Effect of surgical volume on short-term outcomes of cytoreductive surgery for advanced-stage ovarian cancer: A population-based study from the Dutch Gynecological Oncology Audit.

OBJECTIVE: Despite lacking clinical data, the Dutch government is considering increasing the minimum annual surgical volume per center from twenty to fifty cytoreductive surgeries (CRS) for advanced-stage ovarian cancer (OC). This study aims to evaluate whether this increase is warranted. METHODS: This population-based study included all CRS for FIGO-stage IIB-IVB OC registered in eighteen Dutch hospitals between 2019 and 2022. Short-term outcomes included result of CRS, length of stay, severe complications, 30-day mortality, time to adjuvant chemotherapy, and textbook outcome. Patients were stratified by annual volume: low-volume (nine hospitals, <25), medium-volume (four hospitals, 29-37), and high-volume (five hospitals, 54-84). Descriptive statistics and multilevel logistic regressions were used to assess the (case-mix adjusted) associations of surgical volume and outcomes. RESULTS: A total of 1646 interval CRS (iCRS) and 789 primary CRS (pCRS) were included. No associations were found between surgical volume and different outcomes in the iCRS cohort. In the pCRS cohort, high-volume was associated with increased complete CRS rates (aOR 1.9, 95%-CI 1.2-3.1, p = 0.010). Furthermore, high-volume was associated with increased severe complication rates (aOR 2.3, 1.1-4.6, 95%-CI 1.3-4.2, p = 0.022) and prolonged length of stay (aOR 2.3, 95%-CI 1.3-4.2, p = 0.005). 30-day mortality, time to adjuvant chemotherapy, and textbook outcome were not associated with surgical volume in the pCRS cohort. Subgroup analyses (FIGO-stage IIIC-IVB) showed similar results. Various case-mix factors significantly impacted outcomes, warranting case-mix adjustment. CONCLUSIONS: Our analyses do not support further centralization of iCRS for advanced-stage OC. High-volume was associated with higher complete pCRS, suggesting either a more accurate selection in these hospitals or a more aggressive approach. The higher completeness rates were at the expense of higher severe complications and prolonged admissions.

Outcomes of patients with early stage mucinous ovarian carcinoma: a Dutch population-based cohort study comparing expansile and infiltrative subtypes.

OBJECTIVE: This study aimed to assess the outcomes of patients with early stage mucinous ovarian carcinoma based on subtype (expansile vs infiltrative). METHODS: We retrospectively analyzed all surgically treated patients with mucinous ovarian carcinoma in the Netherlands (2015-2020), using data from national registries. Subtypes were determined, with any ambiguities resolved by a dedicated gynecologic pathologist. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage I were categorized into full staging, fertility-sparing, or partial stagings. Outcomes were overall survival and recurrence free survival, and recurrence rates. RESULTS: Among 409 identified patients, 257 (63%) had expansile and 152 (37%) had infiltrative tumors. Patients with expansile tumors had FIGO stage I more frequently (n=243, 95% vs n=116, 76%, p<0.001). For FIGO stage I disease, patients with expansile and infiltrative tumors underwent similar proportions of partial (n=165, 68% vs n=78, 67%), full (n=32, 13% vs n=23, 20%), and fertility-sparing stagings (n=46, 19% vs n=15, 13%) (p=0.139). Patients with expansile FIGO stage I received less adjuvant chemotherapy (n=11, 5% vs n=24, 21%, p<0.001), exhibited better overall and recurrence free survival (p=0.006, p=0.012), and fewer recurrences (n=13, 5% vs n=16, 14%, p=0.011). Survival and recurrence rates were similar across the expansile extent of staging groups. Patients undergoing fertility-sparing staging for infiltrative tumors had more recurrences compared with full or partial stagings, while recurrence free survival was similar across these groups. Full staging correlated with better overall survival in infiltrative FIGO stage I (p=0.022). CONCLUSIONS: While most patients with FIGO stage I underwent partial staging, those with expansile had better outcomes than those with infiltrative tumors. Full staging was associated with improved overall survival in infiltrative, but not in expansile FIGO stage I. These results provide insight for tailored surgical approaches.

Textbook outcome as a composite outcome measure to compare hospital performances regarding cytoreductive surgery for ovarian cancer: A nationwide population-based study.

