Factor In Advanced Ovarian Cancer Research Articles

Circulating small extracellular vesicles microRNAs plus CA-125 for treatment stratification in advanced ovarian cancer

BackgroundNo residual disease (R0 resection) after debulking surgery is the most critical independent prognostic factor for advanced ovarian cancer (AOC). There is an unmet clinical need for selecting primary or interval debulking surgery in AOC patients using existing prediction models.MethodsRNA sequencing of circulating small extracellular vesicles (sEVs) was used to discover the differential expression microRNAs (DEMs) profile between any residual disease (R0, n = 17) and no residual disease (non-R0, n = 20) in AOC patients. We further analyzed plasma samples of AOC patients collected before surgery or neoadjuvant chemotherapy via TaqMan qRT-PCR. The combined risk model of residual disease was developed by logistic regression analysis based on the discovery-validation sets.ResultsUsing a comprehensive plasma small extracellular vesicles (sEVs) microRNAs (miRNAs) profile in AOC, we identified and optimized a risk prediction model consisting of plasma sEVs-derived 4-miRNA and CA-125 with better performance in predicting R0 resection. Based on 360 clinical human samples, this model was constructed using least absolute shrinkage and selection operator (LASSO) and logistic regression analysis, and it has favorable calibration and discrimination ability (AUC:0.903; sensitivity:0.897; specificity:0.910; PPV:0.926; NPV:0.871). The quantitative evaluation of Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI) suggested that the additional predictive power of the combined model was significantly improved contrasted with CA-125 or 4-miRNA alone (NRI = 0.471, IDI = 0.538, p < 0.001; NRI = 0.122, IDI = 0.185, p < 0.01).ConclusionOverall, we established a reliable, non-invasive, and objective detection method composed of circulating tumor-derived sEVs 4-miRNA plus CA-125 to preoperatively anticipate the high-risk AOC patients of residual disease to optimize clinical therapy.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in ovarian cancer

The achievement of macroscopically complete tumor resection in primary debulking surgery is the most important prognostic factor in advanced ovarian cancer. This results in amedian survival benefit of >5 years. Systematic lymphadenectomy (LNE) is not indicated in advanced ovarian cancer with inconspicuous lymph nodes as it does not prolong overall survival and therefore should no longer be carried out above stage IIB with inconspicuous lymph nodes in imaging and by palpation. Primary cytoreductive surgery is the standard in advanced ovarian cancer. Neoadjuvant therapy is currently an option only if primary cytoreduction does not appear to be possible. For the use of hyperthermic intraperitoneal chemotherapy (HIPEC) in primary debulking surgery asurvival benefit has so far not been proven and therefore HIPEC is not recommended in this setting.

Circulating tumor-derived small extracellular vesicles micro RNAs plus CA-125 objectively tests residual tumor prior to debulking surgery in advanced ovarian cancer (525)

<b>Objectives:</b> No residual disease after debulking surgery (R0 resection) is the most critical independent prognostic factor for advanced ovarian cancer (AOC). There is an unmet clinical need for selecting primary or interval debulking surgery in AOC patients using existing prediction models, such as CA-125, CT, PET-CT, or laparoscopy. Therefore, it is of paramount importance to preoperatively estimate the likelihood of R0 resection for choosing the best therapeutic strategy. In this study, we sought to develop a novel, non-invasive, and objective detection method. <b>Methods:</b> Differentially expressed microRNAs (miRNA) in circulating small extracellular vesicles (sEVs) between any residual disease (R0) and no residual disease (non-R0) AOC patients were revealed using small RNA sequencing. miRNA expression of plasma samples was measured by TaqMan qRT-PCR. The prediction model of residual disease risk was established via LASSO and logistic regression analysis based on the discovery-validation set. Tissue sEVs were extracted from primary tumor tissue, metastatic tumor tissue, adjacent tissue, or non-tumor tissue by differential ultracentrifugation and size exclusion chromatography (SEC). Cell-type-specific markers (EpCAM, FAP, CD45, CD31) in tumor sEVs pool were evaluated by western blot analysis. Plasma sEVs were captured by the magnetic bead sorting system (MACS) using specific surface proteins as markers (EpCAM, CD45, CD235a). <b>Results:</b> A total of 270 subjects were recruited in this study from four clinical centers. According to the comprehensive plasma sEVs miRNAs profile in AOC patients, we identified and optimized a risk model consisting of plasma sEVs 5-miRNA and CA-125 for predicting residual disease (AUC:0.912; sensitivity:0.964; specificity:0.884; PPV:0.911; NPV:0.905;). Moreover, there were significant differences in model index scores between AOC patients and patients with benign ovarian tumors, early-stage ovarian cancer with FIGO I or II, and advanced colorectal cancer. Our data showed that EpCAM-positive sEVs accounted for the highest in tumor sEVs pool. Besides, these 5-miRNAs were a high concentration horizontal packaging in plasma EpCAM-sEVs. By further comparing the sEVs 5-miRNA expression in paired tumor and non-tumor tissue as well as plasma, we found that they were mainly originated from epithelial ovarian cancer cells and their tumor microenvironment. These results indicated that plasma sEVs 5-miRNA in AOC patients was associated with residual disease. <b>Conclusions:</b> Collectively, our study demonstrated a distinct profile of circulating sEVs miRNAs between R0 and non-R0 patients and obtained a robust model of circulating tumor-derived sEVs 5-miRNA combined with CA-125 to preoperatively anticipate a high risk of residual disease for optimizing clinical treatment and guiding differential diagnosis. This prediction panel, as a tool of non-invasive liquid biopsy, can be part of a standard monitoring strategy for screening high-risk patients who are allowed for neoadjuvant chemotherapy.

