Stakeholder Opinions: Bladder Cancer - New drugs needed to challenge ineffective 20-year old drugs

The overall incidence of bladder cancer in the seven major markets is forecast to exceed 160,000 by the end of 2008. Treatment of bladder cancer employs mainly immunotherapy and chemotherapy. However, both these methods are ineffective in improving long-term survival. Thus, there is a lucrative commercial opportunity for drug developers to enter this market, especially in the metastatic setting.

Report Highlights
Discovery of more effective systemic therapies is crucial for the treatment of patients with advanced or metastatic disease as current therapies have little impact on survival.

BCG therapy, the current standard treatment for non-invasive bladder cancer has limited use in patients who experience multiple recurrences. Patients who become refractory or intolerant to further BCG treatment have few options. There is therefore a large patient potential for drugs that can replace BCG or treat BCG-refractory patients.

Bladder cancer therapy consists of cytotoxics and immunotherapy agents that have been genericized for many years. Late-stage pipeline drugs consist of targeted therapies and cytotoxics including Urocidin and EOquin. Some late stage drugs have demonstrated favourable efficacy in trials and look to fill some of the unmet needs in bladder cancer.
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ABOUT DATAMONITOR HEALTHCARE 2
About the Oncology pharmaceutical analysis team 2
CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of analysis 3
Datamonitor insight into the bladder cancer market 3
Related reports 4
Upcoming reports 4
CHAPTER 2 DISEASE OVERVIEW 6
Introduction 6
Disease overview 6
Insufficient treatment options for advanced stages of disease 6
The recurring nature of non-invasive tumors leads to a great economic burden 6
Anatomy of the bladder 7
Bladder cancer 8
Definition 8
Pathology/histology 8
Transitional cell carcinoma is the most common cancer type in developed countries 9
Squamous cell carcinoma accounts for 75% of bladder tumors in developing countries 9
Adenocarcinoma is common in patients with exstrophy 10
Uncommon bladder cancer types 10
Clinical classifications 11
Epidemiology 11
Aging population contributes to rising incidence rates 11
Rising mortality rates highlight the need for better treatment options 13
Risk factors 15
Older age 15
Active and passive smokers are more likely to develop bladder cancer 15
Chemical industry employees are at greater risk 16
Medical risk factors and prior cyclophosphamide-based chemotherapy increases chances of developing bladder cancer 16
Urinary tract infections are directly related to invasive SCC 16
Greater incidence in men than women 16
Ethnicity and geographical location affect prognosis and risk of developing disease 17
Genetic factors also affect the chances of developing bladder cancer 17
Symptoms 18
All cases of hematuria should be investigated for bladder cancer 18
Screening 18
Urinary markers have not been embraced for bladder cancer screening 18
Diagnosis 19
Cystoscopy is the most widely used test for bladder cancer 19
Staging 20
The TNM system is the more descriptive method of staging 20
The World Health Organization (WHO) offers a modified grading system 21
75% of tumors are non-invasive at the time of diagnosis 22
Prognosis and survival 23
High-grade tumors have the worst prognosis as progression is more likely to occur 23
Growth factor receptors may serve as prognostic markers and therapy targets 23
Prevention 24
Lifestyle changes are advised to prevent bladder cancer. 24
CHAPTER 3 CURRENT TREATMENT OPTIONS AND CONTROVERSIES 25
Introduction 25
Treatment guidelines 25
National Comprehensive Cancer Network treatment guidelines 25
Transurethral resection followed by intravesical BCG is the standard treatment for non-invasive tumors and CIS in the US 25
Radical cystectomy is the preferred treatment for continually recurring tumors 27
European treatment guidelines 28
EU clinicians use BCG therapy less than clinicians in the US 28
Japanese treatment guidelines 29
Cystectomy is the main treatment used for bladder cancer in Japan 29
Treatment by stage 30
Non-invasive bladder cancer 30
Recurrence and progression must be prevented by surgery and adjuvant intravesical therapy if long-term survival is to be achieved 30
TURBT is an appropriate primary treatment because it eliminates visible tumors 31
Immunotherapy is preferred to chemotherapy as an adjuvant to TURBT 32
Few options are available for BCG-refractory patients 33
Combination chemotherapy is more effective than single-agent chemotherapy 34
Invasive bladder cancer 36
Cystectomy is the standard therapy for invasive tumors... 36
...however, only 50% of patients will survive past 5 years unless adjuvant chemotherapy is administered 37
Metastatic bladder cancer 39
Bladder-removing surgery remains the best life-saving strategy as adequate treatment has yet to be identified 39
Neoadjuvant chemotherapy is recommended for metastatic tumors 39
Cisplatin-based combination chemotherapy forms the cornerstone of first-line therapy for metastatic bladder cancer 40
Patients with a poor performance history receive radiotherapy 42
Recurrent tumors 42
CHAPTER 4 UNMET NEEDS 43
Introduction 43
Unmet needs 43
No treatment available to prevent recurrent tumors in non-invasive bladder cancer 43
Limited treatment options for patients who are unfit for current treatment options 44
