Association of guideline-concordant care with survival, health care utilization, and costs among older women with advanced epithelial ovarian cancer.

OBJECTIVES: To examine guideline-concordant care (GCC) for ovarian cancer, identify its predictors, and evaluate the associations between GCC and survival, health care expenditures, and utilization. STUDY DESIGN: A retrospective cohort study using Surveillance, Epidemiology, and End Results-Medicare data. METHODS: Women aged 66 to 90 years who received a diagnosis of stage II or higher epithelial ovarian cancer during 2011-2015 were included (N = 3237). The National Comprehensive Cancer Network clinical practice guidelines were used to identify GCC. Logistic regression was conducted to identify predictors of GCC, a Cox proportional hazards model was used to examine mortality, and generalized linear models were used to examine mean monthly Medicare expenditures and health care utilization. RESULTS: Approximately 57% of women received GCC and 11.6% of women did not receive any cancer-specific treatment. Women who were relatively older (adjusted odds ratio [AOR], 0.272; 95% CI, 0.210-0.351), had Census tract income of $50,000 or less (AOR, 0.709; 95% CI, 0.551-0.913), had a psychiatric condition (AOR, 0.655; 95% CI, 0.464-0.923), and had adenocarcinoma histology (AOR, 0.564; 95% CI, 0.441-0.721) were significantly less likely to receive GCC. Race/ethnicity was not found to be a significant predictor of GCC. Women who received surgery only or chemotherapy only had a significant higher hazard of all-cause mortality and ovarian cancer-specific mortality compared with those who received GCC (surgery only: adjusted HR [AHR], 2.307; chemotherapy only: AHR, 1.802). Receiving chemotherapy only was associated with 45% (P < .0001) higher mean monthly expenditures compared with those who received GCC. CONCLUSIONS: Non-GCC was associated with worsened survival, higher health care utilization, and increased expenditures. It is important to highlight that women who received GCC were associated with better survival likely due to favorable prognostic clinical factors.

Peritoneal metastasis of advanced epithelial ovarian carcinoma treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: A retrospective international multicentric data analysis.

INTRODUCTION: The purpose of our study was to evaluate outcome data after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal metastasis originating from advanced epithelial ovarian carcinoma (PMOC). PATIENTS AND METHODS: A retrospective international multi-institutional registry was established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group. RESULTS: One thousand four hundred and ninety-one patients from 11 specialized units underwent CRS and HIPEC that of those 326 (21.9%) upfront surgeries, 504 (33.8%) interval surgery, and 661(44.3%) recurrent cases. Complete Cytoreduction(CC0/1) was achieved in 1213 patients (81.3%). Treatment -related mortality was 0.8%, major operative complications (Grades 3-5) was 25.1%. Factors associated with major operative complications include prior surgical score (PSS for recurrent cases; RC) PSS>2,p = 0.000), PCI(≤15, >15 cut-off level; p ≤ 0.000), completeness of cytoreduction (CC, p=0.000), high CA125 levels (>25 mg/dl), presence of ascites, high CRP (>5 mg/dl) levels and low albumin levels (below to 2.5 mg/dl) (p ≤ 0.05). The median survival was 58 months in upfront surgery(UFS), 60 months in interval surgery(IS), and 42 months in RC. The overall survival for five years was 45% for UFS, 37% for IS, 28% for RC cases. CCscore (p = 0.000), CA125, CRP and albumin levels (p ≤ 0.05) were predictors for progression free survival. PCI(p ≤ 0.000), major postoperative complications (p = 0.004), incomplete CRS(CC2/3)(p < 0.001), prior chemotherapy (hazard ratio [HR], 3-8; p < 0.001) and PSS>2 for RC were independent predictors of poor overall survival. CONCLUSION: The combined treatment strategy for PMOC may be performed safely with acceptable morbidity and mortality in the specialized units.

Role of Hyperthermic Intraperitoneal Chemotherapy Combined with Cytoreductive Surgery as Consolidation Therapy for Advanced Epithelial Ovarian Cancer.