OBJECTIVE: Textbook outcome (TO) is a composite outcome measure used in surgical oncology to compare hospital outcomes using multiple quality indicators. This study aimed to develop TO as an outcome measure to assess healthcare quality for patients undergoing cytoreductive surgery (CRS) for advanced-stage ovarian cancer. METHODS: This population-based study included all CRS for FIGO IIIC-IVB primary ovarian cancer registered in the Netherlands between 2017 and 2020. The primary outcome was TO, defined as a complete CRS, combined with the absence of 30-day mortality, severe complications, and prolonged length of admission (≥ten days). Delayed start of adjuvant chemotherapy (≥six weeks) was not included in TO because of missing data. Logistic regressions were used to assess the association of case-mix factors with TO. Hospital variation was displayed using funnel plots. RESULTS: A total of 1909 CRS were included, of which 1434 were interval CRS and 475 were primary CRS. TO was achieved in 54% of the interval CRS cohort and 47% of the primary CRS cohort. Macroscopic residual disease after CRS was the most important factor for not achieving TO. Age ≥ 70 was associated with lower TO rates in multivariable logistic regressions. TO rates ranged from 40% to 69% between hospitals in the interval CRS cohort and 22% to 100% in the primary CRS cohort. In both analyses, one hospital had significantly lower TO rates (different hospitals). Case-mix adjustment significantly affected TO rates in the primary CRS analysis. CONCLUSIONS: TO is a suitable composite outcome measure to detect hospital variation in healthcare quality for patients with advanced-stage ovarian cancer undergoing CRS. Case-mix adjustment improves the accuracy of the hospital comparison.

Low probability of disease cure in advanced ovarian carcinomas before the PARP inhibitor era.

BACKGROUND: In ovarian carcinomas, the likelihood of disease cure following first-line medical-surgical treatment has been poorly addressed. The objective was to: (a) assess the likelihood of long-term disease-free (LDF) > 5 years; and (b) evaluate the impact of the tumour primary chemosensitivity (assessed with the modelled CA-125 KELIM) with respect to disease stage, and completeness of debulking surgery. METHODS: Three Phase III trial datasets (AGO-OVAR 9; AGO-OVAR 7; ICON-7) were retrospectively investigated in an "adjuvant dataset", whilst the Netherlands Cancer Registry was used in a "neoadjuvant dataset". The prognostic values of KELIM, disease stage and surgery outcomes regarding the likelihood of LDF were assessed using univariate/multivariate analyses. RESULTS: Of 2029 patients in the "adjuvant dataset", 82 (4.0%) experienced LDF (Stage I-II: 25.9%; III: 2.1%; IV: 0.5%). Multivariate analyses identified disease stage and KELIM (OR = 4.24) as independent prognostic factors. Among the 1452 patients from the "neoadjuvant dataset", 36 (2.4%) had LDF (Stage II-III: 3.3%; IV: 1.3%). Using multivariate tests, high-risk diseases (OR = 0.18) and KELIM (OR = 2.96) were significant. CONCLUSION: The probability of LDF > 5 years after first-line treatment in 3486 patients (<4%) was lower than thought. These data could represent a reference for future studies meant to assess progress related to PARP inhibitors.

Impact of the COVID-19-pandemic on patients with gynecological malignancies undergoing surgery: A Dutch population-based study using data from the 'Dutch Gynecological Oncology Audit'.

OBJECTIVE: The COVID-19-pandemic caused drastic healthcare changes worldwide. To date, the impact of these changes on gynecological cancer healthcare is relatively unknown. This study aimed to assess the impact of the COVID-19-pandemic on surgical gynecological-oncology healthcare. METHODS: This population-based cohort study included all surgical procedures with curative intent for gynecological malignancies, registered in the Dutch Gynecological Oncology Audit, in 2018-2020. Four periods were identified based on COVID-19 hospital admission rates: 'Pre-COVID-19', 'First wave', 'Interim period', and 'Second wave'. Surgical volume, perioperative care processes, and postoperative outcomes from 2020 were compared with 2018-2019. RESULTS: A total of 11,488 surgical procedures were analyzed. For cervical cancer, surgical volume decreased by 17.2% in 2020 compared to 2018-2019 (mean 2018-2019: n = 542.5, 2020: n = 449). At nadir (interim period), only 51% of the expected cervical cancer procedures were performed. For ovarian, vulvar, and endometrial cancer, volumes remained stable. Patients with advanced-stage ovarian cancer more frequently received neoadjuvant chemotherapy in 2020 compared to 2018-2019 (67.7% (n = 432) vs. 61.8% (n = 783), p = 0.011). Median time to first treatment was significantly shorter in all four malignancies in 2020. For vulvar and endometrial cancer, the length of hospital stay was significantly shorter in 2020. No significant differences in complicated course and 30-day-mortality were observed. CONCLUSIONS: The COVID-19-pandemic impacted surgical gynecological-oncology healthcare: in 2020, surgical volume for cervical cancer dropped considerably, waiting time was significantly shorter for all malignancies, while neoadjuvant chemotherapy administration for advanced-stage ovarian cancer increased. The safety of perioperative healthcare was not negatively impacted by the pandemic, as complications and 30-day-mortality remained stable.

