Printer Friendly Printed from http://www.researchandmarkets.com/reports/452389 Stakeholder Opinions: Esophageal Cancer Treatment Paradigms Need Revolution Not Evolution Description: Globally, esophageal cancer is the ninth most common tumor type and seventh leading cause of cancer-related death, however, its incidence fluctuates widely depending on geographical area. While relatively uncommon in Western countries, 50% of patients still present with locally advanced unresectable or distant metastatic disease, where treatment is complicated and chances of a cure are reduced. Scope of this title: Current diagnosis and treatment of esophageal cancer, including treatment regimens by stage and ongoing controversies Issues, unmet needs, and geographical variations in screening and treatment strategies Examination of pipeline activity and potential future opportunities for drug developers Stakeholder opinions and interview transcripts based on qualitative interviews with key opinion leaders from the US and Europe Highlights of this title: As the incidence of esophageal cancer subtypes shift due to a changing prevalence of risk factors including an increasing incidence of obesity and gastroesophageal reflux disease, preventative strategies may take on a more prominent role and existing treatment paradigms will need to evolve in order to yield improved patient outcomes. Given that the majority of esophageal cancer patients present with locally advanced unresectable or distant metastatic disease, as reflected by poor overall survival rates and disease prognosis, increased rates of earlier diagnosis and greater research into more effective systemic therapies is crucial. Due to a relatively low incidence in the West, esophageal cancer has not been the most commercially attractive indication for US and EU drug developers, as evidenced by the lack of approved agents for its treatment. However, there are numerous targeted therapies in Phase II trials, which show potential to transform existing treatment paradigms. Reasons to order your copy: Identify the limitations of current therapy available to esophageal cancer patients and the potential of future therapy Understand current epidemiological trends in esophageal cancer and ongoing treatment controversies Assess the opportunities for innovative targeted therapies in esophageal cancer, particularly in metastatic disease Contents: ABOUT OUR HEALTHCARE 2 About the Oncology pharmaceutical analysis team 2 Nish Saini - Lead Analyst, Oncology 2 Chapter 1. Executive summary 3 Scope of analysis 3 Our insight into the esophageal cancer market 4 As the incidence of esophageal cancer subtypes shift due to a changing prevalence of risk factors, preventative strategies may take on a more prominent role and existing treatment paradigms will need to evolve in order to yield improved patient outcomes 4 Conflicting opinions regarding the use of neoadjuvant chemoradiotherapy for locally advanced disease requires clarification, potentially via the future use of genetic profiling 6 Given that the majority of patients present with advanced disease, reflected by poor overall survival rates and disease prognosis, increased rates of earlier diagnosis and greater research into more effective systemic therapies is crucial 7 Due to its relatively low incidence in the West, esophageal cancer has not been the most commercially attractive indication for US and European drug developers, as evidenced by the lack of approved agents for its treatment. However, there are numerous targeted therapies in Phase II trials, which have the potential to transform existing treatment paradigms 9 Chapter 2. Disease overview 15 Introduction 15 Disease overview 15 Esophageal cancer: a major source of cancer-related death 15 Anatomy of the esophagus 15 Esophageal cancer 18 Definition 18 Increasing number of distal esophageal tumors 18 Pathology 19 Predominance of histolological subtypes varies by geographical region 19 Epidemiology 20 Increasing rates of adenocarcinoma in the West drive an increasing incidence of esophageal cancer across the seven major markets 20 Mortality from esophageal cancer is high in comparison to its incidence due to a typically advanced stage at diagnosis 23 Risk factors 25 Risk factors are better defined for squamous cell carcinoma than for adenocarcinoma 25 Genetic and environmental factors 26 Precursor conditions 30 Symptoms 33 A lack of initial symptoms mean half of patients present with advanced disease 33 Screening 35 Regular surveillance of patients with Barretts esophagus is recommended 35 Diagnosis 38 Endoscopy is used most frequently in the West to diagnose esophageal cancer 38 Staging 39 Esophageal cancer has been pathologically staged since 2002 39 Survival 42 The high rate of advanced-stage diagnoses is reflected by relatively poor survival rates 42 Prognosis 43 Stage of disease is the main prognostic indicator for esophageal cancer 43 Prevention 44 For Barretts esophagus, a variety of preventative measures exist to halt progression to malignancy 44 Weight reduction may form a viable preventative strategy for GERD, and ultimately, esophageal cancer 45 Chemoprevention of esophageal cancer may be possible using NSAIDs or aspirin 46 Chapter 3. Current treatment options and controversies 47 Introduction 47 Treatment guidelines 47 US treatment