Randomized phase II BGOG/ENGOT-cx1 study of paclitaxel-carboplatin with or without nintedanib in first-line recurrent or advanced cervical cancer.

OBJECTIVE: Nintedanib is an oral tyrosine kinase inhibitor targeting, among others, vascular endothelial growth factor receptor. The aim was to establish the role of nintedanib in addition to paclitaxel and carboplatin in first-line recurrent/metastatic cervical cancer. METHODS: Double-blind phase II randomized study in patients with first-line recurrent or primary advanced (FIGO stage IVB) cervical cancer. Patients received carboplatin-paclitaxel with oral nintedanib 200 mg BID/placebo. The primary endpoint was progression-free survival (PFS) at 1.5 years and α = 0.15, ß = 80%, one sided. RESULTS: 120 patients (62 N, 58C) were randomized. Median follow-up was 35 months. Baseline characteristics were similar in both groups (total population: squamous cell carcinoma 62%, prior radiotherapy 64%, primary advanced 25%, recurrent 75%). The primary endpoint was met with a PFS at 1.5 years of 15.1% versus 12.8% in favor of the nintedanib arm (p = 0.057). Median overall survival (OS) was 21.7 and 16.4 months for N and C, respectively. Confirmed RECIST response rate was 48% for N and 39% for C. No new adverse events were noted for N. However, N was associated with numerically more serious adverse events for anemia and febrile neutropenia. Global health status during and at the end of the study was similar in both arms. CONCLUSION: The study met its primary endpoint with a prolonged PFS in the N arm. No new safety signals were observed.

Analysis of 108 patients with endometrial carcinoma using the PROMISE classification and additional genetic analyses for MMR-D.

OBJECTIVES: To apply the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) to a consecutive series of endometrial cancer (EC) patients diagnosed at a tertiary referral center and assign EC specimens to one of four molecular subgroups using immunohistochemistry (IHC) for p53/mismatch repair protein expression and sequencing for Polymerase Epsilon Exonuclease Domain Mutations (POLE-EDM). Mismatch Repair Deficient (MMR-D) cases were more thoroughly investigated to identify underlying somatic or germline genetic defects. METHODS: Hundred-and eight consecutive endometrial cancer patients, diagnosed between March 2017 and April 2019, were subjected to immunohistochemical and molecular analysis, according to ProMisE. IHC for p53 and the mismatch repair proteins (MLH1, PMS2, MSH6 and PMS2) was performed. All patients were also tested for POLE-EDM by Sanger sequencing. In addition, tumor and corresponding normal tissue of cases with abnormal MMR IHC were tested by PCR for microsatellite instability (MSI) (MSI analysis system, Promega). Hypermethylation of MLH1 promotor was tested with (methylation specific) multiplex ligation dependent probe amplification. MMR-D cases were subjected to germline mutation analysis of the mismatch repair genes, using next generation sequencing on MiSeq (Illumina) with the BRCA Hereditary Cancer MASTR Plus, (Multiplicom/Agilent), RNA mutation analysis and MLPA. RESULTS: FIGO classification was stage IA (n = 54), IB (n = 22) II(n = 8), III(n = 18) and IV(n = 6). Of the 33 patients with MMR-D on IHC (31%), 26 showed MLH1 promotor hypermethylation as the probable cause of MMR-D. The remaining 7 patients without MLH1 promotor hypermethylation were referred for germline analysis of Lynch syndrome. Six patients carried a pathogenic germline mutation in one of the mismatch repair genes: MSH6(n = 3), PMS2(n = 1), MLH1(n = 1) and MSH2 (n = 1). Pathogenic POLE-EDM were identified in 7 (6%) patients. Multiple molecular features (POLE-EDM + MMR-D or POLE-EDM + p53 abnormal) were observed in 4 patients (4%). A high concordance between MMR-D and microsatellite instability was observed in our cohort. In cases of a genetic defect in the MMR genes, we do note a large proportion of cases exhibiting microsatellite instability. On the contrary a hypermutation state, as seen in POLE EDM, does not result in accompanied phenotypic changes in MSI status. CONCLUSION: The ProMisE classification proved to be an efficient and easily implementable system. Future research should elucidate the precise biological and prognostic meaning of the cases with multiple molecular markers.

