Contents:

Chapter 1. Executive summary 3 Scope of analysis 3 Our insight into the gynecological cancers market 4 Chapter 2. Disease overview 22 Introduction 22 Disease overview 22 The female reproductive system 22 Gynecological cancers 23 Definition 23 Endometrial cancer 24 Cervical cancer 24 Vaginal cancer 24 Vulvar cancer 25 Pathology and classification 25 Endometrial cancer: adenocarcinomas account for majority of incidence 25 Cervical cancer: squamous cell carcinoma is the most common pathology 27 Vaginal cancer: clear distinction between pathologies must be made 28 Vulvar cancer: any malignancy of the skin can occur here 28 Epidemiology 29 Incidence of gynecological tumors 29 Mortality from gynecological tumors 34 Risk factors 37 Endometrial cancer: genetic and environmental factors 38 Endometrial cancer: precursor conditions 41 Cervical cancer: genetic and environmental factors 42 Cervical cancer: precursor conditions 45 Risk factors for vaginal cancer 46 Risk factors for vulvar cancer 47 Symptoms 48 Endometrial cancer: abnormality of early signs means most cases are diagnosed rapidly 48 Cervical cancer: routine screening means any changes in the cervix are observed at an early stage 48 Vaginal cancer: most cases are diganosed at an early stage despite a lack of initial symptoms 49 Vulvar cancer: early symptoms are non-specific 49 Screening 49 Endometrial cancer: absence of screening programs is offset by a high rate of early patient presentation 49 Cervical cancer: widespread screening has significantly reduced mortality 50 Vaginal cancer: routine pelvic examinations can detect early cases 51 Vulvar cancer: routine pelvic examinations can detect early cases 51 Diagnosis 51 Endometrial cancer: dilation and curettage is the gold standard for diagnosis 51 Cervical cancer: following a Pap smear test, diagnosis can be made via biopsies 52 Vaginal cancer and vulvar cancer: colposcopy and biopsy are used to make diagnoses 52 Staging 53 Endometrial cancer: FIGO staging takes into account prognostic factors 53 Cervical cancer: staged clinically 55 Vaginal cancer: standard TNM and FIGO staging 56 Vulvar cancer: also surgically staged 57 Survival 59 Propensity for early diagnosis is reflected in encouraging five-year survival rates for most gynecological cancers 59 Prognosis 60 Prognosis of gynecological cancers depends primarily upon stage of disease and tumor characteristics 60 Prevention 63 Endometrial cancer: countering estrogen with progestin may aid prevention 63 Cervical cancer: prevention of HPV via vaccination will be key in prevention of tumors 64 Vaginal and vulvar cancer: prevention of HPV and regular screening should aid prevention of tumors 64 Chapter 3. Current treatment options 65 Introduction 65 Endometrial cancer 65 Treatment guidelines 65 The NCCN has recommended treatment guidelines for endometrial cancer 65 Stage-specific treatment 68 Stage I endometrial cancer: surgery alone is normally sufficient 68 Stage II endometrial cancer: radical hysterectomy is the standard 69 Stage III endometrial cancer: adjuvant radiotherapy can be administered at this stage 69 Stage IV endometrial cancer: depending on disease characteristics, radiotherapy, chemotherapy and/or hormonal therapy can be administered 70 Recurrent endometrial cancer: radiotherapy or chemotherapy is the standard, depending on site of recurrence 70 Cervical cancer 70 Treatment guidelines 70 Stage-specific treatment 73 Stage 0 cervical cancer: limited uterus-preserving surgery has the greatest utility 73 Stage IA cervical cancer: surgery is the standard here, although options to preserve fertility in younger patients are available 74 Stage IB cervical cancer: adjuvant radiotherapy can be adminstered in high-risk cases 74 Stage IIA cervical cancer: adjuvant chemoradiotherapy has been shown to increase survival 74 Stage IIB cervical cancer: nearly all patients at this stage receive chemoradiotherapy 75 Stage III cervical cancer: primary chemoradiotherapy is the standard at this stage 75 Stage IVA cervical cancer: treatment is similar to that for stage III cervical cancer 75 Stage IVB cervical cancer: treatment serves only palliative purposes at this