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.

Evaluation of various apparent diffusion coefficient measurement techniques in pre-operative staging of early cervical carcinoma.

PURPOSE: DW-MRI parameters such as ADC hold the potential for more reliable staging of cervical cancer. We compared 2D region of interest (ROI) measurement techniques to 3D tumor analysis in the evaluation of ADC for cervical cancer. Secondly, we evaluated the utility of ADC for assessing parametrial and/or lymph node involvement. METHOD: This prospective patient cohort registered cervical cancer patients who underwent pre-operative MRI with T1, T2W, and axial DWI. Retrospectively, two observers independently and blindly scored mean, minimum, and maximum ADC using three methods: a) 3D-Tumor analysis, b) single freehand ROI (2D-Slice), and c) single circular ROI (2D-Circle). Another observer scored parametrial and lymph node involvement on T1/T2W sequences. Parametrial and/or lymph node involvement were determined by surgical-pathologic results. The diagnostic performance of ADC for predicting the latter was evaluated by ROC curve, uni and multivariate analyses. RESULTS: Of 58 included patients, parametrial and/or lymph node involvement was found in 9 and 11 patients, respectively. Mean ADC (ADCMean) was least dependent on ROI technique, with interobserver variability (ICC: 0.88-0.90) and linear correlation (Pearson's r: 0.95-0.96). To the contrary, minimal and maximal ADC were significantly influenced by 2D-ROI techniques. ADCMean was shown to be an independent predictor of parametrial (AUC: 0.80-0.86; OR: 16, 1.4-178) and/or lymph node involvement (AUC: 0.74-0.79; OR: 5.1, 1.1-24). CONCLUSIONS: Single ROI measurements are a reliable method for determining ADCMean in cervical cancer. Second, ADCMean serves as a potential parameter for prediction of parametrial involvement prior to radical hysterectomy.

Overview of non-epithelial ovarian tumours: Incidence and survival in the Netherlands, 1989-2015.

INTRODUCTION: About 5% of ovarian tumours have a non-epithelial histology, including germ cell tumours (GCTs), sex cord-stromal tumours (SCSTs) and sarcomas. Because these non-epithelial ovarian tumours are rare and population-based studies are scarce, the aim of this population-based study is to describe trends in the incidence, treatment and survival of women with these tumours in the Netherlands. METHODS: All women diagnosed with non-epithelial ovarian malignant tumours in the Netherlands between 1989 and 2015 were identified from the Netherlands Cancer Registry. Data on demographics, tumour characteristics and initial treatment were collected, and overall survival was analysed. RESULTS: A total of 1258 non-epithelial ovarian tumours were identified comprising 752 GCTs (60%), 341 SCSTs (27%) and 165 sarcomas (13%). The European age-standardised incidence rate (ESR) was 0.4 per 100,000 persons per year for GCTs, 0.2 for SCSTs and 0.1 for sarcomas. Approximately 97% of patients underwent surgical resection for the primary tumour, 31% received systemic treatment and 3% radiotherapy. Between the late 1980s and 2015, five-year overall survival improved for all histologic subtypes: GCTs rose from 73% to 88% (p = 0.03), SCSTs from 64% to 81% (p = 0.57) and sarcomas from 20% to 29% (p = 0.14). CONCLUSION: Malignant GCTs and SCSTs are rare, and their incidence has not significantly changed over recent decades. They have a good prognosis, which also improved slightly during this period. Primary sarcomas of the ovary are extremely rare and still have a poor prognosis.

Outcome of surgery in advanced ovarian cancer varies between geographical regions; opportunities for improvement in The Netherlands.