Assessment of protein biomarkers for preoperative differential diagnosis between benign and malignant ovarian tumors.

OBJECTIVE: To estimate the diagnostic value of tumor and immune related proteins in the discrimination between benign and malignant adnexal masses, and between different subgroups of tumors. METHODS: In this exploratory diagnostic study, 254 patients with an adnexal mass scheduled for surgery were consecutively enrolled at the University Hospitals Leuven (128 benign, 42 borderline, 22 stage I, 55 stage II-IV, and 7 secondary metastatic tumors). The quantification of 33 serum proteins was done preoperatively, using multiplex high throughput immunoassays (Luminex) and electrochemiluminescence immuno-assay (ECLIA). We calculated univariable areas under the Receiver Operating Characteristic Curves (AUCs). To discriminate malignant from benign tumors, multivariable ridge logistic regression with backward elimination was performed, using bootstrapping to validate the resulting AUCs. RESULTS: CA125 had the highest univariable AUC to discriminate malignant from benign tumors (0.85, 95% confidence interval 0.79-0.89). Combining CA125 with CA72.4 and HE4 increased the AUC to 0.87. For benign vs borderline tumors, CA125 had the highest univariable AUC (0.74). For borderline vs stage I malignancy, no proteins were promising. For stage I vs II-IV malignancy, CA125, HE4, CA72.4, CA15.3 and LAP had univariable AUCs ≥0.80. CONCLUSIONS: The results confirm the dominant role of CA125 for identifying malignancy, and suggest that other markers (HE4, CA72.4, CA15.3 and LAP) may help to distinguish between stage I and stage II-IV malignancies. However, further research is needed, also to investigate the added value over clinical and ultrasound predictors of malignancy, focusing on the differentiation between subtypes of malignancy.

Assessment of parametrial invasion of cervical carcinoma, the role of T2-weighted MRI and diffusion weighted imaging with or without fusion.

AIM: To evaluate the diagnostic performance of diffusion-weighted imaging (DWI), with and without fusion images, in addition to regular T2-weighted (T2W) sequences for assessment of parametrial invasion. MATERIALS AND METHODS: This prospective cohort included cervical cancer patients who underwent preoperative magnetic resonance imaging (MRI) with T2W and axial DWI sequences prior to radical hysterectomy. Retrospectively, two radiologists independently and blindly scored the likelihood of parametrial invasion by means of a six-point confidence scale. Parametrial invasion was determined by surgical-pathological results. Performance indices for diagnostic tests and area under the receiver operating characteristic curve (AUC) analyses were performed. P-Values of <0.05 were considered statistical significant. Ethical board approval was obtained. RESULTS: Of 65 included patients, parametrial invasion was found in eight patients. A statistically significant increase in diagnostic performance for the assessment of parametrial invasion was found when T2W MRI was fused with DWI (fusion T2W/DWI), especially decreasing false-positive findings: the positive predictive value of parametrial invasion using T2W MRI versus fusion T2W MRI/DWI increased from 29% to 50% for observer 1 and from 23% to 50% for observer 2 (AUC=0.80-0.67 versus 0.94-0.94). CONCLUSIONS: Fusion T2W MRI/DWI shows a significant increase in diagnostic performance for the assessment of parametrial invasion in early-stage cervical carcinoma.

Preliminary stop of the TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC) trial.

The "TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia" (TOPIC) trial was stopped preliminary, due to lagging inclusions. This study aimed to evaluate the treatment efficacy and clinical applicability of imiquimod 5% cream in high-grade cervical intraepithelial neoplasia (CIN). The lagging inclusions were mainly due to a strong patient preference for either of the two treatment modalities. This prompted us to initiate a new study on the same subject, with a non-randomized, open-label design: the 'TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC)-3' study. Original TOPIC-trial: Medical Ethics Committee approval number METC13231; ClinicalTrials.gov Identifier: NCT02329171, 22 December 2014. TOPIC-3 study: Medical Ethics Committee approval number METC162025; ClinicalTrials.gov Identifier: NCT02917746, 16 September 2016.