BACKGROUND: Patients with advanced epithelial ovarian cancer who undergo incomplete surgery followed by six cycles of chemotherapy could benefit from second-look or consolidation cytoreductive surgery (CCRS). The primary goal of this study was to evaluate the overall survival (OS) in patients undergoing complete CCRS and the factors affecting survival. The secondary goal was to study the benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in these patients. METHODS: This was a retrospective analysis of 173 patients with CCRS with (n = 118) or without (n = 55) HIPEC treated at 12 French centers. Only patients having a completeness of cytoreduction (CC) 0/1 resection and a minimum of 5 years of follow-up were included. HIPEC was performed systematically for all patients except those treated at the four centers that did not perform HIPEC. RESULTS: The median Peritoneal Cancer Index was 6 (range 0-33). Closed HIPEC was performed in 59 (34.1%) patients and open HIPEC was performed in 56 (32.3%) patients. Grade 3-4 complications occurred in 64 (36.9%) patients. The median OS was 35.67 months (95% confidence interval [CI] 29.8-46.1) and was significantly longer for CCRS + HIPEC (31.4 months without HIPEC and 42.5 months with HIPEC; p = 0.022). On multivariate analysis, closed HIPEC (hazard ratio [HR] 0.46, 95% CI 0.29-0.73; p < 0.001) resulted in a longer OS, and age > 65 years (HR 2.17, 95% CI 1.14-4.11; p = 0.018) and bowel resection (HR 1.98, 95% CI 1.27-3.08; p = 0.020) led to a shorter OS. On multivariate logistic regression analysis, closed HIPEC (odds ratio 0.18; p = 0.001) was associated with a lower risk of dying at 5 years. CONCLUSIONS: CCRS was performed with an acceptable morbidity and resulted in good overall survival. The role of HIPEC in addition to CCRS should be evaluated in prospective, randomized studies and the closed technique prospectively compared with the open technique.

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

OBJECTIVE: 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). MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSION: HIPEC at the time of first platinum-sensitive relapse may lead to favorable PFS in the treatment ROC. However, HIPEC as salvage treatment even with R0 cytoreductive surgery does not seem effective.

Evaluation of external validity of the OVHIPEC-1 trial in a real-world population.

OBJECTIVE: The OVHIPEC-1 trial (Phase III randomised clinical trial for stage III ovarian carcinoma randomising between interval cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy) showed improved survival when interval cytoreductive surgery (CRS) was combined with hyperthermic intraperitoneal chemotherapy in patients with stage III epithelial ovarian cancer (EOC). The authors compared the control arm of the trial with a real-world population treated in the Netherlands during the same period to explore generalizability of the trial results. METHODS: For this nationwide comparative cohort study, all patients with EOC undergoing interval CRS between 2007 and 2016 were identified from the Netherlands Cancer Registry if they fulfilled the eligibility criteria of OVHIPEC-1 (n = 1376). Patient and treatment characteristics, and overall survival (OS) were compared between trial and real-world populations. RESULTS: Age, comorbidity, BRCA status, histologic subtype, and residual disease were similar in trial and real-world patients. Trial patients had a better performance status, higher socioeconomic status, and underwent bowel surgery more often. In a real-world setting, patients more often received more than six cycles. The difference in OS between the trial and the real-world populations was not statistically significant (unadjusted hazard ratio, 1.09 [95% confidence interval, 0.87-1.37]; P = 0.44). CONCLUSION: Despite differences in patient characteristics, OS of patients treated in the control arm of OVHIPEC-1 was similar to patients treated outside the trial. The trial population accurately represents real-world patients with stage III EOC undergoing interval CRS in terms of outcome.

The Activity of Vitamin C Against Ovarian Cancer Cells Is Enhanced by Hyperthermia.

