Treatment Of Recurrent Ovarian Cancer Research Articles

Efficacy and safety of PD-1/PD-L1 immune checkpoint inhibitors in the treatment of recurrent ovarian cancer: A systematic review and meta-analysis.

Recurrent ovarian cancer (OC) presents a significant therapeutic challenge with limited treatment success. Programmed cell death protein 1 (PD-1/PD-L1) immune checkpoint inhibitors have emerged as a potential treatment avenue, necessitating a systematic review and meta-analysis to evaluate their efficacy and safety. Adhering to preferred reporting items for systematic reviews and meta-analyses guidelines, we conducted a comprehensive literature search across PubMed, Embase, Web of Science, and Cochrane Library, culminating in the inclusion of studies focusing on the treatment of recurrent OC with PD-1/PD-L1 inhibitors. Studies were evaluated using the Newcastle-Ottawa Scale and analyzed using fixed or random effects models depending on heterogeneity levels. Our search yielded 1215 articles, with 6 meeting the inclusion criteria for final analysis. Studies varied in size and reported median age, overall survival (OS), progression-free survival (PFS), and adverse events. The meta-analysis showed improved Objective Response Rates (ORR), Disease Control Rate (DCR), and PFS in patients treated with PD-1/PD-L1 inhibitors. The overall adverse event rate was 17.9%, indicating a need for careful patient selection and monitoring. No significant publication bias was detected, enhancing the reliability of our findings. PD-1/PD-L1 inhibitors offer a promising treatment option for recurrent OC, improving ORR, DCR, and PFS. However, the higher incidence of adverse events necessitates a cautious approach to their use. Future research should focus on long-term outcomes, biomarker identification, and optimal combination therapies.

Abstract IA003: Advancing novel therapeutics through reverse translation

Abstract Background: The established paradigm for cancer drug development was designed to advance cytotoxic agents targeting tumor cells. An increased appreciation of the role of the tumor microenvironment in treatment efficacy and disease outcomes has identified tumor-extrinsic therapeutic targets. The different mechanisms of action employed by anti-angiogenic drugs or immunotherapeutics highlight the need for updated study endpoints to identify the maximally effective dose for clinical applications. These advances, and the translation of novel therapeutics, can be accelerated through reverse translation, a term used to describe research using patient samples to inform mechanistic studies – going from bedside-to-bench. Objective: To present an example of reverse translation in the development of an immune therapy combination for ovarian cancer. Preclinical studies demonstrated therapeutic synergy of CTLA4 immune checkpoint blockade and poly(ADP ribose) polymerase (PARP) inhibition in high grade serous ovarian cancer models. These results were translated to two clinical trials for the treatment of recurrent ovarian cancer. Tumor samples from study subjects have been collected to support ongoing mechanistic investigations and exploratory biomarker studies. Both targeted and unbiased approaches identified candidate biomarkers of response to treatment for further development. Ongoing mechanistic studies are examining the significance of top prognostic markers. Conclusions: Strategies are needed to support the integration of translational studies with clinical research to inform next generation trials and to optimize clinical applications of novel therapeutics. Citation Format: Sarah F. Adams. Advancing novel therapeutics through reverse translation [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA003.

Minimally-Invasive Secondary Cytoreduction in Recurrent Ovarian Cancer.

The role of secondary cytoreductive surgery (SCS) in the treatment of recurrent ovarian cancer (ROC) has been widely increased in recent years, especially in trying to improve the quality of life of these patients by utilising a minimally-invasive (MI) approach. However, surgery in previously-treated patients may be challenging, and patient selection and surgical planning are crucial. Unfortunately, at the moment, validated criteria to select patients for MI-SCS are not reported, and no predictors of its feasibility are currently available, probably due to the vast heterogeneity of recurrence patterns. The aim of this narrative review is to describe the role of secondary cytoreductive surgery and, in particular, minimally-invasive procedures, in ROC, analyzing patient selection, outcomes, criticisms, and future perspectives.

