Therapy For Epithelial Ovarian Cancer Research Articles

Extended duration of response with second-line intraperitoneal platinum-based therapy for epithelial ovarian cancer.

5073 Background: For epithelial ovarian cancer (EOC), a longer duration of response after second-line intravenous (IV) therapy as compared to first-line (IV) platinum therapy occurs in only 3% of patients (Markman et al., 2004). The purpose of this study was to examine the time to progression interval (TPI) in patients treated with surgery and intraperitoneal (IP) chemotherapy for first recurrence of their disease. Methods: We retrospectively reviewed the medical records at our institution for women treated with second-line IP chemotherapy between January 2005 and April 2010. TPI was defined as the time from the end of previous therapy to the start of next therapy for both first-line and second-line platinum therapy. Results: We identified 56 women who received second-line IP chemotherapy for their EOC recurrence. All patients had previously undergone primary surgical cytoreduction (82.3% were considered optimally cytoreduced) followed by IV platinum-based chemotherapy. The mean age was 56.7 years (range 43-79). All patients underwent secondary cytoreduction at the time of IP port placement for treatment of recurrent disease and 65.3% of patients were considered optimally cytoreduced (< 1 cm residual disease) at the end of the secondary debulking surgery. In 13 patients (23.2%) a longer TPI after second-line IP chemotherapy was observed compared to TPI after primary IV chemotherapy. The median first-line TPI for those 13 women was only 8 months, while median TPI after second-line IP chemotherapy was 24 months. In comparison, the 43 patients with shorter TPI after IP chemotherapy had median TPI of 22.5 mos after first-line IV chemotherapy and 8 months after IP chemotherapy. Conclusions: A longer duration of second-line response was observed in 23.2% of patients treated with IP chemotherapy after IV chemotherapy and the duration of response was clinically significant. The use of IP platinum treatment for recurrent EOC should be further studied in a prospective trial in women who do not do receive front-line IP platinum chemotherapy.

Bortezomib and vorinostat as antitumor therapy for epithelial ovarian cancer.

e15542 Background: Treatment of women with advanced-stage epithelial ovarian cancer (EOC) has limited efficacy. Aberrant expression of ubiquitin-mediated protein degradation pathways occurs in ovarian cancer, thus we sought of determining the potential therapeutic efficacy of proteasome and HDACs inhibitors (Bortezomib and Vorinostat) as combinatorial approach for ovarian cancer treatment. Methods: The synergistic effect of bortezomib and vorinostat was evaluated by XTT assay and expressed as combination index (CI). Primary ovarian cancer cells were obtained by mechanically dissociating solid ovarian cancer specimens into single-cell suspensions and the epithelial nature of the derived cell population was confirmed with Ber-EP4 and MOC-31 markers. Activation of caspase-3 was determined by measuring the levels of PARP cleavage. Results: Isobologram analysis of EOC cell lines and primary EOC cells exposed to combinatorial treatment with bortezomib and Vorinostat revealed a strong synergistic effect with CI as low as 0.43 and no reduction in cell viability in immortalized ovarian surface cells or in normal surface epithelium. Reduction in the cell viability observed in cancer cells following exposure to bortezomib and vorinostat was consistent with onset of apoptosis as determined by morphological analysis and measurements of PARP cleavage levels. Importantly, primary EOC cells derived from borderline and recurrent ovarian carcinoma revealed highly sensitivity to bortezomib and vorinostat combination suggesting that this approach could be a new alternative treatment for recurrent EOC and borderline EOC with advance stage or invasive feature. Conclusions: This study provides the foundation for clinical testing of bortezomib and vorinostat combination as a therapy for ovarian cancer and may lead to an alternative therapeutic approach for patients affected by type of ovarian cancer that typically do not respond to conventional chemotherapy approach or who develop resistant tumor and relapse. Importantly, this combinatorial approach has potential to achieve significant anti-cancer activity using lower doses of the individual compounds, thus reducing “off-target” toxicity.

