Front-line Treatment Of Ovarian Cancer Research Articles

Real-world outcomes associated with use of front-line bevacizumab in ovarian cancer

BackgroundIn the pivotal ICON7 study, addition of bevacizumab to front-line treatment of ovarian cancer (OC) significantly improved overall survival (OS) (p = 0.03) in a high-risk subgroup of patients with suboptimally debulked/unresectable stage III or IV disease, leading to approval in Ontario, Canada in March 2016. Here we describe utilization of bevacizumab for front-line, high-risk OC and determine outcomes in routine clinical practice. MethodsProvincial administrative databases were utilized to identify all patients treated with front-line bevacizumab following its approval. Median OS (mOS) was determined using the Kaplan-Meier method. Factors associated with OS were identified using a Cox proportional hazard model. A comparative effectiveness analysis was performed to determine mOS pre- (2006–2016) and post- (2016–2019) approval. ResultsFrom March 2016 to October 2019, 282 patients received bevacizumab. Mean age was 64 years old, and 58% had stage IV disease. Median survival was 29 months and was longer in stage III (37 months) compared to stage IV disease (28 months). In a comparative effectiveness analysis of patients with stage IV serous OC, post-approval uptake of bevacizumab was low (23%). Median OS was similar pre (26 months) and post (27 months) approval (HR 0.92, 0.75–1.12, p = 0.383). ConclusionsSurvival in real-world patients treated with front-line bevacizumab is shorter than in pivotal clinical trials. Survival in stage IV serous patients has not significantly improved post public reimbursement of bevacizumab. This analysis was limited by poor uptake, however mOS was similar in patients who did and did not receive bevacizumab.

Lapatinib and poziotinib overcome ABCB1-mediated paclitaxel resistance in ovarian cancer.

Conventional frontline treatment for ovarian cancer consists of successive chemotherapy cycles of paclitaxel and platinum. Despite the initial favorable responses for most patients, chemotherapy resistance frequently leads to recurrent or refractory disease. New treatment strategies that circumvent or prevent mechanisms of resistance are needed to improve ovarian cancer therapy. We established in vitro paclitaxel-resistant ovarian cancer cell line and organoid models. Gene expression differences in resistant and sensitive lines were analyzed by RNA sequencing. We manipulated candidate genes associated with paclitaxel resistance using siRNA or small molecule inhibitors, and then screened the cells for paclitaxel sensitivity using cell viability assays. We used the Bliss independence model to evaluate the anti-proliferative synergy for drug combinations. ABCB1 expression was upregulated in paclitaxel-resistant TOV-21G (q < 1x10-300), OVCAR3 (q = 7.4x10-156) and novel ovarian tumor organoid (p = 2.4x10-4) models. Previous reports have shown some tyrosine kinase inhibitors can inhibit ABCB1 function. We tested a panel of tyrosine kinase inhibitors for the ability to sensitize resistant ABCB1-overexpressing ovarian cancer cell lines to paclitaxel. We observed synergy when we combined poziotinib or lapatinib with paclitaxel in resistant TOV-21G and OVCAR3 cells. Silencing ABCB1 expression in paclitaxel-resistant TOV-21G and OVCAR3 cells reduced paclitaxel IC50 by 20.7 and 6.2-fold, respectively. Furthermore, we demonstrated direct inhibition of paclitaxel-induced ABCB1 transporter activity by both lapatinib and poziotinib. In conclusion, lapatinib and poziotinib combined with paclitaxel synergizes to inhibit the proliferation of ABCB1-overexpressing ovarian cancer cells in vitro. The addition of FDA-approved lapatinib to second-line paclitaxel therapy is a promising strategy for patients with recurrent ovarian cancer.

Confirming whether novel rhein derivative 4a induces paraptosis-like cell death by endoplasmic reticulum stress in ovarian cancer cells