BACKGROUND/AIM: Vitamin C is essential for the proper functioning of the human body and plays a crucial role in many biological processes as a cofactor for enzymes. The anticancer activity of vitamin C has been indicated for years. Hyperthermia used in clinics allows increasing the effectiveness of anticancer therapies and may also be useful in enhancing the action of other substances. The purpose of this study was to enhance the anticancer activity of vitamin C through hyperthermia against ovarian cancer cells. MATERIALS AND METHODS: The ovarian cancer cell lines Caov-3, NIH:OVCAR-3, and human fibroblasts CCD-1064Sk were tested in the present study. Vitamin C was used in the following concentrations: 0.24, 2.50 and 5.25 mM. Each of the selected concentrations was combined with the different temperatures (37°C, 40°C and 43°C). Cell survival, adhesion and changes at the molecular level were assessed. RESULTS: The obtained results revealed that hyperthermia enhances the anticancer activity of vitamin C. Ovarian cancer cells showed greater sensitivity to vitamin C at elevated temperatures. Cells may have different sensitivity to vitamin C due to the activation of different gene signatures associated with redox reactions and apoptosis, therefore we examined the following genes: BCAP31, BCL2L13, BID, CASP7, FADD and HTRA2. The increase in expression of these genes in cancer cells generated a stronger proapoptotic response. CONCLUSION: The present study showed that hyperthermia enhanced the anticancer activity of vitamin C in vitro.

Cytoreductive Surgery (CRS) Combined With Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Platinum-Sensitive Recurrence Epithelial Ovarian Cancer With HRR Mutation: A Phase III Randomized Clinical Trial.

Background: Epithelial ovarian cancer (EOC) remains the leading cause of gynecologic cancer death worldwide due to the high recurrence rate. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is an alternative modality for platinum-sensitive recurrent EOC. The latest studies demonstrate homologous recombination-related (HRR) mutation status increases the sensitivity to platinum-based chemotherapy drugs in EOC. However, the molecular analysis of recurrent EOC patient benefits from HIPEC is unknown. Thus, we aimed to evaluate the efficacy and safety of CRS combined with HIPEC for platinum-sensitive in recurrent EOC with HRR mutation. Methods: This is a phase III randomized controlled clinical trial in patients with platinum-sensitive recurrent EOC. Participants were divided into 2 groups based on the HRR mutation status and randomized to receive CRS + HIPEC. The patients then received periodic chemotherapy and follow-up. Results: The primary objective of this study was to evaluate the effect of CRS + HIPEC compared to CRS alone in patients with a platinum-sensitive recurrent EOC stratified for HRD status. We hypothesize that the addition of HIPEC to CRS improves the progression-free survival (PFS) of platinum-sensitive recurrent EOC patients with HRR mutation compared with patients without HRR mutation. Conclusion: Recurrent EOC has a poor prognosis due to implantation and metastasis in the abdominal cavity. Intraperitoneal chemotherapy reduced seeding by removing free tumor cells. HIPEC utilizes physical and biological properties to significantly increase the clearance rate of tumors. Van Driel WJ et al proposed that HIPEC using platinum-based chemotherapy improves the survival of patients with ovarian cancer. HRR mutation, as a common pathogenic mutation in ovarian cancer, has a predictive effect on the platinum sensitivity of ovarian cancer patients. Whether lobaplatin-based HIPEC will play a greater role in ovarian cancer patients with HRR mutations is currently unknown.

Interval cytoredutive surgery and HIPEC in advanced ovarian cancer with small-bowel disease: results and reflections.

INTRODUCTION: Small-bowel involvement in patients with ovarian cancer has been strongly correlated with the possibility of cytoreduction and thus with survival. The main objective of this study was to evaluate the prognostic significance of small-bowel involvement in patients undergoing optimal-complete interval cytoreductive surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC). METHODS: We included a series of patients diagnosed with stage IIIC-IVA (pleural effusion) high-grade serous epithelial ovarian cancer and in whom CRS + HIPEC was indicated after neoadjuvant systemic chemotherapy (NACT). The study period extended from January 2008 to January 2020, with a minimum follow-up of 12 months from the inclusion of the last patient. A multivariate analysis using Cox regression allowed us to identify the variables that were independently related to disease-free survival. RESULTS: A total of 144 patients were selected, 13 (9%) of whom were excluded from the analysis, because their disease was considered unresectable. The study included a series of 131 patients with a median age of 62 years (34-79 years) and a median Peritoneal Cancer Index (PCI) calculated during surgery of 9 (1-35). The median PCI of bowel areas 9-12 (SB-PCI) was 3 (1-10). Performance of a CC-1 cytoreduction (HR: 1.93, 95% CI: 1.02-3.64, p = 0.042) and SB-PCI greater than 3 (HR: 2.25, 95%CI: 1.13-4.48, p = 0.21) were independent factors associated with shorter disease-free survival. CONCLUSION: Small-bowel involvement, even in patients with a macroscopically complete resection, showed a correlation with worse prognostic outcomes and could be considered as a variable in the postoperative management of these patients.

