treatment. 

Defining Advanced Disease

Biochemical recurrence, a rise in PSA after treatment with surgery or radiation, occurs in approximately 40% of men receiving localized treatment [5,6], and has become the most common form of advanced prostate cancer [7,8,9]. Other categories of patients also can be defined as having advanced forms of the disease: patients with significant risk for progressive disease and/or death from prostate cancer should be included in the definition of advanced prostate cancer [10]. Likewise, those men with cancer outside the prostate capsule (with disease stages as low as T3/N0/M0) are considered to have advanced disease [11,12]. With high-risk localized disease and biochemical recurrence as common presentations of advanced prostate cancer, most of these patients are entering into treatment long before they develop metastases [10]. In the absence of guidelines for treating patients with advanced disease in whom local therapy has failed, the decision algorithm for initiation of treatment for biochemical recurrence remains controversial. Patient- and drug-related factors to be considered include the previous local therapy, the patient’s life expectancy and quality of life (QOL), the risk for increased morbidity, and the likelihood of cure/palliative therapy.

Treatment of Advanced Disease

Androgen deprivation therapy (ADT), the use of gonadotropin-releasing hormone (GnRH) agonist/antagonists with or without antiandrogens, continues to be first-line therapy in men with advanced and/or metastatic prostate cancer. Once it was approved, GnRH agonist therapy replaced bilateral orchiectomy in initial ADT, because of the potential for reversal and the lack of the emotional stigma associated with surgical castration [13]. Currently, there is a single GnRH antagonist and several GnRH agonists available that vary in their frequency of dosing and method of administration (Table 1). 

A meta-analysis of 24 randomized controlled trials involving more than 6000 patients found that survival with GnRH agonists is equivalent to that after orchiectomy [14]. Although approved for the treatment of advanced prostate cancer, GnRH agonists have been used in other prostate cancer settings, including primary therapy for older patients with locally advanced prostate cancer, treatment of patients with biochemical recurrence after radical prostatectomy or external beam radiation therapy (EBRT), and neoadjuvant or adjuvant treatment for high-risk patients undergoing prostatectomy or EBRT [13]. Notably, ADT has increased steadily throughout the 1990s among men of all ages with prostate cancer who had all stages and tumor grades [15].

The optimal timing for starting ADT in various prostate cancer settings remains controversial, because of the potential for adverse effects (AEs) and emergence of castrate-resistant prostate cancer (CRPC) as a result of widespread and long-term use of treatment. Antiandrogens are approved by the US Food and Drug Administration (FDA) for the treatment of advanced prostate cancer in combination with a GnRH agonist/antagonist (combined androgen-deprivation therapy {CADT}), but they are not approved for use as monotherapy. This article provides a review of the data on the use and timing of ADT (monotherapy with a GnRH agonist/antagonist) and CADT in various prostate cancer settings, as well as the role of intermittent ADT in decreasing AEs, maintaining efficacy, and delaying emergence of CRPC in patients with advanced disease. Side effects of ADT/CADT and ways to prevent or manage them are also discussed. 

Optimal Timing of ADT

Timing of ADT in Advanced Disease

The optimal time to begin ADT in prostate cancer varies with the disease state. The optimal timing in an asymptomatic man with PSA failure alone is not known, but in practice, most men in North America opt for earlier rather than late treatment. Recent literature supports that early intervention with ADT is more beneficial than treatment initiated later in the disease course [16,17]

Patients with advanced disease also appear to benefit from early hormonal therapy. The Medical Research Council in England conducted a randomized controlled trial of 938 patients with locally advanced or asymptomatic metastatic prostate cancer [18]. The trial compared patients who received immediate ADT (orchiectomy or GnRH agonist/antagonist) within 6 weeks of entry versus those who deferred treatment until an indication for ADT occurred. Of the 938 patients, 600 (53%) had nonmetastatic disease at the time of enrollment and had follow-up information available. 

Results showed that immediate ADT significantly improved cause-specific survival of patients with confirmed nonmetastatic disease compared with deferred treatment. The median actuarial cause-specific survival duration was 7.5 years for immediate treatment and 5.8 years for deferred treatment (P = 0.003). Additionally, the incidence of tumor-related morbidity associated with immediate treatment was lower than with deferred treatment [18]

Timing of ADT in Other Settings, With or Without EBRT

Biochemical recurrence, a rise in PSA in prostate cancer patients after treatment with surgery or radiation, is not uncommon. In fact, biochemical recurrences in the setting of prior definitive therapy are estimated to affect approximately 30% of men treated for localized prostate cancer [7,8,9]. The natural history of disease relapse after radical prostatectomy involves development of metastases and eventual death, usually over a period of several years [19]. The optimal treatment of patients with rising PSA (biochemical recurrence) after radical prostatectomy (salvage treatment) or treatment of patients who are at high risk for relapse based on histologic features (adjuvant treatment) is uncertain [20]. Analysis of previously performed studies as well as future studies may help to resolve these issues. 

One study involving men with node-positive prostate cancer (T1 or T2 N1M0) demonstrated that early adjuvant ADT (GnRH agonist/orchiectomy) after radical prostatectomy and lymphadenectomy significantly improved all-cause (P = 0.02) and cause-specific (P < 0.01) survival compared with delayed treatment [16]. Bolla et al noted that patients with high-risk, locally advanced disease (T3 or T4 N0M0 or T1-T2 N1M0) treated with a GnRH agonist started during EBRT and continuing for 3 years also significantly improved all-cause (P = 0.0002) and cause-specific (P = 0.0001) survival compared with EBRT alone [17]

Updated results of the phase 3 Radiation Therapy Oncology Group 85-31 trial evaluating the potential benefit of ADT following standard EBRT for disease in patients with an unfavorable prognosis demonstrated that ADT in addition to definitive EBRT resulted in highly significant improvement in local control, freedom from distant metastases, and biochemical-free survival [21]. Furthermore, the Agency for Health Care Research and Quality (formerly the Agency for Health Care Policy and Research) performed a systematic review of the available randomized clinical trial evidence comparing EBRT with EBRT and prolonged ADT. The review found a difference in 5-year overall survival in favor of EBRT plus ADT using a GnRH agonist or orchiectomy compared with EBRT alone (hazard ratio {HR}, 0.631; 95% confidence interval {CI}: 0.479-0.831) [22].

Sasse and colleagues analyzed data from 10 trials published from 1988 to 2011 (6555 patients) and reported a statistically significant advantage with the use of ADT in terms of overall and disease-free survival compared with EBRT alone [23]. Long-term goserelin (up to 3 years) provided the higher magnitude of clinical benefit. There were no trials evaluating other forms of GnRH agonist/antagonist as monotherapy. Additionally, a Cochrane review evaluating hormone therapy for localized and locally advanced prostate cancer concluded that ADT combined with either prostatectomy or EBRT is associated with significant clinical benefits [24]. Significant long-term control may be achieved when administered prior to prostatectomy or EBRT, which may improve patient QOL. However, these disease-related benefits are associated with significant side effects as well as cost. The optimal duration of ADT treatment remains to be determined. 

Adverse Events and the Emergence of CRPC

The main limitations of ADT include the common side effects of this type of treatment, as well as potential for the emergence of CRPC (androgen-insensitive prostate cancer) when ADT is used long term. In October 2010, the FDA announced that the prescribing information for a GnRH agonist/antagonist would include new warnings on the increased risk for heart disease and diabetes [25].

Major Adverse Effects of ADT

The incidence of some of the adverse effects of ADT is shown in Table 2 [26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49]. Common side effects include skeletal-related complications, metabolic and cardiovascular complications, sexual dysfunction, hot flashes, periodontal disease, cognitive effects, and mood disorders [50-56]. Androgen deprivation therapy decreases bone mineral density, which may lead to an increased risk for skeletal fracture [55,57,58]. The risk may be further compounded by preexisting bone mineral density loss. Lifestyle modifications and other treatments are available to prevent and mitigate bone-related complications in men on ADT. Lifestyle modifications include: smoking cessation, decreased alcohol intake, weight-bearing exercise, and calcium and vitamin D supplementation. 

Zoledronate has been shown to increase bone density in men on ADT [59]. Pamidronate in combination with leuprolide acetate preserved bone density in a small study of men with prostate cancer on leuprolide acetate ADT [60]. Although these and other bisphosphonates have been shown to be effective in preventing bone loss based on bone marrow density studies, most studies have been underpowered and of too short a duration to address fracture issues. 

Denosumab was shown to be effective in bone loss prevention as well as reductions in new osteoporotic fractures in a double-blind, multicenter, 3-year study [61]. Compared with the placebo group, the denosumab group showed significant increases in bone marrow density as early as 1 month and sustained through 36 months. Patients who received denosumab also showed a decreased incidence of new vertebral fractures at 36 months (1.5% vs. 3.9% with placebo, P = 0.006). Rates of adverse events were similar between the groups. Because denosumab can cause hypocalcemia, vitamin D supplementation may be necessary. Other side effects include fatigue, decreased phosphate levels, and nausea [62].

In a review of major AEs associated with ADT in men with prostate cancer, Taylor et al found only 3 studies that met inclusion criteria and investigated diabetes and cardiovascular morbidity secondary to ADT treatment [39]. Using retrospective cohort study designs, all 3 studies reported a significantly increased risk for diabetes (36% to 49%) or cardiovascular morbidity after the start of ADT [34,35,63]

Specifically, Lage and colleagues followed patients for up to 18 months after the start of ADT and noted a significant increase in the risk for diabetes after adjustment for covariates (treatment for 12 months: relative risk {RR}, 1.36; 95% CI, 1.07-1.74; treatment for 18 months: RR, 1.49; 95% CI, 1.12-1.99) [63]. In a retrospective cohort study of a population-based registry, Saigal and colleagues noted that men who underwent ADT had a 20% increased risk for cardiovascular morbidity compared with men who did not undergo ADT. Increased risk for cardiac morbidity was observed within the first 12 months of treatment [35]. For men with metastatic disease, efforts to reduce cardiac risk factors through diet, exercise, or the use of lipid-lowering agents may mitigate some of the risks of ADT. 

Sexual dysfunction (lack of desire, erectile dysfunction) and hot flashes are common side effects of ADT. A variety of therapies have been used for the management of sexual dysfunction and hot flashes (Table 3) [64].

The Emergence of CRPC

Long-term exposure to ADT may lead to resistance, which can result in CRPC, which is defined as 3 consecutive rises in serum PSA of ≥ 10% each after nadir has been reached, castrate levels of serum testosterone (< 50 ng/dL, ideally < 20 ng/mL), and a trial of antiandrogen therapy [65]. In patients on ADT with bone metastases, the median time to symptomatic progression after a rise in PSA level of > 4 ng/mL is approximately 6 to 12 months, with a median time to death of 18 months [66]. Once the patient exhibits symptoms, median survival historically has been approximately 1 year in untreated patients. Fortunately, the advent of new therapeutic options for CRPC has led to significant improvements in survival. Typically, if patients are not responding to therapy with a GnRH agonist/antagonist, an antiandrogen is added.

In practice, serum testosterone levels should be checked in men with increasing PSA levels while receiving a GnRH agonist/antagonist. Based on those results, the GnRH could be changed; surgical castration could be considered with a noncastrate testosterone level > 50 ng/mL. If a castrate testosterone level is observed, an antiandrogen can be added for combination ADT (CADT). The rational for CADT is that androgen production arises from both testicular and adrenal sources, but the GnRH agonist/antagonist affects only the testicular production. Combination therapy would affect the production of testosterone as well as its action. 

Studies have shown mixed results of the impact of CADT. Initial studies suggested that there was a benefit to CADT on both duration of response and survival [67]. Three large studies demonstrated a survival advantage to use of CADT [68-70]; however, the Prostate Cancer Trialists’ Collaborative Group failed to show such an advantage [71]. A Cochrane analysis of combination therapy showed variable results, depending on the study [72]. A comparison of results found with monotherapy versus combination therapy is shown in Table 4 [68,69,70,71,72].

Decreasing Morbidity and Resistance to ADT: The Role of Intermittent ADT

Typically administered on a continuous basis, ADT can be associated with significant morbidity and eventual progression of disease. Efforts to improve morbidity while maintaining efficacy have led to the technique of intermittent ADT (IADT). Guidelines for IADT vary, but the concept is the continuous administration of ADT for a certain time period to sufficiently lower the PSA, followed by a period of cessation of ADT when the PSA rises over time to a predefined level, at which time ADT is resumed (Figure 1 and Figure 2) [73]. Figure 1 is an algorithm for the patient on CADT for decision to start a nontreatment cycle of IADT (i.e., the patient has been on CADT for a defined period of time/PSA nadir, which in this algorithm is 8 months) and is ready to be evaluated for IADT. Figure 2 illustrates a suggested management algorithm for the patient who is in the nontreatment cycle of IADT. These on- and off-treatment cycles are continued until ADT resistance emerges. The goal of IADT is to maintain disease control, but also to allow for periods of time off ADT to decrease morbidity and improve QOL. Studies examining efficacy of IADT and ADT, effects of ADT on QOL, effects of IADT on morbidity and QOL, and duration of response to IADT are reviewed below. 

Clinical Trial Findings With IADT

Several studies on the effects on IADT compared with CADT have been conducted. So-Rosillo et al evaluated the use of IADT in 43 men with nonmetastatic, progressive noncastrate prostate cancer treated with IADT: 21 men had received no prior primary therapy and 22 had developed recurrent disease after previous local therapy [74]. Treatment included use of CADT in 32 men and use of monotherapy (a GnRH agonist) in 11 men. Patients were allowed to stop ADT when: (a) PSA became undetectable, (b) after 9 to 12 months of ADT, or (c) at the patient’s request. Progressive disease and androgen independence were defined by rising PSA despite ADT. Follow-up ranged from 18 to 153 months (median, 68.2 months) from the start of treatment.

Patients spent an average of 50.7% of the time on ADT and 49.3% off ADT. Eleven men developed androgen-independent progressive disease, with a median time to progression of 47 months. Investigators could not identify any potential risk factors for development [74].

