In most developed countries, ovarian carcinoma is the second most common malignancy of the female genital tract, following endometrial carcinoma. This chapter reviews the major morphological sub-types of ovarian carcinoma including their pathogenesis, and discusses problematic areas in typing. Most of the grading systems are universal in that they can be applied to all the major morphological sub-types of ovarian carcinoma. The major morphological sub-types of ovarian carcinoma are serous, endometrioid, clear cell and mucinous. Two relatively recent population-based studies that included central pathology review have provided updated information regarding the relative frequencies of the major sub-types. The perceived relationship between benign, borderline and malignant ovarian serous neoplasms was controversial. The morphological features of ovarian carcinomas treated by chemotherapy often differ markedly from native tumours. The chapter also summarizes the evidence that most high-grade pelvic serous carcinomas arise from the fimbria of the fallopian tube.

Current treatments for advanced endometrial cancer are chemotherapy or hormonal therapy. This chapter describes the molecular genetic alterations associated with hereditary and sporadic endometrial carcinomas and explores potential treatment strategies arising from this knowledge. In approximately 5-10% of endometrial carcinoma cases there is an inherited predisposition to cancer. Classically, endometrial cancer has been categorised into two groups based on clinical and histopathological features: type I (endometrioid) and type II (non-endometrioid) endometrial carcinoma. The identification of activating mutations in FGFR2 in endometrioid endometrial cancers provides a potential theraputic target. Pre-clinical studies have shown that endometrial cancer cell lines with activating FGFR2 mutations are selectively sensitive to the pan-FGFR inhibitor PD173074. Future clinical trials should explore the role of PTEN as a synthetic lethality target for PARP inhibitors in endometrial cancer. Other potential strategies include targeting FGFR2 and microsatellite instability (MSI).

Tumour biomarkers and an understanding of the mechanisms of epigenetic regulation are a key to identify novel epigenetic therapies, and epigenetic biomarkers also have potential to impact on clinical management in gynaecological cancer. DNA methylation has many potential advantages as a cancer biomarker since it is stable, provides a binary read-out and is frequently aberrant in cancer. Methylation profiling of tumours has allowed the identification of genome-wide DNA methylation patterns as well as the identification of loci that are associated with response or survival of women with ovarian cancer following chemotherapy. EZH2 knockdown in ovarian cell lines has been shown to lead to reduced cell growth/proliferation, as well as cell migration and/or invasion in vitro. It has also led to the re-sensitisation of drug-resistant ovarian cancer cells to cisplatin. Histone deacetylase (HDAC) and DNA methyltransferases (DNMT) inhibitors are now used in the treatment of certain haematological malignancies.

This chapter concentrates on recent robust advances that are likely to affect clinical care over the short to medium term. It discusses potential biomarkers for stratified treatment of high-grade serous (HGSOC) and their relationship with platinum sensitivity and resistance. The accurate diagnosis of sub-type before chemotherapy treatment is vital as it provides strong prognostic and biological information. Many expression microarray studies have attempted to define prognostic and predictive signatures for chemoresistance in epithelial ovarian cancer (EOC). DNA copy number analysis has also been investigated as a predictive marker. Ultrasound- or computed tomography (CT)-guided biopsy is the standard of care for initial diagnosis of women with suspected ovarian cancer. Intratumoral genetic heterogeneity in HGSOC has been demonstrated both within a region of tumour and between different metastatic sites. These genetic differences could be expected to alter chemosensitivity.

The importance of BRCA1 and BRCA2 genes stems from the fact that they are 'caretaker' cancer-susceptibility genes, which encode molecules that act as sensors of DNA defects and participate in the repair process. The main function of BRCA2 is its role in HR-mediated DNA DSB repair through its direct interaction with RAD51. Most ovarian cancers occur sporadically, although approximately 10% of patients report an associated family history of the disease. In unselected series, about 6-15% of ovarian cancers have been found to be due to BRCA mutations. The ability to predict an individual's cancer risk accurately is limited by the influence of factors other than whether a BRCA1 or BRCA2 mutation has been inherited. The demonstration of single-agent anti-tumour activity and the wide therapeutic index of PARP inhibitors in BRCA1 and BRCA2 mutation carriers with advanced ovarian and breast cancers provide strong evidence for the clinical application of this approach.

This chapter outlines the DNA repair pathways involved in PARP inhibitor sensitivity, how deficiencies in these pathways are exploited by PARP inhibitors and finally how aberrations of these pathways may be identified and thus used as predictive biomarkers for treatment. Evidence suggests that there can be overlap between the pathways under certain circumstances, for instance in repairing DNA crosslink lesions. There is substantial evidence that tumours associated with germline mutations of the BRCA genes are associated with high initial sensitivity to platinum and overall slightly improved outcome compared with other high-grade serous ovarian cancers. DNA repair pathways would appear to be an attractive target for the development of new therapies. Cancer cells are intrinsically and genetically unstable and therefore susceptible to further DNA damage. Accurate biomarkers would allow identification of people with tumours that are not normally recognised to respond to a particular treatment.

