Gynecological Cancers - Niche opportunities in advanced disease
Scope
Report Highlights
Reasons to Purchase
Table of Contents
- ABOUT DATAMONITOR HEALTHCARE - page 2
- About the Oncology pharmaceutical analysis team - page 2
- CHAPTER 1 EXECUTIVE SUMMARY - page 3
- Scope of analysis - page 3
- Datamonitor insight into the gynecological cancers market - page 4
- CHAPTER 2 DISEASE OVERVIEW - page 21
- Introduction - page 21
- Disease overview - page 21
- The female reproductive system - page 21
- Gynecological cancers - page 22
- Definition - page 22
- Endometrial cancer - page 23
- Cervical cancer - page 23
- Vaginal cancer - page 23
- Vulvar cancer - page 24
- Pathology and classification - page 24
- Endometrial cancer: adenocarcinomas account for majority of incidence - page 24
- Cervical cancer: squamous cell carcinoma is the most common pathology - page 26
- Vaginal cancer: clear distinction between pathologies must be made - page 27
- Vulvar cancer: any malignancy of the skin can occur here - page 27
- Epidemiology - page 28
- Incidence of gynecological tumors - page 28
- Mortality from gynecological tumors - page 33
- Risk factors - page 36
- Endometrial cancer: genetic and environmental factors - page 37
- Endometrial cancer: precursor conditions - page 40
- Cervical cancer: genetic and environmental factors - page 41
- Cervical cancer: precursor conditions - page 44
- Risk factors for vaginal cancer - page 45
- Risk factors for vulvar cancer - page 46
- Symptoms - page 47
- Endometrial cancer: abnormality of early signs means most cases are diagnosed rapidly - page 47
- Cervical cancer: routine screening means any changes in the cervix are observed at an early stage - page 47
- Vaginal cancer: most cases are diganosed at an early stage despite a lack of initial symptoms - page 48
- Vulvar cancer: early symptoms are non-specific - page 48
- Screening - page 48
- Endometrial cancer: absence of screening programs is offset by a high rate of early patient presentation - page 48
- Cervical cancer: widespread screening has significantly reduced mortality - page 49
- Vaginal cancer: routine pelvic examinations can detect early cases - page 50
- Vulvar cancer: routine pelvic examinations can detect early cases - page 50
- Diagnosis - page 50
- Endometrial cancer: dilation and curettage is the gold standard for diagnosis - page 50
- Cervical cancer: following a Pap smear test, diagnosis can be made via biopsies - page 51
- Vaginal cancer and vulvar cancer: colposcopy and biopsy are used to make diagnoses - page 51
- Staging - page 52
- Endometrial cancer: FIGO staging takes into account prognostic factors - page 52
- Cervical cancer: staged clinically - page 54
- Vaginal cancer: standard TNM and FIGO staging - page 55
- Vulvar cancer: also surgically staged - page 56
- Survival - page 58
- Propensity for early diagnosis is reflected in encouraging five-year survival rates for most gynecological cancers - page 58
- Prognosis - page 59
- Prognosis of gynecological cancers depends primarily upon stage of disease and tumor characteristics - page 59
- Prevention - page 62
- Endometrial cancer: countering estrogen with progestin may aid prevention - page 62
- Cervical cancer: prevention of HPV via vaccination will be key in prevention of tumors - page 63
- Vaginal and vulvar cancer: prevention of HPV and regular screening should aid prevention of tumors - page 63
- Definition - page 22
- Introduction - page 21
- CHAPTER 3 CURRENT TREATMENT OPTIONS - page 64
- Introduction - page 64
- Endometrial cancer - page 64
- Treatment guidelines - page 64
- The NCCN has recommended treatment guidelines for endometrial cancer - page 64
- Stage-specific treatment - page 67
- Stage I endometrial cancer: surgery alone is normally sufficient - page 67
- Stage II endometrial cancer: radical hysterectomy is the standard - page 68
- Stage III endometrial cancer: adjuvant radiotherapy can be administered at this stage - page 68
- Stage IV endometrial cancer: depending on disease characteristics, radiotherapy, chemotherapy and/or hormonal therapy can be administered - page 69
- Recurrent endometrial cancer: radiotherapy or chemotherapy is the standard, depending on site of recurrence - page 69
- Treatment guidelines - page 64
- Cervical cancer - page 69
- Treatment guidelines - page 69
- Stage-specific treatment - page 72
- Stage 0 cervical cancer: limited uterus-preserving surgery has the greatest utility - page 72