Klotz and colleagues conducted a phase 3, open-label, randomized noninferiority trial of IADT versus CADT for PSA progression after radical therapy [75]. Eligible patients had rising PSA > 3.0 ng/mL more than 1 year post radical therapy or salvage EBRT with or without up to 1 year of neoadjuvant ADT for localized disease. Stratification factors included time since EBRT (> 1 to 3 years vs. > 3 years), initial PSA (< 15 vs. > 15 ng/mL), and prior radical prostatectomy or ADT. The primary end point was overall survival; secondary end points included QOL, heart rate, cholesterol levels (total, high-density lipoprotein, low-density lipoprotein), length of nontreatment periods, testosterone and potency recovery. 

In this study, median overall survival was 8.8 versus 9.1 years on IADT and CADT, respectively (HR: 1.02; 95% CI: 0.86 to 1.21; P for noninferiority {HR, IADT vs. CADT: ≥ 1.25} 0.009). Time to hormone refractory status was statistically significantly improved in the IADT arm (HR: 0.80; 95% CI: 0.67-0.98; P = 0.024). Other than reduced hot flashes in patients randomized to IADT, there was no difference in AEs for IADT versus CADT, including myocardial events or osteoporotic fractures [75].

Miller at al. performed a multicenter, randomized, 2-arm study comparing treatment with intermittent goserelin plus bicalutamide versus continuous goserelin plus bicalutamide [76]. The primary endpoint was time to clinical and/or biochemical progression despite androgen suppression. Secondary endpoints were survival time, QOL, and toxicity. After the induction phase of 24 weeks with combined androgen blockade, 335 patients whose PSA decreased < 4 ng/mL or + 90% from baseline were randomized. Approximately two-thirds of patients in both the IADT and CADT arms (65% vs. 66%, respectively) experienced a clinical and/or biochemical progression during the study. The median time to progression was longer for patients on IADT compared with CADT (16.6 months vs. 11.5 months, respectively); however, the difference was not statistically significant (P = 0.1758). The median time to death from any cause was 52.4 months in the IADT group compared to 53.8 months in the CADT arm (P = 0.658). Patient self-assessment of overall health and sexual activity appeared to be more favorable in the IADT arm compared with the CADT arm [76].

Investigators have also explored the role of IADT in patients with CRPC. (Note that in patients with CRPC, ADT is continued while patients undergo additional therapy, such as chemotherapy.) Organ and colleagues conducted a multicenter randomized trial to compare IADT with CADT in patients with CRPC [77]. Patients were randomized 1:2 to CADT or IADT with a GnRH agonist, and were followed every 2 months with clinical assessments, laboratory evaluations, and QOL questionnaires. If the serum testosterone level increased above castrate levels (1.75 nmol/L), the GnRH agonist was resumed. The primary endpoints were overall survival, health-related QOL, and cost. 

In total, 31 patients were followed for a median of 26.8 months. Time to resuming ADT in the IADT arm was a median of 17.9 months. There was no difference in overall or cancer-specific survival or QOL between the IADT and CADT arms at 0 and 12 months; however, the total mean costs at 24 months were significantly lower in the IADT arm [77].

Factors Predicting Response to IADT

Several studies have assessed whether certain factors can predict response to IADT. Howlader and colleagues found that a shorter PSA doubling time during the first or last “off treatment” cycle of IADT was associated with a shorter time to development of CRPC in patients who were treated for biochemical relapse after primary radical prostatectomy or EBRT [78]. Keizman and colleagues noted that pre-treatment PSA doubling time (> 6 vs. < 6), first off-treatment interval PSA doubling time (≥ 3 vs. < 3), and PSA nadir during the first treatment interval (< 0.1 vs. > 0.1) were associated with disease progression [79].

In a study by Strum et al, PSA measurement 1 month after CADT and slow testosterone recovery off CADT were associated with prolonged time off CADT [80]. Chaudhary and colleagues noted that with each consecutive cycle of IADT, there appeared to be a progressive decrease in the time off ADT, despite achieving a low nadir PSA [81]. Lastly, Scholz and colleagues reviewed responses on IADT for the first and subsequent cycle of IADT, and found that, compared with patients who successfully reached undetectable PSA on the second cycle, those failing the second cycle had a significantly lower mean baseline testosterone (387 ng/mL vs. 481 ng/mL, P < 0.001), predominantly clinical stage D disease (4/6 patients vs. 3/25 patients, chi-square = 132, P < 0.001), and a longer time to reach undetectable PSA (median 4.5 months vs. 8.0 months, P = 0.072) [82].

Effects of IADT on Morbidity and QOL

The potential for decreased morbidity and improved QOL were the impetus for consideration of IADT in the management of advanced prostate cancer. Machado and colleagues evaluated the natural history of bone mineral density in patients receiving CADT versus IADT, and noted that CADT induced 50% of the patients to a sustained bone disorder. In the IADT patients who developed osteoporosis after initial administration of ADT (50%), 70% could migrate to osteopenia or normal scan during follow-up (P < 0.05) [83]. In a randomized international phase 3 trial comparing IADT with CADT in men with an increasing PSA > 3.0 ng/mL more than 1 year after radical therapy or salvage radiotherapy with or without up to 1 year of neoadjuvant ADT completed 12 months prior to randomization, IADT was noted to improve several global QOL measures, including physical function (P < 0.01), fatigue (P < 0.01), urinary problems (P = 0.01), hot flashes (P < 0.01), desire for sexuality (P < 0.01), and erectile function (P < 0.01) [73].

CONCLUSION

Androgen deprivation therapy remains the first-line therapy for advanced prostate cancer. Although initially used in men with metastatic prostate cancer, it is more frequently used in men with biochemical recurrence. The role of CADT in the treatment of advanced prostate cancer is controversial; however, it is often employed in men failing GnRH agonist/antagonist monotherapy. ADT is associated with significant side effects, some of which may develop as early as 3 months on therapy, and long-term use is associated with the emergence of CRPC. Thus, investigators have sought ways to decrease the risk of side effects and the emergence of CRPC without affecting survival. Intermittent use of ADT has yielded comparable survival rates compared with continuous ADT, while improving QOL in men with advanced prostate cancer in a variety of settings.

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  28. Smith MR, Lee H, McGovern F, et al. Metabolic changes during gonadotropin-releasing hormone agonist therapy for prostate cancer: differences from the classic metabolic syndrome. Cancer. 2008;112:2188-2194. 
  29. Dockery F, Bulpitt CJ, Agarwal S et al. Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinemia. Clin Sci (Lond). 2003;104:195-201. 
  30. Eri LM, Urdal P, Bechensteen AG. Effects of the luteinizing hormone-releasing hormone agonist leuprolide on lipoproteins, fibrinogen, plasminogen activator inhibitor in patients with benign prostatic hyperplasia. J Urol. 1995;154:100-104. 
  31. Saylor PJ, Smith MR. Androgen deprivation therapy: defining the problem and promoting health among men with prostate cancer. J Natl Compr Canc Netw. 2010;8(2):211-223. 
  32. Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab. 2006;91:1305-1308. 
  33. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2009;32(suppl 1):S62-S67. 
  34. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24:4448-4456. 
  35. Saigal CS, Gore JL, Krupski TL, et al. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer. 2007;110(7):1493-1500. 
  36. Efstathiou JA, Bae K, Speight J, et al. Cardiovascular mortality and duration of androgen deprivation for locally advanced prostate cancer: analysis of RTOG 92-02. Eur Urol. 2008;54:816-823. 
  37. Roach M III, Bae K, Speight J, et al. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long term results of RTOG 8610. J Clin Oncol. 2008;26:585-591. 
  38. Efstathiou JA, Bae K, Shipley WU, et al. Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31. J Clin Oncol. 2009;27:92-99. 
  39. Taylor LG, Canfield SE, Du XL. Review of major adverse effects of androgen-deprivation therapy in men with prostate cancer. Cancer. 2009;115(11):2388-2399. 
  40. Smith MR, McGovern FJ, Zeitman AL, et al. Pamidronate to prevent bone loss in men receiving gonadotropin releasing hormone agonist therapy for prostate cancer. N Engl J Med. 2001;23:7897-7903. 
  41. Diamond TH, Winters J, Smith A et al. The antiosteoporotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade: a double blind, randomized, placebo-controlled crossover study. Cancer. 2001;92:1444-1450. 
  42. Smith MR, Eastham J, Gleason D et al. Randomized controlled trial of zoledronic acid to prevent bone loss in men undergoing androgen deprivation therapy for nonmetastatic prostate cancer. J Urol. 2003;169:2008-2012.
  43. Michaelson MD, Kaugman DS, Lee H et al. Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin Oncol. 2007;25:1038-1042. 
  44. Greenspan SL, Nelson JB, Trump DL, Resnick NM. Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: a randomized trial. Ann Intern Med. 2007;146:416-424. 
  45. Izumi K, Mizokami A, Sugimoto K et al. Risedronate recovers bone loss in patients with prostate cancer undergoing androgen-deprivation therapy. Urology. 2009;73:1342-1346. 
  46. Saad F, Smith MR, Egerdie B, et al. Denosumab for prevention of fracture in men receiving androgen deprivation therapy (ADT) for prostate cancer PC). Presented at: American Society of Clinical Oncology 45th Annual Meeting; May 29-June 2, 2009; Orlando FL. Abstract 5056. 
  47. Smith MR, Morton RA, Malkowicz B, et al. A phase III randomized controlled trial of toremifene to prevent fractures and other adverse effects of androgen deprivation therapy in men with prostate cancer. Presented at: American Association for Cancer Research Annual Meeting; April 18-22, 2009; Denver, CO. 
  48. Watts NB, Lewiecki EM, Miller PD, Baim S. National Osteoporosis Foundation 2008 Clinician's Guide to Prevention and Treatment of Osteoporosis and the World Health Organization Fracture Risk Assessment Tool (FRAX): what they mean to the bone densitometrist and bone technologist. J Clin Densitom. 2008;11:473-477.
  49. Autorino R, Perdona S, D’Armiento M, et al. Gynecomastia in patients with prostate cancer: update on treatment options. http://www.ncbi.nlm.nih.gov/pubmed/16432533. Gynecomastia in patients with prostate cancer: update on treatment options. Prostate Cancer Prostatic Dis. 2006;9(2):109-114. 
  50. Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer (review). JAMA. 2005;294(2):238-244. 
  51. Green HJ, Pakenham KI, Headley BC, et al. Quality of life compared during pharmacological treatments and clinical monitoring for non-localized prostate cancer: a randomized controlled trial. BJU Int. 2004;93(7):975-979. 
  52. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of the “androgen deprivation syndrome” in men receiving androgen deprivation for prostate cancer. Arch Intern Med. 2006;166(4):465-471. 
  53. Famili P, Cauley JA, Greensplan SI. The effect of androgen deprivation therapy on periodontal disease in men with prostate cancer. J Urol. 2007;177(3):921-924. 
  54. Guise TA, Oefelein MG, Eastham JA, Cookson MS, Higano CS, Smith MR. Estrogenic side effects of androgen deprivation therapy. Rev Urol. 2007;9(4):163-180. 
  55. Alibhai SM, Gogov S, Alibhai Z. Long-term side effects of androgen deprivation therapy in men with non-metastatic prostate cancer: a systematic literature review. Crit Rev Oncol Hematol. 2006;60(3):201-215.
  56. Shahani S, Braga-Basaria M, Basaria S. Androgen deprivation therapy in prostate cancer and metabolic risk for atherosclerosis. J Clin Endocrin Metab. 2008;93(6):2042-2049. 
  57. Kiratli BJ, Srinivas S, Perkash I, Terris MK. Progressive decrease in bone density over 10 years of androgen deprivation therapy in patients with prostate cancer. Urology. 2001;57(1):127-132. 
  58. Preston DM, Torréns JI, Harding P, Howard RS, Duncan WE, McLeod DG. Androgen deprivation in men with prostate cancer is associated with an increased rate of bone loss. Prostate Cancer Prostatic Dis. 2002;5(4):304-310. 
  59. Campbell SC, Bhoopalam N, Moritz TE, et al. The use of zoledronic acid in men receiving androgen deprivation therapy for prostate cancer with severe osteopenia or osteoporosis. Urology. 2010;75(5):1138-1143. 
  60. Smith MR, McGovern FJ, Zietman AL, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med. 2001;345(13):948-955. 
  61. Smith MR, Egerdie B, Toriz NH, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361(8):745-755. 
  62. Denosumab [prescribing information]. Thousand Oaks, CA: Amgen Inc; 2011. 
  63. Lage MJ, Barber BL, Markus RA. Association between androgen-deprivation therapy and incidence of diabetes among males with prostate cancer. Urology. 2007;70(6):1104-1108. 
  64. Ellsworth P. 100 Q&A About Prostate Cancer. 2nd ed. Sudbury, MA: Jones and Bartlett Publishers; 2009.
  65. Scher HI, Halabi S, Tannock I, et al; Prostate Cancer Clinical Trials Working Group. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26(7):1148-1159.
  66. Terris MK, Qureshi SM, Rhee A. Prostate cancer – metastatic and advanced prostate cancer. http://emedicine.medscape.com/article/454114. Updated June 22, 2011. Accessed June 27, 2011. 
  67. Labrie F, Belanger A, Cusan L, et al. History of LHRH agonist and combination therapy in prostate cancer. Endocr Relat Cancer. 1996;3:243-278.
  68. Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989;321:419-424.
  69. Denis LJ, Carneiro de Moura JL, Bono A, et al. Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III EORTC trial (30853). EORTC GU Group and EORTC Data Center. Urology. 1993;42(2):119-130.
  70. Janknegt RA, Abbou CC, Bartoletti R, et al. Orchiectomy and nilutamide or placebo as treatment of metastatic prostate cancer in a multinational double-blind randomized trial. J Urol. 1993;149(1):77-83.
  71. Prostate Cancer Trialists’ Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomized trials. Lancet. 2000;355(9214):1491-1498 
  72. Schmitt B, Bennet C, Seidenfeld J, Samdson D, Wilt T. Maximal androgen blockade for advanced prostate cancer (review). Cochrane Database Syst Rev. 2000;(2):CD001526.
  73. Crook JM, O'Callaghan CJ, Ding K, et al. A phase III randomized trial of intermittent versus continuous androgen suppression for PSA progression after radical therapy. Presented at: 2011 American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL. Abstract 4514.
  74. So-Rosillo R, Small EJ, Weinberg V. Intermittent androgen deprivation therapy (ADT) for patients with nonmetastatic prostate cancer: a retrospective review (abstract). J Clin Oncol. 2007;25(18S, Pt I):15635.
  75. Klotz L, O’Callaghan CJ, Ding K, et al. A phase III randomized trial comparing intermittent versus continuous androgen suppression for patients with PSA progression after radical therapy NCIC CTGPR.7/SWOG JPR.7/CTSU JPR.7/UK Intercontinental Trial CRUKE/01/013. Presented at: American Society of Clinical Oncology – Genitourinary Cancer Symposium 2011, February 17-19, 2011; Orlando, FL. Abstract 3.
  76. Miller K, Steiner U, Lingrau A, et al. Randomised prospective study of intermittent versus continuous androgen suppression in advanced prostate cancer (abstract). J Clin Oncol. 2007;25(18S):5015.
  77. Organ M, Wood L, Wilke D, et al. Intermittent androgen-deprivation therapy in the management of castrate-resistant prostate cancer (CRPCa): results of a multi-institutional randomized prospective clinical trial (abstract). J Clin Oncol. 2011;29:(suppl 7):abstract 131. 
  78. Howlader N, Tam S, Etzioni R, Higan CS. PSA doubling time (PSA-DT) during the “off treatment” interval in men with biochemical relapse of prostate cancer treated with intermittent androgen suppression (IAS) (abstract). J Clin Oncol. 2005;23(16S, Pt I):4670.
  79. Keizman D, Huang P, Antonarakis ES, et al. The change of PSA doubling time and its association with disease progression in patients with biochemically relapsed prostate cancer treated with intermittent androgen deprivation. Prostate. 2011;71(15):1608-1615.
  80. Strum SB, Scholz MC. Intermittent hormone blockade (IHB): Optimal induction duration and predictive factors for prolonged time off hormone blockade (HB). Presented at: American Society of Clinical Oncology 34th Annual Meeting; May 17-19, 1998; Los Angeles, CA. Abstract 1204.
  81. Chaudhary, Grossfeld G, Reese D, Carroll P, Small E. Intermittent androgen deprivation (IAD): Patterns of failure in clinically localized prostate cancer (PCA). Presented at: American Society of Clinical Oncology 36th Annual Meeting; May 20-24, 2000; New Orleans, LA. Abstract 1309.
  82. Scholz M, Stru S, Madgen L, McDermed J. Intermittent androgen deprivation (IAD) therapy for prostate cancer (PC): PSA response on cycle 1 (C1) can predict response on subsequent cycle (abstract). Presented at: American Society of Clinical Oncology 35th Annual Meeting; May 15-18, 1999; Philadelphia, PA. Abstract 1359.
  83. Machado MT, Wroclawski ER, del Giglio A. Natural history of bone loss induced by androgen deprivation in hormone sensitive prostate cancer patients: A prospective comparison between continuous and intermittent therapy. Presented at: American Society of Clinical Oncology – Prostate Cancer Symposium 2006; February 24-26, 2006; San Francisco, CA. Abstract 188.

