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Cibula D.,Gynecologic Oncology Center | Oonk M.H.M.,University of Groningen | Abu-Rustum N.R.,Sloan Kettering Cancer Center
Current Opinion in Obstetrics and Gynecology | Year: 2015

PURPOSE OF REVIEW: To summarize current knowledge and recent advances in sentinel lymph node (SLN) concept in the three most frequent gynecological cancers. RECENT FINDINGS: In cervical cancer, SLN biopsy and ultrastaging has high sensitivity in lymph node staging in patients with bilaterally detected SLN. The presence of micrometastasis is associated with shortened survival. In endometrial cancer, SLN biopsy incorporating an institutional mapping algorithm and ultrastaging has been shown to significantly reduce false-negative rates and increase sensitivity and negative predictive value. SUMMARY: SLN biopsy and ultrastaging is useful in current management of patients with early-stage cervical cancer for multiple reasons, such as the reliable detection of key lymph nodes, identification of micrometastasis and intraoperative triage of patients. Although a complete or selective pelvic and paraaortic lymphadenectomy for adequate staging remains the standard treatment approach in patients with early-stage endometrial cancer, SLN biopsy has been shown to be safe and effective in detecting lymph node metastases. The application of the SLN procedure is safe in patients with early-stage unifocal squamous cell cancer of the vulva (<4 cm) and no suspicious enlarged lymph nodes at imaging. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Oza A.M.,Princess Margaret Cancer Center | Cook A.D.,University College London | Pfisterer J.,Gynecologic Oncology Center | Embleton A.,University College London | And 20 more authors.
The Lancet Oncology | Year: 2015

Background: The ICON7 trial previously reported improved progression-free survival in women with ovarian cancer with the addition of bevacizumab to standard chemotherapy, with the greatest effect in patients at high risk of disease progression. We report the final overall survival results of the trial. Methods: ICON7 was an international, phase 3, open-label, randomised trial undertaken at 263 centres in 11 countries across Europe, Canada, Australia and New Zealand. Eligible adult women with newly diagnosed ovarian cancer that was either high-risk early-stage disease (International Federation of Gynecology and Obstetrics [FIGO] stage I-IIa, grade 3 or clear cell histology) or more advanced disease (FIGO stage IIb-IV), with an Eastern Cooperative Oncology Group performance status of 0-2, were enrolled and randomly assigned in a 1:1 ratio to standard chemotherapy (six 3-weekly cycles of intravenous carboplatin [AUC 5 or 6] and paclitaxel 175 mg/m2 of body surface area) or the same chemotherapy regimen plus bevacizumab 7·5 mg per kg bodyweight intravenously every 3 weeks, given concurrently and continued with up to 12 further 3-weekly cycles of maintenance therapy. Randomisation was done by a minimisation algorithm stratified by FIGO stage, residual disease, interval between surgery and chemotherapy, and Gynecologic Cancer InterGroup group. The primary endpoint was progression-free survival; the study was also powered to detect a difference in overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN91273375. Findings: Between Dec 18, 2006, and Feb 16, 2009, 1528 women were enrolled and randomly assigned to receive chemotherapy (n=764) or chemotherapy plus bevacizumab (n=764). Median follow-up at the end of the trial on March 31, 2013, was 48·9 months (IQR 26·6-56·2), at which point 714 patients had died (352 in the chemotherapy group and 362 in the bevacizumab group). Our results showed evidence of non-proportional hazards, so we used the difference in restricted mean survival time as the primary estimate of effect. No overall survival benefit of bevacizumab was recorded (restricted mean survival time 44·6 months [95% CI 43·2-45·9] in the standard chemotherapy group vs 45·5 months [44·2-46·7] in the bevacizumab group; log-rank p=0·85). In an exploratory analysis of a predefined subgroup of 502 patients with poor prognosis disease, 332 (66%) died (174 in the standard chemotherapy group and 158 in the bevacizumab group), and a significant difference in overall survival was noted between women who received bevacizumab plus chemotherapy and those who received chemotherapy alone (restricted mean survival time 34·5 months [95% CI 32·0-37·0] with standard chemotherapy vs 39·3 months [37·0-41·7] with bevacizumab; log-rank p=0·03). However, in non-high-risk patients, the restricted mean survival time did not differ significantly between the two treatment groups (49·7 months [95% CI 48·3-51·1]) in the standard chemotherapy group vs 48·4 months [47·0-49·9] in the bevacizumab group; p=0·20). An updated analysis of progression-free survival showed no difference between treatment groups. During extended follow-up, one further treatment-related grade 3 event (gastrointestinal fistula in a bevacizumab-treated patient), three grade 2 treatment-related events (cardiac failure, sarcoidosis, and foot fracture, all in bevacizumab-treated patients), and one grade 1 treatment-related event (vaginal haemorrhage, in a patient treated with standard chemotherapy) were reported. Interpretation: Bevacizumab, added to platinum-based chemotherapy, did not increase overall survival in the study population as a whole. However, an overall survival benefit was recorded in poor-prognosis patients, which is concordant with the progression-free survival results from ICON7 and GOG-218, and provides further evidence towards the optimum use of bevacizumab in the treatment of ovarian cancer. Funding: The National Institute for Health Research through the UK National Cancer Research Network, the Medical Research Council, and Roche. © 2015 Oza et al. Open Access article distributed under the terms of CC BY.