Ovarian cancer is the leading cause of death among gynecologic cancer patients. Although platinum-based chemotherapy as a frontline treatment for ovarian cancer has been widely used in clinical settings, its clinical efficacy is not satisfactory due to the resistance of ovarian cancer cells to apoptosis. Therefore, it is of great significance to induce non-apoptotic programed cell death patterns, such as paraptosis, in ovarian cancer. In this study, we aimed to explore the potential anticancer mechanisms of novel rhein derivative 4a, which was modified with rhein as a lead compound. The results showed that a wide range of vacuoles from the endoplasmic reticulum and mitochondria appeared in ovarian SKOV3, SKOV3-PM4, and A2780 cells treated with derivative 4a, and the cell death caused by derivative 4a is a type of non-apoptotic and non-autophagic death, which is caused by expansion and damage of the endoplasmic reticulum or mitochondria, showing the characteristics of para-apoptotic death. Furthermore, derivative 4a stimulated the unfolded protein reaction of ovarian cancer cells by upregulating the expression of Bip78 and activating the PERK-eIF2α-ATF4 pathways. Notably, rhein derivative 4a-induced cell death was positively correlated with activation of p38, ERK, and JNK, and negatively correlated with Alix, a known protein that inhibits paraptosis. In addition, derivative 4a treatment also induced G2/M phase arrest in ovarian cancer cells. Taken together, our study reveals that derivative 4a induces paraptosis, and this finding can serve as a basis in developing a new strategy for the treatment of antiapoptotic ovarian cancer.

Movement of Poly-ADP Ribose (PARP) Inhibition into Frontline Treatment of Ovarian Cancer.

The use of poly (ADP-ribose) polymerase (PARP) inhibitors in the front-line management of advanced ovarian cancer has recently emerged as an exciting strategy with the potential to improve outcomes for patients with advanced ovarian cancer. In this article, we review the results of four recently published Phase III randomised controlled trials evaluating the use of PARP inhibitors in the primary treatment of ovarian cancer (SOLO1, PRIMA, PAOLA-1, and VELIA). Collectively, the studies suggest that PARP maintenance in the upfront setting is most beneficial among patients with BRCA-associated ovarian cancers (hazard ratios range from 0.31 to 0.44), followed by patients with tumours that harbour homologous recombination deficiencies (hazard ratios range from 0.33 to 0.57). All three studies that included an all-comer population were able to demonstrate benefit of PARP inhibitors, regardless of biomarker status. The FDA has approved olaparib for front-line maintenance therapy among patients with BRCA-associated ovarian cancers, and niraparib for all patients, regardless of biomarker status. In determining which patients should be offered front-line maintenance PARP inhibitors, and which agent to use, there are multiple factors to consider, including FDA indication, dosing preference, toxicity, risks versus benefits for each patient population, and cost. There are ongoing studies further exploring the front-line use of PARP inhibitors, including the potential downstream effects of PARP-inhibitor resistance in the recurrent setting, combining PARP-inhibitors with other anti-angiogenic drugs, immunotherapeutic agents, and inhibitors of pathways implicated in PARP inhibitor resistance.

Abstract 1407: MicroRNA-18a targeting inhibits the tumor growth of cisplatin-resistant ovarian cancer

Abstract Platinum-based therapy remains as the front-line treatment for ovarian cancer. However, despite initial response to treatment, most patients develop platinum resistance and eventually succumb to the malignancy. In an attempt to identify novel targets in cisplatin-resistant ovarian cancer, we studied the role of the microRNA-18a-5p (miR-18a) in cisplatin-resistant ovarian cancer. miR-18a is part of the vastly researched miR-17-92 cluster. Although most members of this cluster have been associated with pro-tumorigenic roles in several cancers, recent findings suggest that miR-18a plays a tumor-suppressive role in ovarian cancer. However, the specific role of miR-18a in platinum resistance has yet to be elucidated. In this study, Real-Time PCR analysis was performed to measure the levels of miR-18a in several ovarian cancer cell lines. We found miR-18a downregulation in cisplatin-resistant ovarian cancer cells relative to their sensitive counterparts. Therefore, we assessed the effect of miR-18a upregulation by oligonucleotide microRNA mimics (OMM) in tumor growth using a xenograft mouse model of cisplatin-resistant ovarian cancer. As ovarian tumors have been shown to overexpress the Folate Receptor α (FRα), we used nanoliposomes conjugated to folic acid as vehicles to deliver the OMMs. Following intraperitoneal injections of OMM-loaded liposomes (twice per week for three weeks), there was a significant decrease in tumor weight of miR-18a-OMM treated mice in comparison to the control-OMM group. Moreover, immunohistochemical analysis was performed on the mice tumor tissues to assess the levels of cell proliferation and angiogenesis markers (ki67 and CD31, respectively). Our study suggests that miR-18a halts cisplatin-resistant ovarian cancer tumor progression. This work was supported by the RCMI grant: U54 MD007600, UPR Comprehensive Cancer Center and NIGMS-RISE R25-GM061838. Citation Format: Blanca Iris Quiñones-Díaz, Jeyshka M. Reyes-González, Fatma Valiyeva, Pablo E. Vivas-Mejía. MicroRNA-18a targeting inhibits the tumor growth of cisplatin-resistant ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1407.