- Stage IA cervical cancer: surgery is the standard here, although options to preserve fertility in younger patients are available - page 73
- Stage IB cervical cancer: adjuvant radiotherapy can be adminstered in high-risk cases - page 73
- Stage IIA cervical cancer: adjuvant chemoradiotherapy has been shown to increase survival - page 73
- Stage IIB cervical cancer: nearly all patients at this stage receive chemoradiotherapy - page 74
- Stage III cervical cancer: primary chemoradiotherapy is the standard at this stage - page 74
- Stage IVA cervical cancer: treatment is similar to that for stage III cervical cancer - page 74
- Stage IVB cervical cancer: treatment serves only palliative purposes at this stage - page 75
- Recurrent cervical cancer: depending on the site of recurrence, chemotherapy, radiotherapy or pelvic exenteration may be of use - page 75
- Vaginal cancer - page 75
- Treatment overview - page 75
- Stage-specific treatment - page 76
- Stage 0 vaginal cancer: limited surgery preserves the vagina - page 76
- Stage I vaginal cancer: surgery is the standard, with adjuvant radiotherapy for those with high-risk features - page 76
- Stage II vaginal cancer: radiotherapy is the standard at this stage - page 77
- Stage III vaginal cancer: treatment is similar to that for stage II disease - page 77
- Stage IV vaginal cancer: chemotherapy can be adminstered for palliation of symptoms - page 78
- Recurrent vaginal cancer: depending on the site of recurrence, radiotherapy or pelvic exenteration may be suitable - page 78
- Vulvar cancer - page 78
- Treatment overview - page 78
- Stage-specific treatment - page 79
- Stage 0 vulvar cancer: minimally invasive surgery is preferred - page 79
- Stage I vulvar cancer: surgery typically forms the main treatment modality - page 79
- Stage II vulvar cancer: adjuvant radiotherapy is administered where high-risk features are present - page 79
- Stage III vulvar cancer: neoadjuvant radiotherapy can be used in selected cases to downgrade bulky tumors - page 80
- Stage IV vulvar cancer: neoadjuvant chemoradiotherapy may be of some utility at this stage - page 80
- Recurrent vulvar cancer: a combination of surgery and radiotherapy can be employed, depending on the site of recurrence - page 81
- CHAPTER 4 CURRENT TREATMENT REGIMENS AND CONTROVERSIES - page 82
- Introduction - page 82
- Endometrial cancer - page 82
- Surgery - page 82
- Surgery for staging is relatively standard... - page 82
- ...however controversy exists over value of l ymphadenectomy - page 82
- Adjuvant therapy - page 85
- Many early-stage patients receive adjuvant radiotherapy despite a lack of definitive evidence for its use and defined standard regimens - page 85
- Adjuvant chemotherapy plus radiotherapy confers clinical benefit in advanced disease, although further investigation in randomized trials is necessary - page 86
- Benefits of adjuvant chemotherapy over radiotherapy in stage III and IV disease come at the price of increased toxicity - page 87
- Meta-analysis demonstrates adjuvant use of progestins provides no clinical benefit - page 88
- Neoadjuvant therapy - page 89
- Neoadjuvant radiotherapy generally reserved for stage II patients with a large amount of cervical involvement - page 89
- Chemotherapy for advanced disease - page 90
- Cisplatin and doxorubicin are considered the most active agents in endometrial cancer - page 90
- The randomized GOG-107 initially demonstrated clinical benefit via a cisplatin and doxorubicin combination - page 90
- Subsequent trials have shown utility of paclitaxel in endometrial cancer... - page 91
- ...however, dropping cisplatin for paclitaxel was not of clinical benefit - page 94
- A platinum and doxorubicin combination with or without paclitaxel is the current standard for advanced or recurrent disease - page 94
- Despite recommendations, no cytotoxic is formally approved specifically for endometrial cancer - page 95
- Actual use of cytotoxics relies heavily upon the platinum agents - page 95
- Hormonal therapy - page 98
- Progestational agents can be used in the primary treatment of advanced disease where surgery is not an option - page 98
- To date, combined chemotherapy and hormonal therapy has demonstrated little clinical value - page 99
- Tamoxifen may be of use in some patients, although overall utility is limited - page 100
- Other hormonal agents require further investigation - page 100
- Actual use of hormonal therapy relies heavily upon single-agent medroxyprogesterone - page 101
- Novel molecular targeted therapies - page 103