PubMed | University of Lyon, University of Oslo, University of Marburg, Gynecologic Oncology Center and 4 more.
Type: Journal Article | Journal: Gynecologic oncology | Year: 2016

Since almost two decades standard 1st-line chemotherapy for advanced ovarian cancer (AOC) has been a platinum/taxane combination. More recently, this general strategy has been challenged because different types of AOC may not benefit homogenously. Low-grade serous ovarian cancer (LGSOC) is one of the candidates in whom efficacy of standard chemotherapy should be revised.This study is an exploratory case control study of the AGO-metadatabase of 4 randomized phase III trials with first-line platinum combination chemotherapy without any targeted therapy. Patients with advanced FIGO IIIBIV low-grade serous ovarian cancer were included and compared with control cases having high-grade serous AOC.Out of 5114 patients in this AGO database 145 (2.8%) had LGSOC and of those thirty-nine (24.1%) had suboptimal debulking with post-operative residual tumor >1cm, thus being eligible for response evaluation. An objective response was observed in only 10 patients and this 23.1% response rate (RR) was significantly lower compared to 90.1% RR in the control cohort of high-grade serous ovarian cancer (HGSOC) (p<0.001). Both, LGSOC and HGSOC patients who underwent complete cytoreduction had significantly better progression free survival (PFS) and overall survival (OS) in comparison to those with residuals after primary surgery, accordingly (p<0.001).Our observation indicates that low-grade serous cancer is not as responsive to platinum-taxane-based chemotherapy as high-grade serous AOC. In contrast, surgical debulking showed a similar impact on outcome in both types of AOC thus indicating different roles for both standard treatment modalities. Systemic treatment of low grade serous AOC urgently warrants further investigations.


PubMed | University Hospital of Tuebingen, Elbland Hospital Meissen Radebeul, University of Cologne, Erlangen University Hospital and 24 more.
Type: | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2016