Abstract 2975: Collagen type XI alpha 1 confers cisplatin chemoresistance in ovarian cancer through inhibitor of apoptosis proteins (IAPs)

Abstract Ovarian cancer is the most lethal gynecological cancer, which affects one in 70 females in the United States during their lifetime. While cisplatin is the frontline treatment for ovarian cancer, chemoresistance severely limits the treatment success. The goal of this study is to identify novel therapeutic targets to overcome cisplatin resistance. We recently identified Collagen type XI alpha 1 (COL11A1) as a novel biomarker associated with cisplatin resistance in ovarian cancer. COL11A1 is a component of the tumor stroma and its expression is restricted to cancer-associated fibroblasts (CAFs) adjacent to tumor cells. We further showed that COL11A1 protects ovarian cancer cells from cisplatin-induced apoptosis, yet the underlying mechanism is largely unknown. To understand the molecular mechanism by which COL11A1 protects cancer cells from cisplatin-induced apoptosis, we overexpressed COL11A1 in ovarian cancer cells and performed RNA-Seq. Our RNA-Seq data revealed that COL11A1 did not change the levels of genes involved in cisplatin transport, inactivation, and DNA repair pathways in cancer cells, which are well-established mechanisms to confer cisplatin resistance. Rather, COL11A1 enhances the expression of the Inhibitors of Apoptosis Proteins (IAPs), including XIAP, BIRC2 (c-IAP1) and BIRC3 (c-IAP2). Using a full-length COL11A1 protein, genetic manipulation, and co-culture method, we confirmed that COL11A1 significantly increases the expression of IAPs upon cisplatin treatment. The inhibition of XIAP, BIRC2 and BIRC3 with an IAP antagonist BV6 attenuated the ability of COL11A1 to inhibit cisplatin-mediated apoptosis. Our data indicates that COL11A1 activates Akt, and Akt is known to phosphorylate XIAP at serine-87, which protects it from ubiquitination and degradation in response to cisplatin. Collectively, our data identify IAP as a mediator of COL11A1’s action in blocking cisplatin-induced apoptosis. Note: This abstract was not presented at the meeting. Citation Format: Miran Rada, Jennifer Cha, Jessica Sage, Sandra Orsulic, Dong-Joo Cheon. Collagen type XI alpha 1 confers cisplatin chemoresistance in ovarian cancer through inhibitor of apoptosis proteins (IAPs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2975. doi:10.1158/1538-7445.AM2017-2975

The cost-effectiveness of bevacizumab for the treatment of advanced ovarian cancer in Canada.

The overall survival (os) analysis of the icon7 trial demonstrated that frontline ovarian cancer patients with a high risk of progression (stage iii suboptimally debulked, and stage iii or iv with unresectable disease) benefited from the addition of bevacizumab to standard chemotherapy compared with standard chemotherapy alone. The objective of the present study was to investigate the cost-effectiveness, from a Canadian publicly funded perspective, of adding bevacizumab to frontline treatment of ovarian cancer at high risk of progression. An area-under-the-curve, Markov-structured model was used to estimate the cost-effectiveness of the treatments. Long-term progression-free survival (pfs) and os were extracted from the icon7 trial (subgroup at high risk of relapse) and extrapolated by parametric time-to-event functions over a time horizon of 10 years. Canadian pfs health state utility values were obtained from the EQ-5D (EuroQoL Group, Rotterdam, Netherlands) questionnaires in the icon7 high-risk patient population. Canadian post-progression utility values were consistent with those for other gynecologic cancers. Cost inputs were informed by public sources. An annual 5% efficacy and cost discount rate was applied. A probabilistic sensitivity analysis and one-way sensitivity analyses were conducted. Ovarian cancer patients at high risk of progression receiving bevacizumab plus standard chemotherapy experienced a mean incremental quality-adjusted life year (qaly) gain of 0.374 years. At an additional cost of $35,901.54, the incremental cost-effectiveness ratio (icer) for the addition of bevacizumab to standard chemotherapy, relative to standard chemotherapy alone, was $95,942 per qaly. No formal health technology assessment willingness-to-pay threshold exists in Canada. However, at a threshold of $100,000 per qaly, bevacizumab in addition to chemotherapy is a cost-effective alternative for ovarian cancer patients who are at high risk of progression (stage iii suboptimally debulked, and stage iii or iv with unresectable disease). Using the $100,000 per qaly threshold in a probabilistic sensitivity analysis, it was determined that, compared with standard chemotherapy, the addition of bevacizumab to chemotherapy is cost-effective in 56% of tested scenarios.

