Treatment Of Advanced Epithelial Ovarian Cancer Research Articles

The role of minimally invasive surgery in epithelial ovarian cancer treatment: a narrative review.

The aim of this narrative review is to summarize the available evidence on the use of minimal invasive surgery (MIS) in the management of epithelial ovarian cancer (EOC). MIS is currently performed to stage and treat EOC at different stage of presentation. We will evaluate risks and benefits of minimally invasive surgery for early stage EOC treatment, then potential advantages provided by staging laparoscopy in identifying patients suitable for primary cytoreductive surgery (PDS) will be discussed. Finally we will investigate the growing role of MIS in the treatment of advanced EOC after neoadjuvant chemotherapy (NACT) and in the treatment of EOC recurrence. An electronic database search was performed on PubMed, Medline, and Google Scholar for relevant studies up to December 2022. LPS represents a feasible surgical procedure for the staging and treatment in early, advanced and EOC relapse in selected patients treated in high-volume oncological centers by surgeons with adequate experience in advanced surgical procedures. Despite the increasing use of MIS over the last few years, randomized clinical trials are still needed to prove its effectiveness.

Pattern of Care in Real-World Scenario on Advanced Epithelial Ovarian Cancer in a Tertiary Referral Oncology Centre in India - ISPSM Collaborative Study.

The treatment of advanced epithelial ovarian cancer (EOC) has evolved over time. With advent of platinum-based chemotherapy and hyperthermic intraperitoneal chemotherapy (HIPEC), there is a paradigm shift in the patterns of care with improved survival. In this study, we analysed our advanced EOC patients aiming to gain insights into the pattern of care. An ambispective study of 250 patients of advanced EOC was done from our prospectively maintained computerised database in the Department of Surgical Oncology, tertiary care referral centre from 2013 to 2020. We analysed the demographic profile, treatment patterns, and perioperative outcomes. In this study, there were 83.6% stage III and 16.4% stage IVA. There were 62 (24.8%) upfront and 112 (44.8%) in interval settings. There was a higher number of patients receiving neo-adjuvant chemotherapy. One hundred twenty-six (50.4%) underwent cytoreductive surgery (CRS) only and 124 (49.6%) underwent CRS and HIPEC. CC-0 was achieved in 84.4% and CC-1 in 15.6% patients. HIPEC programme was started in 2013. With advent of RCTs in HIPEC, there was a substantial increase in the number of patients receiving HIPEC from 2015 (n = 10), 2017 (n = 20) to 2019 (n = 41). We offer secondary CRS in a limited subset of patients, n = 76 (30.4%). There was 24.8% early and 8.4% late postop complications. We have median follow-up of 50months with attrition rate of 4%. With practice changing updates, the treatment of advanced EOC has been evolving over time. Though the primary CRS followed by systemic therapy is the standard to date, there is change in pattern of care with neo-adjuvant chemotherapy followed by interval CRS and HIPEC because of various RCTs. The addition of HIPEC has acceptable morbidity and mortality. There is a definite learning curve and the team has to evolve as a whole. In a tertiary care referral centre from LMIC, good patient selection, logistics, and implementing recent advances will definitely add to improved survival.

Abstract 3232: Combined inhibition of mTOR and HSP90 potentiates cisplatin antitumor effect and reverts cisplatin resistance in vitro and in vivo models of epithelial ovarian cancer by modulating HSF1-dependent transactivation