29P Plasma tumor-derived small extracellular vesicles microRNAs plus CA-125 objectively detect residual disease risk after surgical debulking in advanced ovarian cancer

29P Plasma tumor-derived small extracellular vesicles microRNAs plus CA-125 objectively detect residual disease risk after surgical debulking in advanced ovarian cancer

Serum Albumin as a Predictor of Survival after Interval Debulking Surgery for Advanced Ovarian Cancer (AOC): A Retrospective Study

Objective To investigate the impact of serum albumin (at diagnosis and pre-operatively) on survival in patients undergoing cytoreductive surgery for advanced ovarian cancer(AOC) and whether improvement in albumin achieved following neoadjuvant chemotherapy (NACT) affects overall survival (OS). Methods Outcomes of 441 patients who underwent cytoreduction for AOC were reviewed. Albumin was recorded at diagnosis and pre-operatively. Further analysis was performed if patients were hypoalbuminaemic at diagnosis.Analysis was stratified according to whether the patientreceived primary debulking surgery (PDS) or interval debulking surgery (IDS) and if their albumin was corrected. Results 308 patients had a serum albumin level at diagnosis and 400 patients had a pre-operative albumin available for analysis. For patients with an albumin at diagnosis ≤ 35g/L and ≥36 g/L, median OS was 31.5 (95% CI 23.5–39.5) and 50.4 (95% CI 38.9–61.9) months respectively (P = 0.003). Followingmultivariate analysis (MVA), albumin at diagnosis remained statistically significant as an independent marker for survival, even after adjusting for cytoreductive outcome, stage and grade(p = 0.04, Hazard ratio 1.38, 95% CI 1.01–1.89). Hypoalbuminaemic patients at diagnosis achieved complete cytoreduction in 53% of cases.For PDS patients, median OS was 19.7 months (95% CI 11.5–27.9). For IDS patients, median OS was 27.9 months (n = 1).IDS patients with a corrected albumin had a median OS of 42.9 months (95% CI 31.5–54.3) (p > 0.05). Conclusion Hypoalbuminaemia at diagnosis is a poor prognostic factor in AOC. Normalization of serum albumin after NACT is a potential predictor of survival.

The Significance of Preoperative Computed Tomography for Predicting Optimal Cytoreduction in Advanced Ovarian Cancer.