A tumour-free pathological resection margin of 8mm is considered state-of-the-art. Available evidence is based on heterogeneous cohorts. This study was designed to clarify the relevance of the resection margin for loco-regional control in vulvar cancer.AGO-CaRE-1 is a large retrospective study. Patients (n=1618) with vulvar cancerFIGO stage IB treated at 29 German gynecologic-cancer-centres 1998-2008 were included. This subgroup analysis focuses on solely surgically treated node-negative patients with complete tumour resection (n=289).Of the 289 analysed patients, 141 (48.8%) had pT1b, 140 (48.4%) pT2 and 8 (2.8%) pT3 tumours. One hundred twenty-five (43.3%) underwent complete vulvectomy, 127 (43.9%) partial vulvectomy and 37 (12.8%) radical local excision. The median minimal resection margin was 5mm (1mm-33mm); all patients received groin staging, in 86.5% with full dissection. Median follow-up was 35.1 months. 46 (15.9%) patients developed recurrence, thereof 34 (11.8%) at the vulva, after a median of 18.3 months. Vulvar recurrence rates were 12.6% in patients with a margin <8mm and 10.2% in patients with a margin 8mm. When analysed as a continuous variable, the margin distance had no statistically significant impact on local recurrence (HR per mm increase: 0.930, 95% CI: 0.849-1.020; p=0.125). Multivariate analyses did also not reveal a significant association between the margin and local recurrence neither when analysed as continuous variable nor categorically based on the 8mm cutoff. Results were consistent when looking at disease-free-survival and time-to-recurrence at any site (HR per mm increase: 0.949, 95% CI: 0.864-1.041; p=0.267).The need for a minimal margin of 8mm could not be confirmed in the large and homogeneous node-negative cohort of the AGO-CaRE database.


PubMed | Albert Ludwigs University of Freiburg, University of Marburg, Gynecologic Oncology Center, Ludwig Maximilians University of Munich and 2 more.
Type: | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2016

We evaluated in a large study meta-database of prospectively randomised phase III trials the prognostic factors for progression-free survival (PFS) and overall survival (OS) in patients < and >40 years of age with advanced epithelial ovarian cancer.A total of 5055 patients of the AGO, GINECO, NSGO intergroup studies AGO-OVAR 3, 5, 7 and 9 were merged to identify 294 patients <40 years and 4761 patients 40 years. We conducted survival analyses and Cox proportional hazard regression models and additionally analysed a very homogeneous subcohort of 405 patients with serous epithelial ovarian cancer, excellent performance status, who had received complete macroscopic upfront cytoreduction and 5 chemotherapy cycles.For patients <40 years, the median PFS was 28.9 months and the median OS was 75.3 months, while the median PFS for patients 40 years was 18.1 months and the median OS was 45.7 months. Independent prognostic factors were similar in both age groups. In a multivariate analysis including prognostic factors potentially leading to confounding, young age appeared to improve PFS (hazard ratio [HR], 0.86; 95% confidence interval [CI]: 0.72-1.03) and OS (HR, 0.73; 95% CI: 0.59-0.91). The observed effect was even stronger in the subcohort of optimally treated patients with SEOC: PFS (HR, 0.34; 95% CI: 0.19-0.59) and OS (HR, 0.23; 95% CI: 0.09-0.56).Prognostic factors were similar in both age groups. Young age appeared a strong independent protective prognostic factor for PFS and OS in the subcohort.


PubMed | Elbland Hospital Meissen Radebeul, University of Cologne, Alb Fils Kliniken, Jerusalem Hospital and 21 more.
Type: | Journal: Annals of surgical oncology | Year: 2016