Estimating risk of malignancy in adnexal masses: external validation of the ADNEX model and comparison with other frequently used ultrasound methods.

OBJECTIVES: To validate externally the performance of the Assessment of Different NEoplasias in the adneXa (ADNEX) model and compare this model with other frequently used models in the differentiation between benign and malignant adnexal masses. METHODS: In this retrospective diagnostic accuracy study, we assessed data collected prospectively from patients with adnexal pathology who underwent real-time transvaginal or transrectal ultrasound by a single expert ultrasonographer in a tertiary care hospital between July 2011 and July 2015. The presence of a malignancy was determined by subjective assessment and use of four prediction models: the ADNEX model, simple ultrasound-based rules (simple rules), Logistic Regression model 2 (LR2) and the Risk of Malignancy Index (RMI), of which three different variants were assessed. Pathology was the clinical reference standard. RESULTS: In total, 851 consecutive patients underwent ultrasound examination for an adnexal mass. For 326 patients (128 premenopausal and 198 postmenopausal), pathology results were available (211 (64.7%) benign; 115 (35.3%) malignant) and these were included in the analysis. The area under the receiver-operating characteristics curve (AUC) of the ADNEX model for the discrimination between benign and malignant tumors was 0.93 (95% CI, 0.89-0.95). AUCs for the subtypes of malignancy (i.e. borderline, Stage I-IV and metastatic adnexal tumors) ranged between 0.60 and 0.90. Only subjective assessment (AUC, 0.96 (95% CI, 0.93-0.98)) was superior to the ADNEX model (P = 0.01) in differentiating malignant from benign tumors. AUCs for the other models were 0.92 (95% CI, 0.89-0.95) for LR2, 0.85 (95% CI, 0.81-0.89) for RMI-I, 0.82 (95% CI, 0.77-0.86) for RMI-II and 0.84 (95% CI, 0.80-0.88) for RMI-III. At the proposed cut-off of ≥ 10%, the ADNEX model had the highest sensitivity (0.98 (95% CI, 0.93-1.00)) but the lowest specificity (0.62 (95% CI, 0.55-0.68)) compared with the other models. Both subjective assessment (sensitivity, 0.90 (95% CI, 0.83-0.95); specificity 0.91 (95% CI, 0.86-0.94)) and the simple rules model with inconclusive cases classified by subjective assessment (sensitivity, 0.89 (95% CI, 0.81-0.94); specificity, 0.90 (95% CI, 0.85-0.94)) had lower sensitivity, but their sensitivity and specificity were better balanced. CONCLUSIONS: Although the test performance of subjective assessment by an expert remains superior, the ADNEX model can help in the differentiation between benign and malignant ovarian tumors. The advantage of the ADNEX model as a polytomous model remains to be shown. © 2016 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC trial): study protocol for a randomized controlled trial.

BACKGROUND: Cervical intraepithelial neoplasia (CIN) is the premalignant condition of cervical cancer. Whereas not all high grade CIN lesions progress to cervical cancer, the natural history and risk of progression of individual lesions remain unpredictable. Therefore, high-grade CIN is currently treated by surgical excision: large loop excision of the transformation zone (LLETZ). This procedure has potential complications, such as acute haemorrhage, prolonged bleeding, infection and preterm birth in subsequent pregnancies. These complications could be prevented by development of a non-invasive treatment modality, such as topical imiquimod treatment. The primary study objective is to investigate the efficacy of topical imiquimod 5% cream for the treatment of high-grade CIN and to develop a biomarker profile to predict clinical response to imiquimod treatment. Secondary study objectives are to assess treatment side-effects, disease recurrence and quality of life during and after different treatment modalities. METHODS/DESIGN: The study design is a randomized controlled trial. One hundred forty women with a histological diagnosis of high-grade CIN (CIN 2-3) will be randomized into two arms: imiquimod treatment during 16 weeks (experimental arm) or immediate LLETZ (standard care arm). Treatment efficacy will be evaluated by colposcopy with diagnostic biopsies at 20 weeks for the experimental arm. Successful imiquimod treatment is defined as regression to CIN 1 or less, successful LLETZ treatment is defined as PAP 1 after 6 months. Disease recurrence will be evaluated by cytology at 6, 12 and 24 months after treatment. Side-effects will be evaluated using a standardized report form. Quality of life will be evaluated using validated questionnaires at baseline, 20 weeks and 1 year after treatment. Biomarkers, reflecting both host and viral factors in the pathophysiology of CIN, will be tested at baseline with the aim of developing a predictive biomarker profile for the clinical response to imiquimod treatment. DISCUSSION: Treatment of high-grade CIN lesions with imiquimod in a selected patient population may diminish complications as a result of surgical intervention. More knowledge on treatment efficacy, side effects and long-term recurrence rates after treatment is necessary. TRIAL REGISTRATION: EU Clinical Trials Register EU-CTR2013-001260-34 . Registered 18 March 2013. Medical Ethical Committee approval number: NL44336.068.13 (Medical Ethical Committee Maastricht University Hospital, University of Maastricht). Affiliation: Maastricht University Hospital. Registration number ClinicalTrials.gov: NCT02329171.