Introduction Optimal cytoreduction is the most important prognostic factor in advanced ovarian cancer. Although staging and assessment of operability are made by exploratory surgery, preoperative computed tomography (CT) of the abdomen is regarded as standard. The aim of this study was to examine various CT parameters with regard to prediction of optimal cytoreduction. Patients and Methods The retrospective study included 131 patients with ovarian cancer newly diagnosed between 2010 and 2014. Of these, n = 36 with FIGO stage I to IIB were excluded from the study. A preoperative abdominal CT was available for n = 75 of the 95 patients with FIGO stage IIC to IV. The CT scans underwent blinded review. The 11 evaluated CT parameters were examined by means of χ 2 test and logistic regression analysis with regard to the endpoints of macroscopic residual tumour and residual tumour > 1 cm. Survival analyses used the Kaplan-Meier method and log rank test. Results Of 75 patients, 28 (37.3%) had complete tumour resection and 26 (34.7%) had residual tumour ≤ 1 cm. Residual tumours > 1 cm were found in 21 (28%) patients, five of which were not resectable. Overall survival with residual tumour > 1 cm differed significantly from the group with no macroscopic residual tumour (p = 0.003) and with residual tumour ≤ 1 cm (p = 0.04). The CT parameters tumour foci in the diaphragm, mesocolon, greater omentum and peritoneum as well as ascites correlated with macroscopic residual tumour. In the multivariate logistic regression analysis only the CT parameter intraparenchymal liver metastasis was statistically significant with regard to prediction of suboptimal tumour resection (> 1 cm) (OR 8.04; 95% CI 1.57 – 42.4; p = 0.0134). The sensitivity, specificity, PPV and NPV were 37.5, 89.7, 66.7 and 72.2%. Conclusion Although risk parameters for suboptimal tumour reduction can be identified by CT of the abdomen, surgical exploration with histological confirmation of the diagnosis is essential because of the poor diagnostic accuracy.

Gonadotropin-Releasing Hormone Receptor-Targeted Near-Infrared Fluorescence Probe for Specific Recognition and Localization of Peritoneal Metastases of Ovarian Cancer.

Background: Peritoneal dissemination is common in advanced ovarian cancer. The completeness of cytoreduction is an independent prognostic factor. The intraoperative fluorescence imaging via tumor-specific near-infrared fluorophore might improve staging and surgical completeness. A promising target for ovarian cancer is the gonadotropin-releasing hormone receptor (GnRHR). This study aimed to develop a GnRHR-targeted near-infrared imaging probe for the detection of peritoneal metastases of ovarian cancer.Methods: Indocyanine green (ICG) was conjugated with GnRH antagonist peptide to develop an ovarian cancer-selective fluorescence probe GnRHa-ICG. GnRHR expression was detected in ovarian cancer tissues. The binding capacity of GnRHa-ICG and ICG was detected in both cancer cell lines and mouse models of peritoneal metastatic ovarian cancer using fluorescence microscopy, flow cytometry, and near-infrared fluorescence imaging.Results: Tissue microarray analysis revealed the overexpression of GnRHR in ovarian cancer. GnRH-ICG exhibited the binding capacity in a panel of cancer cell lines with different expression levels of GnRHR. In ovarian cancer mouse models, GnRHa-ICG signals were detected in peritoneal tumor lesions rather than normal peritoneal and intestines tissues. ICG showed intensive fluorescence signals in intestines. The tumor-to-muscle ratio and tumor-to-intestine ratio of GnRHa-ICG was 7.41 ± 2.82 and 4.37 ± 1.66, higher than that of ICG (4.60 ± 0.50 and 0.57 ± 0.06) at 2 h post administration. The fluorescence signal of peritoneal metastases peaked in intensity at 2 h and maintained for up to 48 h. ICG also showed a weak signal in the tumor lesions due to the enhanced permeability and retention effect, but the intensity decreased quickly within 48 h.Conclusions: The developed GnRHR-targeted imaging agent GnRHa-ICG could specifically detected peritoneal tumor lesions from normal peritoneal and intestines tissues because of the modification of GnRHa to ICG. The plateau period of GnRHa-ICG accumulation may be feasible for clinical applications in fluorescence-guided surgery. Our GnRHR imaging concept may be effective in other hormone-related tumors with upregulated GnRHR expression.

Prognostic Factors in Advanced Ovarian Cancer - A Clinical Trial.