- Further research is needed to determine the utility of targeted therapies in endometrial cancer - page 103
- The future treatment of endometrial cancer - page 104
- Results from the ongoing GOG-210 trial should help to identify optimal treatment regimens for individual patients - page 104
- Surgery - page 82
- Cervical cancer - page 104
- Surgery - page 104
- The clinical staging used for cervical cancer is inferior in predicting extent of disease - page 104
- Surgery and radiotherapy are equally effective as curative treatment modalities for early-stage disease - page 105
- Pelvic exenteration may offer a cure for recurrent cervical cancer - page 107
- Neoadjuvant therapy - page 108
- Neoadjuvant chemoradiotherapy is only recommended for those patients with bulky early-stage tumors, although further research is necessary - page 108
- Adjuvant therapy - page 110
- Adjuvant radiotherapy is recommended for treatment of node-negative stage I and II patients with high-risk tumor characteristics - page 110
- Adjuvant chemoradiotherapy is recommended for treatment of node-positive stage I and II patients - page 111
- First-line chemoradiotherapy - page 112
- Consistency of positive clinical trial data means first-line chemoradiotherapy is recommended for the treatment of stages IIB-IVA cervical cancer - page 112
- Chemotherapy for advanced or recurrent disease - page 113
- Cisplatin-based chemotherapy remains the standard of care for advanced and recurrent cervical cancer - page 113
- Cisplatin is consistently the most active single agent - page 113
- Combination regimens have shown marginal increases in efficacy - page 114
- 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 - page 116
- A number of other new cytotoxics are under investigation in clinical trials - page 118
- Actual use of cytotoxics shows an initial heavy reliance on cisplatin, which decreases as multiple lines of therapy are adminstered - page 120
- Novel molecular targeted therapies - page 125
- Further research is needed to determine the utility of targeted therapies in cervical cancer - page 125
- Prevention of cervical cancer - page 125
- Advent of anti-HPV vaccines will cause a great impact the cervical cancer market - page 125
- Surgery - page 104
- CHAPTER 5 UNMET NEEDS - page 129
- Introduction - page 129
- Unmet needs - page 129
- Reducing incidence of gynecological malignancies - page 129
- Awareness must be raised with regards to potential for early diagnosis - page 129
- Anti-HPV vaccines must be made available in developing countries to reduce worldwide incidence of cervical cancer - page 130
- Altering patient lifestyle factors may reduce incidence of endometrial cancer - page 132
- Improved treatment options - page 133
- Less invasive surgery is required for early-stage tumors - page 133
- Better systemic therapy is required for metastatic and recurrent disease - page 134
- More large-scale, randomized clinical trials are necessary to define optimal treatment strategies across all gynecological malignancies - page 135
- Despite being the most common gynecological malignancy, the endometrial cancer pipeline is relatively sparse - page 137
- No sign of increasing activity in the cervical cancer pipeline - page 138
- Reducing incidence of gynecological malignancies - page 129
- Summary of unmet needs - page 140
- CHAPTER 6 PIPELINE ANALYSIS - page 141
- Introduction - page 141
- The endometrial cancer pipeline - page 142
- Phase III development - page 142
- Phase III pipeline for endometrial cancer is characterized by an absence of innovative targeted treatments - page 142
- Phase I/II development - page 142
- Future treatment is likely to depend on successfully incorporating innovative targeted therapies, although identification of optimal targets is required - page 142
- Commonality of mutations to mTOR pathway in endometrial cancer means its inhibition is a rational treatment strategy - page 144
- EGFR family inhibitors require further research in order to reach optimal response rates - page 145
- VEGF levels are a potential indicator of more aggressive endometrial cancer - page 146
- Phase III development - page 142
- The cervical cancer pipeline - page 147
- Phase III development - page 147
- Eli Lilly's Gemzar (gemcitabine) - a potential alternative treatment option? - page 147
- Sanofi-Aventis's Tirazone (tirapazamine) - a viable option for potentiating standard chemoradiotherapy? - page 151
- Phase I/II development - page 153
- Targeted therapies likely to play a large role in the future of cervical cancer - page 153