guidelines 47 US treatment guidelines for esophageal cancer focus on the use of chemoradiotherapy for most patients 47 European treatment guidelines 48 European treatment guidelines focus on the use of chemoradiotherapy when surgery is not a viable option 48 Treatment of esophageal cancer in Japan 49 Greater emphasis is placed on surgery in Japan for the treatment of esophageal cancer 49 Treatment of early-stage and locally advanced esophageal cancer 50 Surgery 50 Resection has the greatest utility in the treatment of early-stage esophageal cancer patients 50 Primary chemoradiotherapy for locally advanced disease 51 Primary chemoradiotherapy may provide a cure for locally advanced esophageal cancer patients 51 Neoadjuvant therapy 56 Neoadjuvant radiotherapy has been shown of little use in improving either resectability or survival 56 Neoadjuvant chemotherapy has demonstrated a survival advantage without increasing postoperative complications 57 Neoadjuvant chemoradiotherapy confers a high level of treatment-related mortality 59 Several Phase III studies are ongoing to further investigate the utility of neoadjuvant therapy 63 Adjuvant therapy 65 Adjuvant radiotherapy may result in decreased survival in comparison with surgery alone 66 Adjuvant chemotherapy: some regimens have conferred a survival benefit, however, this treatment modality has not been widely investigated 67 Adjuvant chemoradiotherapy is not associated with survival benefits and has not been widely investigated 68 Clinical trial activity investigating adjuvant therapy in esophageal cancer is somewhat limited 69 Surgery versus systemic therapy or combined modality treatment for locally advanced disease 70 Genetic testing may eventually resolve the issue of what constitutes ideal treatment for individual esophageal cancer patients 70 Treatment of advanced-stage and metastatic esophageal cancer 72 Radiotherapy 72 Primary radiotherapy is reserved for palliative purposes or for those patients medically unfit to undergo chemotherapy 72 Chemotherapy for advanced disease 73 No standard chemotherapy regimen exists for advanced disease due to a lack of large-scale, randomized clinical trial data 73 Cisplatin forms the basis of chemotherapy for esophageal cancer, given that its single-agent activity is higher than any other cytotoxic tested to date 73 Phase II studies have shown combination chemotherapy to confer increased survival, albeit at the expense of increased toxicity and morbidity 74 The NCCN recommends 5-fluorouracil or cisplatin-based chemotherapy for metastatic esophageal cancer, since no Phase III studies have been completed for 15 years 75 The ECF (epirubicin, cisplatin and 5-fluorouracil) regimen is used as standard chemotherapy for metastatic disease in the UK 76 Despite an urgent need for more definitive data, no Phase III clinical trials are currently ongoing 79 Photodynamic therapy 80 Photodynamic therapy forms an alternative palliative treatment option in advanced esophageal cancer 80 Axcan Pharmas Photofrin is approved for the palliation of advanced esophageal cancer 81 Estimated treatment of esophageal cancer in the five major European markets 83 Estimated use of surgery 83 Heavier reliance on potentially curative surgery at the earlier stages of esophageal cancer 83 Estimated use of chemotherapy 84 Not surprisingly, a heavy reliance is placed upon a combination of cisplatin and 5-fluorouracil in the first-line treatment of esophageal cancer in the EU 84 Chapter 4. Unmet needs 89 Introduction 89 Unmet needs 89 Improving prognosis of esophageal cancer 89 50% of patients present with advanced disease, therefore better or facilitated techniques to increase earlier diagnosis are needed 89 Improving patient lifestyle factors could prevent or delay the onset of esophageal cancer 90 Enhanced treatment options required across all stages of disease 91 New and more effective systemic therapies for advanced disease are required 91 More effective neoadjuvant or adjuvant therapy for patients who undergo surgery, to reduce relapse rates 93 Adequate palliative treatment options for metastatic esophageal cancer patients are still necessary 94 Future treatment of esophageal cancer 94 More large-scale, randomized clinical trials are necessary to define optimal treatment strategies at all stages of esophageal cancer 94 Espohageal cancer fails to generate significant commercial interest 95 Summary of unmet needs 97 Chapter 5. Pipeline analysis 98 The esophageal cancer pipeline 98 Phase III pipeline 98 Pfizers Camptosar (irinotecan) - current off-label use may mean that formal approval may not be sought 99 Sanofi-Aventiss Eloxatin (oxaliplatin) - results from the REAL-2 trial and recent genericization in Europe may increase uptake 102 Roches Xeloda (capecitabine) - pharmacoeconomic issues may hinder uptake 104 Phase I/II pipeline 106 Already proven a popular target in colorectal cancer, EGFR inhibitors have shown some antitumor activity to date in early-phase trials for esophageal cancer 109 Inhibition of angiogenesis appears a successful strategy in gastroesophageal junction cancer, however, ongoing trials need to focus only on esopahgeal cancer patients 112 Definitive conclusions regarding the full potential of targeted therapies in esophageal cancer cannot be made yet. 114 Chapter 6. Key opinion leader interview