Safety and efficacy of the tumor-selective adenovirus enadenotucirev with or without paclitaxel in platinum-resistant ovarian cancer: a phase 1 clinical trial.

BACKGROUND: Treatment outcomes remain poor in recurrent platinum-resistant ovarian cancer. Enadenotucirev, a tumor-selective and blood stable adenoviral vector, has demonstrated a manageable safety profile in phase 1 studies in epithelial solid tumors. METHODS: We conducted a multicenter, open-label, phase 1 dose-escalation and dose-expansion study (OCTAVE) to assess enadenotucirev plus paclitaxel in patients with platinum-resistant epithelial ovarian cancer. During phase 1a, the maximum tolerated dose of intraperitoneally administered enadenotucirev monotherapy (three doses; days 1, 8 and 15) was assessed using a 3+3 dose-escalation model. Phase 1b included a dose-escalation and an intravenous dosing dose-expansion phase assessing enadenotucirev plus paclitaxel. For phase 1a/b, the primary objective was to determine the maximum tolerated dose of enadenotucirev (with paclitaxel in phase 1b). In the dose-expansion phase, the primary endpoint was progression-free survival (PFS). Additional endpoints included response rate and T-cell infiltration. RESULTS: Overall, 38 heavily pretreated patients were enrolled and treated. No dose-limiting toxicities were observed at any doses. However, frequent catheter complications led to the discontinuation of intraperitoneal dosing during phase 1b. Intravenous enadenotucirev (1×1012 viral particles; days 1, 3 and 5 every 28-days for two cycles) plus paclitaxel (80 mg/m2; days 9, 16 and 23 of each cycle) was thus selected for dose-expansion. Overall, 24/38 (63%) patients experienced at least 1 Grade ≥3 treatment-emergent adverse event (TEAE); most frequently neutropenia (21%). Six patients discontinued treatment due to TEAEs, including one patient due to a grade 2 treatment-emergent serious AE of catheter site infection (intraperitoneal enadenotucirev monotherapy). Among the 20 patients who received intravenous enadenotucirev plus paclitaxel, 4-month PFS rate was 64% (median 6.2 months), objective response rate was 10%, 35% of patients achieved stable disease and 65% of patients had a reduction in target lesion burden at ≥1 time point. Five out of six patients with matched pre-treatment and post-treatment biopsies treated with intravenous enadenotucirev plus paclitaxel had increased (mean 3.1-fold) infiltration of CD8 +T cells in post-treatment biopsies. CONCLUSIONS: Intravenously dosed enadenotucirev plus paclitaxel demonstrated manageable tolerability, an encouraging median PFS and increased tumor immune-cell infiltration in platinum-resistant ovarian cancer. TRIAL REGISTRATION NUMBER: NCT02028117.

Nurse-led exercise and cognitive-behavioral care against nurse-led usual care between and after chemotherapy cycles in Han Chinese women of ovarian cancer with moderate to severe levels of cancer-related fatigue: A retrospective analysis of the effectiveness.