Abstract INTRODUCTION: Epithelial ovarian cancer (EOC) represents the most lethal gynecological disease, with a 5-year relative survival rate of 46% after the diagnosis. The standard treatment of advanced EOC is based on surgery, followed by platinum (Pt)-based chemotherapy. However, the development of platinum resistant disease could occur and strongly impact on the survival of EOC patients for whom we still do not have valid therapeutic options. By using a proteomic approach followed by a bioinformatic analysis, we previously validated the role of HSP90 in the mechanism of platinum-resistance. Here, we propose a novel therapeutic strategy based on the combined pharmacologic inhibition of HSP90 and mTOR to further potentiate Pt-based chemotherapy and to revert Pt-resistance in EOC and non-small-cell lung cancer (NSCLC) models. METHODS: TOV-112D parental and Pt-resistant cells were characterized by phosphoproteomics followed by functional analysis and proteins validation by western blot. Synergistic anti-tumor effect was evaluated in Pt-sensitive and Pt-resistant EOC and NSCLC cell lines by calculating combination indexes (CI), colony formation assay, apoptosis and DNA damage, as well as on 3D in vitro microtissues obtained by co-culturing cancer cells with normal fibroblasts and in vivo EOC and NSCLC xenograft models. RESULTS: 542 differentially phosphorylated expressed proteins were identified in Pt-resistant TOV-112D compared with parental cells, and mTOR and the transcription factor HSF1 emerged as the most enriched pathways. The up-regulation of the phosphorylated form of PDK1, AKT, mTOR and rpS6 was observed in Pt-resistant compared to parental cells. Moreover, we also demonstrated the up-regulation of the activity of HSF1 along with the elevation of its targets such as heat shock proteins HSP90, HSP70 and HSP40, crucial components of chaperone complex machinery. Interestingly, among the differentially expressed proteins, we identified the kinase DYRK2 able to phosphorylate HSF1, supporting its transactivation. Accordingly, the combination of HSP90 inhibitor ganetespib and the mTOR inhibitor temsirolimus plus cisplatin, synergistically reduced colony formation, cancer cells and microtissues cell growth in vitro by increasing DNA-damage and apoptosis and in vivo by enhancing mouse survival. Mechanistically, the triple combination treatment, impaired the proteins involved in mTOR signalling and HSF1 transactivation. Notably, all these data were confirmed in Pt-resistant NSCLC models, supporting the possibility that the same mechanism is present in different tumor types. CONCLUSIONS: Our findings identify a promising new antitumor strategy based on the combination of HSP90 and mTOR inhibitors to revert Pt-resistance that that warrant further clinical evaluation. Citation Format: Rita Lombardi, Laura Addi, Biagio Pucci, Maura Sonego, Maria Serena Roca, Francesca Capone, Federica Iannelli, Francesca Bruzzese, Gustavo Baldassarre, Alfredo Budillon. Combined inhibition of mTOR and HSP90 potentiates cisplatin antitumor effect and reverts cisplatin resistance in vitro and in vivo models of epithelial ovarian cancer by modulating HSF1-dependent transactivation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3232.

Patterns of first-line systemic therapy delivery and adoption of bevacizumab in advanced ovarian cancer in Ontario, Canada.

292 Background: Initial treatment of epithelial ovarian cancer (EOC) consists of combination of cytoreductive surgery (CSR) and/or chemotherapy. Targeted therapies such as bevacizumab have shown to improve outcomes in a subset population with high-risk features. Real-world patterns of systemic therapy delivery in EOC in the modern era are not well understood. Our objective is to evaluate the patterns of first-line systemic treatment of advanced EOC in Ontario, focusing on adoption of bevacizumab, which was approved for use in 2016. Methods: We conducted a retrospective, population cohort study using administrative databases held at the ICES in Ontario, Canada. Patients diagnosed with non-mucinous EOC between 2014 and 2018 were identified from the Ontario Cancer Registry; early-stage disease was excluded. Information on systemic therapy was obtained from Activity Level Reporting and New Drug Funding Program databases. Provider of care (gynecologic oncologist vs medical oncologist) information was obtained from billing codes. Academic cancer centers were identified using validated systemic facility codes from Cancer Care Ontario. Statistical analyses include descriptive statistics, t-tests, and multivariable logistic regression using SAS. Results: Out of 4,680 cases diagnosed with EOC during the study period, 3,632 (77.6%) were considered advanced stage. Median age of cohort was between 65-70, and the majority had Charlson score of 1-2 (97%) and are urban (91.8%). A total of 3,181 (87.6%) patients underwent CRS and 2,722(74.9%) patients underwent chemotherapy. Of those who received chemotherapy, 1,259 (46.2%) received neoadjuvant chemotherapy, 1,012 (37.2%) received upfront CRS, and 451(16.5%) received chemotherapy only. The majority of chemotherapy was delivered by gynecologic oncologists (60.6%) and in academic cancer centres (61.7%). There was no significant difference in use of neoadjuvant chemotherapy between medical oncologists and gynecologic oncologists (p = 0.67). Only 53 chemotherapy patients (1.9%) received bevacizumab containing-regimen in the first-line setting. Medical oncologists were 4 times more likely to administer bevacizumab-containing regimen compared to gynecologic oncologists (OR 4.03, 95% CI.29 – 7.36) after adjusting for age, stage, Charlson score and rurality score on logistic regression. Delivery of bevacizumab is relatively higher in non-academic cancer centres (OR 2.61, 95% CI 2.32- 2.94) while 83% of intraperitoneal chemotherapy is delivered in academic cancer centres. Conclusions: Patterns of care of EOC in Ontario remain heterogenous between care providers and institutions, while uptake of bevacizumab for first-line treatment of EOC remains low. Factors leading to low uptake and real-world outcomes should be explored.