This chapter discusses the results of recent clinical trials of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors, either as single agents or in combination with chemotherapy, and considers the future role of PARP inhibitors in the treatment of cancer. PARP-1 has shown to regulate gene transcription, mediate p53-regulated apoptosis and initiate necrotic cell death in response to extensive DNA damage such as that occurring after myocardial infarction, stroke and septic shock, suggesting that there may be wider clinical applications for inhibitors of PARP-1. BRCA1/2 mutations account for the majority of hereditary breast and ovarian cancers but this represents only 5-15% of all ovarian and breast cancer cases. PARP inhibitors were originally developed not for single-agent use but to enhance the cytotoxicity of chemotherapy. A crucial recent development has been that, in addition to BRCA-mutated cancers, a role for PARP inhibitors is emerging in sporadic cancers, in particular high-grade serous ovarian carcinomas (HGSOC).

Laparoscopic surgery has become an essential part of the surgical treatment for gynaecological conditions including malignancy. This chapter describes the use of conventional laparoscopic surgery in gynaecological cancer, the advantages and disadvantages of robotic surgery, and the feasibility and outcomes of the use of robotics in gynaecological cancer surgery. The da Vinci Surgical System is equipped with a three-dimensional vision system. Robotic surgery is well suited to virtual reality training as the operation is computer guided. 3D virtual reality images can be projected into the console of the robot. A number of virtual reality training simulators have been created. Several authors have reported that robotically assisted staging surgery in endometrial cancer is comparable to conventional laparoscopic and open laparotomy approaches in terms of surgical outcomes. A phase III randomised clinical trial comparing laparoscopic with robotically assisted surgery in women with early-stage cervical cancer is under way.

Effective chemotherapy allows the performance of surgical cytoreduction to have improved outcomes. This chapter provides an outline for the rationale and implementation of a comprehensive cytoreductive surgical approach in advanced ovarian cancer. The most important prognostic factors refer primary surgical outcome and the response to postoperative chemotherapy. Multiple retrospective studies, pooled exploratory analyses and meta-analyses have demonstrated that the amount of residual disease after cytoreductive surgery inversely correlates with progression-free survival (PFS) and overall survival (OS). Disease involving the upper abdomen cephalad to the greater omentum (UAD) is frequently seen in women with ovarian cancer. Complications involving debulking of the left upper quadrant during cytoreduction have been evaluated. In centres where a comprehensive primary surgical approach can be offered, a primary cytoreductive approach should be the standard of care except for the high-risk group of women.

The great majority of women with advanced ovarian cancer will relapse and die from the disease. Angiogenesis is particularly relevant to ovarian cancer. Tumour vascular endothelial growth factor (VEGF) overexpression is associated with tumour angiogenesis, malignant progression and metastasis, ascites formation and early recurrence and death from the disease. Chemotherapy and vascular disrupting agents (VDAs) can cause mobilisation of bone marrow progenitor cells, including circulating endothelial progenitor cells (CEPs), which could theoretically increase angiogenesis. Two trials of combination therapy that included bevacizumab have suggested discrepancies between CA125 and RECIST response evaluation. VDAs selectively target pre-existing tumour vasculature, leading to rapid tumour cell ischaemia and death. The decrease in vascular tumour perfusion seen using dynamic contrast imaging suggests dynamic methods such as DCE-MRI, positron emission tomography-computed tomography (PET/CT) and MR spectroscopy in phase I and II trials may give an early indication of antivascular effect.

This chapter reviews the biology of adenoviruses, clinical trials of oncolytic viral gene therapy in ovarian cancer and recent developments that may give cause for cautious optimism. There are 49 serotypes of human adenoviruses, divided into six groups. There have only been a small number of clinical trials of gene therapy in ovarian cancer. Mutations in p53 are almost universal in high-grade serous ovarian cancer, there were early attempts to re-introduce wild-type p53 gene expression using a non-replicating adenovirus. Following primary debulking surgery, women whose tumours had demonstrable p53 mutations were randomised to conventional platinum and paclitaxel chemotherapy with or without IP SCH58500. Most importantly, there remain many questions about the biology of adenoviruses that are unanswered-many of these relate to the role of host cell factors in determining cell fate following infection and the potential role of immune responses in cell death in whole organisms.

Endometrial cancer is the fourth most common female malignancy. This chapter provides a synopsis of the published and continuing clinical research in several controversial areas, from initial surgical management through adjuvant systemic therapy to the management of recurrent disease. While surgery alone is adequate treatment for many women with low-risk endometrial cancers, it is clear that a substantial minority of cases are at significant risk of disease recurrence. The management of recurrent endometrial cancer can be complex and requires the assessment of several factors including the site(s) of disease recurrence, histological grade and the patient's performance status, comorbidities and wishes. Three uncommon histological sub-types account for 10-15% of all endometrial carcinomas. Serous carcinomas, clear-cell carcinomas and carcinosarcomas differ in their clinical behaviour from endometrioid carcinomas as they are more likely to present at an advanced stage and consequently have poorer prognosis.

