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