Esophageal Cancer Treatment paradigms need revolution not evolution

ABOUT DATAMONITOR HEALTHCARE
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About the Oncology pharmaceutical analysis team
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Nish Saini - Lead Analyst, Oncology
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CHAPTER 1 EXECUTIVE SUMMARY
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Scope of analysis
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Datamonitor insight into the esophageal cancer market
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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
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Conflicting opinions regarding the use of neoadjuvant chemoradiotherapy for locally advanced disease requires clarification, potentially via the future use of genetic profiling
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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
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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
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CHAPTER 2 DISEASE OVERVIEW
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Introduction
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Disease overview
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Esophageal cancer: a major source of cancer-related death
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Anatomy of the esophagus
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Esophageal cancer
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Definition
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Increasing number of distal esophageal tumors
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Pathology
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Predominance of histolological subtypes varies by geographical region
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Epidemiology
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Increasing rates of adenocarcinoma in the West drive an increasing incidence of esophageal cancer across the seven major markets
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Mortality from esophageal cancer is high in comparison to its incidence due to a typically advanced stage at diagnosis
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Risk factors
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Risk factors are better defined for squamous cell carcinoma than for adenocarcinoma
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Genetic and environmental factors
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Precursor conditions
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Symptoms
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A lack of initial symptoms mean half of patients present with advanced disease
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Screening
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Regular surveillance of patients with Barrett's esophagus is recommended
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Diagnosis
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Endoscopy is used most frequently in the West to diagnose esophageal cancer
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Staging
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Esophageal cancer has been pathologically staged since 2002
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Survival
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The high rate of advanced-stage diagnoses is reflected by relatively poor survival rates
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Prognosis
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Stage of disease is the main prognostic indicator for esophageal cancer
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Prevention
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For Barrett's esophagus, a variety of preventative measures exist to halt progression to malignancy
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Weight reduction may form a viable preventative strategy for GERD, and ultimately, esophageal cancer
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Chemoprevention of esophageal cancer may be possible using NSAIDs or aspirin
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CHAPTER 3 CURRENT TREATMENT OPTIONS AND CONTROVERSIES
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Introduction
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Treatment guidelines
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US treatment guidelines
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US treatment guidelines for esophageal cancer focus on the use of chemoradiotherapy for most patients
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European treatment guidelines
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European treatment guidelines focus on the use of chemoradiotherapy when surgery is not a viable option
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Treatment of esophageal cancer in Japan
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Greater emphasis is placed on surgery in Japan for the treatment of esophageal cancer
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Treatment of early-stage and locally advanced esophageal cancer
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Surgery
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Resection has the greatest utility in the treatment of early-stage esophageal cancer patients
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Primary chemoradiotherapy for locally advanced disease
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Primary chemoradiotherapy may provide a cure for locally advanced esophageal cancer patients
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Neoadjuvant therapy
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Neoadjuvant radiotherapy has been shown of little use in improving either resectability or survival
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Neoadjuvant chemotherapy has demonstrated a survival advantage without increasing postoperative complications
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Neoadjuvant chemoradiotherapy confers a high level of treatment-related mortality
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Several Phase III studies are ongoing to further investigate the utility of neoadjuvant therapy
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Adjuvant therapy
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Adjuvant radiotherapy may result in decreased survival in comparison with surgery alone
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Adjuvant chemotherapy: some regimens have conferred a survival benefit, however, this treatment modality has not been widely investigated
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Adjuvant chemoradiotherapy is not associated with survival benefits and has not been widely investigated
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Clinical trial activity investigating adjuvant therapy in esophageal cancer is somewhat limited
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Surgery versus systemic therapy or combined modality treatment for locally advanced disease
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Genetic testing may eventually resolve the issue of what constitutes ideal treatment for individual esophageal cancer patients
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Treatment of advanced-stage and metastatic esophageal cancer
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Radiotherapy
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Primary radiotherapy is reserved for palliative purposes or for those patients medically unfit to undergo chemotherapy
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Chemotherapy for advanced disease
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No standard chemotherapy regimen exists for advanced disease due to a lack of large-scale, randomized clinical trial data
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Cisplatin forms the basis of chemotherapy for esophageal cancer, given that its single-agent activity is higher than any other cytotoxic tested to date
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Phase II studies have shown combination chemotherapy to confer increased survival, albeit at the expense of increased toxicity and morbidity
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The NCCN recommends 5-fluorouracil or cisplatin-based chemotherapy for metastatic esophageal cancer, since no Phase III studies have been completed for 15 years
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The ECF (epirubicin, cisplatin and 5-fluorouracil) regimen is used as standard chemotherapy for metastatic disease in the UK
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Despite an urgent need for more definitive data, no Phase III clinical trials are currently ongoing
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Photodynamic therapy
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Photodynamic therapy forms an alternative palliative treatment option in advanced esophageal cancer
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Axcan Pharma's Photofrin is approved for the palliation of advanced esophageal cancer
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Estimated treatment of esophageal cancer in the five major European markets
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Estimated use of surgery
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Heavier reliance on potentially curative surgery at the earlier stages of esophageal cancer
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Estimated use of chemotherapy
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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
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CHAPTER 4 UNMET NEEDS
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Introduction
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Unmet needs
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Improving prognosis of esophageal cancer
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50% of patients present with advanced disease, therefore better or facilitated techniques to increase earlier diagnosis are needed
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Improving patient lifestyle factors could prevent or delay the onset of esophageal cancer
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Enhanced treatment options required across all stages of disease
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New and more effective systemic therapies for advanced disease are required
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More effective neoadjuvant or adjuvant therapy for patients who undergo surgery, to reduce relapse rates
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Adequate palliative treatment options for metastatic esophageal cancer patients are still necessary
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Future treatment of esophageal cancer
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More large-scale, randomized clinical trials are necessary to define optimal treatment strategies at all stages of esophageal cancer
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Espohageal cancer fails to generate significant commercial interest
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Summary of unmet needs
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CHAPTER 5 PIPELINE ANALYSIS
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The esophageal cancer pipeline
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Phase III pipeline
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Pfizer's Camptosar (irinotecan) - current off-label use may mean that formal approval may not be sought
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Sanofi-Aventis's Eloxatin (oxaliplatin) - results from the REAL-2 trial and recent genericization in Europe may increase uptake
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Roche's Xeloda (capecitabine) - pharmacoeconomic issues may hinder uptake
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Phase I/II pipeline
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Already proven a popular target in colorectal cancer, EGFR inhibitors have shown some antitumor activity to date in early-phase trials for esophageal cancer
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Inhibition of angiogenesis appears a successful strategy in gastroesophageal junction cancer, however, ongoing trials need to focus only on esopahgeal cancer patients
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Definitive conclusions regarding the full potential of targeted therapies in esophageal cancer cannot be made yet.
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CHAPTER 6 KEY OPINION LEADER INTERVIEW TRANSCRIPTS
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Contributing experts
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Key opinion leader interview transcripts
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APPENDIX
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Bibliography
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List of tables
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List of figures
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About Datamonitor
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About Datamonitor Healthcare
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About the Oncology analysis team
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Disclaimer
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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 Barrett's 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  108

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