Introduction: Ovarian cancer is one of most fatal gynecological condition. The number of patients diagnosed in advanced stages is very high, hence the recurrence rate is high, and the chance of survival at 5 years is less than 45%. Purpose: To evaluate correspondance between overall survival with clinical, paraclinical, tumor or treatment characteristics and to identify prognostic factors in patients with advanced ovarian cancer - stage III and IV FIGO. Material and Method: We performed a retrospective study in 65 patients with advanced ovarian cancer - stages III and IV FIGO operated during 2010-2018, with a follow-up period of at least one year. There were correlations with clinical and paraclinical charateristics, tumor or treatment characteristics and with overall survival. Results: In the univariate statistical analysis of survival, a significant statistical association is obtained by the presence of pelvic pain at presentation (p_value = 0.033744), with the stage III (p_value = 0.007595, respectively p_value = 0.022090), with the type of citoreduction (p_value = 0.035) , with postoperative complications (p_value = 0.000685) within the pathological subtypes (p_value = 0.046266), with adjuvant treatment (p_value = 0.000083). Cox multivariate regression analysis showed that adjuvant chemotherapy (HR = 0.046, 95% CI = (0.008, 0.261), (p_value = 0.000492), suboptimal cytoreduction (HR = 0.346, 95% CI = (0.140, 0.853), (p_value) = 0.021219) and postoperative complications (HR = 53,751, 95% CI = (4,672, 618,365), (p_value = 0.001389) are independent prognostic factors. Conclusions: Absence of pelvic pain at diagnosis, FIGO IIIC stage, suboptimal cytoreduction, presence of postoperative complications, inadequate adjuvant treatment and pathological type of clear cell cancer have been shown to be prognostic factors for overall survival. In patients with advanced ovarian cancer, the type of optimal citoreduction and adjuvant treatment are independent protective factors for overall survival, and the presence of postoperative complications has been shown to be an independent risk factor.

Clinical significance of miRNA-21, -103, -129, -150 in serous ovarian cancer.

We aimed to compare expression levels of miRNA-21, -103, -129, -150 in primary tumour tissues and its omental metastases from patients operated for advanced ovarian serous cancer. Expression levels of selected miRNAs were correlated with clinicopathological features, including chemosensitivity and survival. We performed total RNA extraction from archival formalin-fixed paraffin-embedded tissue samples of primary serous ovarian cancer and omental metastases. The study included 48 patients with advanced ovarian cancer. The reference group consisted of 48 normal ovarian tissue samples. We performed cDNA synthesis, real time polymerase chain reaction and assessed relative expression of selected miRNAs. Samples derived from serous ovarian cancer were characterized by higher expression levels of miRNA-150 in comparison to omental metastases (p=0.045). Furthermore, we observed that shorter progression free-survival was associated with lower levels of miRNA-150 in metastatic tissues. We did not find similar relationships for other miRNAs. MiRNA-150 may potentially serve as a prognostic factor in advanced ovarian cancer. However, further studies are required to clearly confirm such hypothesis.

Pretreatment neutrophil-to-lymphocyte ratio and its dynamic change during neoadjuvant chemotherapy as poor prognostic factors in advanced ovarian cancer.

ObjectiveThe purpose of this study was to determine the prognostic implications of the pretreatment neutrophil-to-lymphocyte ratio (NLR) and its dynamic change during chemotherapy in patients with advanced epithelial ovarian cancer undergoing neoadjuvant chemotherapy.MethodsWe performed a retrospective analysis of 203 patients who underwent neoadjuvant chemotherapy prior to interval debulking surgery for advanced-stage ovarian cancer at Yonsei Cancer Hospital between 2007 and 2015. Pretreatment NLR was evaluated before starting neoadjuvant chemotherapy. Change in NLR was defined as the post-neoadjuvant NLR value divided by the initial value. The correlation of NLR and its dynamic change with chemotherapy response score, response rate, and recurrence was analyzed.ResultsThe NLR ranged from 0.64 to 22.8. In univariate analyses, a higher pretreatment NLR (>3.81) was associated with poor overall survival (OS), but not progression-free survival (PFS). Through multivariate analysis, high pretreatment NLR was shown to be an independent parameter affecting OS, but not necessarily PFS. Changes in NLR during chemotherapy were better predictors of PFS than baseline NLR. Patients with increased NLR during chemotherapy showed significantly poor PFS, and this change was an independent predictor of PFS.ConclusionPretreatment NLR and its dynamic change during chemotherapy may be important prognostic factors in patients who undergo neoadjuvant chemotherapy.