Cost-effective analysis of rotational intraperitoneal aerosol chemotherapy (RIPAC) in patients with platinum-resistant ovarian cancer.

e17585 Background: We developed RIPAC, which improves distribution and penetration compared to pressurized intraperitoneal aerosol chemotherapy (PIPAC). To introduce this newly developed device in the real world, we analyzed the cost-effectiveness of rotational intraperitoneal aerosol chemotherapy (RIPAC) device to improve quality of life (QoL) compared to conventional palliative chemotherapy for platinum-resistant ovarian cancer patients. Methods: A decision tree was designed to compare the quality-adjusted life year (QALY) and cost consisting of RIPAC and palliative chemotherapy regimens, such as pegylated liposomal doxorubicin (PLD), gemcitabine (GEM), and topotecan (TOP). Also, to reflect the clinician’s variable preferred regimens for palliative chemotherapy, the average direct and indirect medical costs of belotecan, docetaxel, vinorelbine, and vinblastine were also considered in addition to the three regimens (ANY). The model included quality of life which was measured by European Organization for Research and Treatment of Cancer (EORTC)-Quality of life Questionnaire 30 (QLQ-C30) data gathered from previous clinical trial reports on PIPAC and palliative chemotherapy for recurrent ovarian cancer willingness-to-pay (WTP) threshold was set at US$40,000 per quality-adjusted life year saved. Results: To complete three cycles of palliative chemotherapy using PLD, GEM, TOP, and ANY, the total medical costs were US$15,267, US$9,013, US$16,144, and US$12,631, respectively, and the corresponding QALYs for each regimen were 0.633, 0.553, 0.783, and 0.65. Since RIPAC has not yet been introduced into the medical market, when the maximum RIPAC cost is calculated from ANY considering WTP, the cost of RIPAC excluding the ward, outpatient, and anesthesia-related costs among direct medical costs was estimated to be up to US$4,391. Conclusions: The cost-effective analysis results for the palliative treatment of recurrent ovarian cancer implied that RIPAC could be a cost-effective strategy to improve the QoL of platinum-resistant recurrent ovarian cancer patients.

MODERN APPROACHES TO THE SYSTEMIC TREATMENT OF RECURRENT OVARIAN CANCER

Introduction: Introduction: Recurrent ovarian cancer is one of the most challenging issues in medical oncology. Being the fifth in the cancer mortality list among women, ovarian cancer is the reason of more deaths than any other cancer of the female reproductive system. A meta-analysis was conducted to investigate the optimal treatment options for recurrent platinum-sensitive and platinum-resistant ovarian cancer. Methods: Data for writing this article was collected from the publications in English, Russian and Italian from 2002 to 2023. PubMed and Web of Science were searched for the relevant articles. Survival rates, particularly overall survival (OS), progression-free survival (PFS), and adverse events (AEs) of the chemotherapy regimens were discussed. We analyzed the literature data comparing the effectiveness and safety of chemotherapy, antiangiogenic therapy, the use of poly-ADP ribose polymerase (PARP) inhibitors, and checkpoint inhibitors in the treatment of recurrent ovarian cancer. Results: An overview of the literature devoted to modern approaches to the systemic treatment of recurrent ovarian cancer is given in the article. General principles of classification and treatment of recurrent ovarian cancer are analyzed. The existing regimens of chemotherapy in combination with targeted therapy are given separately for various types of ovarian cancer relapses. Chemotherapy with doublet platinum compounds (carboplatin or cisplatin) continues to be the standard of care in platinum-sensitive relapsed ovarian cancer with or without targeted therapy. Treatment with poly-ADP ribose polymerase inhibitors, vascular endothelial growth factor inhibitors, immunotherapy with checkpoint inhibitors, and antibody-drug conjugate for patients with folate receptor alpha-positive, can be considered in platinumresistant epithelial ovarian cancer. Conclusion: In summary, we can conclude that despite the success of the primary treatment of ovarian cancer, the majority of patients with a widespread tumor process develop a relapse of the disease over the next two years, which is the cause of death of these patients. The development of effective treatment regimens for recurrent ovarian/fallopian tube/primary peritoneal cancer remains particularly acute and important in gynecological oncology and requires further study.

Efficacy of gemcitabine in combination with nanoparticle albumin-bound paclitaxel in the treatment of recurrent ovarian cancer: A retrospective single institution review.

The objective of this study was to evaluate the efficacy of gemcitabine plus nab-paclitaxel in patients with recurrent ovarian cancer. We performed a single institution retrospective review of patients with recurrent ovarian cancer who were treated with gemcitabine plus nab-paclitaxel from 2012 to 2018 at the Mayo Clinic in Florida. Twenty patients were identified and the median PFS for patients treated with gemcitabine plus nab-paclitaxel was 9months (95% CI, 5.7-20.7). Overall, 17 of the 20 patients (85%) achieved a clinical benefit (complete response 5%, partial response 55%, or stable disease at 3months 25%). For platinum-sensitive disease and platinum-resistant disease, the median OS were 38.7months (95% CI, 5.8-63.1) and 31.2months (95% CI, 12.8-51.8), respectively (p= 0.4306). This well-tolerated regimen shows promising activity in recurrent ovarian cancer and is a viable option for patients who are intolerant to paclitaxel or carboplatin because of allergic reactions.

