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Recent perspectives of epithelial ovarian carcinoma

Epithelial ovarian tumours have been reported to mainly arise from the simple cuboidal surface epithelium of the ovary, and account for 75% of all ovarian tumours, and 90–95% of ovarian malignancies. Epithelial ovarian carcinoma (EOC) is responsible for the highest number of deaths in women due to gynecologic malignancy, with a low 5-year relative survival of only 44%. The possible reasons for these low survival rates are the high incidence of chemoresistance found with EOC and a lack of consideration of the high degree of heterogeneity of EOC in the current standard of care. The present review highlights the recent perspectives of EOC including screening strategies of EOC, current therapeutic regimens for EOC and the recent strategies in pipeline in order to improve therapeutics for EOC. We searched the electronic database PubMed for pre-clinical as well as clinical controlled trials reporting diagnostic as well as therapeutic advances against epithelial ovarian cancer. It was observed that great effort is applied in research for the development of both highly efficient diagnostic as well as therapeutic strategies against EOC.


Introduction
Ovarian cancer is defined as any malignant tumour that develops in the ovarian tissues (1). Globally, ovarian cancer is the eighth most common type of cancer among women, with 225,500 women estimated to have been diagnosed with ovarian cancer in 2008 (2). Despite its relatively low incidence, ovarian cancer is the seventh most frequent cause of cancer-related deaths in women, causing more than 140,000 deaths worldwide annually (2). Based on the presumed cells of origin, ovarian cancer is commonly classified as epithelial ovarian carcinoma (EOC), ovarian germ cell tumour or sex cord-stromal tumour. EOC is believed to derive from epithelial cells that cover the outer surface of the ovary and alone accounts for 95% of all cancers in the ovaries (3). In addition, EOC is the most lethal group among ovarian cancers and the prime cause of death for patients with gynecological malignancies (4). Thus, as the most common and most dangerous type of ovarian cancer, EOC has been the focus of most ovarian cancer research and is also the focal point in the present review.
On the contrary, ovarian germ cell tumours and sex cord-stromal tumours are rare events, accounting for only 2-3 and 1.2% of all ovarian cancers, respectively (5). Ovarian germ cell tumours arise from primitive germ cells in the embryonic gonad (6), which tend to occur in teenagers and women in their twenties. Sex cord-stromal tumours are a morphologically diverse group of neoplasms composed of cells derived from gonadal sex cords, specialised gonadal stroma and fibroblasts (7). Unlike germ cell tumours, sex cord-stromal tumours are more common in adult women and can be found in peri-and post-menopausal women. The majority of germ cell tumours as well as sex cord-stromal tumours are presented as early-stage disease and usually considered as low-grade malignancies (8). Owing to the advancements in surgical management and chemotherapy regimens, the overall prognosis of these rare tumours are very favourable today, and most patients survive the disease devoid of treatment-related toxicities, such as loss of fertility (5). Even in the setting of advanced disease, the patients could be cured (6).

Screening strategies for EOC
The non-specific symptoms and the lack of reliable early screening strategy hinder the diagnosis of EOC at the more curable early stage. Consequently, only 15% of the patients present with localised disease (9). In addition, it was suggested that on average, EOCs have already progressed to a late stage for ~1 year prior to their discovery (10). Thus, given the inverse relationship between survival and disease stage at diagnosis, the ability to detect early disease and prevent their progression to invasive disease may offer the most effective way to save lives.
In order for early detection tests to be clinically useful, they should be able to identify the precursors of advanced stage disease with both high sensitivity and specificity (11). However, we currently know little of the early natural history of EOCs. Efforts are being made to achieve 50% or more sensitivity in detecting early stage EOC in normal-risk women. Accordingly, it is a great challenge to identify specific molecular markers and develop assays that can provide the necessary sensitivity and specificity to detect this low prevalence disease.
At present, CA125 tumour antigen measurement, transvaginal ultrasonography (TVU) and pelvic examination are used as diagnostic tests to detect the presence of EOC. Among these tests, only CA125 is recommended for monitoring ovarian cancer patients' response to therapy, as well as post-treatment monitoring for recurrent disease (12). However, for the purpose of early detection, these tests have limited clinical utility, as they are often associated with false-positive and false negative results (13). Since further diagnostic evaluation usually involves invasive surgical procedure, such false-positive results will lead to unnecessary surgical intervention and could even cause serious complications. Indeed, the recently completed Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial concluded that annual screening performed with CA125 and TVU does not reduce ovarian cancer mortality in normal-risk women, but instead increases unnecessary surgical interventions (14).