Cytoreductive Surgery for Advanced Ovarian Cancer

The amount of the largest diameter of visible residual tumor after cytoreductive surgery remains one of the strongest prognostic factors in advanced ovarian cancer. The implementation of a more aggressive surgical approach to increase the proportion of patients without visible residual tumor is, therefore, a rational concept. Thus, the surgical management of advanced ovarian, primary peritoneal and fallopian tube cancers now incorporates more comprehensive surgical procedures. However, these more extensive surgical procedures are associated with an increased risk of morbidity, which may have a negative impact on the oncologic outcome. In addition, it is unclear whether all patients benefit from a comprehensive surgical intervention in the same way or if there are patients whose disease course will not be influenced by this approach. The methodologic analysis of surgical effectiveness is complex and controversial owing to a lack of prospective surgical trials. This review acknowledges controversies and aims to discuss novel developments in the field of cytoreductive surgery for patients with ovarian, primary peritoneal and fallopian tube cancers. The focus of the review is to discuss the role of surgery at initial diagnosis. The role of secondary and tertiary surgery in the recurrent setting is beyond the scope of this review.

Diagnostic accuracy of hand-assisted laparoscopy in predicting resectability of peritoneal carcinomatosis from gynecological malignancies

Residual disease after excision surgery is the main prognostic factor in advanced ovarian cancer. Open surgery can delay neoadjuvant chemotherapy initiation. Therefore, a minimally invasive method for evaluating resectability would be of great interest. Aim of our study is to evaluate a new technique for assessing the extent of peritoneal carcinomatosis, combining manual palpation and standard laparoscopy. Prospective single-center study from October 2008 to January 2010. Patients with peritoneal carcinomatosis from gynecological malignancies were investigated by standard laparoscopy followed by laparoscopy plus manual palpation using Lapdisc(®) (Ethicon Inc.), at 43 abdominopelvic sites. When both techniques indicated resectability, standard cytoreduction surgery was performed via a midline laparotomy. The Fagotti, modified Fagotti, and Sugarbaker scores were computed. The diagnostic performance of each evaluation criterion was assessed by computing sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver-operating characteristic curves (ROC-AUCs). Of the 29 included patients, 18 (62.1%) were considered to have resectable disease. Fourteen (14/18, 77.8%) had macroscopically complete cytoreduction. With Lapdisc(®), sensitivity was 100%, specificity 73.3%, PPV 77.8%, NPV 100%, and ROC-AUC 0.87. Corresponding values were as follows: laparoscopy, 100%, 40%, 60.9%, 100%, and 0.70; Fagotti and modified Fagotti scores, 100%, 46.7%, 63.6%, 100%, and 0.73; Sugarbaker score, 64.3%, 93.3%, 90%, 73.7%, and 0.79. The ROC-AUCs showed significantly better performance of Lapdisc(®) than of standard laparoscopy (P = 0.008). Hand-assisted laparoscopy may perform better than laparoscopy alone for predicting the resectability of peritoneal carcinomatosis by increasing the number of sites evaluated.

Clinical significance of CA125 regression in chemotherapy of advanced ovarian cancer

The aim of this study was to compare the serum CA125 regression in advanced ovarian carcinoma patients treated with paclitaxel/platinum (TP) and platinum/epirubicin/ifosfamide (PAC) during early chemotherapy. The relationship between survival and CA125 regression during first line chemotherapy was evaluated. This retrospective investigation assessed 122 and 95 patients with stages IIc-IV ovarian carcinoma who underwent initial surgery followed by TP or PAC chemotherapy, respectively. Only epithelial ovarian cancers were included. CA125 half-life was calculated by mono-compartmental logarithmic regression. Every patient’s nadir CA125 concentration was also studied. T-test was used in comparing CA125 half-life and nadir CA125 between two groups. Survival analyses for progression-free survival (PFS) and overall survival (OS) used univariate (Kaplan-Meier) and multivariate (Cox) models for all of the patients. There was not significant difference in CA125 half-life and nadir CA125 concentration between two groups (P > 0.05). CA125 half-life and nadir CA125 concentration had a univariate prognostic value for PFS and OS (P 0.05, for each). In Cox models, CA125 half-life (P = 0.0006), residual tumour (P < 0.0001), and nadir concentration (P = 0.0032) were significant prognostic factors for disease free survival (DFS). For OS, CA125 half-life (P = 0.0013), residual tumor (P < 0.0001), and nadir concentration (P = 0.0118) were also the significant prognostic factors. There isn’t significant difference in serum CA125 regression between patients who are treated with PAC or PT during early chemotherapy. CA125 half-life and nadir CA125 concentration are independent prognostic factor in advanced ovarian cancer.