ABSTRACT: Women with ovarian cancer are reported to fatigue over time. Moderate to severe levels of cancer-related fatigue is fluent in Han Chinese patients with cancer. Comprehensive Cancer Network guidelines are recommending exercise and cognitive behavioral therapy to reduce cancer-related fatigue. Exercise is an easy, cost-effective, and non-pharmacological approach. The objective of the study was to evaluate the effectiveness of nurse-led exercise and cognitive-behavioral care against nurse-led usual care in Han Chinese women of ovarian cancer regarding cancer-related fatigue, depressive symptoms, and sleep quality.Han Chinese women with moderate to severe levels of cancer-related fatigue have received 30 minutes, 5 times/week nurse-led exercise and 60 min/week cognitive-behavioral care (EC cohort, n = 118) or nurse-led usual care regarding educations and recommendations only (UC cohort, n = 126) or have not received nurse-led exercise, cognitive-behavioral care, educations, and recommendations (NC cohort, n = 145) between and after chemotherapy cycles. The Piper Fatigue Scale, the Zung Self-rating Depression Scale, and Pittsburgh Sleep Quality Index questionnaires were evaluated at the start and the end of non-pharmacological treatment.At the end of treatment as compared to the start of treatment, only women of EC cohort had decrease Piper Fatigue Scale (5.40 ±â€Š1.49/woman vs 6.06 ±â€Š1.49/woman, P < .0001, q = 4.973) and Zung Self-rating Depression Scale score (48.67 ±â€Š4.24/woman vs 49.93 ±â€Š4.29/woman, P = .001, q = 3.449). Also, at the end of treatment, as compared to the start of treatment, only women of EC cohort have increased Pittsburgh Sleep Quality Index score (14.76 ±â€Š2.18/woman vs 13.94 ±â€Š2.90/woman, P = .045, q = 3.523). Only exercise and cognitive-behavioral care were successful in a decrease in the numbers of women with depression (the Mandarin Chinese version of the Zung Self-rating Depression Scale score >53, 32 vs 16, P = .015).Nurse-led exercise and cognitive-behavioral care can help Han Chinese women with ovarian cancer to decrease cancer-related fatigue and depression. Also, it can improve the quality of sleep.Evidence Level: 4.Technical Efficacy: Stage 5.

Role of hsa­miR­105 during the pathogenesis of paclitaxel resistance and its clinical implication in ovarian cancer.

More than 70% of patients with epithelial ovarian cancer (EOC), one of the leading cause of gynecological cancer­related deaths worldwide, are diagnosed at an advanced stage of the disease. Currently, the mainstay for treatment of advanced EOC is tumor debulking surgery followed by combined platinum­ and paclitaxel (PTX)­based chemotherapy. However, most patients eventually develop chemoresistance, which remains a major obstacle to successful treatment. Herein, by using clinical specimens and experimentally induced cell models, we found that the expression levels of hsa­miR­105 were significantly decreased in PTX­resistant EOC tissues and cell lines. Follow­up functional experiments demonstrated that repression of hsa­miR­105 conferred resistance to paclitaxel in EOC cells, whereas restoration of hsa­miR­105 expression in situ via intratumoral injection of hsa­miR­105 micrON™ agomir potentiated in vivo sensitivity to PTX and thereafter significantly inhibited tumor growth in a PTX­challenged xenograft model. Mechanistically, hsa­miR­105 exerted its tumor suppressor function by directly inhibiting the zinc and ring finger 2 (ZNRF2) signaling pathway. Importantly, aberrant expression of hsa­miR­105 in both tumor and circulating samples predicted a poor post­chemotherapy prognosis in EOC patients. These findings collectively suggest that hsa­miR­105 may act as a potent tumor suppressor miRNA during the progression of EOC, likely affecting cell proliferation, invasiveness and chemosensitivity to PTX, and functioning at least in part via inhibition of ZNRF2 signaling. The stability and availability and ease in measurement of circulating hsa­miR­105 make it a valuable diagnostic/prognostic biomarker candidate for chemotherapy of EOC.

HIPEC: Turning up the heat on ovarian cancer.

Clinical trials of heated intraperitoneal chemotherapy (HIPEC ) for the treatment of advanced ovarian cancer are showing promising survival outcomes. HIPEC has the potential to eliminate ovarian cancer cells from peritoneal surfaces more effectively than systemic chemotherapy through enhanced pharmacokinetic and hyperthermia effects. However, many questions remain to be answered, particularly regarding the true place of HIPEC in the current era of new and effective targeted treatments. Concerns around the potential for increased morbidity, adverse effects on quality of life, and increased resource use following HIPEC use, can only be properly evaluated with ongoing high-quality clinical trials.

Combination therapy with B7H3-redirected bispecific antibody and Sorafenib elicits enhanced synergistic antitumor efficacy.