Hyperthermic intraperitoneal chemotherapy in the treatment of recurrent ovarian cancer: When, and for whom?

The aim of this study is to evaluate the progression-free survival (PFS) of recurrent ovarian cancer (ROC) patients treated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC). ROC patients who underwent cytoreductive surgery plus HIPEC between 2015 and 2021 were retrospectively evaluated. Patients' demographic information and clinicopathological characteristics including cancer type, histology, platinum status, presence of ascites, type of surgery, complications, chemotherapy history, and disease progression were documented. PFS was calculated using the Kaplan-Meier method. A total of 104 patients with ROC were included. The median age was 57 years and the median follow-up time was 15 months (range: 5-69 months). In Cox regression multivariate analyses, platinum resistance (hazard ratio[HR]: 3.32, 95% confidence interval [CI]: 1.91-5.76, p = 0.00), more than one relapse prior HIPEC (HR: 2.81, 95% CI: 1.65-4.87, p = 0.024), and presence of ascites (HR: 1.88, 95% CI: 1.08-3.26, p = 0.00) were found to be negative prognostic factors for PFS. In subgroup analyses of patients with the first recurrence, the median PFS was 21 months for platinum-sensitive patients and 6 months for platinum-resistant patients (p = 0.032). HIPEC at the time of first platinum-sensitive relapse may lead to favorable PFS in the treatment ROC. However, HIPECas salvage treatment even with R0 cytoreductive surgery does not seem effective.

Recurrent of ovarian cancer with lymph node involvement: surgery or chemotherapy? Retrospective cohort study

Aim. To give a comparative analysis of long-term results of treatment of patients after surgical treatment in combination with systemic chemotherapy with a control group of patients who received only second-line chemotherapy without surgical treatment for recurrent ovarian cancer (OC) with lymph node (LN) involvement, as well as the search of prognostic factors that favorably affect progression-free survival (PFS) and overall survival (OS).
 Materials and methods. The retrospective analysis included patients under the age of 75 after surgical treatment or after only second-line chemotherapy without surgery for isolated recurrence in the LN or a combined form of recurrence of OC at Blokhin National Medical Research Center of Oncology from 2005 to 2020. All patients had previously received combined treatment for primary OC. Exclusion criteria: absence of LN involvement in the recurrence of OC, primary multiple malignant tumors, relapses of non-epithelial ovarian tumors, the presence of concomitant pathology in the decompensation phase and lack of information about the treatment received for the recurrence of OC and the date of subsequent progression, death or last observation. The primary endpoint of the study is PFS and the secondary endpoint is OS.
 Results. The final analysis included 214 patients, who were subsequently divided into 2 main groups: the study group consisted of patients (n=123; 57.5%) who underwent repeated cytoreduction + systemic chemotherapy, and the control group included patients (n=91; 42.5%) who received only second-line chemotherapy. In the general population of patients, the median platinum-free interval was 14.0 months. Platinum-sensitive recurrence of OC developed in 88.3% (189/214) of patients, and platinum-resistant recurrence was observed in 11.7% (25/214) of cases. In the study group, complete repeated cytoreduction was achieved in 70.7% (87/123) of patients, and incomplete in 29.3% (36/123) of patients. All 91 patients in the control group received second-line chemotherapy in the planned volume. The vast majority of patients underwent second-line platinum-containing chemotherapy 87.9% (188/214) of patients. The median follow-up was 33.0 (range 0.7174.0) months. Long-term results in the complete cytoreduction group were significantly higher median PFS and OS were 30.0 months and 87.0 months, respectively, however, in the incomplete cytoreduction group, long-term results were statistically significantly worse: median PFS and OS were 10.0 months and 29.0 months versus 12.0 months and 36.0 months, respectively, in the control group of patients. Surgical treatment in combination with chemotherapy for platinum-resistant recurrence of OC did not improve long-term results of treatment: the median PFS was the same in both groups 7.0 months, and the median OS was 24.0 months versus 21.0 months in the control group (p=0.372).
 Conclusion. Only complete repeated cytoreduction in combination with systemic chemotherapy leads to an improvement in long-term results of treatment compared with incomplete cytoreduction and only second-line systemic chemotherapy. Incomplete repeated cytoreduction, despite combination with systemic chemotherapy, worsens the prognosis and does not improve the results of drug therapy alone in patients with platinum-sensitive recurrence of OC. Combined treatment (surgery + chemotherapy) for platinum-resistant recurrence of OC does not improve long-term results of treatment.