Analyzing the large patient cohort of the multicenter AGO-CaRE-1 study, we compared isolated sentinel lymph node dissection (SLND) with radical lymph node dissection (LND) of the groin in relation to recurrence rates and survival.The AGO-CaRE-1 study retrospectively collected data on treatment patterns and follow-up of vulvar cancer patients [International Federation of Gynecology and Obstetrics (FIGO) stage 1B] treated at 29 gynecologic cancer centers between 1998 and 2008. This subgroup analysis evaluated the influence of SLND alone on progression-free survival (PFS) and overall survival (OS).In 487 (63.1%) of 772 included patients with tumors smaller than 4cm, an LND was performed and no metastatic lymph nodes were detected (LN0). Another 69/772 (8.9%) women underwent SLND alone, showing a negative SLN (SLN0). Tumors in the LN0 group were larger and showed a deeper invasion (LN0 vs. SLN0 tumor diameter: 20.0 vs. 13.0mm, p<0.001; depth of invasion: 4.0 vs. 3.0mm, p=0.002). After a median follow-up of 33months (0-156), no significant differences in relation to isolated groin recurrence rates (SLN0 3.0% vs. LN0 3.4%, p=0.845) were detected. Similarly, univariate 3-year PFS analysis showed no significant differences between both groups (SLN0 82.7% vs. LN0 77.6%, p=0.230). A multivariate Cox regression analysis, including tumor diameter, depth of invasion, age, grading, and lymphovascular space invasion was performed: PFS [hazard ratio (HR) 0.970, 95% confidence interval (CI) 0.517-1.821] and OS (HR 0.695, 95% CI 0.261-1.849) did not differ significantly between both cohorts.This subgroup analysis of the large AGO-CaRE-1 study showed similar results for groin LND and SLND alone with regard to recurrence rates and survival in node-negative patients with tumors <4cm.


PubMed | Gynecologic Oncology Center, Coordinating Center for Clinical Trials, Jan Kochanowski University, University of Duisburg - Essen and 21 more.
Type: Clinical Trial, Phase III | Journal: The Lancet. Oncology | Year: 2016

Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer.In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB-IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m(2)) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2-21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118.Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (172 months [95% CI 166-199] vs 166 months [139-191]; hazard ratio 084 [95% CI 072-098]; p=0024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [<1%] grade 4 vs placebo group nine [2%] of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 [20%] grade 3 and 200 (22%) grade 4 vs placebo group 90 [20%] grade 3 and 72 [16%] grade 4; thrombocytopenia: 105 [12%] and 55 [6%] vs 21 [5%] and eight [2%]; anaemia: 108 [12%] and 13 [1%] vs 26 [6%] and five [1%]). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown).Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability.Boehringer Ingelheim.


Heitz F.,Kliniken Essen Mitte | Du Bois A.,Kliniken Essen Mitte | Harter P.,Kliniken Essen Mitte | Lubbe D.,University of Marburg | And 4 more authors.
Gynecologic Oncology | Year: 2013

Objective Retrospective analyses suggest that the treatment with beta blocker improves survival in patients with breast cancer and melanoma. The aim of this study was to investigate the impact of medication with beta blocker in patients with recurrent ovarian cancer. Methods Included patients received treatment within two prospective clinical trials: AGO-OVAR 2.4 phase I trial (carboplatin/gemcitabine; N = 25, protocol AGO-OVAR 2.4) and AGO led intergroup phase III trial (carboplatin vs carboplatin/gemcitabine; N = 356, protocol AGO-OVAR 2.5, EORTC-GCG, NCIC CTG). Concurrent medication was documented after every cycle and thorough monitoring was conducted. Results During the studies 38 patients (9.97%) received a beta blocker as co-medication. Patients treated with beta blockers were significantly older than patients not treated with beta blockers. Response rates to chemotherapy were not different between patients treated with beta blockers and those who were not. After a median follow-up of 17 months, 349 (91.6%) patients had progressive disease and 267 (70.1%) patients had died. No difference in median progression-free survival (7.79 vs 7.62 months (p = 0.95)) and overall survival (21.2 vs 17.3 months (p = 0.18)) was recorded for patients treated with and without beta blocker. In multivariate analyses including age, platinum free-interval, study treatment and ECOG performance status beta blocker treatment was not associated with a significant impact on progression-free survival (HR: 0.92; 95% CI: 0.65-1.31; p = 0.65) and overall survival (HR:0.74; 95%CI: 0.49-1.11; p = 0.15). Conclusions In this series of recurrent platinum-sensitive ovarian cancer patients it could not be confirmed whether beta blocker treatment was associated with better or worse outcome. © 2013 Elsevier Inc.