- VEGF is expressed in greater levels in larger tumors, thereby implicating a more aggressive type of cervical cancer - page 155
- Overexpression of EGFR is indicative of a worse prognosis, therefore its inhibition may eventually prove successful - page 157
- Prevention of cervical cancer - page 158
- Vaccination against HPV has the potential to significantly reduce incidence of cervical cancer - page 158
- Merck & Co's Gardasil - the first anti-HPV vaccine to reach the market - page 159
- GlaxoSmithKline's Cervarix - still awaiting large-scale clinical trial results - page 160
- Which vaccine will enjoy greater commercial success? - page 162
- Phase III development - page 147
- The vaginal cancer and vulvar cancer pipelines - page 163
- Phase I/II development - page 163
- Low incidence has resulted in an empty pipeline - page 163
- Phase I/II development - page 163
- CHAPTER 7 KEY OPINION LEADER INTERVIEW TRANSCRIPTS - page 165
- Contributing experts - page 165
- Key opinion leader interview transcripts - page 165
- APPENDIX - page 166
- Bibliography - page 166
- List of tables - page 177
- List of figures - page 181
- About Datamonitor - page 182
- About Datamonitor Healthcare - page 182
- About the Oncology analysis team - page 183
- Disclaimer - page 184
- List of Tables
- Table 1: Proportion of different gynecological tumor types in the US - page 22
- Table 2: Pathologies of endometrial cancer - page 25
- Table 3: Histological classification of endometrial cancer - page 25
- Table 4: Pathologies of cervical cancer - page 26
- Table 5: Pathologies of vaginal cancer - page 27
- Table 6: Pathologies of vulvar cancer - page 28
- Table 7: Crude incidence rates of endometrial and cervical cancer per 100,000 in the seven major pharmaceutical markets - page 29
- Table 8: Estimated incidence of endometrial cancer in the seven major pharmaceutical markets, 2000-14 - page 29
- Table 9: Estimated incidence of cervical cancer in the seven major pharmaceutical markets, 2000-14 - page 30
- Table 10: Crude mortality rates of endometrial and cervical cancer per 100,000 in the seven major pharmaceutical markets - page 33
- Table 11: Incidence and mortality from endometrial cancer in 2000 and 2014 across the seven major pharmaceutical markets - page 34
- Table 12: Incidence and mortality from cervical cancer in 2000 and 2014 across the seven major pharmaceutical markets - page 34
- Table 13: Risk factors for the development of endometrial cancer - page 36
- Table 14: Risk factors for the development of cervical cancer - page 37
- Table 15: Risk of progression from endometrial hyperplasia to endometrial cancer - page 40
- Table 16: Risk of developing cervical cancer based on key factors - page 42
- Table 17: FIGO surgical staging of endometrial cancer - page 52
- Table 18: TNM classification system of endometrial cancer - page 53
- Table 19: TNM classification of FIGO staging for endometrial cancer - page 53
- Table 20: TNM and FIGO clinical staging of cervical cancer - page 54
- Table 21: TNM classification of FIGO staging for cervical cancer - page 55
- Table 22: TNM and FIGO staging of vaginal cancer - page 56
- Table 23: TNM classification of FIGO staging for vaginal cancer - page 56
- Table 24: TNM and FIGO staging of vulvar cancer - page 57
- Table 25: Regional lymph node staging for vulvar cancer - page 57
- Table 26: TNM classification of FIGO staging for vulvar cancer - page 58
- Table 27: Stage distribution and five-year survival rates for endometrial cancer - page 58
- Table 28: Stage distribution and five-year survival rates for cervical cancer - page 59
- Table 29: Stage distribution and five-year survival rates for vulvar cancer - page 59
- Table 30: Prognostic factors for endometrial cancer - page 60
- Table 31: Prognostic factors for cervical cancer - page 61
- Table 32: Adjuvant treatment guidelines for stage I endometrial cancer - page 65
- Table 33: Adjuvant treatment guidelines for stage II, III and IV endometrial cancer - page 66
- Table 34: The impact of lymphadenectomy on five-year survival in endometrial cancer - page 83
- Table 35: Results from the RTOG-9708 study - page 87
- Table 36: Results from the GOG-122 study - page 88
- Table 37: Five-year survival rates associated with neoadjuvant brachytherapy for stage I and II endometrial cancer - page 89
- Table 38: Results from the GOG-107 trial - page 91
- Table 39: Results form the GOG-177 trial - page 92
- Table 40: Results from the GOG-163 trial - page 94