EE147 The Cost-Effectiveness of Olaparib Compared to Niraparib in the Treatment of Recurrent Ovarian Cancer Caused By BRCA1 and BRCA2 Gene Mutation from a US Healthcare Payer Perspective.

Poly ADP ribose polymerase (PARP) inhibitors are a new class of drugs to treat recurrent ovarian cancer (ROC) associated with BRCA1 and BRCA2 gene mutation. Since the PARB enzyme inhibitors, Olaparib and Niraparib are relatively new to the market, there is limited research investigating these drugs' cost-effectiveness (CE). This study aimed to evaluate the CE of Olaparib compared to niraparib in treating ROC from a US healthcare perspective.

Platinum vs non-platinum chemotherapy for platinum-resistant ovarian cancer: A meta-analysis.

e17551 Background: recurrent ovarian cancer (OC) patients with platinum-free interval (PFI) < 6 mo. are usually considered platinum-resistant and treated with non-platinum chemotherapy. However, this practice is not based on proper-conducted randomized trials. Methods: we queried the PubMed database for all full-text articles and abstracts on the treatment of patients with platinum-resistant ovarian cancer (PROC) in 01/01/2000-01/06/2019 timeframe. The PRISMA tool was used to ensure transparent reporting of the results. Inclusion criteria were: 1) histologically confirmed epithelial OC; 2) recurrent disease within 6 months after completion of platinum chemotherapy; 3) treatment with platinum- or non-platinum chemotherapy agents that are routinely used for OC; 4) no concomitant therapy with targeted or investigational agents; 5) defined response rate (RR) and assessment criteria. Proportion meta-analysis (random-effect model) and beta-regression were conducted to assess the impact of platinum agents on response rate as well as significance of other variables. In the beta-regression model response rate was a dependent variable, while platinum agents (yes or no), used non-platinum drugs and method of response assessment were independent variables. Statistical analysis was dose with meta and betareg packages of R software. Results: we identified 7156 articles and screened them for title and abstract, 157 studies for further analysis. Efficacy of non-platinum- and platinum-based therapy was assessed in 113 (n = 5272) and 44 (n = 1055) trials respectively. In meta-proportion random-effect model RR among patients treated with platinum-based and non-platinum chemotherapy RR was 36% (95% CI 30-41; I2 = 62%) and 16% (95% CI 14-19; I2= 70%) respectively. Multiple beta-regression model is presented in the Table below. For sensitivity analysis various regression models were made with different subsets of the trials and additional variables (including year of the trial, percentage of serous subtype of OC and median of prior therapy lines). Platinum was the strongest predictor of response in every developed model. Conclusions: this meta-analysis shows that patients with 'platinum-resistant' ovarian carcinoma may derive significant benefit from reintroduction of platinum agents. These results support recent ESMO-ESGO consensus on treatment of recurrent ovarian cancer and randomize trials are required to refine the role of platinum in early relapsed OC.[Table: see text]

Interpatient Heterogeneity in Drug Response and Protein Biomarker Expression of Recurrent Ovarian Cancer.

Simple SummaryRecurrent ovarian-cancer patients face low 5-year survival rates despite chemotherapy. Oncologists may choose from a variety of guideline-recommended second-line therapeutic options without knowing which one works best. Thus, therapy alterations and adjustments are often required. We analyzed the response that 30 tumor lesions had to certain treatments in our patient-derived ovarian-cancer spheroid model. In addition, we characterized samples by immunohistochemical staining for new druggable molecular targets. Our results might help in tailoring future therapies for individual patients with recurrent ovarian cancer.Recurrent ovarian-cancer patients face low 5-year survival rates despite chemotherapy. A variety of guideline-recommended second-line therapies are available, but they frequently result in trial-and-error treatment. Alterations and adjustments are common in the treatment of recurrent ovarian cancer. The drug response of 30 lesions obtained from 22 relapsed ovarian cancer patients to different chemotherapeutic and molecular agents was analyzed with the patient-derived ovarian-cancer spheroid model. The profile of druggable biomarkers was immunohistochemically assessed. The second-line combination therapy of carboplatin with gemcitabine was significantly superior to the combination of carboplatin with PEGylated liposomal doxorubicin (p < 0.0001) or paclitaxel (p = 0.0007). Except for treosulfan, all nonplatinum treatments tested showed a lesser effect on tumor spheroids compared to that of platinum-based therapies. Treosulfan showed the highest efficacy of all nonplatinum agents, with significant advantage over vinorelbine (p < 0.0001) and topotecan (p < 0.0001), the next best agents. The comparative testing of a variety of treatment options in the ovarian-cancer spheroid model resulted in the identification of more effective regimens for 30% of patients compared to guideline-recommended therapies. Recurrent cancers obtained from different patients revealed profound interpatient heterogeneity in the expression pattern of druggable protein biomarkers. In contrast, different lesions obtained from the same patient revealed a similar drug response and biomarker expression profile. Biological heterogeneity observed in recurrent ovarian cancers might explain the strong differences in the clinical drug response of these patients. Preclinical drug testing and biomarker profiling in the ovarian-cancer spheroid model might help in optimizing treatment management for individual patients.