External validation of three prognostic models for overall survival in patients with advanced-stage epithelial ovarian cancer.

BACKGROUND: For various malignancies, prognostic models have shown to be superior to traditional staging systems in predicting overall survival. The purpose of this study was to validate and compare the performance of three prognostic models for overall survival in patients with advanced-stage epithelial ovarian cancer. METHODS: A multi-institutional epithelial ovarian cancer database was used to identify patients and to evaluate the predictive performance of two nomograms, a prognostic index and FIGO (International Federation of Obstetrics and Gynecology) stage. All patients were treated for advanced-stage epithelial ovarian cancer between January 1996 and January 2009 in 11 hospitals in the eastern part of The Netherlands. RESULTS: In total, 542 patients were found to be eligible. Overall performance did not differ between the three prognostic models and FIGO stage. The discriminative performance for Chi's model was moderately good (c indices 0.65 and 0.68) and for the models of Gerestein and Teramukai reasonable (c indices between 0.60 and 0.62). The c indices of FIGO stage ranged between 0.54 and 0.62. After recalibration, the three models showed almost perfect calibration, whereas calibration of FIGO stage was reasonable. CONCLUSION: The three prediction models showed general applicability and a reasonably well-predictive performance, especially in comparison to FIGO stage. To date, there are no studies available that analyse the impact of these prognostic models on decision-making and patient outcome. Therefore, the usefulness of these models in daily clinical practice remains to be investigated.

Lymph-node metastasis in stage I and II sex cord stromal and malignant germ cell tumours of the ovary: a systematic review.

OBJECTIVES: The aim of this systematic review is to determine the incidence of lymph-node metastasis in clinical stage I and II sex cord stromal tumours and germ cell tumours of the ovary. METHODS: Relevant articles were identified from MEDLINE and EMBASE and supplemented with citations from the reference lists of the primary studies. Eligibility was determined by two authors. Included studies were prospective or retrospective cohort and cross-sectional studies analysing at least ten patients with clinical early-stage non-epithelial ovarian cancer who underwent lymphadenectomy or lymph-node sampling as part of a staging laparotomy. RESULTS: For sex cord stromal tumours, five articles including 578 patients were analysed and lymph-node metastasis was not detected in the 86 patients who underwent lymph-node removal. The median number of removed lymph nodes was 13 (range 9-29). For malignant germ cell tumours, three articles were eligible including 2436 patients of whom 946 patients underwent lymph-node resection. The mean number of removed nodes was 10 (range 2-14) with a mean incidence of lymph-node metastasis of 10.9% (range 10.5-11.8%). CONCLUSIONS: The incidence of lymph-node metastasis in patients with clinical stage I and II sex cord stromal tumours is low, whereas the incidence in patients with clinical stage I-II germ cell tumours is considerable, although limited data are available.

Mucinous borderline tumours of the ovary and the appendix: a retrospective study and overview of the literature.