INTRODUCTION: The care for patients with epithelial ovarian cancer(EOC) is organised in eight different geographical regions in the Netherlands. This situation allows us to study differences in practice patterns and outcomes between geographical regions for patients with FIGO stage IIIC and IV. METHODS: We identified all EOC patients who were diagnosed with FIGO stage IIIC or IV between 01.01.2008 and 31.12.2015 from the Netherlands Cancer Registry. Descriptive statistics were used to summarize treatment and treatment sequence(primary cytoreductive surgery(PCS) or neoadjuvant chemotherapy and interval cytoreductive surgery(NACT-ICS)). Moreover, outcome of surgery was compared between geographical regions. Multilevel logistic regression was used to assess whether existing variation is explained by geographical region and case-mix factors. RESULTS: Overall, 6,741 patients were diagnosed with FIGO IIIC or IV disease. There were no differences in the percentage of patients that received any form of treatment between the geographical regions(range 80-86%, P = 0.162). In patients that received cytoreductive surgery and chemotherapy, a significant variation between the geographical regions was observed in the use of PCS and NACT-ICS(PCS: 24-48%, P < 0.001). The percentage of complete cytoreductive surgeries after PCS ranged from 10 to 59%(P < 0.001) and after NACT-ICS from 37 to 70%(P < 0.001). Moreover, geographical region was independently associated with the outcome of surgery, also when adjusted for treatment sequence(P < 0.001). CONCLUSION: We observed a significant variation in treatment approach for advanced EOC between geographical regions in the Netherlands. Furthermore, the probability to achieve no residual disease differed significantly between regions, regardless of treatment sequence. This may suggest that surgical outcomes can be improved across geographical regions.

Localization of distant metastases defines prognosis and treatment efficacy in patients with FIGO stage IV ovarian cancer.

BACKGROUND: Patients with ovarian cancer who are diagnosed with Federation of Gynecology and Obstetrics (FIGO) stage IV disease are a highly heterogeneous group with possible survival differences. The FIGO staging system was therefore updated in 2014. OBJECTIVE: To evaluate the 2014 changes to FIGO stage IV ovarian cancer on overall survival. METHODS: We identified all patients diagnosed with FIGO stage IV disease between January 2008 and December 2015 from the Netherlands Cancer Registry. We analyzed the prognostic effect of FIGO IVa versus IVb. In addition, patients with extra-abdominal lymph node involvement as the only site of distant disease were analyzed separately. Overall survival was analyzed by Kaplan-Meier curves and multivariable Cox regression models. RESULTS: We identified 2436 FIGO IV patients, of whom 35% were diagnosed with FIGO IVa disease. Five-year overall survival of FIGO IVa and IVb patients (including those with no or limited therapy) was 8.9% and 13.0%, respectively (p=0.51). Patients with only extra-abdominal lymph node involvement had a significant better overall survival than all other FIGO IV patients (5-year overall survival 25.9%, hazard ratio 0.77 [95% CI 0.62 to 0.95]). CONCLUSION: Our study shows that the FIGO IV sub-classification into FIGO IVa and IVB does not provide additional prognostic information. Patients with extra-abdominal lymph node metastases as the only site of FIGO IV disease, however, have a better prognosis than all other FIGO IV patients. These results warrant a critical appraisal of the current FIGO IV sub-classification.

Treatment and outcome of elderly patients with advanced stage ovarian cancer: A nationwide analysis.

OBJECTIVE: To provide an overview of treatment strategies for elderly patients with advanced stage epithelial ovarian cancer (EOC) in daily practice, evaluate changes over time and relate this to surgical mortality and survival. METHODS: All women diagnosed with advanced stage (FIGO IIB and higher) EOC between 2002 and 2013 were selected from the Netherlands Cancer Registry (n=10,440) and stratified by age, stage and period of diagnosis. Elderly patients were defined as aged ≥70years. Time trends in treatment patterns and postoperative mortality were described by age category and tested using multivariable logistic regression. Relative survival was calculated. RESULTS: With advancing age, less patients received ((neo-)adjuvant) treatment. Over time, elderly patients were less often treated (OR 2002-2004 versus 2011-2013: 0.73; 95%CI:0.58-0.92). But if treated, more often standard treatment was provided and 30-day postoperative mortality decreased from 4.5% to 1.9% between 2005 and 2007 and 2011-2013. In all age categories treatment shifted from primary surgery towards primary chemotherapy, in patients aged 70-79years combination therapy increased (+5%) between 2002 and 2004 and 2011-2013. Five-year relative survival for patients diagnosed in 2008-2010 aged <70years was 34% compared to 18% for elderly patients. CONCLUSION: Large treatment differences exist between younger and elderly patients. Over time, selection of elderly patients eligible for curative surgical treatment may have improved. More elderly patients were treated with neoadjuvant chemotherapy while less patients underwent surgery and simultaneously postoperative mortality decreased. However, the large and increasing number of elderly patients without treatment and the large survival gap suggests opportunities for further improvements in the care for elderly EOC patients.

Medical students' perspective on training in anatomy.