Paraaortic and pelvic lymph node dissection in the combined treatment of recurrent ovarian cancer with isolated lymph node lesion: a literature review

The aim of the work is to analyze all available literature data on the role of secondary cytoreduction, its effectiveness and safety in the recurrence of ovarian cancer (ОС) with isolated lymph node (LN) lesion.The importance and place of secondary cytoreduction in the combined treatment of recurrent ОС is one of the most controversial topics. The lesion of the LN in recurrent Ос varies from 12 % to 37 %, but an isolated recurrence in the LN is a very rare occurrence, about 5 %. The most common localization in recurrent ОС with isolated LN lesion is the paraaortic LN.The results of this literature review suggest that isolated Ln lesion should be clearly distinguished from recurrence at other sites (such as peritoneal and parenchymal), since patients with isolated recurrence in the LN have a relatively indolent course of the disease. The frequency of complete cytoreduction according to the available data of retrospective studies reaches 100 %. Paraaortic and pelvic lymph node dissection without a macroscopically detectable residual tumor in combination with postoperative systemic chemotherapy leads to improved survival rates compared only with systemic drug treatment of patients with isolated LN lesion in recurrent ОС. median survival from the moment of relapse detection and overall survival varies from about 2.5 to 4 years and &gt;5 years, respectively. Systemic paraaortic and pelvic lymph node dissection is preferable compared to selective lymphadenectomy, as it is accompanied by an increase in progression-free survival, although it doesn’t significantly prolong overall survival.

Prognostic Impact of Circulating Methylated Homeobox A9 DNA in Patients Undergoing Treatment for Recurrent Ovarian Cancer.

Simple SummaryOvarian cancer remains a clinical challenge with considerable mortality. Circulating tumor DNA (ctDNA) has been suggested as a prognostic biomarker and enables the longitudinal evaluation of a patient’s disease and response to treatment. However, the role of ctDNA in treatment monitoring and for guiding treatment decisions in ovarian cancer remains unclear. We aimed to examine a gene methylation biomarker in the plasma of patients suffering a relapse of ovarian cancer in order to investigate prognostic potential and identify patients most likely to benefit from treatment, measured by overall survival. In the study, the methylated gene HOXA9 was found to be significantly related to poor survival, with the potential to observe the progression of the disease at an early stage and spare patients from ineffective treatment. Monitoring ctDNA during treatment is clinically feasible, further efforts are, however, required for standardization and for demonstrating improvement in treatment management.Methylated Homeobox A9 circulating tumor DNA (meth-HOXA9) has been suggested as a blood-based biomarker in epithelial ovarian cancer (EOC), although its prognostic significance remains unproven. The aim of the present study was to investigate the prognostic impact of meth-HOXA9 in patients with recurrent EOC. DNA was purified from 4 mL plasma and, following bilsulfite conversion, meth-HOXA9 was analyzed using a methylation-specific droplet digital PCR. Detection of meth-HOXA9 was reported as a percentage of total DNA and as a binary variable (detectable and undetectable). Meth-HOXA9 status and its dynamics during palliative treatment were correlated with overall survival (OS) as the primary endpoint. At baseline, meth-HOXA9 was detected in 65.9% (83/126) of the patients. The median OS was 8.9 and 17.9 months in patients with detectable and undetectable meth-HOXA9 at baseline (hazard ratio: 2.04, p = 0.002), which remained significant in the multivariate analysis. Median OS in patients with an increase in meth-HOXA9 after one treatment cycle was 5.3 months compared to 33 months in patients with undetectable meth-HOXA9 (p < 0.001). Meth-HOXA9 was significantly related to poor survival and may serve as a prognostic marker in patients with recurrent EOC. The longitudinal monitoring of meth-HOXA9 is clinically feasible with the perspective of aiding clinical decision making.

A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer.