Updates and New Options in Advanced Epithelial Ovarian Cancer Treatment.

The medical and surgical treatment strategies for women with epithelial ovarian cancer continue to evolve. In the past several years, there has been significant progress backed by landmark clinical trials. Although primary epithelial ovarian cancer is still treated with a combination of surgery and systemic therapy, more complex surgical procedures and novel therapeutics have emerged as standard of care. Cytotoxic chemotherapy and maximal surgical effort remain mainstays, but targeted therapies are becoming more widespread and new data have called into question the role of surgery for women with recurrent disease. Poly ADP-ribose polymerase inhibitors have improved progression-free survival outcomes in both the frontline and recurrent settings, and their use has become increasingly widespread. The recent creation of treatment categories based on genetic changes reinforces the recommendation that all women with epithelial ovarian cancer have germline genetic testing, and new biomarker-driven drug approvals indicate that women may benefit from somatic molecular testing as well. To continue to identify novel strategies, however, enrollment on clinical trials remains of the utmost importance. With the evolving data on surgical approaches, targeted therapies such as antiangiogenics and poly ADP-ribose polymerase inhibitors, and the new therapeutic agents and combinations in development, we hope that advanced epithelial ovarian cancer will eventually transition from an almost universally fatal disease to one that can increasingly be cured.

Overview of imaging findings associated with systemic therapies in advanced epithelial ovarian cancer.

To provide an overview for radiologists of the systemic agents used in the treatment of advanced epithelial ovarian cancer (EOC) and their associated toxicities. EOC is a common gynecological malignancy, with the majority of patients presenting with advanced stage disease at the time of diagnosis. Although primary cytoreductive surgery and chemotherapy are the principal treatments for EOC, recurrence rates of disease remain high. As several molecular targeted therapies have been developed in the last decade, various novel agents have shown efficacy in the treatment of advanced EOC. Advanced EOC will be discussed by outlining the relevant radiological features of toxicities. Knowledge of the systemic therapies utilized in the treatment of advanced EOC and their associated radiological features is critical in diagnostic image interpretation.

Prognostic impact of celiac lymph node involvement in patients after frontline treatment for advanced ovarian cancer