Prognostic evaluation of tumour type and other histopathological characteristics in advanced epithelial ovarian cancer, treated with surgery and paclitaxel/carboplatin chemotherapy: Cell type is the most useful prognostic factor

AimOvarian carcinomas have been classified into types I and II according to the hypothesised mode of carcinogenesis and molecular characteristics. The prognostic significance of this classification has not been studied. Patients and methodsFive hundred and sixty-eight patients with histologically confirmed, ovarian, fallopian tube or peritoneal carcinomas, international federation of gynecology and obstetrics (FIGO) stages IIC–IV, treated with paclitaxel/platinum following cytoreductive surgery, were included in this analysis. Type I included low-grade serous, mucinous, endometrioid and clear-cell and type II high-grade serous, unspecified adenocarcinomas and undifferentiated carcinomas. ResultsMedian overall survival (OS) was 49months for type I versus 45 for type II (p=0.576). In contrast to type II, there was considerable prognostic heterogeneity among the subtypes included in type I. Cox regression analysis showed that cell-type classification: low-grade serous, mucinous, endometrioid, clear-cell, type II (high-grade serous, unspecified adenocarcinomas, undifferentiated carcinoma) was an independent predictor of survival (respective median OS 121 versus 15 versus 64 versus 29 versus 45months, p=0.003). On the contrary, histopathological subtype or tumour type (I versus II) did not offer additional prognostic information. ConclusionThe proposed model of ovarian tumourigenesis does not reflect tumour behaviour in advanced disease. Tumour-cell type is the most relevant histopathological prognostic factor in advanced ovarian cancer treated with platinum/paclitaxel.

Optimal primary surgical treatment for advanced epithelial ovarian cancer.

Ovarian cancer is the sixth most common cancer among women. In addition to diagnosis and staging, primary surgery is performed to achieve optimal cytoreduction (surgical efforts aimed at removing the bulk of the tumour) as the amount of residual tumour is one of the most important prognostic factors for survival of women with epithelial ovarian cancer. An optimal outcome of cytoreductive surgery remains a subject of controversy to many practising gynae-oncologists. The Gynaecologic Oncology group (GOG) currently defines 'optimal' as having residual tumour nodules each measuring 1 cm or less in maximum diameter, with complete cytoreduction (microscopic disease) being the ideal surgical outcome. Although the size of residual tumour masses after surgery has been shown to be an important prognostic factor for advanced ovarian cancer, it is unclear whether it is the surgical procedure that is directly responsible for the superior outcome that is associated with less residual disease. To evaluate the effectiveness and safety of optimal primary cytoreductive surgery for women with surgically staged advanced epithelial ovarian cancer (stages III and IV).To assess the impact of various residual tumour sizes, over a range between zero and 2 cm, on overall survival. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 3) and the Cochrane Gynaecological Cancer Review Group Trials Register, MEDLINE and EMBASE (up to August 2010). We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. Retrospective data on residual disease from randomised controlled trials (RCTs) or prospective and retrospective observational studies which included a multivariate analysis of 100 or more adult women with surgically staged advanced epithelial ovarian cancer and who underwent primary cytoreductive surgery followed by adjuvant platinum-based chemotherapy. We only included studies that defined optimal cytoreduction as surgery leading to residual tumours with a maximum diameter of any threshold up to 2 cm. Two review authors independently abstracted data and assessed risk of bias. Where possible, the data were synthesised in a meta-analysis. There were no RCTs or prospective non-RCTs identified that were designed to evaluate the effectiveness of surgery when performed as a primary procedure in advanced stage ovarian cancer.We found 11 retrospective studies that included a multivariate analysis that met our inclusion criteria. Analyses showed the prognostic importance of complete cytoreduction, where the residual disease was microscopic that is no visible disease, as overall (OS) and progression-free survival (PFS) were significantly prolonged in these groups of women. PFS was not reported in all of the studies but was sufficiently documented to allow firm conclusions to be drawn.When we compared suboptimal (> 1 cm) versus optimal (< 1 cm) cytoreduction the survival estimates were attenuated but remained statistically significant in favour of the lower volume disease group There was no significant difference in OS and only a borderline difference in PFS when residual disease of > 2 cm and < 2 cm were compared (hazard ratio (HR) 1.65, 95% CI 0.82 to 3.31; and HR 1.27, 95% CI 1.00 to 1.61, P = 0.05 for OS and PFS respectively).There was a high risk of bias due to the retrospective nature of these studies where, despite statistical adjustment for important prognostic factors, selection bias was still likely to be of particular concern.Adverse events, quality of life (QoL) and cost-effectiveness were not reported by treatment arm or to a satisfactory level in any of the studies. During primary surgery for advanced stage epithelial ovarian cancer all attempts should be made to achieve complete cytoreduction. When this is not achievable, the surgical goal should be optimal (< 1 cm) residual disease. Due to the high risk of bias in the current evidence, randomised controlled trials should be performed to determine whether it is the surgical intervention or patient-related and disease-related factors that are associated with the improved survival in these groups of women. The findings of this review that women with residual disease < 1 cm still do better than women with residual disease > 1 cm should prompt the surgical community to retain this category and consider re-defining it as 'near optimal' cytoreduction, reserving the term 'suboptimal' cytoreduction to cases where the residual disease is > 1 cm (optimal/near optimal/suboptimal instead of complete/optimal/suboptimal).