In recent years, three PARP inhibitors and three CDK4/6 inhibitors have been approved by the FDA for the treatment of recurrent ovarian cancer and advanced ER-positive breast cancer, respectively. However, the clinical benefits of the PARPi or CDK4/6i monotherapy are not as satisfied as expected and benefit only a fraction of patients. Current studies have shown therapeutic synergy for combinations of PARPi and CDK4/6i in breast and ovarian cancers with homologous recombination (HR) proficiency, which represents a new synthetic lethal strategy for treatment of these cancers regardless HR status. Thus, any compounds or strategies that can combine PARP and CDK4/6 inhibition will likely have great potential in improving clinic outcomes and in benefiting more patients. In this study, we developed a novel compound, ZC-22, that effectively inhibited both PARP and CDK4/6. This dual-targeting compound significantly inhibited breast and ovarian cancer cells by inducing cell cycle arrest and severe DNA damage both in vitro and in vivo. Interestingly, the efficacy of ZC-22 is even higher than the combination of PARPi Olaparib and CDK4/6i Abemaciclib in most breast and ovarian cancer cells, suggesting that it may be an effective alternative for the PARPi and CDK4/6i combination therapy. Moreover, ZC-22 sensitized breast and ovarian cancer cells to cisplatin treatment, a widely used chemotherapeutic agent. Altogether, our study has demonstrated the potency of a novel CDK4/6 and PARP dual inhibitor, which can potentially be developed into a monotherapy or combinatorial therapy with cisplatin for breast and ovarian cancer patients with HR proficiency.

Low-dose (7.5 mg/kg) bevacizumab may be a viable option in recurrent ovarian cancer: A retrospective study.

Bevacizumab (BEV) is a humanized monoclonal antibody of vascular endothelial growth factor receptors and, as a result of clinical trials, was approved for the treatment of recurrent ovarian cancer (ROC). The aim of this study was to assess the clinical utility of BEV in patients with ROC in real-world practice beyond clinical trials. In this single-center retrospective cohort study, we evaluated the medical data of all patients with ROC who were treated with BEV between October 2013 and March 2020. A total of 76 females were evaluated. Forty-nine (64.5%) patients were platinum sensitive and 27 (35.5%) patients were platinum resistant. BEV was used in combination with chemotherapy agents in all patients, and the most preferred combinations were gemcitabine/carboplatin (GC) (78.9%) and carboplatin/paclitaxel (14.5%). In all patients, the BEV dose was 7.5 mg/kg every 3 weeks. The median progression-free survival (PFS) was 11.1 months (95% confidence interval [CI]: 9.6-12.6), and the median overall survival (OS) was 22.3 months (95% CI: 17.5-27.2). In multivariate analysis, serous histological type (P = 0.01), maintenance BEV administration (P = 0.001), and combination of GC-BEV (P < 0.001) were associated with better PFS, while serous histological type (P = 0.016) and good performance status (P = 0.006) were associated with prolonged OS. Low-dose (7.5 mg/kg) BEV was found to be effective in the second-line treatment of patients with ROC in our real-life study. In addition, the combination of BEV with GC was shown to be a viable option, especially in the treatment selection of platinum-resistant patients.

A review of robotic surgery in the management of recurrent ovarian carcinoma: indication and techniques

Background: Treatment of recurrent ovarian cancer may consist of salvage chemother-apy or secondary cytoreductive surgery. Retrospective studies suggest that radical secondary cytoreduction resulting in no macroscopic disease (R0) after completion of surgery benefits patients and prolongs survival. The role of robotic-assisted secondary cytoreductive surgery (RASCS) is in its infancy. The aim of this manuscript is to review the literature regarding the role, the indication, and the techniques of RASCS and to summarize the published perioperative, postoperative, and oncologic outcomes of RASCS. Methods: A comprehensive systemic review was conducted in the PubMed, MEDLINE, EMBASE, and Google Scholar databases from 1 January 1980 through 31 December 2021. Keywords searched were “ovarian cancer”, “recurrence”, “robotic-assisted secondary debulking/cytoreductive surgery”, “morbidity and mortality of secondary cytoreductive surgery”, “indications for secondary cytoreductive”, and combinations of these terms. Studies selected and analyzed included randomized controlled trials (RCTs) as well as prospective and retrospective anlayses and case series. RASCS procedures and techniques are described. Results: Several retrospectives, meta-analyses and prospective randomized trials suggest that optimal secondary cytoreductive surgery is associated with extended progression-free and overall survival. Preoperative selection criteria, such as Memorial Sloan Kettering (MSK) criteria and AGO (Arbeitsgemeinschaft Gynaekologische Onkologie) scores demonstrate that clinical-pathological factors can predict optimal secondary cytoreductive surgery and correlate with improved progression-free survival and overall survival. The surgical procedures that are required in secondary cytoreductive surgery can be complex. Limited retrospective studies have demonstrated that secondary cytoreductive surgery utilizing a robotic surgical platform can achieve the same rate of optimal cytoreductive surgery as open laparotomy with decreased morbidity. The effect of RASCS on progression-free and overall survival has not been established. Conclusions: Early literature reports indicate that RASCS, in selected patients, can be applied for surgical treatment of recurrent ovarian cancer without compromising morbidity; long-term studies are warranted to determine the effect on progression-free and overall survival.