Anti-angiogenic therapy versus dose-dense paclitaxel therapy for frontline treatment of epithelial ovarian cancer: review of phase III randomized clinical trials.

The investigation of anti-angiogenic agents and dose-dense paclitaxel therapy in epithelial ovarian cancer is an active area of research. To date several phase III trials have shown both approaches to be effective strategies for the frontline treatment of ovarian cancer over standard every 21 day chemotherapy alone. However, most of the improvement is seen only in progression-free survival, with added toxicity (e.g., hypertension, diarrhea, sensory neuropathy, fatigue). Subset analyses based on clinical predictors (e.g., residual disease) have been able to identify patients more likely to benefit from anti-angiogenic agents. And more recently, molecular profiling of tumor genetics has shown similar promising results. Ongoing research will help enhance our ability to match patients to therapeutic strategies most likely to optimize outcomes and minimize risk.

Patient reported outcomes of a randomized, placebo-controlled trial of bevacizumab in the front-line treatment of ovarian cancer: A Gynecologic Oncology Group Study

PurposeTo analyze quality of life (QOL) in a randomized, placebo-controlled phase III trial concluding that the addition of concurrent and maintenance bevacizumab (Arm 3) to carboplatin and paclitaxel prolongs progression-free survival in front-line treatment of advanced ovarian cancer compared to chemotherapy alone (Arm 1) or chemotherapy with bevacizumab in cycles 2–6 only (Arm 2). Patients and methodsThe Trial Outcome Index of the Functional Assessment of Cancer Therapy-Ovary (FACT-O TOI) was used to assess QOL before cycles 1, 4, 7, 13, and 21; and 6months after completing study therapy. Differences in QOL scores were assessed using a linear mixed model, adjusting for baseline score, and age. The significance level was set at 0.0167 to account for multiple comparisons. Results1693 patients were queried. Arm 2 (p<0.001) and Arm 3 (p<0.001) reported lower QOL scores than those in Arm 1. The treatment differences were observed mainly at cycle 4, when the patients receiving bevacizumab (Arm 2 and Arm 3) reported 2.72 points (98.3% CI: 0.88–4.57; effect size=0.18) and 2.96 points (98.3% CI: 1.13–4.78; effect size=0.20) lower QOL respectively, than those in Arm 1. The difference in QOL scores between Arm 1 and Arm 3 remained statistically significant up to cycle 7. The percentage of patients who reported abdominal discomfort dropped over time, without significant differences among study arms. ConclusionThe small QOL difference observed during chemotherapy did not persist during maintenance bevacizumab.

Quality of Life Outcomes of a Randomized, Placebo-Controlled Trial of Bevacizumab in the Front-Line Treatment of Ovarian Cancer: a Gynecologic Oncology Group Study

Quality of Life Outcomes of a Randomized, Placebo-Controlled Trial of Bevacizumab in the Front-Line Treatment of Ovarian Cancer: a Gynecologic Oncology Group Study

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.

A meta-analysis of the efficacy of intraperitoneal cisplatin for the front-line treatment of ovarian cancer

Ovarian cancer is the fourth leading cause of cancer death among women in the United States. First-line chemotherapy offered to patients with ovarian cancer generally consists of an intravenous (IV) platinum plus taxane regimen and has remained virtually unchanged for the past 10 years. A number of recently completed phase III randomized trials in the United States have reported improved progression-free survival (PFS) and/or overall survival (OS) with the intraperitoneal (IP) administration of cisplatin. The purpose of this study was to pool the published data to perform a meta-analysis of randomized trials of IP cisplatin in the initial chemotherapy treatment of ovarian cancer patients. This study was initiated to obtain a more valid estimate of the therapeutic impact of IP treatment for these patients. A search strategy was initiated that searched published findings of randomized trials of IP cisplatin therapy from multiple sources from January 1990 through January 2006. Six randomized trials of 1716 ovarian cancer patients were identified and included in this analysis. The pooled hazard ratio (HR) for PFS of IP cisplatin as compared to IV treatment regimens is 0.792 (95% CI: 0.688–0.912,P= 0.001), and the pooled HR for OS is 0.799 (95% CI: 0.702–0.910,P= 0.0007). These findings strongly support the incorporation of an IP cisplatin regimen to improve survival in the front-line treatment of stage III, optimally debulked ovarian cancer.