- Table 41: Proportion of patients at each stage of endometrial cancer who receive chemotherapy across the five EU markets - page 95
- Table 42: Percentage of endometrial cancer chemotherapy patients receiving specific regimens across the five EU markets - page 96
- Table 43: Proportion of patients at each stage of endometrial cancer who receive hormonal therapy across the five EU markets - page 102
- Table 44: Clinical trial results comparing primary surgery with radiotherapy in early-stage cervical cancer - page 106
- Table 45: Results from the GOG-123 trial - page 109
- Table 46: Results from the GOG-92 trial - page 110
- Table 47: Results from the GOG-109/SWOG-8797 trial - page 111
- Table 48: Results from five randomized clinical trials that demonstrate the benefit of adding cisplatin-based chemotherapy to radiotherapy - page 112
- Table 49: Single-agent activity of cytotoxics in advanced cervical cancer - page 114
- Table 50: Combination chemotherapy activity in advanced cervical cancer - page 115
- Table 51: Results from the GOG-169 trial - page 116
- Table 52: Results from the GOG-179 trial - page 117
- Table 53: Proportion of patients at each stage of cervical cancer who receive chemotherapy across the five EU markets - page 120
- Table 54: Proportion of stage IV cervical cancer patients who receive multiple lines of chemotherapy across the five EU markets - page 121
- Table 55: Use of first-line chemotherapy regimens in cervical cancer across the five EU markets - page 122
- Table 56: Use of second-, third- and fourth-line chemotherapy regimens in cervical cancer across the five EU markets - page 123
- Table 57: Crude mortality rates of endometrial and ovarian cancer per 100,000 in the seven major pharmaceutical markets - page 137
- Table 58: Phase II endometrial cancer pipeline, 2006 - page 143
- Table 59: Phase I endometrial cancer pipeline, 2006 - page 144
- Table 60: Phase III cervical cancer pipeline, 2006 - page 147
- Table 61: Clinical development for Gemzar in cervical cancer, 2006 - page 148
- Table 62: Results from the Phase II GOG-128F and GOG-127K studies investigating single-agent Gemzar in previously treated cervical cancer - page 149
- Table 63: Results from the Phase II GOG-127Q study investigating cisplatin + Gemzar in refractory or recurrent cervical cancer - page 150
- Table 64: Clinical development for Tirazone in cervical cancer, 2006 - page 151
- Table 65: Results from Phase II clinical trials investigating Tirazone in cervical cancer - page 152
- Table 66: Phase II cervical cancer pipeline, 2006 - page 154
- Table 67: Phase I cervical cancer pipeline, 2006 - page 155
- Table 68: Clinical development for Avastin in cervical cancer, 2006 - page 156
- Table 69: Results from a retrospective analysis of Avastin in combination with chemotherapy in heavily pretreated cervical cancer - page 156
- Table 70: Overview comparison of Gardasil and Cervarix - page 159
- Table 71: Collective clinical trial results for Gardasil - page 160
- Table 72: Ongoing Phase III clinical trials to investigate Cervarix - page 161
- Table 73: Vaginal and vulvar cancer pipeline, 2006 - page 163
- List of Figures
- Figure 1: Anatomy of the female reproductive system - page 21
- Figure 2: Estimated incidence of endometrial and cervical cancer in the seven major pharmaceutical markets, 2000-14 - page 30
- Figure 3: Incidence and mortality from endometrial and cervical cancer in 2000 and 2014 across the seven major markets - page 35
- Figure 4: Endometrial cancer treatment guidelines following diagnosis - page 65
- Figure 5: Endometrial cancer treatment guidelines upon recurrence - page 67
- Figure 6: Primary treatment guidelines for stage I/II cervical cancer - page 70
- Figure 7: Adjuvant therapy guidelines for stage I/II cervical cancer - page 71
- Figure 8: Primary therapy guidelines for stage II, III and IV cervical cancer following surgery - page 71
- Figure 9: Cervical cancer treatment guidelines upon recurrence - page 72
- Figure 10: Percentage of endometrial cancer chemotherapy patients receiving specific regimens across the five EU markets - page 97
- Figure 11: Percentage of endometrial cancer hormonal therapy patients receiving specific regimens across the five EU markets - page 103
- Figure 12: Use of chemotherapy regimens across various lines of treatment in cervical cancer across the five EU markets - page 124
- Figure 13: Summary of unmet needs in the gynecological cancer market - page 140
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