Abstract 3408: Ovarian cancer stem cell cytokine microenvironment

Abstract Objectives: Epithelial ovarian cancer (EOC) is an extremely aggressive disease associated with a lack of early symptoms, rapid progression to peritoneal metastases, and poor prognosis for patients. Currently available treatments are not effective in preventing or slowing metastatic spread, and the therapeutic resistance of EOC remains a major unresolved clinical and scientific problem. Cancer stem cells (CSCs) represent the most aggressive part of the tumor. CSCs are drug resistant and are thought to be responsible for the failure of chemotherapy. Earlier, we demonstrated that chemotherapy can lead to selection of CSCs. We hypothesized that malignancy of CSCs was associated with an efficient cytokine network. Methods: Ovarian CSCs and primary adherent epithelial cultures were established from ascites from ovarian cancer patient with stage III EOC. Ovarian CSCs were isolated using magnetic beads separation columns and human CD133 and CD44 Microbead kits from Miltenyl Biotec and were grown as tumor spheres. The High Content Screening (HCS) and High Content Analysis (HCA) platform from Thermo Scientific Cellomics was applied to study the CSC markers, embryonic markers, transcription factors, epithelial mesenchimal transition markers, cytokines, chemokines, growth and angiogenetic factor receptor expression and intracellular cytokine accumulation. Multiplex xMAP technology was used for the analysis of human cytokines and growth factors in cell culture medium. An in vivo SCID mouse model was used for the analysis of tumorigenity of bulk EOC cells and CSCs. Results: We established primary EOC cell lines and CSCs from ascites of 3 EOC patients. We confirmed that cells growing in tumor spheres demonstrate all the properties of CSCs: they express high levels of CSCs markers and low levels of differentiated markers, they have capacity to self-renew and differentiate, and they are highly tumorigenic in SCID mice. The EMT and CSC phenotypes were both exhibited in ovarian CSCs. We found that ovarian CSCs have a specific cytokine microenvironment involving the up-regulation of multiple cytokine-receptor axes. Conclusions: Our findings provide new knowledge regarding ovarian CSC biology. They elucidate the important role of the specific cytokine-receptor signaling axis for the self-renewal and proliferation of ovarian CSCs. We concluded that an optimal antitumor efficacy will be achieved by inhibiting both tumor cell populations: CSCs and bulk EOC cells. We suggest that combining two treatment modalities, e.g. RTK inhibitor that targets CSCs, and cisplatin that eradicates bulk tumor cells will represent a novel paradigm in EOC therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3408. doi:10.1158/1538-7445.AM2011-3408

Genetic variants in the mammalian target of rapamycin (mTOR) signaling pathway as predictors of clinical response and survival in women with ovarian cancer

Objective: The mTOR pathway promotes cell survival and proliferation and is commonly altered in human tumors. Preliminary evidence suggests this pathway's involvement in chemoresistance to platinum and taxanes, first-line therapy for epithelial ovarian cancer. In this study,a pathway-based approach was used to identify individual germline single-nucleotide polymorphisms (SNPs) and cumulative effects of multiple genetic variants in mTOR pathway genes and their association with clinical outcome in women with ovarian cancer.

The ubiquitin ligase EDD mediates platinum resistance and is a target for therapy in epithelial ovarian cancer

The ubiquitin ligase EDD mediates platinum resistance and is a target for therapy in epithelial ovarian cancer

Successful full-term live birth through assisted reproductive technology in a patient treated with fertility-sparing therapy for epithelial ovarian cancer: A case report

Successful full-term live birth through assisted reproductive technology in a patient treated with fertility-sparing therapy for epithelial ovarian cancer: A case report

Polyfunctional T-Cell Responses Are Disrupted by the Ovarian Cancer Ascites Environment and Only Partially Restored by Clinically Relevant Cytokines