Webinar/CME: Advances in management of castrate-resistant prostate cancer

Presented by the Warren Alpert Medical School of Brown University, Office of Continuing Medical Education.

 

 

 

 

Click Here to View the Webinar

 

Target Audience

This activity is designed for urologists and other healthcare professionals interested in or involved with the management of prostate cancer.

 

 

Educational Objectives

At the conclusion of this activity, participants should be able to:

  • Identify patients with castrate-resistant prostate cancer (CRPC) who could benefit from additional treatment
  • Review current and future modalities available for the treatment of CRPC
  • Discuss therapeutic strategies that may mitigate skeletal-related events (SREs) associated with metastatic prostate cancer and its treatment

 

Faculty

Pamela I. Ellsworth, MD, FACS, Program Chair
Associate Professor of Surgery
Division of Urology
The Warren Alpert Medical School of Brown University
Providence, Rhode Island, USA


Christopher P. Evans, MD, FACS
Professor and Chairman
Department of Urology
University of California, Davis School of Medicine
Sacramento, California, USA


Fred Saad, MD, FRCS
Professor and Chairman of Urology
Director of Urologic Oncology
University of Montreal Endowed Chair in Prostate Cancer
University of Montreal Faculty of Medicine
Montreal, Canada


Support Acknowledgement

This activity is supported by educational grants from Amgen and Dendreon Corporation.

 

Faculty Disclosures

In accordance with the disclosure policy of the Warren Alpert Medical School of Brown University as well as standards set forth by the Accreditation Council for Continuing Medical Education, all speakers and individuals in a position to control the content of a CME activity are required to disclose relevant financial relationships with commercial interests (within the past 12 months). Disclosures of this activity’s speakers and planning committee have been reviewed and all identified conflicts of interest, if applicable, have been resolved.

Pamela I. Ellsworth, MD, indicates that she is a consultant for Allergan, Inc. and Pfizer Inc; a speaker for Pfizer Inc; has participated in speaker training for Novartis Pharmaceuticals Corporation; and has participated in clinical research studies sponsored by Novartis Pharmaceuticals Corporation and Pfizer Inc.

Christopher P. Evans, MD, FACS, indicates that he does not have any relevant financial relationships.

Fred Saad, MD, FRCS, indicates that he has received grant/research support from and has served as a consultant for Amgen and Novartis Pharmaceuticals Corporation.

Activity planners from the Alpert Medical School Office of Continuing Medical Education, Health and Wellness Education Partners, and UroToday have reported that they have no relevant financial relationships with commercial interests.  

 

Accreditation Statement

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Warren Alpert Medical School of Brown University, and Health and Wellness Education Partners. The Alpert Medical School is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

 

Credit Designation Statement

The Alpert Medical School designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only credit commensurate with the extent of their participation in the activity.

 

AAPA Credit

AAPA accepts certificates of participation for educational activities certified for Category 1 credit from AOACCME, prescribed credit from AAFP, and AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 1.5 hours of Category 1 credit for completing this program.

 

Program Release: June 1, 2011

Program Expiration: June 30, 2012

Estimated time to complete: 90 minutes

There are no prerequisites for participation.

 

Method of Participation and How To Receive CME Credit 

  1. There are no fees for participating in and receiving credit for this activity.
  2. Review the activity objectives, faculty information, and CME information prior to participating in the activity.
  3. Complete the CME activity.
  4. For receipt of CME credit, complete the CME posttest and activity evaluation at the conclusion of the activity.
  5. A minimum score of 70% is required to receive a CME credit certificate.
  6. Your CME credit certificate will be emailed to you within four weeks of activity completion.
  7. To complete the posttest and evaluation for this activity and receive CME credit, click here.

 

Privacy Policy

The Office of Continuing Medical Education (CME) and its educational partners protect the privacy of personal and other information regarding participants and educational collaborators. The CME Office maintains its Internet site as an information resource and service for physicians, other health professionals, and the public. The CME Office will keep your personal information confidential when you participate in a CME Internet-based program. CME collects only the information necessary to provide you with the services that you request.

 

Disclaimer

The opinions and recommendations expressed by faculty and other experts whose input is included in this activity are their own. This enduring material is produced for educational purposes only. The use of the Warren Alpert Medical School of Brown University name implies review of educational format, design, and approach. Activity participants have the professional responsibility to review the complete prescribing information of specific drugs or combination of drugs including indications, contraindications, warnings, and adverse effects before administering pharmacologic therapy to patients. The Warren Alpert Medical School assumes no liability for the information herein.

 

To Receive CME Credit

To complete the posttest and evaluation for this activity and receive CME credit, click here.

 

Click Here to View the Webinar

 

CME - Frequently Asked Questions in Improving Detection and Initial Treatment of Bladder Cancer

Presented by the Warren Alpert Medical School of Brown University, Office of Continuing Medical Education.

Target Audience

This activity is designed for urologists and other healthcare professionals interested in or involved with the management of bladder cancer.

Educational Objectives

Upon completion of this activity, participants should be able to:

  • Discuss the epidemiology of bladder cancer including prevalence, mortality, and risk factors
  • Describe the economic impact of bladder cancer and how improved techniques for initial detection and at the time of transurethral resection of bladder tumor (TURBT) may decrease the economic burden
  • Compare and contrast new urine biomarkers when compared to urine cytology
  • Discuss the role of photodynamic diagnosis using hexaminolevulinate-guided fluorescence cystoscopy in detecting carcinoma in situ and residual disease at the time of TURBT compared to traditional white-light cystoscopy (WLC)
  • Optimize use of intravesical therapy after TURBT to prevent recurrence of bladder cancer and treat patients who do not respond to bacillus Calmette-Guérin (BCG) therapy
  • Discuss potential future treatment methods for patients with bladder cancer

Faculty

Pamela I. Ellsworth, MD, FACS, Program Chair

Associate Professor of Surgery

Division of Urology

The Warren Alpert Medical School of Brown University

Providence, Rhode Island

 

Muhammad Choudhury, MD, FACS

Professor and Chairman

Department of Urology

New York Medical College

Valhalla, New York

Support Acknowledgement

This activity is supported by educational grants from ENDO Pharmaceuticals and GE Healthcare.  

Faculty Disclosures

In accordance with the disclosure policy of the Warren Alpert Medical School of Brown University as well as standards set forth by the Accreditation Council for Continuing Medical Education, all speakers and individuals in a position to control the content of a CME activity are required to disclose relevant financial relationships with commercial interests (within the past 12 months). Disclosures of this activity’s speakers and planning committee have been reviewed and all identified conflicts of interest, if applicable, have been resolved. 

Pamela I. Ellsworth, MD, is a consultant for Allergan, Inc. and Pfizer Inc; she is a speaker for Pfizer Inc; she has participated in speaker training for Novartis Pharmaceuticals Corporation; and she has participated in clinical research studies sponsored by Novartis Pharmaceuticals Corporation and Pfizer Inc. 

Muhammad Choudhury, MD, has disclosed no relevant financial relationships. He does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States in his presentation.

Accreditation Statement

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Warren Alpert Medical School of Brown University and Health and Wellness Education Partners. The Alpert Medical School is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.  

Credit Designation Statement

The Alpert Medical School designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.  

AAPA Credit

AAPA accepts certificates of participation for educational activities certified for Category 1 credit from AOACCME, prescribed credit from AAFP, and AMA PRA Category 1.5 Credits™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 1.5 hour of Category 1 credit for completing this program.  

Program Release: September 1, 2011

Program Expiration: September 30, 2012

Estimated time to complete: 90 minutes

There are no prerequisites for participation.

Method of Participation and How To Receive CME Credit

  • There are no fees for participating in and receiving credit for this activity.
  • Review the activity objectives, faculty information, and CME information prior to participating in the activity.
  • Complete the CME Activity.
  • For receipt of CME credit, complete the CME posttest and activity evaluation at the conclusion of the activity.
  • A minimum score of 80% is required to receive a CME credit certificate.
  • Your CME credit certificate will be emailed to you within four weeks of activity completion.
  • To complete the posttest and evaluation for this activity and receive CME credit, click here

Privacy Policy

The Office of Continuing Medical Education (CME) and its educational partners protect the privacy of personal and other information regarding participants and educational collaborators. The CME Office maintains its Internet site as an information resource and service for physicians, other health professionals, and the public. The CME Office will keep your personal information confidential when you participate in a CME Internet-based program. CME collects only the information necessary to provide you with the services that you request.

Disclaimer

The opinions and recommendations expressed by faculty and other experts whose input is included in this activity are their own. This enduring material is produced for educational purposes only. The use of the Warren Alpert Medical School of Brown University name implies review of educational format, design, and approach. Activity participants have the professional responsibility to review the complete prescribing information of specific drugs or combination of drugs including indications, contraindications, warnings, and adverse effects before administering pharmacologic therapy to patients. The Warren Alpert Medical School assumes no liability for the information herein.

To Receive CME Credit

To complete the posttest and evaluation for this activity and receive CME credit, click here. 

Introduction

As the fourth most common malignancy in the United States, bladder cancer results in nearly 15,000 deaths annually. Bladder cancer has the highest lifetime treatment costs per patient of all cancers, followed by colorectal, breast, prostate, and lung cancers. The tremendous human, psychological, and economic burden that follow a bladder cancer diagnosis underscores the importance of optimizing diagnostic and treatment protocols.

In this expert interview, UroToday® faculty experts—Pamela I. Ellsworth, MD, FACS, and Muhammad Choudhury, MD, FACS—will address some questions and challenges regarding the detection and initial treatment of bladder cancer.


Q1

UroToday: How common is bladder cancer? What are the trends in incidence and mortality of bladder cancer?

Bladder cancer is a common malignancy affecting both men and women, but men more commonly. In US men, bladder cancer is the fourth most common cancer and ranks eighth among cancer-related causes of death (Figure 1) [1]. It has been estimated that in 2011 there will be 52,020 new cases of bladder cancer in men and 17,230 new cases in women. In addition, nearly 15,000 deaths related to bladder cancer will occur in men and women in 2011 [2]. Based on rates from 2005 to 2007, the lifetime risk for being diagnosed with bladder cancer among men and women born today is 2.39%; 1.17% of men will develop bladder cancer between 50 and 70 years of age compared to 0.34% of women [3].

Figure 1. Leading Sites of New Cancer Cases and Deaths—2011 Estimates [1]  Enlarge Image

American Cancer Society. Cancer Facts and Figures 2011. Atlanta: American Cancer Society, Inc. 