Surgical treatment of recurrent ovarian cancer: A review

Aim. To analyze the data available in the modern literature on the role of repeated cytoreduction in the complex treatment of relapses ovarian cancer (OC).&#x0D; Materials and methods. Sources were searched in the following systems Clinicaltrials.gov, PubMed, Medline, NCCN, Scopus, Gynecol Oncol, Elibrary. After analyzing the literature review, 31 sources were used, published from January 1989 to December 2020.&#x0D; Results. The main method of treatment relapses of ОС is administration of systemic chemotherapy. The role of surgical treatment has been actively discussed for several decades. According to the available data of retrospective, prospective, randomized trials, performing surgery following chemotherapy had a favorable effect on the long-term results of treatment just in case of achieving complete cytoreduction in comparison with only chemotherapeutic treatment of platinum-sensitive recurrence of ОС. A validated prognostic model helps to perform the selection of suitable patients for surgical treatment, therefore, the correct selection for secondary cytoreduction allows to identify the patients with a high chance of achieving сomplete cytoreduction, which reduces the number of ineffective operations in patients with residual tumors.&#x0D; Conclusion. Complete cytoreduction of all macroscopically detectable recurrent tumor lesions in combination with subsequent systemic chemotherapy leads to an improvement in progression-free survival and life expectancy in a carefully selected group of patients with platinum-sensitive recurrent OC. Secondary cytoreduction in platinum-refractory and platinum-resistant relapses deteriorates the prognosis and doesn't lead to an increase in survival rates. Patient selection is the key point in secondary cytoreductive surgery. The choice of the methodology of selection of patients is in the process of discussion. When planning treatment, all patients with recurrent OC should be discussed at multidisciplinary teams with the participation of specialists in related specialties. Considering a surgical treatment option should be performed it in large centers with extensive experience in the surgical treatment of OC, relapses, performing complex multi-organ resections.

Abstract P068: Different treatment schemes cause distinct PARP inhibitor resistance mechanisms in BRCA2-mutant ovarian cancer cells

Abstract Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a major advance in ovarian cancer management, now as treatment for recurrent ovarian cancer and as a maintenance therapy following platinum-based chemotherapy in the upfront and platinum-sensitive recurrent settings. Yet, a growing number of patients progress through PARPis, creating a need for further understanding on resistance mechanisms. We hypothesized that different treatment dosing/timing schemes would cause distinct mechanisms of acquired resistance to PARPis. To test this hypothesis, we exposed BRCA2-mutant PEO1 ovarian cancer cells to 0.5 μM olaparib, doubling its concentration up to 40 μM over 3–4 months (PEO1/OlaJR). The second PARPi-resistant PEO1 cell line (PEO1/OlaR) was developed using a relatively low initial dose of 5 nM olaparib, and gradually increasing its concentration up to 20 μM over 6 months. To confirm PARPi resistance, cell proliferation and viability were measured by MTT and colony formation assay, respectively. Both cell lines were resistant to two different PARPis beyond clinically achievable concentrations (olaparib IC50 141.7–372.8 μM and rucaparib IC50 37.1–51.2 μM) and demonstrated restored homologous recombination (HR) repair as evidenced by increased HR-reporter activity (1.32 to 1.45-fold compared to PEO1, p &amp;lt; 0.05) and RAD51 foci formation (5.2 to 6.1-fold compared to PEO1, p &amp;lt; 0.001). For PEO1/OlaJR, distinct resistance mechanisms to PARPi were noted: 1) promoting drug efflux confirmed by increased MDR efflux activity (1.92-fold compared to PEO1, p &amp;lt; 0.001) and increased protein levels of an ABCB1 transporter (7.2-fold compared to PEO1); and 2) enhancing HR repair restoration, likely via reduced REV7 protein expression (0.43-fold compared to PEO1). On the other hand, PEO1/OlaR exhibited a mesenchymal cell phenotype with greater invasion ability as measured by transwell invasion assay (2.25-fold compared to PEO1, p &amp;lt; 0.001) and restored HR repair with upregulation of TRIP13 protein (1.85-fold compared to PEO1). PEO1/OlaR also showed increased cell survival, possibly via activation of PI3K/AKT signaling, as evidenced by increased p-AKT (2.12-fold compared to PEO1). No loss of 53BP1 was observed in either PEO1/OlaJR or PEO1/OlaR based on whole exome sequencing and immunoblotting of 53BP1. BRCA2 reversion mutation status is currently under investigation. Altogether, our findings suggest that mechanisms of resistance to PARPis arise differently based on the duration and concentrations of drug treatment, highlighting the importance of appreciating interplay between specific treatment schemes and the downstream consequences. Thus, developing tailored therapeutic strategies should consider various mechanisms of PARPi resistance. Citation Format: Tzu-Ting Huang, Jayakumar R. Nair, Nitasha Gupta, Tomomi M. Yamamoto, Benjamin G. Bitler, Jung-Min Lee. Different treatment schemes cause distinct PARP inhibitor resistance mechanisms in BRCA2-mutant ovarian cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P068.