BackgroundHost T-cell responses are associated with favorable outcomes in epithelial ovarian cancer (EOC), but it remains unclear how best to promote these responses in patients. Toward this goal, we evaluated a panel of clinically relevant cytokines for the ability to enhance multiple T-cell effector functions (polyfunctionality) in the native tumor environment.Methodology/Principal FindingsExperiments were performed with resident CD8+ and CD4+ T cells in bulk ascites cell preparations from high-grade serous EOC patients. T cells were stimulated with α-CD3 in the presence of 100% autologous ascites fluid with or without exogenous IL-2, IL-12, IL-18 or IL-21, alone or in combination. T-cell proliferation (Ki-67) and function (IFN-γ, TNF-α, IL-2, CCL4, and CD107a expression) were assessed by multi-parameter flow cytometry. In parallel, 27 cytokines were measured in culture supernatants. While ascites fluid had variable effects on CD8+ and CD4+ T-cell proliferation, it inhibited T-cell function in most patient samples, with CD107a, IFN-γ, and CCL4 showing the greatest inhibition. This was accompanied by reduced levels of IL-1β, IL-1ra, IL-9, IL-17, G-CSF, GM-CSF, Mip-1α, PDGF-bb, and bFGF in culture supernatants. T-cell proliferation was enhanced by exogenous IL-2, but other T-cell functions were largely unaffected by single cytokines. The combination of IL-2 with cytokines engaging complementary signaling pathways, in particular IL-12 and IL-18, enhanced expression of IFN-γ, TNF-α, and CCL4 in all patient samples by promoting polyfunctional T-cell responses. Despite this, other functional parameters generally remained inhibited.Conclusions/SignificanceThe EOC ascites environment disrupts multiple T-cell functions, and exogenous cytokines engaging diverse signaling pathways only partially reverse these effects. Our results may explain the limited efficacy of cytokine therapies for EOC to date. Full restoration of T-cell function will require activation of signaling pathways beyond those engaged by IL-2, IL-12, IL-18, and IL-21.

Molecular blockade of VEGFR2 in human epithelial ovarian carcinoma cells

Human epithelial ovarian cancer (EOC) is the most lethal neoplasm affecting the female genital tract, and is characterized by overexpression of vascular endothelial growth factor (VEGF) and growth as ascites. Anti-VEGF strategies are currently used in EOC therapy with promising results; however, molecular targeting of specific VEGF receptors on the cancer cells themselves has not been explored to date. We previously showed that activation of a VEGF/VEGFR2 signaling loop in EOC cells supports their survival in suspension, and short-term pharmacological inhibition of this loop increased EOC cell apoptosis in vitro. In this study, we stably knocked down VEGFR2 in OVCAR-3 and SKOV-3 EOC cells using short hairpin RNA (shRNA), an RNA interference strategy that could potentially overcome chemoresistance arising with angiogenic inhibitors. Unexpectedly, we observed an induction of more aggressive cellular behavior in transfected cells, leading to increased growth in mouse xenografts, enhanced accumulation of ascites, increased VEGF and neuropilin-1 (NRP-1) expression, and decreased expression of adhesion proteins, notably cadherins and integrins. Sonic hedgehog (SHH) pathways do not seem to be involved in the upregulation of NRP-1 message in VEGFR2 knockdown cells. Supporting our mouse model, we also found a significant increase in the ratio between NRP-1 and VEGFR2 with increasing tumor grade in 80 cases of human EOC. The change in EOC behavior that we report in this study occurred independent of the angiogenic response and shows the direct effect of VEGF blockade on the cancer cells themselves. Our findings highlight the possible confounding events that may affect the usefulness of RNAi in a therapeutic setting for disrupting EOC cell survival in ascites.

Targeted therapies in epithelial ovarian cancer.