The activated transforming growth factor‐beta signaling pathway in peritoneal metastases is a potential therapeutic target in ovarian cancer

Peritoneal dissemination including omental metastasis is the most frequent route of metastasis and an important prognostic factor in advanced ovarian cancer. We analyzed the publicly available microarray dataset (GSE2109) using binary regression and found that the transforming growth factor (TGF)-beta signaling pathway was activated in omental metastases as compared to primary sites of disease. Immunohistochemical analysis of TGF-beta receptor type 2 and phosphorylated SMAD2 indicated that both were upregulated in omental metastases as compared to primary disease sites. Treatment of the mouse ovarian cancer cell line HM-1 with recombinant TGF-β1 promoted invasiveness, cell motility and cell attachment while these were suppressed by treatment with A-83-01, an inhibitor of the TGF-β signaling pathway. Microarray analysis of HM-1 cells treated with TGF-β1 and/or A-83-01 revealed that A-83-01 efficiently inhibited transcriptional changes that are induced by TGF-β1. Using gene set enrichment analysis, we found that genes upregulated by TGF-β1 in HM-1 cells were also significantly upregulated in omental metastases compared to primary sites in the human ovarian cancer dataset, GSE2109 (false discovery rate (FDR) q = 0.086). Therapeutic effects of A-83-01 in a mouse model of peritoneal dissemination were examined. Intraperitoneal injection of A-83-01 (150 μg given three times weekly) significantly improved survival (p = 0.015). In summary, these results show that the activated TGF-β signaling pathway in peritoneal metastases is a potential therapeutic target in ovarian cancer.

Comparison between serous and non-serous ovarian cancer as a prognostic factor in advanced epithelial ovarian carcinoma after primary debulking surgery

Residual tumor size after primary surgery is the most important prognostic factor in advanced ovarian cancer. We conducted a retrospective study in Japanese women to evaluate the association of various residual disease diameters and histological subtypes with overall survival (OS) in patients with residual disease ≥1cm. Demographic and clinicopathological data were obtained from the Tokai Ovarian Tumor Study Group; 294 patients with International Federation of Gynecology and Obstetrics stage III and IV epithelial ovarian carcinoma who had undergone primary debulking surgery between 1986 and 2007 and had ≥1cm residual tumor were identified. A Cox proportional hazards model was used to assess the association of prognostic factors with OS. Non-serous advanced ovarian cancer was associated with a significant increase in the risk of death. For serous ovarian cancer, residual tumor size was not an independent prognostic factor [multivariate hazard ratio (HR)=1.63, 95% confidence interval (CI)=0.96-2.79 (2-5cm); HR=1.25, 95% CI=0.72-2.17 (>5cm); trend P=0.480], whereas taxane-based chemotherapy was associated with a better prognosis (HR=0.66, 95% CI=0.44-0.99, P=0.046). For non-serous ovarian cancer, in contrast, residual tumor size was associated with an increased risk of death [multivariate HR=0.87, 95% CI=0.36-2.14 (2-5cm); HR=2.21, 95% CI=0.96-5.08 (>5cm); trend P=0.067], whereas taxane-based chemotherapy was not a prognostic factor [HR=0.70, 95% CI=0.29-1.65, P=0.409 (taxane-based)]. Although primary maximal cytoreduction is essential to improving OS in advanced ovarian cancer, our findings suggest the management of patients with suboptimal residual tumor should take into account differences between histological subtypes.