Rationale: Current traditional treatment options are frequently ineffective to fight against ovarian cancer due to late diagnosis and high recurrence. Therefore, there is a vital need for the development of novel therapeutic agents. B7H3, an immune checkpoint protein, is highly expressed in various cancers, representing it a promising target for cancer immunotherapy. Although targeting B7H3 by bispecific T cell-engaging antibodies (BiTE) has achieved successes in hematological malignancies during recent years, attempts to use them for the treatment of solid cancers are less favorable, in part due to the heterogeneity of tumors. Sorafenib is an unselective inhibitor of multiple kinases currently being tested in clinical trials for several tumors, including ovarian cancer which showed limited activity and inevitable side effect for ovarian cancer treatment. However, it is able to enhance antitumor immune response, which indicates sorafenib may improve the efficiency of immunotherapy. Methods: We evaluated the expression of B7H3 in ovarian cancer using online database and validated its expression of tumor tissues by immunohistochemistry staining. Then, B7H3 expression and the effects of sorafenib on ovarian cancer cell lines were determined by flow cytometry. In addition, 2D and 3D ovarian cancer models were established to test the combined therapeutic effect in vitro. Finally, the efficiency of B7H3×CD3 BiTE alone and its combination with sorafenib were evaluated both in vitro and in vivo. Results: Our data showed that B7H3 was highly expressed in ovarian cancer compared with normal samples. Treatment with sorafenib inhibited ovarian cancer cell proliferation and induced a noticeable upregulation of B7H3 expression level. Further study suggested that B7H3×CD3 BiTE was effective in mediating T cell killing to cancer cells. Combined treatment of sorafenib and B7H3×CD3 BiTE had synergistic anti-tumor effects in ovarian cancer models. Conclusions: Overall, our study indicates that combination therapy with sorafenib and B7H3×CD3 BiTE may be a new therapeutic option for the further study of preclinical treatment of OC.

HIPEC in advanced epithelial ovarian cancer: why is there controversy?

PURPOSE OF REVIEW: The randomized OVHIPEC study provided further evidence that adding heated intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery significantly improved recurrence-free and overall survival in stage III epithelial ovarian cancer (EOC) patients, who were ineligible for primary cytoreductive surgery due to extensive intraperitoneal disease. Because opinions have been divided as to whether HIPEC is now a new standard of care for advanced EOC, the pros and cons of this approach are examined. A comparison with the ongoing discussion about the role of intraperitoneal chemotherapy is made. RECENT FINDINGS: For both techniques, experience is crucial and a learning curve essential. Compared with intraperitoneal chemotherapy, intraoperative application of HIPEC provides superior distribution through the peritoneal cavity. HIPEC, as given in OVHIPEC, did not significantly increase adverse events, had no negative effect on quality of life and was cost-effective. SUMMARY: Despite the ongoing debate about HIPEC, an important first step in attempting to demonstrate the efficacy of HIPEC in the first-line setting has been made with OVHIPEC. Critics have been of value to optimize future trials with HIPEC in patients with EOC.

Cross­validation of genes potentially associated with neoadjuvant chemotherapy and platinum­based chemoresistance in epithelial ovarian carcinoma.

Ovarian carcinomas have the poorest prognosis and the highest mortality among gynecological malignancies. Neoadjuvant chemotherapy (NACT) is considered as a novel therapeutic strategy and an alternative treatment for advanced epithelial ovarian cancer (AEOC). The aim of the present study was to identify the core genes related to platinum­based NACT resistance in AEOC and to allow screening at the molecular level for the most appropriate ovarian cancer patients for NACT. We obtained three drug­resistant microarrays GSE114206, GSE41499 and GSE33482 from the Gene Expression Omnibus (GEO) database as well as a microarray representing NACT, GSE109934. Bioinformatics analysis revealed the nature of the four potential candidate genes for using in functional enrichment analyses and interaction network construction. The potential associations and possible genetic alterations among the DEGs were summarized using the STRING database in Cytoscape and the cBioPortal visualization tool, respectively. A total of 63 genes were identified as DEGs from GSE109934 representing NACT. From the drug­resistant GSE114206 and GSE41499 datasets, 106 DEGs containing 36 upregulated genes and 70 downregulated genes were selected, and from the drug­resistant GSE114206 and GSE33482 datasets, 406 DEGs with 157 upregulated genes and 249 downregulated genes were selected. The 36 upregulated DEGs and the 70 downregulated genes were notably abundant in the different categories. In KEGG pathway analysis, the 157 upregulated genes and the 249 downregulated genes were concentrated in distinctive signaling pathways. Four potential genes associated with NACT and platinum­based chemoresistance were screened, including nuclear factor of activated T­cells, cytoplasmic 1 (NAFTc1), Kruppel­like factor 4 (KLF4), nuclear receptor subfamily 4 group A member 3 (NR4A3) and hepatocyte growth factor (HGF). Our study showed that the mRNA expression levels of NAFTc1, NR4A3 and HGF were increased in drug­resistant OC cell lines (all P<0.01), whereas the mRNA expression levels of KLF4 were notably lower in the SKOV3­CDDP and HeyA8­CDDP cell line (all P<0.01) but higher in the A2780­CBP cell line. The NAFTc1, KLF4, NR4A3 and HGF genes may be potential therapeutic targets for NACT and platinum­based chemoresistance factors as well as candidate biomarkers in AEOC. Determination of the expression levels of these four genes in tumor tissues before planning NACT treatment or initial surgery would be beneficial for AEOC patients.