Molecularly targeted therapy is relatively new to ovarian cancer despite the unquestionable success with these agents in other solid tumours such as breast and colorectal cancer. Advanced ovarian cancer is chemosensitive and patients can survive several years on treatment. However chemotherapy diminishes in efficacy over time whilst toxicities persist. Newer biological agents that target explicit molecular pathways and lack specific chemotherapy toxicities such as myelosuppression offer the advantage of long-term therapy with a manageable toxicity profile enabling patients to enjoy a good quality of life. In this review we appraise the emerging data on novel targeted therapies in ovarian cancer. We discuss the role of these compounds in the front-line treatment of ovarian cancer and in relapsed disease; and describe how the development of predictive clinical, molecular and imaging biomarkers will define the role of biological agents in the treatment of ovarian cancer.

Targeted therapies in epithelial ovarian cancer: Molecular mechanisms of action

Ovarian cancer is the leading cause of death in women with gynecological cancer. Most patients are diagnosed at an advanced stage and have a poor prognosis. Currently, surgical tumor debulking, followed by platinum- and taxane-based chemotherapy is the standard treatment for advanced ovarian cancer. However, these patients are at great risk of recurrence and emerging drug resistance. Therefore, novel treatment strategies are required to improve outcomes for women with advanced ovarian cancer. A variety of molecular targeted agents, the majority of which are monoclonal antibodies and small-molecule protein-kinase inhibitors, have been explored in the management of ovarian cancer. The targets of these agents include angiogenesis, the human epidermal growth factor receptor family, ubiquitin-proteasome pathway, epigenetic modulators, poly(ADP-ribose) polymerase (PARP), and mammalian target of rapamycin (mTOR) signaling pathway, which are aberrant in tumor tissue. The antiangiogenic agent, bevacizumab, has been reported as the most effective targeted agent and should be included in the standard chemotherapeutic regimen for advanced ovarian cancer. PARP inhibitors, which are mainly used in breast and ovarian cancer susceptibility gene-mutated patients, and mTOR inhibitors are also attractive treatment strategies, either alone or combination with chemotherapy, for ovarian cancer. Understanding the tumor molecular biology and identification of predictive biomarkers are essential steps for selection of the best treatment strategies. This article reviews the molecular mechanisms of the most promising targeted agents that are under early phase clinical evaluation for ovarian cancer.

Targeted Therapies in Epithelial Ovarian Cancer

Epithelial ovarian cancer remains a major women's health problem due to its high lethality. Despite great efforts to develop effective prevention and early detection strategies, most patients are still diagnosed at advanced stages of disease. This pattern of late presentation has resulted in significant challenges in terms of designing effective therapies to achieve long-term cure. One potential promising strategy is the application of targeted therapeutics that exploit a myriad of critical pathways involved in tumorigenesis and metastasis. This review examines three of the most provocative targeted therapies with current or future applicability in epithelial ovarian cancer.

Histone Deacetylase Inhibitor Therapy in Epithelial Ovarian Cancer

Since epigenetic alterations are believed to be involved in the repression of tumor suppressor genes and promotion of tumorigenesis in ovarian cancers, novel compounds endowed with a histone deacetylase (HDAC) inhibitory activity are an attractive therapeutic approach. In this review, we discuss the biologic and therapeutic effects of HDAC inhibitors (HDACIs) in treating ovarian cancer. HDACIs were able to mediate inhibition of cell growth, cell cycle arrest, apoptosis, and expression of genes related to the malignant phenotype in a variety of ovarian cancer cell lines. Furthermore, HDACIs were able to induce the accumulation of acetylated histones in the chromatin of the p21WAF1 gene in human ovarian carcinoma cells. In xenograft models, some of HDACIs have demonstrated antitumor activity with only few side effects. Some clinical trials demonstrate that HDACI drugs provide an important class of new mechanism-based therapeutics for ovarian cancer. In this review, we discuss the biologic and therapeutic effects of HDACIs in treating ovarian cancer, especially focusing on preclinical studies and clinical trials.