OBJECTIVES: Appendectomy is often recommended in patients with mucinous borderline ovarian tumours (mBOTs) based on studies suggesting that metastatic disease from a primary appendiceal tumour can mimic mBOT. The present study assessed the incidence of mucinous neoplasms in the appendix associated with the presence of mBOT. METHODS: A retrospective cohort study was performed in two university hospitals in the Netherlands between 1990 and 2011. All patients with mBOT and/or a mucinous appendiceal tumour were included. RESULTS: Of 127 patients included, 98 had a primary mBOT and 29 had a primary mucinous appendiceal tumour. In patients with a mBOT, the appendix was either removed at prior surgery (4%), resected as part of the staging procedure showing no pathological abnormalities (13%), described as normal and not resected (58%), or not described and not resected (25%). During a median follow-up period of 5 years (range 2-23), two patients developed a recurrence in which the appendix was not involved. In all patients with a primary mucinous tumour of the appendix, the appendix appeared abnormal at the time of surgery. Eight of these patients (28%) were diagnosed with invasive ovarian metastases. A review of the literature including the cases from this study identified 510 mucinous ovarian tumours with borderline features and 214 associated appendectomies, of which 4 (1.9%) contained a primary appendiceal malignancy. CONCLUSIONS: A thorough inspection of the appendix should be performed in patients with a mucinous ovarian tumour with borderline features. An appendectomy should only be performed when the appendix is macroscopically abnormal.

Are serum HE4 or ROMA scores useful to experienced examiners for improving characterization of adnexal masses after transvaginal ultrasonography?

OBJECTIVE: To determine whether serum human-epididymis protein-4 (HE4) levels or Risk of Ovarian Malignancy Algorithm (ROMA) scores are useful second-stage tests for tumors thought to be difficult to characterize as benign or malignant on the basis of ultrasound findings by experienced examiners, and to investigate whether adding information on serum HE4 levels or ROMA scores to ultrasound findings improves diagnostic performance. METHODS: This was a prospective cross-sectional diagnostic accuracy study conducted in a tertiary referral center that enrolled consecutive women with a known adnexal mass scheduled for surgery. Experienced level III examiners classified each mass as certainly or probably benign, difficult to classify, or probably or certainly malignant after preoperative ultrasound examination. Serum HE4 and CA 125 levels were measured before surgery. RESULTS: The final database comprised 360 women, of whom 216 (60%) had benign and 144 (40%) had malignant disease. Examiners were highly confident in 196 cases (54%), moderately confident in 135 (38%) and completely uncertain about their diagnosis in 29 (8%) cases. With a sensitivity of 67% and specificity of 70%, subjective assessment outperformed HE4 and ROMA in the subgroup of difficult tumors. Both tests had low discriminatory capacity with poor areas under the receiver-operating characteristics curve of 0.536 (95% CI, 0.302-0.771) and 0.565 (95% CI, 0.294-0.836), respectively. A strategy that incorporates sequential testing of serum HE4 or ROMA scores after transvaginal ultrasonography resulted in a deterioration in overall test performance. CONCLUSION: Measurement of serum HE4 or calculating scores using the ROMA as secondary tests does not seem useful for classifying adnexal tumors after subjective assessment with transvaginal ultrasonography.

Preoperative HE4 expression in plasma predicts surgical outcome in primary ovarian cancer patients: results from the OVCAD study.

OBJECTIVES: Epithelial ovarian cancer (EOC) is the major cause of death due to gynecological malignancies. The most important prognostic factors are residual tumor mass after surgery and platinum-response. No predictive biomarkers are available to identify patients who will benefit from standard treatment. The aim of our study was to analyze the role of HE4 in predicting surgical and clinical outcome in primary EOC. METHODS: In the European multicentric project "OVCAD", 275 consecutive patients with primary EOC were enrolled. Patients were eligible if radical cytoreductive surgery was performed and platinum-based chemotherapy was applied. Plasma and ascites samples were collected before or during surgery. The concentrations of HE4 and CA125 was determined using ELISA and Luminex technique, respectively. RESULTS: Median age at first diagnosis was 58 years (range 18-85 years). Most patients presented with advanced stage disease, FIGO III or IV (94.6%), grades II-III (96%) and serous histology (86.2%). In most cases a complete cytoreduction to no residual tumor mass was achieved (68.4%). Higher plasma HE4 levels correlated with poor surgery outcome in terms of macroscopically residual tumor mass (p<0.001) and platinum-resistance (p=0.009). Plasma CA125 and the risk index (HE4 and CA125) were independent predictive factors for surgical outcome (p=0.001, OR=3.37, 95% CI=1.61-7.06 and p<0.001, OR=6,041, 95% CI=2.33-15.65, respectively). FIGO stage III was an independent predictive factor for platinum response (p=0.039, OR=0.436, 95% CI=0.198-0.960). CONCLUSIONS: The presented data are showing that the combination of HE4 and CA125 expression in plasma might predict the surgical outcome in EOC and by this may have a prognostic impact on PFS and OS.