SJI 2020 special issue: A catalogue of Ovarian Cancer targets for CAR therapy.

Ovarian Cancer (OC) is currently difficult to cure, mainly due to its late detection and the advanced state of the disease at the time of diagnosis. Therefore, conventional treatments such as debulking surgery and combination chemotherapy are rarely able to control progression of the tumour, and relapses are frequent. Alternative therapies are currently being evaluated, including immunotherapy and advanced T cell-based therapy. In the present review, we will focus on a description of those Chimeric Antigen Receptors (CARs) that have been validated in the laboratory or are being tested in the clinic. Numerous target antigens have been defined due to the identification of OC biomarkers, and many are being used as CAR targets. We provide an exhaustive list of these constructs and their current status. Despite being innovative and efficient, the OC-specific CARs face a barrier to their clinical efficacy: the tumour microenvironment (TME). Indeed, effector cells expressing CARs have been shown to be severely inhibited, rendering the CAR T cells useless once at the tumour site. Herein, we give a thorough description of the highly immunosuppressive OC TME and present recent studies and innovations that have enabled CAR T cells to counteract this negative environment and to destroy tumours.

An overview and update of hyperthermic intraperitoneal chemotherapy in ovarian cancer.

INTRODUCTION: Despite, the strong rationale and evidence of the benefit of postoperative intraperitoneal chemotherapy in advanced ovarian cancer, it has not been widely adopted, mainly due to its high morbidity and logistical difficulties. Intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) is a more tolerable and technically feasible method of intraperitoneal chemotherapy, whereas other potential advantages include homogenous drug distribution, application before tumor regrowth and combination with hyperthermia, which is directly cytotoxic and enhances the efficacy of many drugs. AREAS COVERED: In this review, the authors explain the rationale and indications for cytoreductive surgery (CRS) and HIPEC in advanced ovarian cancer. Data of major clinical studies, meta-analyses, and recent randomized trials are discussed. EXPERT OPINION: After many encouraging clinical studies and meta-analyses, a recent randomized study demonstrated survival benefit for HIPEC during interval CRS in primary ovarian cancer, without increased morbidity, whereas another implied its benefit in recurrent ovarian cancer. Results of recently completed and numerous ongoing randomized studies will further determine the benefit of HIPEC in ovarian cancer at different time points. Patient selection and appraisal of the best protocols are crucial. The field of gynecological oncology will most likely evolve to include HIPEC eventually as a routine treatment for ovarian cancer.

Prognostic factors of overall survival for patients with FIGO stage IIIc or IVa ovarian cancer treated with neo-adjuvant chemotherapy followed by interval debulking surgery: A multicenter cohort analysis from the FRANCOGYN study group.