Surveillance Epidemiology and End Results (SEER) incidence data from 2004 to 2008 demonstrated that the median age at diagnosis for bladder cancer was 73 years, and white men and women had a higher incidence compared with black, Asian/Pacific Islander, American Indian/Alaska Native, and Hispanic men and women [2]. Similarly, death rates by race were higher among white men; however, black women had a higher death rate than white women (2.7/100,000 vs 2.2/100,000). Bladder cancer incidence declined in women from 2004 to 2008, although there has been no change in the bladder cancer rate among men from 1986 to 2008. There appears to be a decrease in the mortality trend for both men and women from 1977 to 2007 [2].


Q2

UroToday: Bladder cancer management is known to be highly resource intensive. Will new techniques in bladder cancer detection and initial treatment impact the serious economic impact of bladder cancer?

Bladder cancer is associated with the highest lifetime treatment cost per patient of all cancers, followed by colorectal, breast, and lung cancer [3,4]. Bladder cancer also has the fifth highest overall cost, estimated at 3.4 billion dollars annually with 2.9 billion related to direct treatment-related costs per patient [4,5]. Avritscher and colleagues estimated that the lifetime mean treatment cost was $99,270 for muscle-invasive bladder cancer (MIBC) patients and $120,684 for non-muscle-invasive bladder cancer (NMIBC) patients [6]. The annual average of hospitalization days per year for patients with MIBC is more than 27 times higher than for patients with NMIBC (36 vs 1.3 days, respectively) [6]. In this study, the mean cost of bladder cancer was $65,158; 50% of the total cost ($32,559) was attributable to admissions and surgical procedures, whereas surveillance for and treatment of local recurrences accounted for 60% ($39,393). Also, 30% of the total cost ($19,811) was related to treatment of complications, 26% ($16,934) for MIBC, and 4% ($2312) for NMIBC [4,6].

The economic impact of disease progression is also significant. Treatment costs for patients with MIBC are nearly 3 times those for patients with stage Tis/Ta, and twice those for patients with T1 bladder cancer [4].

Several strategies have been proposed for reducing the economic burden of bladder cancer:

  • Use of urine-based markers to identify incident or recurrent tumors earlier [7];
  • Use of outpatient facilities for transurethral resection of bladder tumor (TURBT) reducing hospitalizations if surgical risks can be minimized [7]; and
  • Improvement in the efficacy of intravesical treatments.

In addition, photodynamic diagnosis (PDD) has been proposed as a tool to improve the efficacy of initial TURBT and potentially decrease the residual risk for NMIBC [4,8,9]. TURBT is the largest bladder cancer expenditure and accounts for 71% of treatment costs in the United Kindgom [7]. The quality and result of the initial TURBT can have a significant effect on the bladder cancer patient’s overall prognosis and treatment costs. Several studies have concluded that the use of PDD can help to reduce the cost of bladder cancer treatment.

Daniltchenko and colleagues hypothesized that the initial PDD costs can be offset by a reduction in the number of TURBT follow-up visits [10]. In a prospective series of 115 patients without adjuvant treatment, recurrence rates after 5 years were 50% after PDD and 75% after white-light cystoscopy (WLC). It was estimated that, over a 5-year period, use of PDD avoided at least 20 additional TURBTs. The authors concluded that the benefits of PDD outweighed the initial costs [10]. Similarly, 2 European studies have demonstrated an economic benefit with use of PDD. Malmstrom and colleagues concluded that use of PDD in high-risk patients could save as much as 500,000 euros ($665,000) in the first year alone. Further, if PDD were used for all TURBTs in high- and medium-risk patients, the first year savings would be approximately 450,000 euros ($536,650) and 363,000 euros ($482,790), respectively [11]. A German study also demonstrated that PDD significantly reduces costs related to recurrent NMIBC [12].

Early detection of incident and recurrent disease has a key role in decreasing the risk and cost of disease progression [4]. Currently, WLC is the primary approach for diagnosis and surveillance of bladder cancer. It is estimated, however, that 10% to 20% of bladder tumors are missed during WLC [13]. Urine cytology might help with detection of bladder cancer; however, it lacks the immediate result warranted during TUR. Emerging technologies such as PDD and adjuvant intravesical therapies including mitomycin C and bacillus Calmette-Guérin (BCG) may help to improve the diagnosis of bladder cancer and decrease the risk for recurrence and progression [4].


Q3

UroToday: Although cystoscopy is the “gold standard” for the detection of bladder cancer, it is costly and invasive. What are the advantages and disadvantages of various urine markers for diagnosing or monitoring bladder cancer?

Flexible cystoscopy remains the primary diagnostic tool for detecting bladder cancer because it confers a low risk for infection and injury, causes minimal discomfort, and can be performed routinely in the physician’s office under local anesthesia. However, the procedure provokes anxiety in many patients, visibility can be reduced by bleeding, and small tumor and flat lesion (eg, carcinoma in situ) can be difficult to distinguish from normal tissue [14,15]. For these reasons, use of adjunctive urine tumor markers as in urine cytology can assist in identifying occult cancer. Cytology is used commonly to monitor tumor recurrence in patients with a previous diagnosis of bladder cancer, in the initial assessment of patients who present with hematuria or irritative voiding symptoms to rule out (or in) bladder tumor, and following TURBT to assess the adequacy of treatment [16]. Unfortunately, the usefulness of urine cytology is limited by its low sensitivity especially in low-grade NMIBC [17].

In recent years, numerous urine-based biomarkers have been evaluated to determine whether these tests can complement or replace the existing “gold standard” cystoscopy and urine cytology in monitoring patients at risk for recurrent bladder cancer.

An ideal biomarker for urothelial cancer should have high sensitivity and specificity and should be based on a voided urine specimen, cost effective, easy to interpret, and available as a point-of-care test. 

URINE BIOMARKERS

The biomarkers shown in Table 1 are FDA approved and available for clinical use. A brief review of the molecular basis for the test, published results, and the advantages and disadvantages of each test is provided.

 

Table 1. Current FDA-Approved and Commercially Available Bladder Tumor Markers

 

Marker

Target

Point of Care

Comment

BTA stat®

Complement factor H–related protein

Yes

  • Low specificity among patients with benign urologic conditions

BTA TRAK® Assay

Complement factor H–related protein

No

  • Same as BTA stat (above)

FISH

Chromosomes 3, 7, 17, and 9p 21

No

  • High specificity
  • May predict tumor recurrence before cytologic abnormalities appear
  • Sensitivity unclear

ImmunoCyt™

Sulfated cellular mucin glycoprotein and glycosylated carcinoembryonic antigen

No

  • Low specificity compared to cytology
  • Difficult to interpret

NMP22® BladderChek® Test

Nuclear matrix protein

Yes

  • Low specificity compared to cytology
  • Hematuria and pyuria lead to
    false-positive results

 

FISH, fluorescent in situ hybridization.

 

Nuclear Matrix Protein 22 (NMP22)

Nuclear matrix proteins (NMPs)are part of the mitotic apparatus of the cell, which consists of a 3-dimensional web of RNA and protein that supports the nuclear shape; organizes DNA; and coordinates DNA replication, transportation, and gene expression [18,19]. NMP22 may be present at up to 25-fold higher concentration in tumor cells than in normal urothelial cells [20,21]. NMP22 is released from the nuclei of the tumor cell during apoptosis into the urine and the level can be measured at point of care.

Advantages

In a 15-study meta-analysis, the reported sensitivity of NMP22 was 73%, compared with 34% for urine cytology [22]. Other studies have reported estimated sensitivity of NMP22 ranging from 32% to 100% when the test was used alone or in conjunction with urine cytology for surveillance of bladder tumor [23]. Overall, NMP22 has a higher sensitivity than urine cytology especially in the detection of low-grade and low-stage bladder tumors.

The point-of-care NMP22® BladderChek® test has shown sensitivities ranging from 40% to 90% [24,25,26,27,28]. In addition, the point-of-care test does not require expert analysis or laboratory time, is not dependent on intact cells, and provides unambiguous results [24].

Disadvantages

The same studies point out the lower specificity of NMP22 when compared with urine cytology. The median specificity in a meta-analysis was 80% compared to 99% for cytology [22]. Major sources of false positive results with NMP22 are related to hematuria and pyuria common with many benign urologic conditions [29].

Multitarget Multicolor FISH Assay

Chromosomal abnormalities in urothelial tumors can be detected by fluorescent in situ hybridization (FISH) using DNA probes to chromosome centromeres or unique loci that are altered in tumor cells [30].

The Vysis® UroVysion test is a multi-target, multicolored FISH assay that uses probes to identify aneuploidy of chromosomes 3, 7, and 17, combined with a probe to the 9p21 locus. This combination of probes has been shown to have the best sensitivity and specificity [31].

Advantages

Most studies report high specificity with the Vysis UroVysion test, ranging between 75% and 100%, which is comparable to cytology [30,32,33,34,35,36,37]. The test appears to maintain its high specificity among patients with a variety of benign urology conditions including microhematuria, benign prostatic hyperplasia (BPH), infection, and inflammation [34,38,39].

The test may also be able to predict tumor recurrence before urinary cytology. Skacel and colleagues reported that 8 of 9 patients with positive FISH test, atypical cytology, and negative bladder biopsy had biopsy-proven recurrence of bladder cancer within 12 months [40].

Overall, the specificity of urine FISH test is high and comparable to that of cytology. FISH testing may also predict tumor recurrence before cytology becomes abnormal. Thus, it may prove useful in surveillance for recurrent tumor in patients with normal cytology. The test can also be used as a confirmatory test for patients with atypical cytology.

Disadvantages

Most recent studies have reported sensitivity of the Vysis UroVysion test in the range of 30% to 86% [32,41,42,43]. The assay has increased sensitivity for detecting higher grade and higher stage tumors, however, the sensitivity for detecting lower grade tumors is not clear [30]. Lack of consensus on the criteria used to evaluate abnormal urothelial cells, relatively high cost and the need for specialized laboratory to perform the test are other drawbacks.

ImmunoCyt

The ImmunoCyt™ test is a combination of cytology and immunofluorescent assay. Using monoclonal antibodies, the test detects tumor-associated antigens that are present in urothelial carcinoma. Two fluorescent labeled monoclonal antibodies are targeted at mucin antigens expressed on most bladder cancer cells but not on normal transitional epithelial cells. A third probe detects a glycosylated form of high molecular carcinoembryonic antigen that is present in bladder cancer cells [44,45].

Advantages

The ImmunoCyt test for bladder tumor has a reported sensitivity of 67% to 100% for all tumors, which is an improvement over conventional cytology [30,44,45,46,47,48,49,50]. One of the 3 antibodies used in this test appears to be quite sensitive for low-grade tumor cells and thus may offer an important advantage for detecting low-grade tumors [30].

Disadvantages

The main drawback of the ImmunoCyt test is its low specificity—63% compared with 97% for cytology and 90% for Vysis UroVysion [30]. Moreover, the interpretation of the test may be difficult for many cytologists, and false-positive results have been reported in patients with urinary tract obstruction secondary to stone or BPH. 

Bladder Tumor Antigen (BTA)

The qualitative point-of-care test BTA stat® and the quantitative BTA-TRAK assays detect human complement factor H–related protein. BTA stat is an immunoassay that can be performed in 5 minutes, whereas BTA TRAK® is a standard enzyme-linked immunosorbent assay (ELISA) that quantitatively measures the amount of complement factor H–related protein and complement factor H in urine [51].

Advantages

The overall sensitivity of BTA testing ranges from 9.3% to as high as 89%, with higher sensitivity in higher-grade tumors [38,52,53,54,55,56]. BTA stat also has the advantage of being a point-of-care test. 

Disadvantages

The BTA stat has low specificity (approximately 50%) among patients with urinary tract infections, urinary calculi, nephritis, cystitis, BPH, hematuria and proteinuria [55,57,58,59]. The low specificity in these conditions is secondary to the test’s ability to detect both complement factor H–related protein and complement factor H. Complement factor H is present in human serum at high concentrations and therefore BTA stat testing may be falsely positive in benign, hematuria-causing conditions [19]

Markers Under Investigation

A number of biomarkers are under investigation and have not yet received FDA approval. A selection of these biomarkers is described in Table 2.

Table 2. Biomarkers Under Investigation

In summary, review of data on urine biomarkers for the detection of bladder cancer reveals that several have higher sensitivity than cytology, but most of these markers have lower specificity than cytology. An ideal biomarker must have both high sensitivity and high specificity. Unfortunately, none of these biomarkers meets this standard currently. Some biomarkers can be used to complement the present gold standard of cystoscopy and urine cytology, but none is ready to replace them. 


Q4

UroToday: What is hexaminolevulinate-guided fluorescence cystoscopy? What is its role in the evaluation of bladder cancer?

The rationale for the use of photosensitizing drugs is based on the preferential accumulation of a photosensitizing compound in cancer cells. This compound emits fluorescence in the red part of the spectrum under blue-violet excitation or illumination and enhances detection of the tumor. The first prodrug used for this purpose was 5-aminolevulinic acid (5-ALA). Although 5-ALA itself has no photochemical activity, it induces the formation of endogenous photoactive porphyrins. Protoporphyrin IX is a photoactive derivative of ALA. Hexaminolevulinic acid (HAL) is a more potent ester of aminolevulinic acid that provides better selectivity, brighter fluorescence, and permits a shorter instillation time [70].

Hexaminolevulinate was approved the FDA on May 28, 2010, for the detection of NMIBC or suspected bladder cancer. Fluorescence-guided biopsy and resection have been confirmed as more sensitive than conventional procedures in detecting malignant tumor, particularly CIS [71,72,73].

Technique

The Cysview kit contains a 10 mL vial of 100 mg powder of hexaminolevulinate and a 50 mL vial of diluent [74]. The reconstituted solution is administered intravesically and retained for 1 hour. Standard WLC (Figure 2a) and blue light cystoscopy (Figure 2b) using a D-light cystoscope (Karl Storz, Germany) is then performed. 