The time interval from surgery to start of chemotherapy significantly impacts prognosis in patients with advanced serous ovarian carcinoma - analysis of patient data in the prospective OVCAD study.

OBJECTIVE: Cytoreductive surgery and platinum-based systemic therapy constitute the standard treatment of patients with advanced ovarian cancer. The aim of the present study was to evaluate whether the time interval from surgery to start of chemotherapy has an impact on clinical outcome. METHODS: Data of 191 patients with advanced serous (FIGO III-IV) ovarian cancer from the prospective multicenter study OVCAD (OVarian CAncer Diagnosis) were analyzed. All patients underwent primary surgery followed by platinum-based chemotherapy. RESULTS: The 25%, 50%, and 75% quartiles of intervals from surgery to start of chemotherapy were 22, 28, and 38 days, respectively (range, 4-158 days). Preoperative performance status (P<0.001), extent of surgery (P<0.001), and perioperative complications (P<0.001) correlated with intervals from surgery to initiation of chemotherapy. Timing of cytotoxic treatment [≤ 28 days versus >28 days; hazard ratio (HR) 1.73 (95% confidence interval 1.08-2.78), P=0.022], residual disease [HR 2.95 (95% confidence interval 1.87-4.67), P<0.001], and FIGO stage [HR 2.26 (95% confidence interval 1.41-3.64), P=0.001] were significant prognostic factors for overall survival in multivariate analysis. While the interval from surgery to start of chemotherapy did not possess prognostic significance in patients without postoperative residual disease (n=121), it significantly correlated with overall survival in patients with postoperative residual disease [n=70, HR 2.24 (95% confidence interval 1.08-4.66), P=0.031]. CONCLUSION: Our findings suggest that delayed initiation of chemotherapy might compromise overall survival in patients with advanced serous ovarian cancer, especially when suboptimally debulked.

The value of imaging of the lungs in the diagnostic workup of patients with endometrial cancer.

OBJECTIVE: Imaging of the lungs is part of the routine diagnostic workup of patients with endometrial cancer. The present study aimed to determine the incidence of lung metastases in patients with endometrial cancer and to evaluate the clinical relevance of preoperative chest imaging in this population. METHODS: A retrospective cross-sectional study was performed in four regional and one university hospital in the southeastern part of the Netherlands. A total of 784 patients with epithelial endometrial cancer diagnosed between 2002 and 2010 in five hospitals were included. Patients were followed up for at least 1 year. RESULTS: Of 784 patients, 541 (69.0%) underwent thoracic imaging and 11 showed findings suspicious for metastases perioperatively or during the 1-year follow-up period. In eight patients, the thoracic metastases were related to their endometrial cancer, resulting in an overall incidence of 1.0% (8/784, 95% CI=0.3-1.7%). These eight patients had high-risk subtypes of endometrial cancer (serous, clear cell or poorly differentiated endometrioid), and the incidence was 4.1% (8/193, 95% CI=1.9-8.3%) for these subtypes. Lung metastases were not detected in any of the patients with low-risk subtypes of endometrial cancer (n=566) at the time of diagnosis (95% CI=0-0.8%). CONCLUSIONS: The probability of detecting thoracic metastases during the diagnostic workup of patients with endometrial cancer is low. The present data suggest that thoracic imaging could be omitted from the diagnostic workup of patients with low-risk endometrial cancer.

Incomplete surgical staging in clinical early-stage ovarian cancer: guidelines versus daily practice.