Influence of Residual Tumor on Outcome in Ovarian Cancer Patients With FIGO Stage IV Disease

One of the most important prognostic factors in advanced ovarian cancer is the macroscopic absence of residual tumor after primary surgery. The impact of surgical outcome on the survival of patients with International Federation of Gynecology and Obstetrics (FIGO) stage IV disease is less clear and is the subject of this study. Surgical and survival data were documented throughout the multicenter prospective randomized phase III trials of the AGO-OVAR (OVAR-3/-5/-7) and were used for this exploratory analysis. In these studies, 573 patients with FIGO stage IV disease were first operated, then randomized and homogenously treated with a combination therapy comprising the intravenous application of platinum and paclitaxel. The median progression-free survival and overall survival of patients with stage IV ovarian cancer were 12.6 and 26.1 months, respectively. Multivariable Cox regression analysis for overall survival revealed that residual tumor, mucinous histological type, multiple sites of metastases, and Eastern Cooperative Oncology Group performance status were statistically significant prognostic variables. Whereas patients with macroscopically complete resection had a statistically significant improved outcome, patients with residual disease of 0.1-1 cm and patients with residual tumor of >1 cm showed similar outcome. Macroscopically complete resection in FIGO stage IV disease, irrespective of the site of distant tumor spread, is an important prognostic factor and the only prognosticator amenable to improvement by therapy. Our results suggest possible advantages of a reasonable attempt at complete cytoreduction even in FIGO stage IV disease. In addition, tumor biology could be an important factor for achieving complete resection.

Gonadotropin and steroid receptors as prognostic factors in advanced ovarian cancer: a retrospective study

Ovarian cancer is a chemosensitive tumour, but two thirds of women have a recurrence during the follow- up, even after an optimal surgical debulking followed by chemotherapy with a platinum and a taxane compound. Cytotoxic drugs are used in a second- or third-line setting but tumour progression is the rule. Also patients with the same histology achieve different outcomes in terms of survival. We decided to study gonadotropin and steroid receptors and to consider if these histological markers could select patients with different prognosis. In our study we have measured by immunohistochemistry oestrogen, progestin and gonadotropin- releasing hormone receptors (Gn-RHRs) in paraffinembedded ovarian cancer tissue in a sample of 62 consecutive patients with advanced ovarian cancer treated with surgery and adjuvant chemotherapy. Descriptive methods, a survival analysis (Kaplan-Meier) and a Cox regression analysis were done. Oestrogen receptors (ERs) were positive in 65% of patients and the same positivity was obtained for progestin receptors (PRs), with 74% showing some positivity for Gn-RHR receptors. Maximal cytoreduction and ERs, but not gonadotropin receptors, were independently associated with overall survival, with better survival for oestrogennegative tumours. No association was established for progression- free survival. We can conclude that ER status in our series is an independent prognostic factor for ovarian cancer with better survival for oestrogen-negative receptor tumours. PRs could also have a prognostic role in association with ERs.

Maintenance immunotherapy in recurrent ovarian cancer: Long term follow-up of a phase II study

Objectives Vascular endothelial growth factor (VEGF), a mediator of tumor-associated immunodeficiency, plays a key role in angiogenesis and is a prognostic factor in advanced ovarian cancer (AOC). Previously, we showed that low-dose interleukin-2 (IL-2) and 13-cis-retinoic acid (RA) improved the tumor-associated immunodeficiency and decreased VEGF in patients with AOC. Here, we report long term follow-up of a group of patients with platinum-sensitive AOC who were treated with IL-2 and RA. Methods Sixty-five patients with AOC who had a clinical benefit from second line chemotherapy and elevated serum levels of VEGF were entered into the study from 04/98 to 04/05. Therapy consisted of low-dose subcutaneous IL-2 and oral RA, administered on intermittent schedules for up to 5 years. Results A statistically significant improvement in lymphocyte and NK counts and a decrease in VEGF levels were observed with respect to baseline values among the 65 evaluable patients. Five-year progression-free survival and overall survival rate were 29% and 38%, respectively. Conclusions These data show that patients treated with low-dose IL-2 and RA have a statistically significant improvement in their lymphocyte and NK counts, a decrease in VEGF, and seem to have an improved clinical outcome.