BCG-refractory patients usually fail to respond to chemotherapy 44
Patients who are unfit for cystectomy receive substandard treatment due to a lack of options 45
Metastatic disease treatment is not effective 45
No standard treatment schedule is available for adjuvant therapy with immunotherapy or chemotherapy 46
Better routes of administration than intravesically may lead to longer exposure time and better drug absorption 46
More sensitive detection methods as well as prognostic markers are needed to combat the high cost of follow-up 47
New drugs required for non-urothelial cell tumor treatment 48
Summary of unmet needs 48
CHAPTER 5 PIPELINE ANALYSIS 50
Pipeline overview 50
The bladder cancer pipeline 50
Phase III pipeline 50
Phase II pipeline 51
Targeted therapy strives for a place in the bladder cancer market 52
Phase III drug profiles 52
EOquin (apaziquone; Spectrum Pharmaceuticals) 52
Drug overview 52
Key historical events 53
Clinical development in bladder cancer 53
Datamonitor comments 58
Iressa (gefitinib; AstraZeneca) 58
Drug overview 58
Key historical events 59
Clinical development in bladder cancer 60
Datamonitor comments 62
Urocidin (MCC; Bioniche Life Science) 64
Drug overview 64
Key historical events 64
Clinical development in bladder cancer 64
Datamonitor comments 68
Valstar (valrubicin; Indevus) 69
Drug overview 69
Key historical events 69
Clinical development in bladder cancer 70
Datamonitor comments 70
Larotaxel (XRP9881; Sanofi-Aventis) 71
Drug overview 71
Key historical events 71
Clinical development in bladder cancer 72
Datamonitor comments 73
CHAPTER 6 KEY OPINION LEADER INTERVIEW TRANSCRIPTS 75
Contributing experts 75
Key opinion leader interview transcripts 75
APPENDIX 76
Bibliography 76
List of tables 86
List of figures 87
About Datamonitor 88
About Datamonitor Healthcare 88
About the Oncology analysis team 89
Disclaimer 90
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Table 1: Clinical subtypes of bladder cancer 11
Table 2: Crude incidence rates for bladder cancer (per 100,000 persons) in the seven major markets, 2002 12
Table 3: Forecast incidence of bladder cancer in the seven major markets, 2002-2017 12
Table 4: Crude mortality rates for bladder cancer in the seven major markets, 2002 14
Table 5: Risk factors associated with bladder cancer 15
Table 6: Diagnostic tests for bladder cancer 19
Table 7: TNM and Jewett staging systems for primary bladder tumors 20
Table 8: Lymph node classifications in the TNM staging system 21
Table 9: Distant metastasis classification in the TNM staging system 21
Table 10: World Health Organization grading system for non-invasive bladder tumors 22
Table 11: Rate of progression and survival of non-invasive tumors in bladder cancer 23
Table 12: National Comprehensive Cancer Network (NCCN) guidelines for primary bladder cancer treatment in the US, 2008 26
Table 13: National Comprehensive Cancer Network (NCCN) guidelines for recurrent bladder cancer treatment in the US, 2008 28
Table 14: European treatment guidelines for bladder cancer, 2008 28
Table 15: Japanese treatment guidelines for bladder cancer 29
Table 16: Late-phase bladder cancer pipeline, 2008 50
Table 17: Phase II bladder cancer pipeline, 2008 51
Table 18: EOquin: key historical events, 2007-08 53
Table 19: Ongoing clinical trials involving EOquin, 2008 54
Table 20: Iressa: key historical events, 2002-08 59
Table 21: Ongoing clinical trials involving Iressa, 2008 60
Table 22: Cost of TICE BCG and Iressa per week based on price of drugs alone 62
Table 23: Ongoing trials in the metastatic transitional cell carcinoma (TCC) setting 63
Table 24: Urocidin: key historical events, 2006-08 64
Table 25: Ongoing clinical trials involving Urocidin, 2008 65
Table 26: Valstar: key historical events, 1998-2007 69
Table 27: Larotaxel: key historical events, 2004-08 71
Table 28: Ongoing clinical trials involving larotaxel, 2008 72
Figure 1: Anatomy of the bladder 7
Figure 2: Bladder tumor histology and their abundance in the US, 2008 8
Figure 3: Forecast incidence of bladder cancer in the seven major markets, 2002-2017 13
Figure 4: Incidence and mortality of bladder cancer in the seven major markets, 2008 and 2017 14
Figure 5: Stage of bladder cancer at diagnosis 22
Figure 6: Phase III trial demonstrating that GC is less toxic than MVAC in metastatic bladder cancer patients 27
Figure 7: Phase III trial of neoadjuvant MVAC combination therapy in invasive transitional cell carcinoma (TCC) 38
Figure 8: Phase III trial comparing CG and MVAC combination chemotherapy in metastatic bladder cancer 41
Figure 9: Summary of unmet needs in bladder cancer, 2008 49
Figure 10: Phase III study design of EOquin in low-grade papillary tumors 55
Figure 11: Phase II 'marker' tumor trial of EOquin in non-invasive bladder cancer 56
Figure 12: Phase I trial to demonstrate safety of EOquin following surgery 57
Figure 13: Phase III trial of Iressa in patients with high-risk non-invasive transitional cell carcinoma (TCC) 61
Figure 14: Phase III trial of Urocidin monotherapy in BCG-refractory non-invasive transitional cell carcinoma (TCC) 65
Figure 15: Phase II study investigating Urocidin in high-risk non-invasive bladder cancer 66
Figure 16: Phase I/II study of Urocidin monotherapy in patients with carcinoma in situ (CIS) tumors 67
Figure 17: Phase III study design for larotaxel in combination with cisplatin in metastatic transitional cell carcinoma (TCC) 73
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