IntroductionCompleteness of cytoreduction is the most important prognostic factor in patients with advanced ovarian cancer (OC). Extensive upper abdominal surgery has allowed to increase the rate complete cytoreduction and the feasibility of resection of celiac lymph nodes (CLN) and porta hepatis disease in these patients has been demonstrated. The aim of our study was to assess the prognostic impact of CLN involvement in patients with primary advanced OC undergoing a complete cytoreductive surgery (CRS). Material and methodsWe designed a retrospective unicentric study. We reviewed data from patients who underwent CLN resection with or without porta hepatis disease resection, within upfront or interval complete CRS in the frontline treatment of advanced epithelial OC between January 2008 and December 2015. Patients were classified in two groups according to CLN status. Univariate and multivariate analyses were conducted. Survival rates were estimated using Kaplan-Meier method. ResultsForty-three patients were included and positive CLN were found in 39.5% of them. The median disease-free survival in the group of patients with positive and negative CLN were 11.3 months and 25.8 months, respectively. In multivariable analysis, both CLN involvement and high peritoneal cancer index were independently associated with decreased disease-free survival. Computed tomography re-reading by an expert radiologist has good sensitivity for detection of positive CLN. ConclusionCLN involvement and high preoperative tumor burden are independently associated with decreased survival after complete cytoreduction for OC. CLN involvement is a marker of diffuse disease and an independent risk factor for early recurrent disease.

PCN46 - Estimating the Budget Impact of Adding Avastin (Bevacizumab) to Front Line Treatment for Advanced Ovarian Cancer in Brazilian Supplementary Health Care System

Ovarian cancer (OC) is one of the most lethal gynecologic cancers worldwide. According to Brazilian Institute of Cancer (INCA), 6,190 new OC cases were estimated in 2012. During the last 15 years, carboplatin plus paclitaxel (CP) has been established as front-line (FL) standard of care therapy for advanced ovarian cancer, with no significant advances in treatment ever since. Bevacizumab (Bev) in combination with CP was approved in Brazil for FL treatment of advanced epithelial OC on May/2013. Therefore, this study aimed to estimate the economic impact of bevacizumab reimbursement for advanced OC in Brazilian Supplementary Healthcare System. The potential number of eligible patients for CP + Bev in FL therapy for advanced OC was estimated following an epidemiologic approach. It was assumed that Supplementary Healthcare System attendance accounts for 40% of all patients. Additional drug costs and infusion fees were evaluated. The ex-factory price (VAT 18%) and labeled dose were considered. Average therapy duration of CP + bevacizumab was 15 months based on GOG-0218 trial. Costs were reported in Brazilian Reais (BRL1.00≈USD0.44; Jun/2013). A total health assistance budget of BRL 88.1 billion was forecasted for 2013, based on the last updated data from Brazilian National Regulatory Agency for Private Health Insurance and Plans (ANS). A total of 1,287 eligible cases in CP + Bev FL therapy for advanced OC are expected in 2013 in the private setting. Adding bevacizumab to the treatment of all these potential patients would yield an increase of BRL 267 million, corresponding only to an increment around 0.30% on health assistance expenses. Treating all eligible FL advanced OC patients with CP + Bev will potentially result in a low impact in Supplementary Healthcare System budget, associated to unprecedented clinical benefits for this population with a high medical unmet need.

Interferon after surgery for women with advanced (Stage II-IV) epithelial ovarian cancer