A meta-analysis of the efficacy of intraperitoneal cisplatin for the front-line treatment of ovarian cancer

Ovarian cancer is the fourth leading cause of cancer death among women in the United States. First-line chemotherapy offered to patients with ovarian cancer generally consists of an intravenous (IV) platinum plus taxane regimen and has remained virtually unchanged for the past 10 years. A number of recently completed phase III randomized trials in the United States have reported improved progression-free survival (PFS) and/or overall survival (OS) with the intraperitoneal (IP) administration of cisplatin. The purpose of this study was to pool the published data to perform a meta-analysis of randomized trials of IP cisplatin in the initial chemotherapy treatment of ovarian cancer patients. This study was initiated to obtain a more valid estimate of the therapeutic impact of IP treatment for these patients. A search strategy was initiated that searched published findings of randomized trials of IP cisplatin therapy from multiple sources from January 1990 through January 2006. Six randomized trials of 1716 ovarian cancer patients were identified and included in this analysis. The pooled hazard ratio (HR) for PFS of IP cisplatin as compared to IV treatment regimens is 0.792 (95% CI: 0.688-0.912, P= 0.001), and the pooled HR for OS is 0.799 (95% CI: 0.702-0.910, P= 0.0007). These findings strongly support the incorporation of an IP cisplatin regimen to improve survival in the front-line treatment of stage III, optimally debulked ovarian cancer.

Topotecan in the treatment of ovarian cancer

Epithelial ovarian cancer is the eighth most common cancer and fifth most common cause of cancer-related death in women in the USA. While most women with Stage III/IV disease respond to first-line therapy with a platinum/taxane combination, only 10–30% are long-term survivors. Topotecan, a topoisomerase I inhibitor, is approved by the US FDA for the treatment of relapsed disease at a dose and schedule of 1.5 mg/m2/day for 5 days every 21 days. This schedule causes significant, noncumulative myelosuppression, and various alternate regimens have been explored. A randomized Phase II Gynecological Oncology Group trial is currently investigating weekly topotecan versus a five-times daily schedule. Multiple randomized trials have evaluated incorporation of topotecan in front-line treatment of ovarian cancer, although none have demonstrated benefit for this approach.

Front-Line Treatment of Epithelial Ovarian Cancer

Epithelial ovarian cancer is the leading cause of death among the gynecologic malignancies. Over the past decade, advances in the field of ovarian carcinoma have brought an improvement in survival. This article focuses on the front-line management of ovarian cancer. While management of this disease is multidisciplinary and access to a trained gynecologic oncology surgeon is important, this article summarizes the most important advances from the medical oncologists’ perspective. It also reviews the current standard of care based on disease stage, as well as areas of investigation in the front-line treatment of ovarian cancer.

Efficacy of intraperitoneal cisplatin as consolidation therapy in patients with pathologic complete remission following front-line therapy for epithelial ovarian cancer: Consolidative intraperitoneal cisplatin in ovarian cancer

Objective. The aim of this study is to evaluate the efficacy of intraperitoneal cisplatin as consolidation treatment in epithelian ovarian cancer patients with complete pathologic response following front-line platin-based chemotherapy. Patients and method. Thirty patients who had no evidence of disease as assessed by second-look laparotomy following chemotherapy for stage III epithelial ovarian cancer were given three courses of intraperitoneal cisplatin (100 mg/m 2) with three weekly intervals as consolidation therapy. Results. Median age was 50 years. After a median follow-up period of 37 months, 16 patients are being followed with no evidence of disease. Eleven patients developed recurrent disease. Median disease-free survival was 50 months. Median overall survival is not reached. WHO grades 3–4 toxicity criteria were emesis in 19 patients (63.3%), abdominal pain in 5 (16.7%) and nephrotoxicity in 2 (6.7%) patients. Catheter-related complications were infection/peritonitis in one and catheter malfunction in one patient. There were no serious hematologic side effects that required transfusions or caused treatment delays. None of the patients developed serious neurologic toxicity. Treatment had to be stopped early in four patients who refused further treatment due to abdominal pain, nausea ::and vomiting. Dose reductions were required in five patients. Conclusion. Our results suggest that intraperitoneal cisplatin is a feasible regimen that may provide a favorable outcome in terms of progression-free survival in patients with a complete pathologic response following front-line treatment for ovarian cancer. Further randomized trials are required to evaluate the role of consolidation treatment in this setting.