stage 76 Recurrent cervical cancer: depending on the site of recurrence, chemotherapy, radiotherapy or pelvic exenteration may be of use 76 Vaginal cancer 76 Treatment overview 76 Stage-specific treatment 77 Stage 0 vaginal cancer: limited surgery preserves the vagina 77 Stage I vaginal cancer: surgery is the standard, with adjuvant radiotherapy for those with high-risk features 77 Stage II vaginal cancer: radiotherapy is the standard at this stage 78 Stage III vaginal cancer: treatment is similar to that for stage II disease 78 Stage IV vaginal cancer: chemotherapy can be adminstered for palliation of symptoms 79 Recurrent vaginal cancer: depending on the site of recurrence, radiotherapy or pelvic exenteration may be suitable 79 Vulvar cancer 79 Treatment overview 79 Stage-specific treatment 80 Stage 0 vulvar cancer: minimally invasive surgery is preferred 80 Stage I vulvar cancer: surgery typically forms the main treatment modality 80 Stage II vulvar cancer: adjuvant radiotherapy is administered where high-risk features are present 80 Stage III vulvar cancer: neoadjuvant radiotherapy can be used in selected cases to downgrade bulky tumors 81 Stage IV vulvar cancer: neoadjuvant chemoradiotherapy may be of some utility at this stage 81 Recurrent vulvar cancer: a combination of surgery and radiotherapy can be employed, depending on the site of recurrence 82 Chapter 4. Current treatment regimens and controversies 83 Introduction 83 Endometrial cancer 83 Surgery 83 Surgery for staging is relatively standard… 83 …however controversy exists over value of l ymphadenectomy 83 Adjuvant therapy 86 Many early-stage patients receive adjuvant radiotherapy despite a lack of definitive evidence for its use and defined standard regimens 86 Adjuvant chemotherapy plus radiotherapy confers clinical benefit in advanced disease, although further investigation in randomized trials is necessary 87 Benefits of adjuvant chemotherapy over radiotherapy in stage III and IV disease come at the price of increased toxicity 88 Meta-analysis demonstrates adjuvant use of progestins provides no clinical benefit 89 Neoadjuvant therapy 90 Neoadjuvant radiotherapy generally reserved for stage II patients with a large amount of cervical involvement 90 Chemotherapy for advanced disease 91 Cisplatin and doxorubicin are considered the most active agents in endometrial cancer 91 The randomized GOG-107 initially demonstrated clinical benefit via a cisplatin and doxorubicin combination 91 Subsequent trials have shown utility of paclitaxel in endometrial cancer… 92 …however, dropping cisplatin for paclitaxel was not of clinical benefit 95 A platinum and doxorubicin combination with or without paclitaxel is the current standard for advanced or recurrent disease 95 Despite recommendations, no cytotoxic is formally approved specifically for endometrial cancer 96 Actual use of cytotoxics relies heavily upon the platinum agents 96 Hormonal therapy 99 Progestational agents can be used in the primary treatment of advanced disease where surgery is not an option 99 To date, combined chemotherapy and hormonal therapy has demonstrated little clinical value 100 Tamoxifen may be of use in some patients, although overall utility is limited 101 Other hormonal agents require further investigation 101 Actual use of hormonal therapy relies heavily upon single-agent medroxyprogesterone 102 Novel molecular targeted therapies 104 Further research is needed to determine the utility of targeted therapies in endometrial cancer 104 The future treatment of endometrial cancer 105 Results from the ongoing GOG-210 trial should help to identify optimal treatment regimens for individual patients 105 Cervical cancer 105 Surgery 105 The clinical staging used for cervical cancer is inferior in predicting extent of disease 105 Surgery and radiotherapy are equally effective as curative treatment modalities for early-stage disease 106 Pelvic exenteration may offer a cure for recurrent cervical cancer 108 Neoadjuvant therapy 109 Neoadjuvant chemoradiotherapy is only recommended for those patients with bulky early-stage tumors, although further research is necessary 109 Adjuvant therapy 111 Adjuvant