Figure 2a. Cystoscopic Examination With White Light

Figure 2b. Cystoscopic Examination With Blue Light

Images courtesy of Priv. Doz. Dr. med. Maximilian Burger Oberarzt, Klinik für Urologie der Universität Regensburg am Caritas- Krankenhaus St. Josef. Provided via GE Healthcare.

Hexaminolevulinate should not be used in patients with porphyria, gross hematuria, BCG immunotherapy or intravesical chemotherapy within the past 90 days, or a known hypersensitivity to HAL or ALA derivatives. Caution should be used in administering hexaminolevulinate to pregnant women and nursing mothers as there is no human or animal data available regarding its use in these populations. The safety and efficacy of hexaminolevulinate has not been established in pediatric patients [74].

Side effects of hexaminolevulinate are infrequent and most commonly minor in severity. The most common adverse effect was bladder spasm occurring in < 3% of patients and dysuria, hematuria, bladder pain, procedural pain, urinary retention and headache, all occurring in ≤ 2% patients. False fluorescence may occur due to inflammation, cystoscopic trauma, scar tissue or previous bladder biopsy [74]

Efficacy

Efficacy of PDD is evaluated by (1) detection of tumors and subsequent resection and (2) tumor recurrence. In a review of the literature, Witjes and colleagues concluded that HAL PDD provides considerable benefits versus WLC in the detection of NMIBC [75]. Furthermore, the benefits are most pronounced for CIS. The ability to detect CIS is approximately 28% greater with the addition of HAL PDD added to WLC compared to WLC alone [71]. Jocham and colleagues demonstrated the clinical benefit of an improved tumor detection rate. In their prospective, phase 3 multicenter study they found that PDD resulted in more complete treatment in 17% of patients (P < .0001) [76]. Mowatt and colleagues performed a systematic review of the effectiveness of PDD at the time of primary TURBT and noted that PDD enhances more complete resection rates and as a result prolongs recurrence-free survival compared with WLC [77]. In 3 trials evaluating tumor-free recurrence rates, PDD was associated with fewer recurrences, and the recurrence-free survival rate was 15.8% to 27% higher at 12 months and 12% to 15% higher at 24 months in the PDD groups than in the WLC-only groups [78,79,80].

Outpatient cystoscopy is typically performed with flexible cystoscopes. Data on the efficacy of PDD has been based on rigid cystoscopy. Loidl and colleagues performed a prospective controlled, within-patient comparison of flexible HAL cystoscopy with standard flexible cystoscopy, HAL rigid and standard white-light rigid cystoscopy. In the 45 patients studied 41 (91%) had exophytic tumors, of which 29 (95.1%) were detected by HAL flexible cystoscopy and 40 (97.5%) by HAL rigid cystoscopy. Seventeen (38%) patients had concomitant or CIS only; of these patients, CIS was identified by HAL flexible cystoscopy in 14 (82.3%), HAL rigid cystoscopy in 15 (88.2%), flexible WLC in 11 (64.7%), and rigid WLC in 13 (76.7%). Thus, HAL flexible cystoscopy was superior to WLC and comparable to HAL rigid cystoscopy in detecting papillary and flat lesions in bladder cancer patients [81].


Q5:

UroToday: What is the role of intravesical therapy after TURBT in the management of bladder cancer? What are current and emerging agents being used in intravesical therapy after TURBT?

Although TURBT is the gold standard for the initial diagnosis and treatment of NMIBC, intravesical therapy has become an integral component in the management of NMIBC [82].

Intravesical therapy is used to reduce and/or delay the risk for recurrence [83,84,85,86,87,88], prevent progression of disease, and as adjunctive therapy in Tis where diffuse tumor prevent complete tumor resection [89,90]. Most of the commonly used intravesical therapies for NMIBC can be categorized in 2 groups, immunomodulatory agents and chemotherapeutic agents, primarily based on their mechanism of action. Table 3 describes the mechanism of action and dosing for commonly used immunotherapeutic and chemotherapeutic agents. 

Table 3. Intravesical Therapy

 

Selection of an agent for intravesical therapy is dictated by the risk for recurrence and progression in an individual patient. For tumors with a high risk for recurrence but low risk for progression (i.e., multiple recurrent Ta G1 tumors), either intravesical chemotherapy or BCG might be given [91]. For other tumors that have a high risk for recurrence and progression (i.e., multiple recurrent T1 G3 tumors), intravesical BCG with maintenance BCG therapy might be initiated.

Treatment guidelines have been published on risk stratification for the management of NMIBC [92,93,94,95,96]. The International Bladder Cancer Group (IBCG) developed treatment algorithms for the management of patients with low-, intermediate-, and high-risk NMIBC (Figures 3-5) [97].

Figure 3. Algorithm for the Treatment and Management of Low-Risk NMIBC

*Except in those with overt or suspected bladder wall perforation. 

†Decision should be based on multifocality, size, grade, and stage.

Lamm DL. Oncology. 1995;9:947-952.


Figure 4. Algorithm for the Treatment and Management of Intermediate-Risk NMIBC

*Except in patients with overt or suspected bladder wall perforation.

†Decision should be based on grade, stage, size of tumor, and multifocality.

Lamm DL. Oncology. 1995;9:947-952.


Figure 3. Algorithm for the Treatment and Management of High-Risk NMIBC

 

Lamm DL. Oncology. 1995;9:947-952.

 

Immunotherapeutic Agents

BCG

BCG, a live, attenuated strain of mycobacterium bovis, is widely used as an intravesical immunotherapy against NMIBC since the 1970s. BCG is the first-line treatment for CIS and has been shown to be effective as prophylaxis to prevent recurrence following TURBT [98,99,100,101].

Initiation of intravesical BCG therapy is usually delayed for 2 to 3 weeks following TURBT to allow for healing of the urothelium and thereby decrease the risk for systemic side effects. Meta-analysis suggests that maintenance BCG therapy should be administered [92], but the optimal schedule and duration of therapy is not well-defined. The best available evidence, however, supports the use of the SWOG regimen comprising a 6-week induction cycle followed by a 3-week maintenance course at 3, 6, 12, 18, 24, 30, and 36 months, if tolerated by the patient [92,102].

Interferon

Recombinant interferon alpha-2b has been used as monotherapy and in combination with low-dose BCG therapy to treat patients with NMIBC [103,104,105,106]. Phase 2 trials have suggested durable response in both BCG-naïve and BCG-refractory patients, but long-term randomized trials have yet to be conducted to validate the results [92].

Chemotherapeutic Agents

Thiotepa

Thiotepa (triethylenethiophosphoramide) is an alkylating agent. Introduced in 1961, thiotepa is the oldest and one of the least expensive of the intravesical agents. The usual regimen consists of 6 to 8 weekly instillations followed by monthly instillations for 1 year [92]. Absorption though the urothelium may lead to systemic side effects—specifically myelosuppression—thus, monitoring of leukocyte and platelet count is needed before each instillation, and treatment should be delayed, if necessary. 

Mitomycin C

Mitomycin C is an antibiotic that inhibits DNA synthesis. Myelosuppression and other systemic side effects are rare. Meta-analysis by the AUA guidelines panel have demonstrated a relative recurrence risk reduction of 17% with a single perioperative dose of mitomycin C in patients with NMIBC with both low- and high-risk features [85,92]. Perioperative mitomycin C should not be administered to patients with a known or suspected bladder perforation following TURBT. 

Intercalating Agents (Doxorubicin, Epirubicin, and Valrubicin)

Doxorubicin is an anthracycline derivative. Absorption from the bladder and systemic toxicities are extremely rare following intravesical therapy.

Epirubicin is not currently available in the United States. 

Valrubicin, a semisynthetic analogue of doxorubicin, is approved by the US FDA for intravesical therapy of BCG-refractory CIS of the bladder. Upon intravesical administration, valrubicin rapidly traverse cell membranes and accumulates in the cytoplasm, where it interferes with the incorporation of nucleoside into the nucleic acids, resulting in chromosomal damage and cell cycle arrest in G2 [107]. The metabolites of valrubicin also inhibit DNA synthesis. The response rate with intravesical valrubicin in patients with BCG-refractory CIS of the bladder is modest (18%) [108]. Thus, valrubicin is used in patients who refuse or are unfit for cystectomy. 

Newer Approaches

Gemcitabine

The chemotherapeutic agent gemcitabine is an antimetabolite analog of the nucleoside pyrimidine. Intravesical gemcitabine has been shown to have activity in NMIBC [109,110,111,112]. A recent randomized prospective study comparing intravesical BCG versus gemcitabine in high-risk superficial bladder cancer demonstrated that gemcitabine is significantly inferior to BCG. At a median followup of 44 months, the recurrence rate in patients treated with BCG was 28.1%, compared to 53% in patients who received gemcitabine (P = .037) [113]. Gemcitabine may be useful in patients intolerant to or otherwise unable to receive BCG. 

A phase 2 trial of intravesical gemcitabine in 30 patients with BCG refractory/intolerant disease who refused cystectomy, showed a 50% complete response (95% CI, 32, 68), and one year recurrence-free survival rate of patients with CR was 21% (95% CI, 0, 43) [111]. 

Docetaxel

Docetaxel is a microtubule, depolymerization inhibitor with antitumor activity. In a dose escalation study 18 patients were treated. Ten (56%) of 18 patients had no evidence of disease at their post-treatment cystoscopy and biopsy [114]. Intravesical docetaxel appeared to be safe and well tolerated. Further studies and long term follow-up is needed. 

Other Emerging Agents

Other emerging agents include nab-paclitaxel, UrocidinTM, and apaziquone. Nab-paclitaxel is a novel agent in the taxane family that has been modified with the addition of albumin particles to form nanoparticles to increase solubility and facilitate drug delivery to tumor cells via biological interaction with albumin receptors that mediate drug transport across epithelial cells. In a phase 1 trial of 18 patients with BCG-refractory NMIBC using intravesical nab-paclitaxel, 5 patients (28%) had no evidence of disease at posttreatment cystoscopy [115]

Urocidin, a mycobacterial cell wall-DNA complex (MCC) formulation, that acts dually to stimulate immunity and has direct anticancer activity, is also being studied as a treatment for patients with bladder cancer. A recent Phase 3 trial demonstrated efficacy and safety of MCC in patients with NMIBC who were refractory to intravesical BCG therapy and at high risk of progression [116]

Apaziquone is another promising future therapy for the treatment of NMIBC. In a study that included 46 patients who had previously failed multiple therapies, apaziquone produced a 67% complete response and was well tolerated. Local side effects were comparable to side effects associated with other chemotherapy instillations [117].  

Role of Intravesical Therapy in NMIBC

Role of immediate, postoperative, single-dose instillation of intravesical chemotherapy following TURBT.

A single, immediate instillation of intravesical mitomycin C following TURBT significantly reduces the risk for recurrence by 17% (95% CI, -28, -8%) when compared to TURBT alone [92].

Meta-analysis by the European Organization for the Research & Treatment of Cancer (EORTC) showed an absolute risk reduction of 12% with the use of a single, immediate post operative (within 24 hours) instillation of a chemotherapeutic agent following TURBT.85 No significant difference in efficacy among the chemotherapeutic agents (doxorubicin, epirubicin, mitomycin C) was noted.

European Association of Urology (EAU) guidelines recommend one immediate post operative instillation of chemotherapy in all patients after TUR of presumed NMIBC [96]. The American Urological Association (AUA) guidelines panel considered the immediate use of intravesical chemotherapy an option and not a standard because of potential cost issues, uncertainty of pathology, side effects and patient preference [92].

Immediate instillation of intravesical chemotherapy should not be done in the event of overt or suspected bladder perforation or excessive bleeding following TURBT. BCG can never be safely administered immediately after TURBT because of the risk for bacterial sepsis and death [118].

Role of intravesical therapy in the treatment of initial, small-volume, low-grade, Ta bladder cancer (low-risk disease)
Following complete TURBT, single-dose, immediate instillation of intravesical chemotherapy is recommended by the AUA and the EAU guidelines on NMIBC [92,96]. Meta-analysis and comparative study by the AUA guideline panel showed combination of TURBT and single-dose, immediate instillation of intravesical mitomycin C results in 17% (95% CI, -8, -28) fewer recurrences then TURBT alone when all patient risk-groups were considered [92]. A meta-analysis by the EAU guideline panel demonstrated that one immediate instillation of intravesical chemotherapy after TUR decreased the percentage of patients with recurrence by 12% (from 48.4% to 36.7%).96 The benefit was confirmed in both single and multiple tumors [85]. There is no evidence that multiple adjuvant instillations of either BCG or chemotherapy have additional benefits in patients at initial diagnosis of Ta Grade 1 bladder cancer [92]

Role of intravesical therapy in the treatment of patients with multifocal and/or large-volume, low-grade Ta or recurrent low-grade Ta bladder cancer (Intermediate-risk group):
Intermediate risk group patients should be treated with TURBT and immediate instillation of intravesical chemotherapy [85]. The AUA guideline panel recommends the use of induction course of intravesical BCG or mitomycin C in this group of patients with the goal of preventing or delaying recurrence [92]. In intermediate-risk patients, recurrences were reduced by 24% (95% CI, 3, 47) with the combination of TURBT and BCG induction only and by 3% (95% CI, -10, 16) with TURBT and mitomycin C induction compared with TURBT alone [92].

Role of maintenance intravesical therapy in intermediate-risk-group patients
Meta-analysis by the AUA guideline panel of randomized controlled trials between 1990 and 2006 demonstrated that compared to TURBT alone, recurrences are decreased by 31% (95% CI, 18, 42) with TURBT and BCG therapy (induction plus maintenance) and by 18% (95% CI, 6, 30) with TURBT and mitomycin C induction plus maintenance regimen [92].

The optimal maintenance schedule and duration has yet to be determined. However, the best available evidence supports the use of SWOG regimen of a 6-week induction course of BCG followed by a 3-week maintenance course at 3, 6, 12, 18, 24, 30, and 36 month if tolerated by the patient [92,119].