BACKGROUND: Incomplete surgical staging of patients with early-stage epithelial ovarian cancer (EOC) has been reported in up to 98% of cases, when based on the International Federation of Obstetrics and Gynecology (FIGO) staging procedure. The aim of the present retrospective study was to clarify the reasons for incomplete staging. METHODS: The PRISMA (Prevention Recovery Information System for Monitoring and Analysis) technique was used to evaluate cases with FIGO I-IIa EOC based on incomplete staging from five gynecologic oncologic center hospitals in the Netherlands in the period 2010-2014. RESULTS: Fifty cases with an incomplete surgical staging of EOC according to national guidelines were included. The most common reasons for incomplete staging were insufficient random biopsies of the peritoneum (n = 34, 68%), and less than ten lymph nodes being resected and/or found at pathology (n = 16, 32%). The most mentioned reason for not performing biopsies was, besides forgetting to do so, believing that after careful inspection and palpation, taking biopsies is irrelevant and/or already are being taken while performing a hysterectomy (peritoneum of cul-de-sac, bladder). The value of contralateral pelvic lymph node dissection in case of a unilateral ovarian malignancy was also doubted, influencing the number of lymph nodes resected. CONCLUSIONS: The most important reasons for incomplete staging in EOC are, besides omitting elements by accident, questioning the importance of obligatory elements of the staging procedure. A structured list of staging steps during surgery and more evidence-based consensus concerning these obligatory elements might increase the number of complete staging procedures in EOC.

HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm.

BACKGROUND: Recently, a Risk of Ovarian Malignancy Algorithm (ROMA) utilising human epididymis secretory protein 4 (HE4) and CA125 successfully classified patients as presenting a high or low risk for epithelial ovarian cancer (EOC). We validated this algorithm in an independent prospective study. METHODS: Women with a pelvic mass, who were scheduled to have surgery, were enrolled in a prospective study. Preoperative serum levels of HE4 and CA125 were measured in 389 patients. The performance of each of the markers, as well as that of ROMA, was analysed. RESULTS: When all malignant tumours were included, ROMA (receiver operator characteristic (ROC)-area under curve (AUC)=0.898) and HE4 (ROC-AUC)=0.857) did not perform significantly better than CA125 alone (ROC-AUC=0.877). Using a cutoff for ROMA of 12.5% for pre-menopausal patients, the test had a sensitivity of 67.5% and a specificity of 87.9%. With a cutoff of 14.4% for post-menopausal patients, the test had a sensitivity of 90.8% and a specificity of 66.3%. For EOC vs benign disease, the ROC-AUC of ROMA increased to 0.913 and for invasive EOC vs benign disease to 0.957. CONCLUSION: This independent validation study demonstrated similar performance indices to those recently published. However, in this study, HE4 and ROMA did not increase the detection of malignant disease compared with CA125 alone. Although the initial reports were promising, measurement of HE4 serum levels does not contribute to the diagnosis of ovarian cancer.

Lymph node metastasis in stages I and II ovarian cancer: a review.

OBJECTIVES: The purpose of this review is to determine the incidence of lymph node metastases in clinical stages I and II ovarian cancer. METHODS: Relevant articles were identified from MEDLINE and EMBASE, supplemented with citations from reference lists from the primary studies. Eligibility was evaluated by two authors. Included studies were prospective or retrospective cohort studies, which analyzed patients with clinical early stage EOC who underwent a complete pelvic and para-aortic lymphadenectomy as a part of a staging laparotomy. RESULTS: Fourteen studies were included in the analysis. The mean incidence of lymph node metastases in clinical stages I-II EOC was 14.2% (range 6.1-29.6%), of which 7.1% only in the para-aortic region, 2.9% only in the pelvic region, and 4.3% both in the para-aortic and pelvic region. Grade 1 tumors had a mean incidence of lymph node metastases of 4.0%, grade 2 tumors 16.5.8% and grade 3 tumors 20.0%. According to histological subtype, the highest incidence of lymph node metastases was found in the serous subtype (23.3%), the lowest in the mucinous subtype (2.6%). In unilateral tumors, pelvic lymph node metastases were found in 9.7% on both sides, 8.3% only at the ipsilateral side, and in 3.5% only at the contralateral side. CONCLUSIONS: The incidence of lymph node metastases in clinical early stage EOC is considerable. Based on the scarce literature data, omitting a systematic lymphadenectomy can only be considered in grade I mucinous tumors.