radiotherapy is recommended for treatment of node-negative stage I and II patients with high-risk tumor characteristics 111 Adjuvant chemoradiotherapy is recommended for treatment of node-positive stage I and II patients 112 First-line chemoradiotherapy 113 Consistency of positive clinical trial data means first-line chemoradiotherapy is recommended for the treatment of stages IIB–IVA cervical cancer 113 Chemotherapy for advanced or recurrent disease 114 Cisplatin-based chemotherapy remains the standard of care for advanced and recurrent cervical cancer 114 Cisplatin is consistently the most active single agent 114 Combination regimens have shown marginal increases in efficacy 115 FDA and EMEA approval of GlaxoSmithKline’s Hycamtin (topotecan) in 2006 represented the first formal US and European approval of a cytotoxic agent for cervical cancer 117 A number of other new cytotoxics are under investigation in clinical trials 119 Actual use of cytotoxics shows an initial heavy reliance on cisplatin, which decreases as multiple lines of therapy are adminstered 121 Novel molecular targeted therapies 126 Further research is needed to determine the utility of targeted therapies in cervical cancer 126 Prevention of cervical cancer 126 Advent of anti-HPV vaccines will cause a great impact the cervical cancer market 126 Chapter 5. Unmet needs 130 Introduction 130 Unmet needs 130 Reducing incidence of gynecological malignancies 130 Awareness must be raised with regards to potential for early diagnosis 130 Anti-HPV vaccines must be made available in developing countries to reduce worldwide incidence of cervical cancer 131 Altering patient lifestyle factors may reduce incidence of endometrial cancer 133 Improved treatment options 134 Less invasive surgery is required for early-stage tumors 134 Better systemic therapy is required for metastatic and recurrent disease 135 More large-scale, randomized clinical trials are necessary to define optimal treatment strategies across all gynecological malignancies 136 Despite being the most common gynecological malignancy, the endometrial cancer pipeline is relatively sparse 138 No sign of increasing activity in the cervical cancer pipeline 139 Summary of unmet needs 141 Chapter 6. Pipeline analysis 142 Introduction 142 The endometrial cancer pipeline 143 Phase III development 143 Phase III pipeline for endometrial cancer is characterized by an absence of innovative targeted treatments 143 Phase I/II development 143 Future treatment is likely to depend on successfully incorporating innovative targeted therapies, although identification of optimal targets is required 143 Commonality of mutations to mTOR pathway in endometrial cancer means its inhibition is a rational treatment strategy 145 EGFR family inhibitors require further research in order to reach optimal response rates 146 VEGF levels are a potential indicator of more aggressive endometrial cancer 147 The cervical cancer pipeline 148 Phase III development 148 Eli Lilly’s Gemzar (gemcitabine) – a potential alternative treatment option? 148 Sanofi-Aventis’s Tirazone (tirapazamine) – a viable option for potentiating standard chemoradiotherapy? 152 Phase I/II development 154 Targeted therapies likely to play a large role in the future of cervical cancer 154 VEGF is expressed in greater levels in larger tumors, thereby implicating a more aggressive type of cervical cancer 156 Overexpression of EGFR is indicative of a worse prognosis, therefore its inhibition may eventually prove successful 158 Prevention of cervical cancer 159 Vaccination against HPV has the potential to significantly reduce incidence of cervical cancer 159 Merck & Co’s Gardasil – the first anti-HPV vaccine to reach the market 160 GlaxoSmithKline’s Cervarix – still awaiting large-scale clinical trial results 161 Which vaccine will enjoy greater commercial success? 163 The vaginal cancer and vulvar cancer pipelines 164 Phase I/II development 164 Low incidence has resulted in an empty pipeline 164 Chapter 7. Key opinion leader interview transcripts 166 Contributing experts 166 Key opinion leader interview transcripts 166 APPENDIX 167 Bibliography List of Tables List of Figures