For intermediate-risk group patients, EAU guideline recommends the use of either BCG or mitomycin C maintenance regimen. The AUA guidelines panel advised that maintenance regimen in this group of patients is an option that should be discussed with the patient [92]

Role of intravesical therapy in the treatment of patients with an initial diagnosis of high-grade Ta, T1, and/or Tis bladder cancer (high-risk disease)
For patients with lamina propria invasion but without muscular propria in the specimen, repeat resection should be performed prior to intravesical therapy.92 Data suggest that 20% to 40% will have either residual tumor and/or unrecognized muscle-invasive disease [120,121,122].

High-grade T1 lesions recur in more than 80% of cases and progress in 50% of patients within 3 years [118]. The goal of treatment in this group of patients is to reduce both the risk for recurrence and progression.

Both the AUA and the EAU guidelines recommend the use of induction course of BCG followed by maintenance regimen.92,96 According to AUA, cystectomy is considered an option for initial therapy in select patients with high-grade Ta, T1 and/or CIS because of the risk of understaging muscle-invasive disease initially or progression to muscle-invasive disease [92]. According to the EAU, immediate radical cystectomy may be offered to the highest-risk patients, such as those with multiple recurrent tumors, high-grade T1 tumors, or high-grade tumors with CIS [96]

Role of BCG in the treatment CIS
A meta-analysis revealed a 68% complete response rate with BCG and 49% complete response rate with chemotherapy in patients with CIS. In the complete responders, 68% of patients treated with BCG remained disease-free as compared to 47% of patients receiving chemotherapy based on a median followup of 3.75 years. The overall disease-free rates were 51% and 27% [91,123].

The AUA guideline for the management of NMIBC and EAU guidelines on the diagnosis and treatment of urothelial carcinoma in situ recommends the use of induction course of BCG followed by maintenance cycle for CIS. BCG intravesical therapy is also approved by the FDA for use in CIS [92,123]

Treatment of patients with high-grade, Ta, T1, and/or CIS bladder cancer that has recurred after prior intravesical therapy
The standard treatment for patients with lamina propria invasion (T1) but without muscularis propria in the specimen, is repeat resection prior to further intravesical therapy. Cystectomy should be considered as a therapeutic alternative for these patients. The high likelihood of intravesical treatment failure and adverse consequence of delaying cystectomy make cystectomy the preferred treatment for these patients [92].

Further intravesical therapy is considered an option by the AUA guideline in these patients. There is some evidence that select patients will respond to second induction regimens, particularly with BCG [96,124,125]. Intravesical valrubicin therapy is approved by the FDA in BCG refractory CIS patients has a reported 18% disease-free rate at 6 months [108]. Repeat intravesical therapy may be appropriate in patients who develop a late recurrence after previous complete response to an intravesical agent.


Concluding Remarks

Bladder cancer is a common genitourinary malignancy with significant impact on quality of life, survival and economics. Early diagnosis and treatment remain the goal. Recent advances in urine markers, diagnostic techniques and intravesical therapies enhance the evaluation and treatment of this condition. An understanding of the advantages and limitations of newer urine biomarkers is critical to identifying the roles they may play in select patients. Furthermore, an understanding of the role of blue light cystoscopy with hexaminolevulinate plays in the detection of bladder cancer will help improve detection and optimize endoscopic treatment of bladder cancer. Lastly, optimal use of current intravesical therapy after TURBT may serve to decrease the risk of recurrent/progressive bladder cancer. 

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  37. Bergman J, Reznichek RC, Rajfer J. Surveillance of patients with bladder carcinoma using fluorescent in situ hybridization on bladder washings. BJU Int. 2008;19:26-29.
  38. Halling KC, King W, Sokolova IA, et al. A comparison of BTA stat, hemoglobin dipstick, telomerase and Vysis UroVysion assays for the detection of urothelial carcinoma in urine. J Urol. 2002;167:2001-2006.
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  84. Tolley DA, Parmar MK, Grigor KM, Lallemand G, Benyon LL, Fellows J, et al. The effect of intravesical mitomycin C on recurrence of newly diagnosed superficial bladder cancer: a further report with 7 years of follow up. J Urol. 1996;155:1233-1238.
  85. Sylvester RJ, Oosterlinck W, van der Meijen AP. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials. J Urol. 2004;171:2186-2190.
  86. Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guérin immunotherapy for recent TA T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000; 163:1124-1129.
  87. Huncharek M, Geschwind JF, Witherspoon B, McGarry R, Adcock D. Intravesical chemotherapy prophylaxis in primary superficial bladder cancer: a meta-analysis of 3703 patients from 11 randomized trials. J Clin Epidemiol. 2000;53:676-680.
  88. Huncharek M, McGarry R, Kupelnick B. Impact of intravesical chemotherapy on recurrence rate of recurrent superficial transitional cell carcinoma of the bladder: results of a meta-analysis. Anticancer Res. 2001;21:765-769.
  89. Shelley MD, Kynaston H, Court J, Wilt TJ, Coles B, Burgon K, et al. A systematic review of intravesical bacillus Calmette-Guérin plus transurethral resection vs transurethral resection alone in Ta and T1 bladder cancer. BJU Int. 2001;88:209-216.
  90. Sylvester RJ, van de Meijden AP, Lamm DL. Intravesical bacillus Calmette-Guérin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol. 2002;168:1964-1970.
  91. Sylvester RJ, van der Meijden A, Witjes JA, et al. High grade Ta urothelial carcinoma and carcinoma in situ of the bladder. Urology. 2005;66:90-107.
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  97. Lamm D, Colombel M, Persad R, et al. Clinical practice recommendation for the management of non-muscle invasive bladder cancer. Eur Urol Suppl. 2008;7:651-666.
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  102. Bohle A, Jocham D, Bock PR. Intravesical bacillus Calmette-Guérin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol. 2003;169:90-95.
  103. Stricker P, Pryor K, Nicholson T, et al. Bacillus Calmette-Guérin plus intravesical interferon alpha-2b in patients with superficial bladder cancer. Urology. 1996;48:957-961.
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Consensus Statement on Neurogenic Detrusor Overactivity: Multiple Sclerosis and Spinal Cord Injury - CME

ABSTRACT

In October 2011, a multidisciplinary panel of health care professionals and representatives from key associations advocating for patients with multiple sclerosis (MS) and spinal cord injury (SCI) met to discuss issues in the diagnosis, management and treatment of adults with symptoms of neurogenic detrusor overactivity (NDO). This supplement discusses the effect of NDO on the quality of life and overall health of patients with MS and SCI, identifies health care provider and patient barriers to care, describes best practices to screen for urinary dysfunction, and summarizes the panel’s recommendations for management of NDO in this patient population. Antimuscarinic agents are first-line therapy, and oxybutynin is the only antimuscarinic agent approved specifically for detrusor overactivity associated with a neurologic condition. Recently, onabotulinumtoxinA intradetrusor injection was approved by the US FDA for the treatment of detrusor overactivity in patients with neurologic conditions, such as MS and SCI. Sacral nerve stimulation is approved for idiopathic OAB but not for the treatment of neurogenic-related bladder dysfunction. Bladder augmentation or urinary diversion is typically reserved for patients who fail less-invasive therapies. Clean intermittent catheterization is performed commonly for urinary retention in patients with SCI and may also be needed for some patients with MS as their disease progresses and increases in residual urine in the bladder contribute to symptoms. Long-term follow-up of patients with NDO is important because changes in detrusor compliance and urodynamic patterns may occur over time.

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Target Audience

This activity is designed for urologists, neurologists, physiatrists, and other health care professionals interested in or involved with the management of patients with multiple sclerosis or spinal cord injury who are at risk for neurogenic detrusor overactivity.

Educational Objectives

  • Describe the effect of bladder dysfunction on health and health-related quality of life in individuals with multiple sclerosis (MS) and spinal cord injury (SCI)
  • Identify factors and barriers influencing optimal management of neurogenic detrusor overactivity (NDO) across specialties
  • Discuss the clinical aspects of NDO including its multiple etiologies, patient evaluation, varying treatment goals, and common coexisting conditions
  • Review current and future options for the management of NDO in patients with MS and SCI
  • Adopt new standards of care for multidisciplinary management of NDO in the practice setting

Faculty

Pamela I. Ellsworth, MD (Program Chair)1; Patricia K. Coyle, MD2; Alberto Esquenazi, MD3; Karl-Erik Andersson, MD, PhD4; Jack S. Burks, MD5; June Halper, NP6; Victor W. Nitti, MD7; William A. Sheremata, MD8; David R. Staskin, MD9; Paul J. Tobin, MSW10; Alan J. Wein, MD, FACS, PhD (hon)11

1 Associate Professor of Surgery, Division of Urology, The Warren Alpert Medical School of Brown University, Providence, RI.

2 Professor and Acting Chair, Department of Neurology, Stony Brook University, and Director, Stony Brook MS Comprehensive Care Center, Stony Brook, NY.

3 Professor and Chair, Department of Physical Medicine and Rehabilitation, MossRehab and Albert Einstein, Philadelphia, PA and Director, Gait & Motion Analysis Laboratory, MossRehab, Elkin Park, PA.

4 Professor, Institute for Regenerative Medicine, Wake Forest University, and Professor, Department of Urology, Wake Forest School of Medicine, Winston-Salem, NC.

5 Chief Medical Officer, Multiple Sclerosis Association of America, Cherry Hill, NJ.

6 Adult Nurse Practitioner, Consortium of Multiple Sclerosis Centers, Hackensack, NJ and Advanced Practice Nurse, Division of Neurology, Department of Neuroscience, Multiple Sclerosis Center, University of Medicine & Dentistry of New Jersey, Newark, NJ.

7 Professor and Vice Chairmen, Department of Urology, and Director of Female Pelvic Medicine and Reconstructive Surgery, NYU Langone Medical Center, New York, NY.

8 Professor of Clinical Neurology, Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL.

9 Associate Professor of Urology, Division of Urology, Tufts University School of Medicine, and Head, Female Urology and Neurourology, Division of Urology, Steward – St. Elizabeth’s Medical Center, Boston, MA.

10 President and CEO, United Spinal Association, Inc., East Elmhurst, NY.

11 Professor and Chief, Division of Urology, Penn Medicine, Perelman School of Medicine, and Chief, Division of Urology, Penn Medicine, University of Pennsylvania Health System, Philadelphia, PA.

Presented by the Warren Alpert Medical School of Brown University, Office of Continuing Medical Education.

This activity is supported by an educational grant from Allergan, Inc.

This consensus statement has been endorsed by the Multiple Sclerosis Association of America and United Spinal Association.

Faculty Disclosures

In accordance with the disclosure policy of the Warren Alpert Medical School of Brown University as well as standards set forth by the Accreditation Council for Continuing Medical Education, all speakers and individuals in a position to control the content of a CME activity are required to disclose relevant financial relationships with commercial interests (within the past 12 months). Disclosures of this activity’s speakers and planning committee have been reviewed and all identified conflicts of interest, if applicable, have been resolved.

Pamela I. Ellsworth, MD, is a consultant/advisory board member for Allergan, Inc.,Astellas Pharma US, Inc.; and Pfizer Inc. She is a speaker for Allergan, Inc. and Pfizer Inc.

Karl-Erik Andersson, MD, PhD, is a consultant for Allergan, Inc.; Astellas Pharma US, Inc.; GlaxoSmithKline plc; and Pfizer Inc.

Jack S. Burks, MD, is a consultant and speaker for Acorda Therapeutics; Allergan, Inc.; Avanir Pharmaceuticals, Inc.; Bayer Corporation; EMD Serono, Inc.; and Novartis AG.

Patricia K. Coyle, MD, is a consultant for Acorda Therapeutics; Avanir Pharmaceuticals, Inc.; Bayer Corporation; Biogen Idec Inc.; EMD Serono, Inc.; Novartis AG; Sanofi-Aventis U.S. LLC; and Teva Neuroscience, Inc. She has received grant/research support from Actelion Pharmaceuticals Ltd and Novartis AG.

Alberto Esquenazi, MD, has received grant/research support from Allergan, Inc., and Ipsen.

June Halper, NP, is a consultant for Acorda Therapeutics; Questcor Pharmaceuticals, Inc.; and Teva Neuroscience, Inc. She is a speaker for non-CME programs for Acorda Therapeutics.

Victor W. Nitti, MD, has received grant/research support from Allergan, Inc., and Astellas Pharma US, Inc. He is a consultant for Allergan, Inc.; Astellas Pharma US, Inc.; Medtronic, Inc., Pfizer Inc; and Uroplasty, Inc.

William A. Sheremata, MD, has received grant/research support from Acorda Therapeutics, Novartis AG, and Roche. He is a consultant for Acorda Therapeutics, Novartis AG, and Teva Neuroscience, Inc.

David R. Staskin, MD, is a consultant for Allergan, Inc.; Antares Pharma; and Astellas Pharma US, Inc. He is a speaker for Allergan, Inc.; Astellas Pharma US, Inc.; and Watson Pharmaceuticals, Inc.

Paul J. Tobin, MSW, is chief executive of the United Spinal Association, which has received grant support from Allergan, Inc.

Alan J. Wein, MD, FACS, PhD (Hon), has served as a consultant for Allergan, Inc.; Astellas Pharma US, Inc.; Endo Pharmaceuticals; Ferring Pharmaceuticals; Medtronic, Inc.; and Pfizer Inc.

 

The planners, reviewers, editors, staff, or other members at Health and Wellness Education Partners and the Alpert Medical School CME Office who control content have no relevant financial relationships to disclose.

This enduring material is produced for educational purposes only. Content is provided by faculty who have been selected because of recognized expertise in their field. The opinions and recommendations expressed by the faculty whose input is included in this activity are their own. The use of the Warren Alpert Medical School of Brown University name implies oversight and review by the CME Office of educational content, format, design, and approach. Participants have the professional responsibility to review the complete prescribing information of specific drugs or combination of drugs including indications, contraindications, warnings, and adverse effects before administering pharmacologic therapy to patients.The Warren Alpert School of Medicine of Brown University assumes no liability for the information herein.