Features of durable response and treatment efficacy for capecitabine monotherapy in advanced breast cancer: real-world evidence from a large single-centre cohort.

PURPOSE: In metastatic breast cancer (MBC) population treated with capecitabine monotherapy, we investigated clinical-pathological features as possible biomarkers for the oncological outcome. METHODS: Retrospective study of consecutive MBC patients treated at University Hospitals Leuven starting capecitabine between 1999 and 2017. The primary endpoint was the durable response (DR), defined as non-progressive disease for > 52 weeks. Other main endpoints were objective response rate (ORR), time to progression (TTP) and overall survival (OS). RESULTS: We included 506 patients; mean age at primary breast cancer diagnosis was 51.2 years; 18.2% had de novo MBC; 98.8% were pre-treated with taxanes and/or anthracycline. DR was reached in 11.6%. Patients with DR, as compared to those without DR, were more likely oestrogen receptor (ER) positive (91.5% vs. 76.8%, p = 0.010) at first diagnosis, had a lower incidence of lymph node (LN) involvement (35.6% vs. 49.9%, p = 0.039) before starting capecitabine, were more likely to present with metastases limited to ≤ 2 involved sites (54.2% vs. 38.5%, p = 0.020) and time from metastasis to start of capecitabine was longer (mean 3.5 vs. 2.7 years, p = 0.020). ORR was 22%. Median TTP and OS were 28 and 58 weeks, respectively. In multivariate analysis (only performed for TTP), ER positivity (hazard ratio (HR) = 0.529, p < 0.0001), HER2 negativity (HR = 0.582, p = 0.024), absence of LN (HR = 0.751, p = 0.008) and liver involvement (HR = 0.746, p = 0.013), older age at capecitabine start (HR = 0.925, p < 0.0001) and younger age at diagnosis of MBC (HR = 0.935, p = 0.001) were significant features of longer TTP. CONCLUSION: Our data display relevant clinical-pathological features associated with DR and TTP in patients receiving capecitabine monotherapy for MBC.

Diaphragmatic surgery during primary debulking in 89 patients with stage IIIB-IV epithelial ovarian cancer.

OBJECTIVES: The aim of this study was to describe the role of diaphragmatic surgery in achieving optimal debulking in patients with advanced ovarian cancer and the assessment of the relative post-operative complications. METHODS: Retrospective review was performed of medical records of 89 patients with epithelial ovarian cancer who underwent diaphragmatic surgery during their primary debulking surgery between September 1993 and December 2007. Four different approaches were performed: coagulation (group 1), stripping (group 2), combination stripping with coagulation (group 3) and diaphragm full thickness resection (group 4). Cytoreductive outcome, morbidity, overall survival (OS) and disease-free survival (DFS) were analysed. RESULTS: Eight (8.9%) patients had FIGO stage IIIB, 64 (72%) stage IIIC and 17 (19.1%) stage IV disease. In 20 patients (22%) the diaphragmatic disease was coagulated, in 31 patients (35%) was only stripped, in 31 patients (35%) a combination of these techniques was applied and in 7 (8%) the disease was resected with the adjacent infiltrated part of the diaphragm muscle and the pleura above it. Debulking to no residual tumor was achieved in 90%, 86%, 86% and 100% for groups 1, 2, 3 and 4 respectively. Median DFS was 15, 15, 17 and overall survival OS for groups 1, 2, and 3 was 40, 42, and 50 months respectively and was not yet reached for group 4. Minor and major complications were comparable among the groups. Pleural effusion was the most frequent associated complication and chest tube placement (17%) or thoracocentesis (12%) was necessary for the relief of respiratory distress. The perioperative mortality rate was 0%. The majority of cases were treated in the last five years of our 15-year experience. CONCLUSIONS: Diaphragmatic surgery increases the rates of optimal primary debulking surgery and improves survival with an acceptable and manageable morbidity rate. In patients with thick (>0.3 cm) or large (>4 cm) lesions stripping the diaphragm or full thickness resection of the diaphragmatic muscle is preferred.