O61 Evaluation of the role of the surveillance in the detection of recurrence after initial therapy for epithelial ovarian cancer

International Journal of Gynecology & ObstetricsVolume 107, Issue S2 p. S110-S111 Free communication (oral) presentations O61 Evaluation of the role of the surveillance in the detection of recurrence after initial therapy for epithelial ovarian cancer T. Ashrafganjooei, T. AshrafganjooeiSearch for more papers by this authorM. Modarres Gillani, M. Modarres GillaniSearch for more papers by this author T. Ashrafganjooei, T. AshrafganjooeiSearch for more papers by this authorM. Modarres Gillani, M. Modarres GillaniSearch for more papers by this author First published: 20 November 2009 https://doi.org/10.1016/S0020-7292(09)60433-1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume107, IssueS2Abstracts of XIX FIGO World Congress of Gynecology and ObstetricsOctober 2009Pages S110-S111 RelatedInformation

A Feasibility Study of Weekly Docetaxel with Capecitabine in Ovarian Cancer: A Promising Combination of Two Active Drugs with a Potential for Synergism

Objectives: To evaluate the safety and efficacy of weekly docetaxel with capecitabine in patients with recurrent/persistent epithelial ovarian cancer (EOC). Patients and Methods: Women treated for recurrent/persistent EOC in our department (January 2004 through December 2005) were recruited into this feasibility study. They received 35 mg/m² docetaxel on days 1 and 8 and 1,000 mg/m² capecitabine twice daily on days 1–14 in a 21-day cycle. Results: Nine patients were enrolled. The median age was 64 years (37–80). Time to progression ranged from 1.67 to 11.27 months: 1 had complete response, 3 had partial responses, 4 had stable disease and 1 had disease progression. There was no grade 3 or 4 bone marrow toxicity. Nonhematological toxicity included partial hair loss (n = 4), fatigue (n = 7), hand and foot syndrome (n = 2), diarrhea (n = 5) and fluid retention syndrome (n = 1). Conclusion: There was good antitumor activity but frequent moderate-to-severe nonhematological toxicities when weekly docetaxel and capecitabine were used as second-line therapy for recurrent EOC. Further investigation of this combination is warranted.

Hexamethylmelamine as Consolidation Treatment for Patients with Advanced Epithelial Ovarian Cancer in Complete Response after First-Line Chemotherapy

The aim of this study was to assess the efficacy of consolidation therapy with hexamethylmelamine (HMM) in patients with advanced epithelial ovarian cancer (EOC). Patients treated at our hospital between January 1997 and November 2006 and in documented clinical complete response from advanced ovarian cancer following front-line platinum-based therapy were retrospectively analyzed. The patients treated with HMM were compared to the patients of matched counterpart without consolidation therapy. Of 102 patients enrolled, 49 were treated with HMM and 53 received no consolidation treatment. For patients with HMM and observed patients, the mean age were 54.6 and 55.6 yr; the distribution of stage was similar (P=0.977); the optimal surgery was performed in 36 (73.5%) and 44 (83%) (P=0.336); the recurrence rate were 27 (55.1%) and 33 (62.3%) (P=0.463); and the median progression-free survival were 38 months and 21 months for patients with HMM and observed patients (P=0.235). No treatment-related adverse events were reported during the follow-up period. Although this study failed to show the significant survival benefit of consolidation therapy with HMM in patients with advanced EOC, we consider that our study can contribute data to investigate the effectiveness of consolidation therapy in epithelial ovarian cancer.