Lentinan Combined with (125)I Brachytherapy for Recurrent Ovarian Cancer.

Objective To investigate the clinical value of lentinan combined with (125)I brachytherapy in the treatment of recurrent ovarian cancer. Methods A total of 160 patients with recurrent ovarian cancer admitted at Jiaozhou Central Hospital from June 2009 to October 2015 were enrolled in this study and randomly divided into observation group (80 cases) and control group (80 cases). The control group received chemotherapy. Observation group (80 cases) was treated with lentinan combined with (125)I brachytherapy on the basis of control group, and the efficacy, adverse reactions, and Karnofsky Performance Scale (KPS) and quality of life scale (QOL) scores of the two groups were analyzed and compared. Results After treatment, the levels of CA125, CA199, and CA724 in the 2 groups were markedly lower than those before treatment, and the observation group was lower than the control group (P < 0.05). After treatment, the proportion of CD4+/CD8+ cells and helper T cells and NK cells in the control group remarkably depleted, while the proportion of CD4+/CD8+ cells, NK cells, and B cells in the observation group increased significantly compared to that before treatment, and the level of IgA, IgG, and IgM in the control group decreased, while that in the observation group showed no conspicuous difference compared with that before chemotherapy (P > 0.05). The effective rate of observation group (85%) was higher than that of control group (75%) (P < 0.05). The overall survival of patients in the control group was (16.2 ± 2.04) months and that of the observation group was (24.8 ± 1.8) months. KPS and QOL scores in both groups were enormously higher than those before treatment, and the observation group was higher than the control group (P < 0.05). The incidence of hemoglobin reduction, leukopenia, aglobulia, granulocytopenia, nausea and vomiting, hepatorenal toxicity, and neurovirulence in the observation group was significantly lower than that in the control group. Conclusion Lentinan combined with (125)I brachytherapy is effective in treating recurrent ovarian cancer, with mild adverse reactions and good tolerance.

Quantitative Analysis of the Efficacy of PARP Inhibitors as Maintenance Therapy in Recurrent Ovarian Cancer.

Objective: This study aimed to establish a pharmacodynamic model and to screen reasonable covariates to quantitatively describe the efficacy of poly (ADP-ribose) polymerase inhibitors (PARPis) as maintenance treatment for recurrent ovarian cancer (ROC). Methods: The log normal hazard function model was established by using progression-free survival (PFS) data of 1,169 patients from published randomized trials on FDA-approved PARP inhibitors (olaparib, niraparib, and rucaparib). Monte Carlo simulation was used to compare PFS values in different scenarios, such as monotherapy (administered alone) and combination therapy (PARPis combined with chemo- or target-therapies), different biomarker statuses, and different PARP inhibitors. PFS was also estimated. Results: The study showed that the median PFS was 8.5 months with monotherapy and 16.0 months with combination therapy. The median PFS of patients with the BRCA mutation, BRCA wild-type, and HRD-positivity were 11.0, 7.5, and 9.0 months in monotherapy, respectively, and 23.0, 14.0 and 17.5 months, in combination therapy, respectively. In addition, the median PFS of olaparib, niraparib, and rucaparib monotherapy were about 9.5, 10.5, and 12.0 months, respectively, and about 19.0, 20.0, and 25 months, respectively, in combination therapy. The median PFS values in combination with cediranib, bevacizumab, and chemotherapy were approximately 17.0, 12.5 and 19.5 months, respectively. Conclusion: PARPi combination therapy is more effective as maintenance treatment for ROC than monotherapy, and the efficacy of PARPis in combination with chemotherapy is higher than that of the combination with antiangiogenic drugs. We found that the PFS of BRCA wild-type was similar to that of HRD-positive patients, and there was no significant difference in PFS between olaparib, niraparib, and rucaparib, which provides necessary quantitative information for the clinical practice of PARPis in the treatment of ROC.