Accreditation Statement

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Warren Alpert Medical School of Brown University and Health and Wellness Education Partners. The Warren Alpert Medical School is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation

The Warren Alpert Medical School designates this enduring material for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Program Release: March 19, 2012

Program Expiration: March 30, 2013

Estimated time to complete: 60 minutes

There are no prerequisites for participation.

CME Credit - EXPIRED

To receive CME credit, please read the entire manuscript and complete the posttest and evaluation. A minimum score of 75% is required to receive a CME credit certificate.

The Office of Continuing Medical Education (CME) is committed to protecting the privacy of its members and customers. The CME Office maintains its Internet site as an information resource and service for physicians, other health professionals, and the public. The CME Office will keep your personal information confidential when you participate in a CME Internet-based program and collects only the information necessary to provide you with the services that you request.

To Receive CME Credit

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Corresponding Author

Pamela I. Ellsworth, MD

University Urological Associates

2 Dudley Street, Suite 185

Providence, RI 02908

Phone: 1-401-421-0710 ext. 1323

Fax: 1-401-421-0720

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INTRODUCTION

In October 2011 a multidisciplinary panel of prominent clinicians (urologists, neurologists, physiatrists, nurse practitioners) and representatives from key associations, including the Consortium of Multiple Sclerosis Centers, the United Spinal Association, Inc., and the Multiple Sclerosis Association of America, met to discuss issues in the assessment, diagnosis, and treatment of adults with neurologic disease or injury and symptoms consistent with overactive bladder (OAB).

In sensate individuals, neurogenic detrusor overactivity (NDO) may cause symptoms similar to OAB, such as urgency, with or without urinary incontinence, often with frequency and nocturia [1]. In individuals with spinal cord injury (SCI), the presenting symptom of NDO is more commonly urinary incontinence. The term OAB, as defined by urgency, with or without urgency urinary incontinence, often with frequency and nocturia, refers to “idiopathic” OAB, in which there is no identifiable cause. In patients with neurologic diseases, lower urinary tract dysfunction may arise from the bladder itself as the result of detrusor overactivity or underactivity (including areflexia), or from the urethral sphincter, in the form of detrusor-sphincter dyssynergia. Neurogenic detrusor overactivity, formerly called “detrusor hyperreflexia” refers to the presence of involuntary bladder contractions on urodynamic study in a patient with a known neurologic condition [1].

These and other terms used throughout this article are defined in Table 1 [1,2]. Signs and symptoms suggestive of obstruction—low urine flow, intermittency of urine stream, and incomplete bladder emptying—also are seen in some patients with neurologic disorders due to impaired bladder contractility or the loss of coordination between bladder and sphincter, a condition referred to as “detrusor-sphincter dyssynergia,” which is typically seen in patients with SCI [3]. Therefore, in the evaluation of lower urinary tract dysfunction in patients with neurologic disease or injury, the potential for both bladder and sphincter dysfunction must be considered.

Two common neurologic causes of detrusor overactivity are multiple sclerosis (MS) and SCI, and these two patient populations will be the focus of this report. Approximately 400,000 people in the United States have MS, and 10,400 new cases are diagnosed annually [4]. Spinal cord injury affects approximately 265,000 individuals in the United States, and 12,000 new cases occur each year [5].

The major differences in these two neurological diseases are the progressive nature of MS and that urinary problems in patients with MS may be related to storage and/or emptying problems. Other complications in patients with MS are mobility impairment, cognitive changes, fatigue, and environmental barriers. The most frequent symptoms are those of frequency, urgency, and urgency urinary incontinence [6]. At least one moderate to severe urinary symptom is reported by 65% of patients with MS [7]. In some studies, 21% to 50% of patients experience frequent episodes of urinary incontinence in addition to hesitancy, and 2% to 52% report obstructive symptoms with urinary retention [7,8,9,10]. The onset of symptoms occurs an average of 6 years (range, 5 to 9 years) after the diagnosis of MS. According to de Sèze et al. [11], detrusor and sphincter problems are inevitable and may be a presenting symptom in 10% to 17.5% of patients [11,12]. Neurogenic detrusor overactivity is the most common urodynamic finding, in association with either a synergistic or dyssynergic striated sphincter (Table 2) [6,13]. Eventually, 37% to 99% of patients with MS may report symptoms of OAB, and 34% to 79% may report voiding or obstructive symptoms, with chronic urinary retention occurring in 25% [11]. The prevalence of urinary symptoms correlates with disease severity; once the patient experiences difficulty walking, the probability of lower urinary tract symptoms is 100% [14].

In SCI, the majority of patients have voiding dysfunction, even if they are ambulatory with incomplete injuries [15]. The location of the lesion determines the urodynamic findings (Table 3) [13,15], and the management of patients with SCI preferably should be based on those urodynamic findings rather than inferences from the patient’s neurologic history and evaluation.

EFFECT OF NEUROGENIC DETRUSOR OVERACTIVITY ON QUALITY OF LIFE AND OVERALL HEALTH IN PATIENTS WITH MS AND SCI

Experience in patients with MS and SCI indicates that symptoms of detrusor overactivity, especially incontinence, affect emotional well-being, social interactions, and relationships. Patients with MS report that incontinence is one of the most troubling aspects of the disease and greatly diminishes quality of life (QoL) [16]. Among a series of patients with MS interviewed regarding QoL, respondents reported that urinary frequency or incontinence negatively affected emotional health (31%), ability to perform household chores (22%), and ability to participate in physical recreation (28%) [9]. Similarly, in patients with SCI the presence of complicating medical problems such as incontinence appears to have a greater negative impact on QoL than the extent of SCI per se [17]. In patients with MS or SCI, effective bladder management has been shown to improve QoL and reportedly improves disability in patients with MS [18,19].

Patients with SCI and MS are at risk for multiple bladder-related morbidities, including urinary tract infection (UTI), sepsis, upper and lower urinary tract deterioration, upper and lower urinary tract calculi, autonomic dysreflexia, skin complications and depression [13,20,21]. In patients with SCI, failure to adequately manage lower urinary tract dysfunction can lead to significant morbidity and mortality. Historically, renal disease was the major cause of death for individuals with paraplegia [22]. More recently, as a result of improved diagnosis and treatment, the leading causes of death in SCI are pneumonia, septicemia, heart disease, accidents, and suicide [23,24,25]. However, overall survival among patients with SCI has increased.

Unlike SCI, MS rarely causes upper urinary tract damage from the standpoint of high-pressure urine storage, but can do so in men [6]. Participants in the consensus panel asserted that long-standing, untreated urinary retention and recurrent pyelonephritis can result in upper-tract damage. Patients with MS are at increased risk for lower UTI, with rates ranging from 13% to 80% reported in the literature [6]. In a recent US survey of patients with MS, 29.2% had a diagnosis of UTI during a 1-year period [26]. Febrile UTIs (pyelonephritis, orchitis, or prostatitis) occur on average in 9% of patients with MS (range, 2% to 23%) [6]. Urinary tract infections have been implicated in exacerbations of symptoms in patients with MS and are a cause of death in this population more often than in the general population [27,28,29,30].

CLINICAL ASPECTS: ACCESS TO CARE

In the evaluation of lower urinary tract dysfunction in patients with MS and SCI, provider and patient barriers to care are important considerations. Principal providers of care for patients with MS are neurologists and primary care doctors, whereas patients with SCI are cared for by neurologists and physiatrists. At the primary provider level, family practitioners, internists, neurologists, physiatrists, nurse practitioners/physician assistants may not be prepared to address bladder issues. They may lack training on screening for bladder dysfunction, may be unprepared to discuss the subject with patients, and may not be aware of all available and recent therapeutic modalities. Physicians should consider referring patients with significant bladder dysfunction to a urologist for assessment.

For the patient with MS, unless care is provided for by a multispecialty MS center, referral is a common option for most neurologists. Patients with MS receive MS-specific care from neurologists, physiatrists, or neurologic specialists such as nurse practitioners or physicians assistants. Primary care needs are usually obtained through community-based care programs. Patients who receive care in specialty MS centers generally have their bladder symptoms assessed and treated as part of their care program. Urologic referral is often made following persistent UTIs or symptoms that are refractory to standard protocols. Community-based neurologists usually refer patients for urologic assessment at the onset of persistent symptoms, since individual practices are not equipped to address these complex MS problems. Urologists are generally consulted for lower urinary tract dysfunction not amenable to simple treatment; thus, neurologists, physiatrists, and primary care providers should be prepared to identify these patients and provide timely referral. Even amongst urologists, great variation exists in urologic practice in terms of initial evaluation, follow-up, and surveillance among spinal injury units [31], which Boone (2004) has attributed to a lack of evidence-based decision-making [32]. Moreover, there are no definitive consensus guidelines in the urologic literature on how to manage lower urinary tract symptoms in patients with MS and SCI.

A number of patient-related barriers to care have been identified. Patients often are reluctant to discuss bladder issues with health care providers because of embarrassment and/or sociocultural stigma related to urinary incontinence. They may feel that their lower urinary tract symptoms are a lower priority relative to other disease-related concerns. Patients may not be aware that serious complications can result from mismanagement of incontinence. Other barriers include the perception that bladder issues are not life-threatening, fear of needing invasive surgical intervention, a lack of awareness that effective treatment options are available, and a lack of access to treatment options covered under insurance plan benefits.

EVALUATION OF BLADDER SYMPTOMS IN PATIENTS WITH MULTIPLE SCLEROSIS AND SPINAL CORD INJURY

A one-page questionnaire is helpful to screen for urinary issues in outpatient departments providing care to patients with MS or SCI and to help identify patients who would benefit from referral to a specialist. Another questionnaire that is pertinent to MS is in development—the ACTIONABLE MS Urinary Function Screening Tool [33].

Multiple Sclerosis

It is believed that urologic symptoms in patients with MS tend to increase with age, length of time from diagnosis, and disease progression [14]. Nevertheless, patients with MS can present with bladder dysfunction even early in their disease. Upper urinary tract complications are uncommon in patients with MS [34]. However, patients with MS are at an increased risk for lower UTIs, which can be associated with disease exacerbation and increased mortality [27,28,29,30]. Figure 1 summarizes the essential elements in the evaluation of lower urinary tract dysfunction in the patient with MS.

Spinal Cord Injury

Considering the risk for upper urinary tract damage if underlying lower urinary tract dysfunction is not managed adequately, patients with SCI should undergo baseline urodynamic studies and, if appropriate, should be evaluated by a urologist. The risk for upper tract damage is far greater in patients with SCI than in patients with progressive neurologic diseases such as MS, even when associated with severe disability and spasticity [13]. Risk factors for upper urinary tract deterioration in patients with suprasacral SCI include high-pressure storage (poor compliance), high detrusor leak-point pressure (> 40 cm H20), chronic bladder overdistension, and vesicoureteral reflux with infection [13]. However, lower detrusor leak-point pressures have also been shown to be a risk factor [35].

In the multidisciplinary care of patients, the urologist should assume the management of lower urinary tract dysfunction. Essential components in the evaluation of lower urinary tract dysfunction in patients with SCI are summarized in Figure 2.

Goals of Treatment

For patients with MS or SCI who have lower urinary tract dysfunction, the primary goals of therapy are to preserve or improve renal function (i.e., upper urinary tract), prevent or control infection, maintain adequate storage and emptying at low intravesical pressure, maintain adequate control of bladder emptying without incontinence, avoid the need for a catheter or stoma, and ensure social and vocational acceptability and adaptability [13]. A given regimen should be changed or augmented if any of the following occur: upper or lower urinary tract deterioration; recurrent sepsis or fever of urinary tract origin; inadequate storage, emptying, or control; unacceptable side effects; or skin changes secondary to incontinence or collecting device [13].

MANAGEMENT OF NEUROGENIC DETRUSOR OVERACTIVITY

According to Wein and Dmochowski [13], “Management of the urinary tract in SCI patients must be based on urodynamic findings and principles rather than inferences from the neurologic history and evaluation. Similarly, although the information regarding “classic” complete lesions is for the most part valid, one should not make neurologic conclusions solely on the basis of urodynamic findings.

Before initiating treatment for a neurologic patient with symptoms of NDO, it is important to discuss the patient’s expectations and goals as well as the physician’s treatment objectives. In particular, patients with SCI need to be educated with regard to the importance of preservation of the upper renal tract, while those with MS need to understand the role that lower UTI can have on their overall physical well-being, disease progression, and function. A number of factors to consider when choosing therapy are listed in Table 4 [13].

Lifestyle Changes, Behavioral Modification, Clean Intermittent Catheterization

Lifestyle changes and behavioral modification are the first line of treatment and may be helpful in combination with pharmacologic therapy in selected patients. Such changes are more likely to have a substantial effect in patients with MS than in those with SCI. Dietary changes to reduce bladder irritation involve decreasing the consumption of caffeine, artificial sweeteners, or alcohol, and avoiding acidic and spicy foods. Either excessive or insufficient fluid intake may aggravate symptoms [36].

Behavioral modification is ideal for ambulatory patients with neurogenic bladder who are voiding volitionally. Timed (scheduled) voiding can help to minimize functional problems such as getting to the bathroom and removing clothing in time [36]. This intervention can be initiated and maintained by caregivers. The usual schedule is every 3 hours during the daytime [37]. Use of pelvic floor exercises (i.e., Kegel maneuver) has been shown to be beneficial in patients with MS [19] and in those with incomplete SCI [38].

Clean intermittent catheterization (CIC) is considered the gold standard for the management of urinary retention or incomplete bladder emptying in patients with neurogenic lower urinary tract dysfunction caused by either detrusor underactivity or detrusor-sphincter dyssynergia [38]. Antimuscarinic agents and intradetrusor injection of onabotulinumtoxinA (OnaBoNT-A) used for the treatment of detrusor overactivity in neurogenic bladder dysfunction may precipitate urinary retention requiring CIC. Self-catheterization requires adequate hand function and sufficient cognitive ability to perform [15]. Patients and/or caregivers require instruction in technique and risks—aseptic catheterization is the method of choice [38]. Additional details are presented in Table 5 [15,34,36,38]. In patients with SCI who are undergoing CIC, asymptomatic bacteriuria does not warrant antibiotic therapy [38,39]. In most patients, use of CIC is preferable to a chronic indwelling Foley catheter or suprapubic tube.