Hormone therapy for epithelial ovarian cancer

Hormonal therapy has been used erratically to treat epithelial ovarian cancer since the mid 1960s; however, there has been little progress until recently in our understanding of which patients might benefit from treatment. Some clarity in the field is now beginning to emerge from recent studies, which have started to define biomarkers within epithelial ovarian cancers that link with hormonal response and thereby indicate which cohort of patients might be amenable to hormonal treatment. Oestrogen-deprivation therapy in the form of the aromatase inhibitor letrozole has demonstrated activity in three clinical studies. As only a minority of patients will benefit from hormonal approaches, recent efforts have focussed on the use of molecular markers to help identify which subgroup of patients might respond to treatment. Parallel laboratory studies using primary cancer material for which endocrine response is known and model-based findings have identified components of oestrogen signalling pathways that may help predict outcome. Use of the antioestrogen letrozole in ovarian cancer has consistently demonstrated a significant level of activity and the larger clinical studies have linked response with oestrogen receptor alpha expression and other biomarkers.

Primary chemotherapy and maintenance therapy in epithelial ovarian cancer

PURPOSE. This overview summarizes the most prominent data on the evolution of first-line and maintenance chemotherapy in epithelial ovarian cancer. METHODS. The literature published on first-line and maintenance chemotherapy in ovarian cancer between 1970 and 2008 was identified systematically by computer-based searches in MEDLINE and the Cochrane Library. RESULTS. In suboptimally debulked and FIGO stage IV ovarian cancer patients the combination of carboplatin and a taxane given intravenously at a three-weekly interval represents the standard of care in first-line chemotherapy. On the contrary, if optimal cytoreduction with residual disease ≤1 cm was achieved during primary surgery and disease was confined to the peritoneal cavity, intraperitoneal chemotherapy should seriously be taken into consideration even at the expense of significantly increased, but manageable toxicity. A more favourable therapeutic index should be expected in IP regimens, when cisplatin will be substituted by the better tolerable carboplatin. Concerning maintenance chemotherapy in ovarian cancer, the only randomized trial showing significant effects on progression-free survival used paclitaxel as a single agent over 12 cycles given once monthly. However, that study was prematurely closed at the first interim analysis because of prominent differences in progression-free survival in favour of the study arm. Translatable effects on overall survival thus remained unevaluated. CONCLUSION. Intravenous platinum-taxane-based chemotherapy remains the first-line post-operative treatment of choice in ovarian cancer, but the option of intraperitoneal chemotherapy should be considered in appropriate patients. In ovarian cancer, maintenance chemotherapy should be performed only in controlled clinical trials.

A phase III trial of cisplatin plus topotecan followed by paclitaxel plus carboplatin versus standard carboplatin plus paclitaxel as first-line chemotherapy in women with newly diagnosed advanced epithelial ovarian cancer (EOC) (OV.16). A Gynecologic Cancer Intergroup Study of the NCIC CTG, EORTC GCG, and GEICO

LBA5505 Background: Topotecan was evaluated in a novel combination regimen in comparison to standard therapy in front-line EOC. Methods: Women with newly diagnosed EOC stages IIB-IV, ECOG PS 0–1, age ≤ 75, and were randomized to one of two q 21 day regimens. Arm 1 cycles 1 to 4: cisplatin 50 mg/m2 d1 plus topotecan 0.75 mg/m2 d1–5 IV; cycles 5 to 8: paclitaxel 175 mg/m2 over 3 hrs d1 followed by carboplatin AUC5 day 1. Arm 2 paclitaxel plus carboplatin as in Arm 1 for 8 cycles. Patients (pts) were stratified for type of primary surgery/residual disease, centre, and age (< 65 vs. > 65 yrs). The primary endpoint was progression free survival (PFS). Progression was defined as the earlier of objective or CA125 progression (GCIG definition) or death. Secondary endpoints were response (in pts with measurable disease), CA125 normalization at 3 mo, overall survival, toxicity and Quality of Life. The sample size required 800 pts and 631 progression events to demonstrate an increase in PFS from 16 to 20 months with a power of 80% and alpha (2-sided) <0.05. Results: 819 pts (409 Arm 1, 410 Arm 2) were entered from Aug 2001 to June 2005. All randomized patients were included in the analysis. 650 pts have had a progression event and 406 have died. Pt characteristics were well balanced. Median age was 57 yrs (range: 28–78); 80% had debulking surgery: of these 55% had < 1 cm residual disease; 8.5% pts were stage II, 66% stage III, 25.5% stage IV. Arm 1 vs Arm 2 pts had more hematological toxicity (gr 3/4 febrile neutropenia 9.9% vs. 2.7%) and hospitalizations (11.3% cycles vs. 7.1% cycles). Conclusions: Topotecan/cisplatin followed by carboplatin/paclitaxel was more toxic and did not show any evidence of improved efficacy compared to standard therapy. Carboplatin plus paclitaxel remains the standard of care for advanced EOC. * stratified log rank; ** stratified Cochran-Mantel-Haenszel No. Pts Arm 1 Arm 2 Hazard Ratio Odds Ratio p value PFS median (mo) 819 14.6 16.2 1.10 (0.94-1.28) 0.25* CR + PR (%) 389 67.9 77.2 0.63 0.04** CA125 normal < 3 mo (%) 819 57.5 66.3 0.63 0.006** Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline

Novel targeted therapies in epithelial ovarian cancer: from basic research to the clinic

The development of new molecularly targeted therapies represents a high priority for the treatment of epithelial ovarian cancer. P-glycoprotein overexpression has been associated with multidrug resistance, and the use of multidrug resistance modulators, such as valspodar, is being explored in combination with chemotherapy. Human epidermal receptor (HER) family members are attractive targets for biological therapies. The addition of erlotinib or cetuximab to first–line paclitaxel- plus carboplatin-based chemotherapy is feasible and well tolerated. Gefitinib is able to inhibit the proliferation of ovarian clear-cell carcinoma in in vitro and in vivo experimental models. Single-agent trastuzumab has a limited value for recurrent epithelial ovarian cancer owing to the low frequency of HER2 overexpression and the low rate of objective responses among HER2-overexpressing patients. A Gynecologic Oncology Group Phase II trial of the proteasome inhibitor bortezomib in recurrent epithelial ovarian cancer is currently ongoing, and the combination of bortezomib and chemotherapeutic agents should be assessed. The mammalian target of rapamycin (mTOR) plays an important role in stimulating the translation of mRNAs encoding key proteins for cell growth and angiogenesis, and mTOR inhibitors, such as AP-23573 (ARIAD), deserve to be tested in selected epithelial ovarian cancer patients. The addition of intraperitoneal treatment with adenovirus containing human wild-type p53 to standard paclitaxel- plus carboplatin-based chemotherapy failed to improve the clinical outcome of patients with mutated p53 epithelial ovarian cancer. The Gynecologic Oncology Group is conducting a Phase II trial of single-agent bevacizumab (antivascular endothelial growth factor monoclonal antibody) in platinum-resistant disease. In conclusion, emerging drugs for epithelial ovarian cancer include agents designed to overcome chemoresistance, HER-targeting agents, proteasome inhibitors, mTOR inhibitors and angiogenesis inhibitors. A new paradigm of treatment could consist of chemotherapy combined with a biological agent for six cycles, and followed by chronic maintenance therapy with the biological agent alone. Advances in genomics and proteomics will elucidate the molecular mechanisms of ovarian carcinogenesis, which will hopefully lead to individualized molecular medicine in the next years.

Hormonal Therapy for Epithelial Ovarian Cancer

Despite the fact that hormonal therapy has been employed in the management of ovarian cancer for more than 40 years, there is limited information available in the peer-reviewed medical literature to document the beneficial impact of the strategy, either on improvement in cancer-related symptoms or prolongation of survival. Existing data suggest that approximately 5-10% of ovarian cancer patients treated with a hormone-based strategy in the second-line setting will achieve evidence of substantial tumor shrinkage, with a larger proportion of individuals likely to demonstrate stabilization of the disease process for a highly variable time interval. The major advantage with the use of hormonal treatments is the well-recognized and highly favorable toxicity profile associated with this class of antineoplastic agents.