Epithelial ovarian cancer (EOC) is a life-threatening disease. Most often women become symptomatic only in the advanced stages of the disease, increasing the difficulty of treatment. Whilst the disease responds well to surgery and chemotherapy, the relapse rate is high. New treatments to prevent disease recurrence or progression, prolong survival, and increase the quality of life are needed. To assess the effectiveness and safety of interferon after surgery in the treatment of advanced (stage II-IV) EOC. The Cochrane Gynaecological Cancer Review Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL) Issue 1, 2012, MEDLINE and EMBASE were searched to January 2012. Handsearching of conference proceedings was also undertaken. Reference lists of reviews and included trials were screened and experts in the field were contacted for additional trials. Clinical trials registers were searched for ongoing trials. Randomised controlled trials (RCTs) involving participants with advanced EOC that compared post-operative chemotherapy alone with post-operative interferon therapy in combination with chemotherapy or post-operative chemotherapy followed by interferon or observation alone Two review authors (AL and AM) independently screened the search results for relevant trials and extracted pre-specified information from each included trial. Data were managed using Review Manager 5.1. Hazard ratios (HR) were calculated for time-to-event outcomes and risk ratios (RR) for dichotomous outcomes, with corresponding 95% confidence intervals (CI). Five trials, including 1476 participants, were included in the review. Two trials compared interferon with observation alone and three trials compared interferon plus chemotherapy with chemotherapy alone. A meta-analysis of two trials involving 370 participants found no significant difference in both overall survival (HR 1.14, 95% CI 0.84 to 1.55) and progression free survival (HR 0.99, 95% CI 0.79 to 1.24) between the interferon and observation alone groups in post-surgical women who had undergone first-line chemotherapy for advanced EOC. One trial with 293 participants found that while no significant difference was observed in incidence of nausea or vomiting between the two treatment groups, significantly more flu-like symptoms (RR 2.25, 95% CI 1.73 to 2.91) and fatigue (RR 1.54, 95% CI 1.27 to 1.88) were reported in the interferon group. For the second comparison, a meta-analysis of two trials comprising 244 participants found that although there was no significant difference in overall survival between the interferon plus chemotherapy and the chemotherapy alone group (HR 1.14, 95% CI 0.74 to 1.76), women in the interferon plus chemotherapy group had worse progression free survival than those in the chemotherapy alone group (HR 1.43, 95% CI 1.02 to 2.00). Compared to chemotherapy alone, adding interferon to chemotherapy did not alter the incidence of adverse events in post-surgical women with advanced EOC. Implications for practice Based on low quality evidence, the addition of interferon to first-line chemotherapy did not alter the overall survival in post-surgical women with advanced EOC compared with chemotherapy alone. There is low quality evidence to suggest that interferon in combination with chemotherapy worsened the progression free survival in post-surgical women with advanced EOC compared with chemotherapy alone. There is not enough evidence that interferon therapy alone alters overall survival or progression free survival compared to observation alone in post-surgical women who have undergone first-line chemotherapy. Three of the five trials included in this review were stopped early and were, therefore, underpowered to detect any true effect of the intervention. The trials did not report the results of important outcomes in a uniform manner, preventing statistical aggregation of the results. Trial methodology was poorly reported resulting in unclear risk of bias. For clear recommendations to be made regarding the effectiveness of interferon in the treatment of advanced EOC, long-term, well conducted and adequately powered RCTs would be needed. However, the available data do not suggest that interferon has an adequately advantageous effect to warrant further investigation.

Consolidation paclitaxel is more cost-effective than bevacizumab following upfront treatment of advanced ovarian cancer

Objective: Standard therapy for advanced epithelial ovarian cancer (EOC) is surgical cytoreduction followed by six cycles of carboplatin and paclitaxel (CT). Randomized, phase III controlled studies have shown significant improvement in progression-free survival (PFS) with consolidation paclitaxel (T) and bevacizumab (B). We sought to evaluate the cost-effectiveness (C/E) of consolidation T versus B in the treatment of advanced EOC.

First-line systemic treatment of ovarian cancer: a critical review of available evidence and expectations for future directions

Epithelial ovarian cancer (EOC) is a prevalent gynecologic malignancy whose prognosis in most cases remains poor despite advances in therapy. In this article, we critically review the available clinical evidence for the choice of first-line chemotherapy in EOC and discuss promising therapeutic strategies. In the last 25 years, first-line chemotherapy regimens and the indication of systemic treatment for early-stage disease have been better established. Significant progress has been made in the treatment of advanced EOC with the optimization of the carboplatin plus paclitaxel regimen and the use of intraperitoneal chemotherapy for selected patients. Targeted therapies may be approved for EOC in the near future and this would bring more specific treatments and improve outcomes for patients. Validated biomolecular signatures to better define prognosis and to predict response to therapeutic agents are still lacking. The standard first-line chemotherapy in EOC is based on the doublet carboplatin plus paclitaxel. It may be possible to improve the efficacy of treatment by means of a more intensive dose-dense regimen or by the intraperitoneal delivery of chemotherapy. Significant improvements in the treatment of EOC are expected from the development of antiangiogenic and other targeted agents and from better patient selection.