A recent survey of the National Spinal Cord Injury Database emphasizes the importance of supportive counseling to help patients avoid the need for indwelling catheters [40]. In this analysis, the patient’s bladder management method was determined at discharge from rehabilitation and at each 5-year follow-up for 30 years. Among individuals using CIC and condom catheterization at discharge home, only 20% and 34.6%, respectively, continued to use these methods. At long-term follow-up, 41.8% of patients initially undergoing CIC and 23.1% of those initially using condom catheters switched to an indwelling catheter. Among patients initially discharged with an indwelling catheter, 71.1% continued using this method for 30 years [40].

Medical Interventions

A number of medical interventions are used for the treatment of patients with NDO, as listed in Table 6 [6,38,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66].

First-Line Therapy: Antimuscarinic Agents

Antimuscarinic agents, traditionally referred to as “anticholinergic agents,” [38] remain the first-line therapeutic option for NDO, and oxybutynin is the only antimuscarinic agent approved for detrusor overactivity associated with a neurologic condition (although trials in adults are limited) [67,68]. Based on clinical experience and a limited number of studies, patients with NDO may need higher doses of antimuscarinic agents than do those with OAB [38,52,69,70,71].

Currently, antimuscarinic use in NDO is recommended by the European Association of Urology [38,69], a UK consensus group on the treatment of patients with MS [34], and an expert panel on the management of patients with neurogenic bladder [72]. Moreover, a survey of the US members of the Society for Urodynamics and Female Urology noted that 84% believe antimuscarinic agents and CIC are the best option for bladder management in persons with SCI who have detrusor overactivity [73].

Adverse effects of antimuscarinic agents are related to a lack of uroselectivity [67]. The most common side effect associated with antimuscarinic agents is dry mouth, but a review of studies in patients with idiopathic OAB found no indication that this had an effect on the numbers of patients who withdrew from treatment [68]. Other common side effects include constipation and blurred vision [67]. Constipation can be of concern in patients with neurologic disease since many already experience this as a result of their neurological problem. It can be quite serious in SCI and very disabling in MS. It is important that patients are provided with nutritional counseling to ensure regular bowel movements and prevent impaction and/or bowel leakage around the impaction resulting in bowel incontinence.

In 2010, angioedema was reported to be an uncommon adverse effect associated with this class of drugs. Because antimuscarinic agents can exacerbate urinary retention, a baseline postvoid residual volume should be obtained in patients with MS not performing intermittent catheterization prior to therapy, and patients should be evaluated periodically while on antimuscarinic therapy [74].

Cognitive changes may occur with the use of antimuscarinic agents. A recent review of randomized, controlled trials evaluating cognitive function in patients with OAB receiving oxybutynin, darifenacin, tolterodine, solifenacin, and/or trospium chloride found that oxybutynin was occasionally reported to be associated with cognitive impairment, whereas darifenacin was not [75]. Other studies have found that trospium chloride does not penetrate the central nervous system and has no significant effect on learning or recall [76,77].

Newer formulations of older antimuscarinic therapies such as extended-release formulations and transdermal applications have decreased the incidence of side effects while maintaining desired efficacy. Intravesical oxybutynin has also been evaluated in limited studies involving detrusor overactivity of neurologic etiology [78]. Its use, however, requires catheterization and can be cumbersome.

Note that alpha-1 adrenergic receptor antagonists are not recommended for the oral therapy of patients with NDO, given a lack of evidence of efficacy [67].

Second-Line Therapy

Several management options are available for patients who do not respond adequately to treatment with antimuscarinic (anticholinergic) agents.

OnabotulinumtoxinA Intradetrusor Injection

In 2011, OnaBoNT-A intradetrusor injection was approved by the US FDA for the treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (e.g., SCI and MS) in adults who have an inadequate response to or are intolerant of an anticholinergic medication [79]. In the bladder, OnaBoNT-A acts at the presynaptic cholinergic junction where it prevents the release of acetylcholine from the presynaptic nerve terminal. This prevents stimulation of the detrusor muscle. It is also thought that in addition to its efferent effects on the detrusor, OnaBoNT-A may affect the afferent limb of the contraction cycle through a multimodal effect on a number of sensory pathways [80].

There are limitations to the total amount of OnaBoNT-A that an individual may receive over a period of time [79]. Prior to use, it is important to ask patients with SCI or MS if they have received OnaBoNT-A for a medical (e.g., spasticity) or cosmetic reason in the past or any other botulinum toxin product within the past 3 months. For detrusor overactivity associated with a neurologic condition, the recommended total dose of OnaBoNT-A is 200 Units, as 1 mL (~6-7 Units) injections across 30 sites into the detrusor, excluding the trigone. The total dose of OnaBoNT-A injected anywhere throughout the body should not exceed 360 Units administered in a 3-month interval, according to the FDA. Autonomic dysreflexia has been associated with intradetrusor injections and SCI patients at risk (injury at level T5 and higher) should be appropriately managed. In clinical trials, the incidence of autonomic dysreflexia was greater in patients treated with OnaBoNT-A 200 Units compared with placebo (1.5% vs 0.4%, respectively). In double-blind, placebo-controlled clinical trials of combined MS and SCI populations, the proportion of patients not using CIC at baseline who required catheterization for urinary retention following intradetrusor injection was 30.6% with OnaBoNT-A 200 Units compared with 6.7% with placebo [79]. Therefore, patients considering this therapeutic option must be agreeable to performing CIC.

A growing body of evidence supports the use of OnaBoNT-A intradetrusor injection in patients with symptoms of detrusor overactivity due to MS and SCI, including prospective, open-label treatment trials, and randomized, controlled trials [43,53,54,55,56,57,58,81]. Most clinical trials report significant improvement in clinical and urodynamic outcomes in patients with MS and SCI following treatment with OnaBoNT-A intradetrusor injections. In a recent multicenter, randomized, double-blind, placebo-controlled study in 154 patients with MS and 121 with SCI who were experiencing a mean of 33.5 episodes per week of urinary incontinence due to NDO at baseline, treatment with 200 Units OnaBoNT-A significantly reduced the number of weekly episodes at 6 weeks compared with placebo (-21.8 vs -13.2; P < .01) [57]. At 6 weeks, a significantly greater proportion of patients receiving OnaBoNT-A compared with placebo (38% vs 7.6%) were fully continent (i.e., dry). Onset of effect typically occurs 2 weeks postinjection, and the median duration of response in the pivotal trials was 295 days to 337 days (42-48 weeks) [79]. No loss of efficacy and no systemic side effects have been observed with repeated injections [67,79,82]. OnaBoNT-A intradetrusor injections have been associated with improved QoL, which was correlated with decreases in micturition frequency, urgency, and incontinence episodes [83]. In patients with SCI refractory to antimuscarinic agents who received at least one OnaBoNT-A injection, satisfaction with treatment was high, and the rate of annual withdrawals was low [84].

In patients with detrusor overactivity associated with a neurologic condition, the most common adverse events associated with OnaBoNT-A in double-blind, placebo-controlled trials were urinary tract infection occurring within the first 12 weeks after intradetrusor injection (OnaBoNT-A, 24% vs placebo 17%) and urinary retention (OnaBoNT-A, 17% vs placebo 3%) [79]. Note that the prescribing information for OnaBoNT-A (and all botulinum products) includes a boxed warning regarding the potential spread of toxin effects beyond the area of injection, which may result in swallowing and breathing difficulties. The risk for symptoms is likely greatest in children treated for spasticity, but symptoms can also occur in adults, particularly in those who have an underlying condition that would predispose them to such symptoms [79].

Sacral Nerve Stimulation/Sacral Neuromodulation

Sacral nerve stimulation (InterStim® implantable pulse generator, Medtronic, Inc., Minneapolis, MN) is FDA approved for the treatment of urinary retention and the symptoms of OAB, including urinary urgency incontinence and significant symptoms of urgency-frequency alone or in combination, in patients who have failed or could not tolerate more conservative treatments [85]. Importantly, the safety and effectiveness of bilateral sacral neuromodulation has not been established for patients with neurologic disease origins such as MS; pregnancy, the unborn fetus, and delivery; and pediatric use under the age of 16 (Medtronic, Inc., Medical affairs phone communication).

Randomized, controlled trials of sacral neuromodulation are lacking, and there have been few off-label studies in patients with NDO associated with SCI and MS [59]. However, a recent review of the literature found a 92% overall success rate (defined as > 50% improvement in bladder diary variables, number of leakages, pad use, number of voids, and number of catheters) with permanent implants in patients with NDO due to MS, SCI, pelvic surgery, and disc disease, with a mean follow-up of 26 months [59]. Other studies suggest that patients with incomplete SCI experiencing lower urinary tract symptoms may benefit from sacral neuromodulation [86,87].

In patients with MS, sacral neuromodulation has been investigated for both urinary retention and detrusor overactivity [61,62]. At present, candidates for sacral neuromodulation may include patients with MS who have mild symptoms, are able to get to the bathroom in time, have no mobility issues, and have no need for future magnetic resonance imaging studies, which are commonly utilized in this patient group [61,88].

A review of charts for 25 consecutive patients with MS who received implants between 2001 and 2009 found that urgency and frequency were decreased significantly in patients in whom the main complaint was detrusor overactivity, and that CIC was significantly decreased in patients with urinary retention due to detrusor-sphincter dyssynergia. Quality of life was improved in patients with both urinary retention and those with incontinence [62]. However, longer follow-up studies are needed.

Posterior Tibial Nerve Stimulation

Posterior tibial nerve stimulation is an alternative form of nerve stimulation. The precise mechanism of action is unclear. It is thought that posterior nerve stimulation inhibits bladder activity by depolarizing somatic sacral and lumbar afferent fibers [89]. There are limited studies available, evaluating the use of posterior tibial nerve stimulation in patients with NDO; however, preliminary findings appear promising [90-93].

Indwelling Catheter

In select individuals, an indwelling Foley catheter or suprapubic tube may be an appropriate intervention. However, in a female patient with NDO, leakage from the urethra with suprapubic drainage may be a persistent issue. Suprapubic tubes tend to be better tolerated over the long-term and avoid the risk of urethral erosion. As with Foley catheters, suprapubic tubes should be changed on a regular basis. The impact of indwelling catheters on the risk of developing bladder cancer is controversial [94,95,96]. Bacterial colonization is common and patients should be cultured and treated if there is fever, and/or a change in urinary symptoms.

Surgical Intervention

When more conservative approaches have failed in patients with SCI or MS in whom catheterization is impossible or incontinence cannot be controlled, urinary diversion may be a more suitable alternative to an indwelling catheter [38,61]. However, these procedures are associated with multiple risks, and complications such as infections, calculi, and ureteroenteric strictures [38,66]. For patients with MS, these procedures generally are considered only for those with secondary progressive/primary progressive disease who have failed nonsurgical treatments and have an increased Expanded Disability Status Scale [61]. According to Stoffel, [61] most patients with MS whom he has seen for surgical intervention will require incontinent urinary diversion because they are unable to catheterize an augmented bladder.

Long-term follow-up of patients with NDO is critical. In 2001, Ciancio et al. [97] reported that a significant proportion (55%) of patients with MS with and without new symptoms will develop changes in their detrusor compliance and urodynamic pattern. Caution should be exercised in recommending irreversible options [13]. Surgical intervention for MS appears to be decreasing with improved pharmacologic management.

CONCLUSIONS

A recent retrospective analysis of medical and pharmacy claims for more than 46,000 patients with neurogenic bladder dysfunction related to incontinence—including more than 9,000 patients with MS and more than 4,000 with SCI—suggests that the management of these patients is suboptimal as indicated by high rates of UTI and hospitalizations [26]. Experts concur that a team approach involving the primary care provider, neurologist, urologist, physiatrist, and nurse practitioner, as well as any other personnel or family members involved in the patient’s care, is essential in order to optimize medical and urologic management. This is not generally the case: During a 1-year follow-up, only 36% of SCI patients and 26% of MS patients were seen by a urologist; 18.5% and 53%, respectively, were seen by a neurologist; and 18% and 7.5%, respectively, received physical medicine and rehabilitation [26].

Education is needed across the specialties involved in the care of neurologically impaired patients. More emphasis needs to be placed on the urologic assessment and management of these patients, especially those with SCI in whom protection of the upper urinary tract is a primary goal. Patients and caregivers also need to be educated about the various resources available to them in the community.

With regard to drug therapy for NDO, current US and European guidelines recommend an antimuscarinic agent as first-line therapy. The availability of newer, more selective antimuscarinic agents, including darifenacin, solifenacin, trospium chloride, tolterodine, and fesoterodine, as well as extended-release formulations has improved the tolerability of antimuscarinic therapy without compromising efficacy.

For patients with detrusor overactivity and incontinence due to a neurologic condition such as MS and SCI who have an inadequate response to or are intolerant of antimuscarinic medications, a recently approved alternative/additional therapy is OnaBoNT-A intradetrusor injection [53,54,58,81]. Onset of effect occurs by 2 weeks postinjection. Patients should be considered for reinjection when the clinical effect of the previous injection diminishes (median time to qualification for retreatment in the double-blind, placebo-controlled clinical studies was 42-48), but no sooner than 12 weeks from the prior bladder injection [79]. There is no loss of efficacy with repeated injections. As urinary retention is a risk with intradetrusor injection of OnaBoNT-A, patients should agree to perform CIC if needed for urinary retention after treatment. This is time limited.

Bladder augmentation/urinary diversion are less commonly performed in patients with NDO due to improvements in pharmacologic therapy and may be decreased further with the approval of OnaBoNT-A.

Importantly, clinicians and patients alike need to understand the potentially detrimental effects of poorly managed or unmanaged NDO on disease outcomes and recognize that a number of effective management options are available.

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