Matsuo K.,University of Southern California | Matsuo K.,Norris Comprehensive Cancer Center | Sheridan T.B.,Mercy Medical Center | Mabuchi S.,Osaka University | And 9 more authors.
Gynecologic Oncology | Year: 2014

Objective Recent studies have demonstrated that lymphovascular space invasion (LVSI) is associated with increased risk of hematogenous and lymphatic metastasis and poor clinical outcome of women with epithelial ovarian cancer. Given the suspected role of estrogen in promoting ovarian cancer metastasis, we examined potential links between estrogen receptor and LVSI in high-grade serous ovarian carcinoma. Methods Tumoral expression of ER, PR, p53, MDR1, EGFR, HER2, DNA ploidy, and S-phase fraction was examined for 121 cases of stage I-IV high-grade serous ovarian carcinoma samples obtained at primary cytoreductive surgery. Biomarker expression was correlated to LVSI and survival outcomes. Results LVSI was observed in 101 (83.5%) of all cases. Immunohistochemistry of tested biomarkers showed ER (86.7%) to be the most commonly expressed followed by p53 (71.4%), HER2 (68.3%), EGFR (52.1%), MDR-1 (14.3%), and PR (8.9%). ER expression was positively correlated to PR expression (r = 0.31, p = 0.001). LVSI was only correlated with ER (odds ratio 6.27, 95%CI 1.93-20.4, p = 0.002) but not with other biomarkers. In multivariate analysis, ER remained significantly associated with LVSI (p = 0.039). LVSI remained a significant prognostic factor for decreased progression-free survival (HR 3.01, 95%CI 1.54-5.88, p = 0.001) and overall survival (HR 2.69, 95%CI 1.18-6.23, p = 0.021) while ER-expression did not remain as a significant variable in multivariate analysis. Conclusion Our data demonstrated that estrogen receptor was positively correlated with LVSI that was an independent prognostic indicator of poor survival outcomes of high-grade serous ovarian carcinoma. This study emphasizes the importance of estrogen pathway in promoting lymphatic or vascular spread of high-grade serous ovarian carcinoma. © 2014 Elsevier Inc.


Watkins J.L.,University of Houston | Thaker P.H.,University of Washington | Nick A.M.,University of Houston | Ramondetta L.M.,University of Houston | And 8 more authors.
Cancer | Year: 2015

BACKGROUND Preclinical evidence has suggested that sustained adrenergic activation can promote ovarian cancer growth and metastasis. The authors examined the impact of beta-adrenergic blockade on the clinical outcome of women with epithelial ovarian, primary peritoneal, or fallopian tube cancers (collectively, epithelial ovarian cancer [EOC]). METHODS A multicenter review of 1425 women with histopathologically confirmed EOC was performed. Comparisons were made between patients with documented beta-blocker use during chemotherapy and those without beta-blocker use. RESULTS The median age of patients in the current study was 63 years (range, 21-93 years). The sample included 269 patients who received beta-blockers. Of those, 193 (71.7%) were receiving beta-1-adrenergic receptor selective agents, and the remaining patients were receiving nonselective beta antagonists. The primary indication for beta-blocker use was hypertension but also included arrhythmia and postmyocardial infarction management. For patients receiving any beta-blocker, the median overall survival (OS) was 47.8 months versus 42 months for nonusers (P =.04). The median OS based on beta-blocker receptor selectivity was 94.9 months for those receiving nonselective beta-blockers versus 38 months for those receiving beta-1-adrenergic receptor selective agents (P<.001). Hypertension was associated with decreased OS compared with no hypertension across all groups. However, even among patients with hypertension, a longer median OS was observed among users of a nonselective beta-blocker compared with nonusers (38.2 months vs 90 months; P<.001). CONCLUSIONS Use of nonselective beta-blockers in patients with EOC was associated with longer OS. These findings may have implications for new therapeutic approaches. © 2015 American Cancer Society.

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