INTRODUCTION: The aim of this study was to identify prognostic factors of overall survival in patients with FIGO stage IIIc or IVa ovarian cancer (OC) treated by neo-adjuvant chemotherapy (NAC) followed by interval debulking surgery. MATERIALS AND METHODS: Data from 483 patients with ovarian cancer were retrospectively collected, from January 1, 2000 to December 31, 2016, from the FRANCOGYN database, regrouping data from 11 centers specialized in ovarian cancer treatment. Median overall survival was determined using the Kaplan-Meier method. Univariate and multivariate analysis were performed to define prognostic factors of overall survival. RESULTS: The median overall survival was 52 after a median follow up of 30 months. After univariate analysis, factors significantly associated with decreased overall survival were; no pelvic and/or para-aortic lymphadenectomy (p = 0.002), residual disease (CC1/CC2/CC3) after surgery (p < 0.001), positive cytology after NAC (p < 0.001), omental disease after NAC (p = 0.002), no pathologic complete response (pCR) (p = 0.002). In multivariate analysis, factors significantly associated with decreased overall survival were; residual disease after surgery (HR = 1.93; CI95% (1.16-3.21), p = 0.01) and positive cytology after NAC (HR = 1.59; CI95% (1.01-2.55), p = 0.05). Patients with no residual disease after surgery had a median overall survival of 64 months versus 35 months for patients with residual disease. Patients with negative cytology after NAC had a median overall survival of 71 months versus 43 months for patients with positive cytology after NAC. CONCLUSION: In this first and largest French based retrospective study, complete cytoreductive surgery in ovarian cancer remains the main prognostic factor of overall survival.

Oncologic outcomes and morbidity following heated intraperitoneal chemotherapy at cytoreductive surgery for primary epithelial ovarian cancer: A systematic review and meta-analysis.

OBJECTIVES: Heated intraperitoneal chemotherapy (HIPEC) has not been universally adopted at the time of interval cytoreductive surgery for primary epithelial ovarian cancer (EOC) despite evidence of a 12-month overall survival (OS) benefit in a recent landmark randomized trial. We performed a systematic review and meta-analysis to assess oncologic outcomes and perioperative morbidity following HIPEC among primary EOC patients. METHODS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews, from inception to August 2019, for observational and randomized studies of primary EOC patients undergoing HIPEC. We assessed risk of bias using the Institute of Health Economics Quality Appraisal Checklist for single-arm cohort studies, Newcastle-Ottawa Scale for comparative cohort studies, and Cochrane Collaboration's Tool for randomized trials. We qualitatively summarized survival outcomes and calculated the pooled proportion of 30-day grade III-IV morbidity and postoperative death. RESULTS: We identified 35 articles including 2252 primary EOC patients; one study was a randomized trial, and only six studies included a comparator group of surgery alone. The timing, temperature, and chemotherapeutic agents used for HIPEC differed across studies. Reported OS was highly variable (3-year OS range: 46-77%); three comparative cohort studies and the sole randomized trial reported statistically significant survival benefits for HIPEC over surgery alone, while two comparative cohort studies did not. The pooled proportions for grade III-IV morbidity and postoperative death at 30 days were 34% (95% CI 20-52) and 0% (95% CI 0-5) respectively. CONCLUSION: One randomized trial suggests that HIPEC at time of interval cytoreductive surgery should be considered in patients with primary EOC. However, there is significant heterogeneity in literature with respect to an appropriate HIPEC regimen, short- and long-term outcomes. High-quality prospective randomized trials are urgently needed to clarify the role of HIPEC in the first-line treatment of primary EOC.

Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Ovarian Cancer: Evaluation of Side Effects in a Single Institution Cohort.

BACKGROUND/AIM: Peritoneal carcinomatosis is a sign of advanced ovarian cancer. If cytoreductive surgery results in a tumor-free situation with the remaining tumor being less than 0.25 cm, Hyperthermic intraperitoneal chemotherapy (HIPEC) may further improve prognosis. PATIENTS AND METHODS: Patients with ovarian cancer and peritoneal carcinomatosis underwent cytoreductive surgery. In 43 patients with optimal tumor debulking, HIPEC was performed. The peri- and post-operative course was observed. Adverse events were recorded after the Clavien-Dindo classification. RESULTS: The median age of the patients was 56 years, the median peritoneal cancer index (PCI) was 13, and the median operation time was 356 min. There was no postoperative surgery associated death. No adverse events were recorded in 16 (37.2%) of 43 patients, no grade III or IV adverse events were reported for 33 (76.7%) patients, and no grade IV adverse events were reported for 41 (95.3%) patients. Grade III adverse events occured in 19 (44.2%) of the 43 patients. Grade IV adverse events occured in 3 (7.0%) of the 43 patients. CONCLUSION: In ovarian cancer, multiple surgical procedures may be necessary in order to have macroscopically eradicated tumor tissue. The combination with HIPEC, further improves survival of patients with peritoneal carcinomatosis.