Therapeutic regimens for EOC
Surgery followed by chemotherapy has been the mainstay of first-line treatment regimen for ovarian cancer patients. Patients are first subjected to surgical cytoreduction to remove all grossly visible tumours, and at the same time provide opportunities for clinicians to accurately establish the diagnosis and extent of the disease (15). Although such surgical procedures are rarely practiced in other malignancies, the removal of tumours in ovarian cancer patients to <1 cm residual disease has consistently been associated with better overall survival.
Given the high chemosensitivity of EOC, chemotherapy was often administered to patients following surgery in order to eradicate residual disease. In the past, commonly used drugs included cyclophosphamide, melphalan and chlorambucil (16). When cisplatin was introduced to clinical practice in 1978, platinum-based therapy was shown to generate a higher number of responsive patients, increase response duration and progression-free interval (16). Since then, platinum derivatives, such as cisplatin and carboplatin, have become the standard of care for ovarian cancer patients.
In the late 1990s, two randomised phase III trials led to the combination of cisplatin with paclitaxel as adjuvant treatment of advanced stage ovarian cancer (17). Compared with cisplatin and cyclophosphamide combination, patients treated with cisplatin and paclitaxel were shown in both studies to have significantly higher overall clinical response rate and complete clinical remission rate, and also experienced significantly longer progression-free and overall survival. Therefore, the combination of platinum and paclitaxel is currently the treatment of choice as first-line therapy for all ovarian cancer patients.
Briefly, paclitaxel is a taxane that binds to the taxoid-binding site of β-tubulin, resulting in the enhancement of microtubule polymerization. Such microtubule stabilising activity suppresses microtubule dynamics, and thus, arrest cell proliferation. Apart from taxanes, other microtubule-targeted agents, such as vinca alkaloids are also currently administered in a broad range of solid tumours and haematological malignancies, while extensive research are dedicated to examine the clinical relevance of other agents (18). A recent study in Japan suggested that dose intensification schedule of weekly paclitaxel administration at lower doses together with standard doses and schedules of carboplatin prolonged progression-free and overall survival compared to the conventional regimen (19). In addition, the peritoneal delivery of chemotherapy has been shown to increase overall survival compared to intravenous therapy (20). Since most of the tumours are confined within the peritoneal cavity, this route of administration is able to achieve high local concentration of the drugs, but is also highly toxic to the patients (21). Both of these approaches are still under evaluation and may have a role in the future management of ovarian cancer patients (15).
At present, 60-80% of patients with advanced EOC respond to the combination of platinum-and taxane-based chemotherapy and achieve complete clinical remission (22), while approximately 20-30% of the advanced-stage patients present with platinum-refractory disease (intrinsic platinum resistance) and continue to have progressive disease even during treatment (23). Despite the high chemosensitivity of the disease to first-line therapy, maintenance of disease-free status has proven to be elusive, with over two-thirds of the patients experiencing recurrent disease (24). Depending on the time interval from completion of first-line platinum-based chemotherapy until recurrence, patients usually receive non-platinum single-agent regimen (relapsed disease within 6 months after treatment) or platinum-based chemotherapy (relapsed disease more than 6 months after treatment) (15). However, due to the development of drug resistance, the response rates and time to progression typically fall with each relapse (25).
Collectively, intrinsic and acquired platinum resistance are among the major reasons of treatment failures, resulting in the low 5-year relative survival of 27.3% for advanced stage disease (9). Additionally, current therapeutic regimens fail to take into account the high degree of heterogeneity in EOC as reported by Vaughan et al (25). Thus, identification of new therapeutic approaches is necessary to improve the survival outcome of patients with advanced EOC.

Strategies to improve therapeutics for EOC
Ovarian cancer research is behind more advanced stages of investigations in other cancer types, leading to the delayed introduction of new targeted therapeutics into clinical practice. In fact, the drugs used in the clinic today for EOC are similar to those used in the late 1970s, albeit with reduced side effects (25). With the possible exception of angiogenesis inhibitors, such as bevacizumab, attempts to improve patient survival by including other drugs have not been encouraging (26). The recently concluded phase 3 randomised trial conducted by International Collaboration on Ovarian Neoplasms (ICON7) showed that bevacizumab treatment improved progression-free survival, particularly in patients at high risk of disease progression, but at the same time, it also declined quality-of-life (27). Thus, much effort is still needed to develop therapeutic regimens with better therapeutic index and smaller negative impact on patients' quality-of-life.
Rather than the current scheme of grouping patients together, one potential approach could be the stratification of patients to molecularly targeted therapies with the highest likelihood of benefit. Such therapies have been successfully incorporated into standard treatment for other malignancies, such as chronic myelogenous leukaemia, ER-or Her2-positive breast cancer, and EGFR-mutated lung cancer (28). A key point of these successes is the development of precision medicine or efficient timely treatment. Despite the high degree of heterogeneity in EOC, all women diagnosed with EOC are given the same regimen, with no prognostic classifications currently powerful enough to identify patients who are most likely to benefit from any particular regimen (25). As a result, therapeutic regimens are less than perfectly adapted to each patient (29). Therefore, there is a need to define molecularly homogeneous subsets that respond similarly to treatment, followed by the development/identification of compounds that can inhibit the biological drivers of each individual subset.
Another approach to improve patient survival would be to circumvent resistance of recurrent EOC disease to standard chemotherapy. Many women respond well to the initial platinum-based treatment, but often relapse with platinum-resistant disease (25). Despite extensive research dedicated to this area, the precise mechanisms of platinum resistance is still not much clearer and is multi-factorial (15). Thus, in order to achieve more durable response to therapy, genome-wide knockdown and expression approaches could be used as a strategy to identify promising candidates for whom inhibition would revert the resistance to platinum-based therapy. In fact, application of such approaches has led to the successful identification of CDK12 as a synthetic lethal partner of the PARP1/2 inhibitor, olaparib (30).

Conclusions
The abovementioned studies indicate that considerable efforts are being applied collectively to improve therapeutic strategies against ovarian cancer. However, more studies are required in the clinical setting to confirm these developments as established clinical therapeutics against ovarian cancer.