Contents:

CHAPTER 1 EXECUTIVE SUMMARY 3. Scope 3 Our insight into the brain cancer market 4 CHAPTER 2 INTRODUCTION: A DIVERSE RANGE OF HETEROGENOUS NEOPLASMS 13. Epidemiology 15 Staging and classification systems for primary brain tumors 21 TNM staging system is of limited utility 21 WHO classifies brain tumors by histological origin of tumor cell 21 WHO grading of brain tumors provides prognostic utility 24 Gliomas account for 77% of the malignant brain tumors 24 Prior cranial irradiation and genetic predisposition are the only established risk-factors for brain tumor development 28 Prognosis for glioma patients is primarily related to histological grade, age and performance status 31 For treatment purposes patients may be stratified according to the recursive partitioning analysis (RPA) classification. 32 Some molecular markers have demonstrated prognostic utility regarding response to chemotherapy 34 CHAPTER 3 CURRENT TREATMENT OPTIONS 38. Supportive care 39 Surgical options for glioma patients 40 Radiotherapy options for glioma patients 41 Treatment of low-grade glioma 43 The ‘gold-standard’ treatment for low-grade glioma may be changing 44 No clinical benefit of immediate radiation therapy following surgery for low-grade glioma 45 No radiotherapy dose-response in patients with low-grade glioma 45 Treatment of glioblastoma 46 Schering-Plough’s temozolomide (Temodal/Temodar) has rapidly become the new gold standard of care for glioblastoma 48 Temozolomide (Temodar, Temodal), Schering-Plough 49 Temozolomide with radiotherapy confers increased survival in glioblastoma patients 49 Temozolomide has a manageable toxicity profile 50 Temozolomide benefits from its oral availability 50 Temozolomide, European Medicines Agency application approved June 2005 51 CHAPTER 4 UNMET NEEDS 52. Disruption of the bloob-brain barrier can cloud accuracy of Imaging techniques 52 Imaging 52 Drug penetration through the blood brain barrier continues to hamper drug development 53 Adverse interaction of supportive therapy with definitive therapy drugs 54 Measuring tumor response requires evolution in the era of targeted treatment 55 Improvements in clinical trial design necessary 57 Alternative Phase II trial design 58 Temozolomide ‘raises the bar’ as suitable clinical endpoints 58 Effective agents needed to counter inevitable tumor recurrence 59 Costs associated with treating glioma patients 59 Despite low incidence brain cancer exerts significant costs on healthcare systems 59 Inpatient stays are the main driver of costs associated with brain cancer patients 63 Agents in development for glioma benefit from fast track and orphan drug status 65 CHAPTER 5 PIPELINE DRUGS 67. Cotara (131I-ch, TNT-1B, 131I-TNT), Peregrine Pharmaceuticals 67 Cintredekin besudotox (IL13-PE38; NK-408), Neopharm 70 Nimotuzumab (TheraCIM h-R3: as Theraloc in Europe), YM Biosciences/Center of Molecular Immunology/Oncoscience 72 TransMID (XR-311), Xenova 74 Phase II trial drugs 76 Enzastaurin (LY-317615; 317615.2HCI), Eli Lilly 77 Erlotinib (Tarceva, Genentech/Roche/OSI) 80 CHAPTER 6 OPINION LEADER TRANSCRIPTS 85. Contributing experts 85 European opinion leader 1 86 European opinion leader 2 94 US opinion leader 1 102 US opinion leader 2 115 US opinion leader 3 126 CHAPTER 7 APPENDIX 132. References 132 Methodology – epidemiology 136 Integrity of incidence data 136 Static incidence data 136 List of tables 138 List of figures 140 About Us 141 About our Healthcare 141 Our Healthcare’s research and analysis methodologies 142 Our Healthcare’s therapy area capabilities 142 About the Oncology analysis team 143 Disclaimer 144