transcripts 115 Contributing experts 115 Key opinion leader interview transcripts 115 APPENDIX 116 Bibliography List of Tables List of Figures 130 About Us 131 About Our Healthcare 131 About the Oncology analysis team 132 Disclaimer List of Tables Table 1: Crude incidence rates of esophageal cancer by gender per 100,000 in the seven major pharmaceutical markets, 2002 20 Table 2: Estimated incidence of esophageal cancer in the seven major pharmaceutical markets, 2001-15 21 Table 3: Crude mortality rates of esophageal cancer by gender per 100,000 in the seven major pharmaceutical markets, 2002 23 Table 4: Incidence and mortality from esophageal cancer in 2001 and 2015 across the seven major pharmaceutical markets 24 Table 5: Comparison of mortality to incidence ratios for selected tumor types in the US, 2001 25 Table 6: Risk factors for the development of esophageal cancer 26 Table 7: Common presenting symptoms of esophageal cancer 34 Table 8: Surveillance guidelines for patients with Barretts esophagus 37 Table 9: TNM classification system for esophageal cancer 40 Table 10: TNM staging system for esophageal cancer 41 Table 11: Stage distribution and five-year survival rates for esophageal cancer in the US 43 Table 12: Five-year survival by stage of esophageal cancer 43 Table 13: Esophageal cancer treatment guidelines in the US 48 Table 14: Esophageal cancer treatment guidelines for recurrent disease in the US 48 Table 15: Esophageal cancer treatment guidelines in Europe 49 Table 16: Extent of resection of esophageal cancer 51 Table 17: Results from the RTOG 85-01 study 52 Table 18: Results from the INT-0123/RTOG 94-05 study 53 Table 19: Results from randomized clinical trials comparing neoadjuvant radiotherapy with surgery alone in potentially resectable esophageal cancer 56 Table 20: Results from the INT-0113 study comparing neoadjuvant chemotherapy with surgery alone 58 Table 21: Results from the MRC study comparing neoadjuvant chemotherapy with surgery alone 58 Table 22: Results from a meta-analysis of 11 studies investigating neoadjuvant therapy for esophageal cancer 60 Table 23: Results from randomized clinical trials comparing neoadjuvant chemoradiotherapy with surgery alone 61 Table 24: Results from a randomized clinical trial comparing neoadjuvant chemoradiotherapy with or without surgery 62 Table 25: Results from a randomized clinical trial comparing adjuvant radiotherapy with surgery alone 67 Table 26: Results from the JCOG-9204 trial comparing adjuvant chemotherapy with surgery alone 68 Table 27: Results from a randomized clinical trial investigating adjuvant chemoradiotherapy 69 Table 28: Single-agent activity of cytotoxics in advanced esophageal cancer 74 Table 29: Results from Phase II studies investigating combination chemotherapy regimens for advanced esophageal cancer 75 Table 30: Results from a randomized trial comparing ECF with FAMTX in advanced esophagogastric cancer 76 Table 31: Results from a randomized trial comparing ECF with MCF in advanced esophagogastric cancer 77 Table 32: Survival results from the REAL-2 study 78 Table 33: Toxicity from the REAL-2 study 79 Table 34: Proportion of patients at each stage of esophageal cancer who undergo surgery across the five EU markets, 2006 83 Table 35: Proportion of patients at each stage of esophageal cancer who receive chemotherapy across the five EU markets, 2006 84 Table 36: Proportion of stage III/IV esophageal cancer patients who receive multiple lines of chemotherapy across the five EU markets, 2006 85 Table 37: Use of first-line chemotherapy regimens in esophageal cancer across the five EU markets, 2006 85 Table 38: Use of second-line chemotherapy regimens in esophageal cancer across the five EU markets, 2006 86 Table 39: Use of third-line chemotherapy regimens in esophageal cancer across the five EU markets, 2006 86 Table 40: Phase III esophageal cancer pipeline, 2007 98 Table 41: Ongoing clinical trials investigating Camptosar for resectable esophageal cancer, 2007 100 Table 42: Ongoing clinical trials investigating Camptosar for metastatic or unresectable esophageal cancer, 2007 101 Table 43: Ongoing clinical trials investigating Eloxatin for esophageal cancer, 2007 103 Table 44: Ongoing clinical trials investigating Xeloda for esophageal cancer, 2007 105 Table 45: Phase II esophageal cancer pipeline (cytotoxics), 2007 106 Table 46: Phase II esophageal cancer pipeline (targeted therapies and miscellaneous), 2007 107 Table 47: Phase I esophageal cancer pipeline, 2007 List of Figures Figure 1: Anatomy of the esophagus 16 Figure 2: Cross section of the esophagus 17 Figure 3: Esophageal cancer belt 19 Figure 4: Estimated incidence of esophageal cancer in the seven major pharmaceutical markets, 2001-15 21 Figure 5: Incidence and mortality from esophageal cancer in 2001 and 2015 across the seven major markets 24 Figure 6: Use of chemotherapy regimens in the treatment of esophageal cancer across the five EU markets, 2006 87 Figure 7: Summary of unmet needs in the esophageal cancer market, 2007 97 Ordering: Order Online - visit http://www.researchandmarkets.com/reports/452389 Order by Fax - using the order form below Order By Post - print the order form below and send to Research and Markets, Guinness Centre, Taylors Lane, Dublin 8, Ireland. 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