This chapter outlines the recent advances in the molecular classification of ovarian cancer and the efforts for rationalised targeted therapies of molecular drivers of individual cancers with a particular emphasis on kinases and their inhibitors. It highlights the challenges that face targeting strategies, particularly at the interface between target discovery and validation that leads to the development of targeting agents. Development of small interfering RNA (siRNA) technology could provide a tool to overcome the shortcomings of some current therapeutic approaches. One of the challenges surrounding the use of siRNA for systemic therapy relates to the need for efficient and biocompatible delivery vehicles. Liposomes, in general, have been shown to be safe in a number of clinical trials using a wide variety of anti-cancer and antimicrobial drugs. Chitosan nanoparticles are highly effective for delivery of siRNA into both tumour and tumour-associated endothelial cells.

This chapter describes the range of techniques available, their relationship to tumour biology and their utility in the context of patient management pathways. In ovarian cancer, functional imaging can be particularly useful for multi-site evaluation of treatment-induced changes, although it is technically challenging because of the extent and convoluted anatomy of the peritoneal cavity. Magnetic resonance spectroscopy (MRS) has been validated sparsely in ovarian malignancy and almost exclusively for lesion characterisation. Cervical cancer shows heterogeneity relating to treatment response and to risk of metastatic spread and gene expression and their relationship to response and outcome is of interest. The presence of lymph node metastases has a detrimental effect on prognosis and a significant impact on management and treatment. The combination of DW-MRI and Magnetic resonance lymphography (MRL) is a very exciting development reported in prostate cancer, with an important reduction in the time taken for interpretation of the images.

Epithelial ovarian cancer (EOC) is the most common cause of death among women who develop gynaecological cancer and the fifth most common cause of cancer related death in females in Western countries. The value of the neoadjuvant approach in the primary treatment of advanced EOC is currently one of the most debated issues in gynaecological oncology worldwide. The disease-free interval, number of recurrence sites, patient's performance status, surgical outcome of the primary surgery and current amount of ascites have been discussed as possible predictive factors of clinical outcome in surgery at recurrence. Anti-angiogenic therapy represents huge effort in translational research, with high expectations from investigators and patients alike. The proliferation of clinical trials in ovarian cancer reflects the focus and determination of investigators internationally and many promising hypotheses are being explored within the international collaborative efforts.

The challenges in treating cervical cancer are centred on improvements in survival and local control and minimising treatment-related morbidity. This chapter focuses on the evidence for current practice and highlights future research issues. For women with International Federation of Gynecology and Obstetrics (FIGO) stage IB2 disease and higher, chemoradiotherapy is the treatment of choice. Theoretical benefits of neoadjuvant chemotherapy include the eradication of micrometastases and reduction in tumour size before definitive treatment. Improving the outcome from radiotherapy might be achieved by improving delivery of treatment, increasing dose to tumour or the addition of radiosensitisers. Much current research in early-stage cervical cancer is focused on developing new drugs to either complement or replace cisplatin-based chemoradiotherapy regimens. The challenge in the coming decade is not only to look for ways to improve local control and survival but also to improve quality of life by minimising morbidity of treatment.

Vulval cancer is rare and constitutes approximately 3% of gynaecological cancers worldwide. The incidence of vulval cancer has increased since the mid-1990s owing to the increased incidence in younger women, which has doubled over the past 30 years. Clinical trials in vulval cancer can be divided into two categories-trials in women with vulval cancer and, more recently, trials on the prevention of vulval cancer by preventing or treating human papillomavirus (HPV)-related vulval intraepithelial neoplasia (VIN). Numerous studies have tried to evaluate the role of neoadjuvant radiotherapy and/or chemotherapy in this disease to reduce the extent of surgery. Early studies involving the medical treatment of VIN with imiquimod, cidofovir and especially therapeutic vaccines appear promising in the prevention of vulval cancer. However, the greatest effect on preventing cancer is likely to arise as a result of vaccination programmes of the prophylactic HPV vaccines, assuming adequate uptake of the vaccine.

This chapter discusses the biology of and therapeutics for gynaecological cancers such as vulval cancer, cervical cancer and ovarian cancer. The most common type of ovarian cancer, high-grade serous cancer, is characterised by mutation of the p53 (TP53) gene. All women with newly diagnosed high-grade serous ovarian carcinoma should have an accurate family history taken, and be referred for genetic assessment and considered for BRCA1 and BRCA2 mutation testing if appropriate. Within clinical trials, central pathological review is needed when treatment depends on morphological sub-type or other pathological parameters. Functional imaging in multicentre trials should be implemented with strict quality control to ensure standardisation and reproducibility. Evaluation of novel surgical strategies, such as robotics, should occur through well-conducted clinical trials. In surgery for ovarian cancer, whether carried out as a primary or a delayed procedure, the aim should be to remove all visible disease.