Gaining sufficient knowledge of anatomy is an important part of medical education. Factors that influence how well students learn anatomical structures include available sources, learning time and study assistance. This study explores the attitude of medical students with regard to studying anatomy and evaluates possibilities for improvement of training in anatomy. Twenty medical students participated in a focus group meeting. Based on this focus group, an online survey consisting of 27 questions was developed and distributed amongst medical students of Maastricht University, the Netherlands. A total of 495 medical students (both Bachelor and Master level) participated in this survey. Master students found studying anatomy less attractive than Bachelor students (36.8% of the Master students vs. 47.9% of the Bachelor students (p=.024)). Although most students responded that they thought it is important to study anatomy, 48% of all students studied anatomy less than 10h per study block of 8 weeks. Only 47.9% of the students rated their knowledge of anatomy as adequate. Students suggested that three-dimensional techniques would help improve their knowledge of anatomy. Therefore investing in three-dimensional tools could prove beneficial in the future.

Positron emission tomography-magnetic resonance imaging (PET-MRI) for response assessment after radiation therapy of cervical carcinoma: a pilot study.

BACKGROUND: Advanced stage cervical cancer is primarily treated by radiotherapy. Local tumor control is a prerequisite for cure. Imaging after treatment is controversial. Positron emission tomography (PET) combined with computer tomography (PET-CT) shows great promise for detecting metastases. On the other hand, magnetic resonance imaging (MRI) is superior in depicting anatomical details. The combination of PET-MRI could result in more accurate evaluation of cervical cancer treatment outcome. The aim of this pilot study is to share our initial experience with PET-MRI in the evaluation of treatment response in cervical cancer after radiation treatment. METHODS: Ten patients with cervical carcinoma (FIGO ≥IB2) were prospectively evaluated. Eleven weeks (median; range 8-15 weeks) after radiation therapy, treatment response was evaluated by PET-MRI. The PET, MRI, and combined PET-MRI images were evaluated for the presence of local residual tumor and metastasis. Diagnostic performance was assessed by area under the receiver operator characteristic (ROC) curve for evaluation of local residual tumor. The readers were blinded for outcome data. Local residual disease, metastasis, diagnostic confidence, and change of opinion were scored on a 5-point Likert scale. The reference standard consisted of pathology and/or follow-up according to the clinical guidelines. RESULTS: Three out of ten patients had local residual abnormalities suggestive for tumor residue after radiation treatment. The availability of both PET and MRI resulted in an increase in diagnostic confidence in 80-90% of all patients. Change of opinion was observed in 70% and change of policy in 50%, especially in the group with residual tumor. The diagnostic accuracy increased significantly for the radiologist if PET-MRI was combined (AUC .54 versus .83). CONCLUSIONS: PET-MRI shows promise for evaluation of treatment response after radiation for cervical cancer, especially increasing diagnostic confidence, while potentially increasing diagnostic performance.

No improvement in long-term survival for epithelial ovarian cancer patients: A population-based study between 1989 and 2014 in the Netherlands.

AIM: This study investigates changes in therapy and long-term survival for patients with epithelial ovarian cancer (EOC) in the Netherlands. METHODS: All patients with EOC, including peritoneal and fallopian tube carcinoma, diagnosed in the Netherlands between 1989 and 2014 were selected from the Netherlands Cancer Registry. Changes in therapy were studied and related to overall survival (OS) using multivariable Cox regression models. RESULTS: A total of 32,540 patients were diagnosed with EOC of whom 22,047 (68%) had advanced stage disease. In early stage, lymph node dissection as part of surgical staging procedures increased over time from 4% in 1989-1993 to 62% in 2009-2014 (P < 0.001). In advanced stage, the number of patients receiving optimal treatment with surgery and chemotherapy increased from 55% in 1989-1993 to 67% in 2009-2014 (P < 0.001). Five-year survival rates improved in both early stage (74% versus 79%) and advanced stage (16% versus 24%) as well as in all patients combined (31% versus 34%). Ten-year survival rates, however, slightly improved in early stage (62% versus 67%) and advanced stage (10% versus 13%) but remained essentially unchanged at 24% for all patients combined. CONCLUSION: Despite intensified treatment and staging procedures, long-term survival for women with EOC has not improved in the last 25 years. The observed improvements in 5-year OS reflect a more prolonged disease control rather than better chances for cure. Furthermore, the apparent better long-term outcome, when early and advanced stage patients are analysed separately, is largely due to improved staging procedures and the ensuing stage migration. These effects disappear in a combined analysis of all patients.

Contribution of cervical cytology in the diagnostic work-up of patients with endometrial cancer.

INTRODUCTION: Abnormal cervical cytology in patients with endometrial cancer (EC) has been associated with poor outcome. The aim of this study was to evaluate whether cervical cytology could contribute to an improved preoperative identification of high-grade EC (serous, clear cell, carcinosarcoma, high-grade endometrioid EC) in final histology. METHODS: A retrospective cohort study was performed in five hospitals in the Netherlands. A total of 554 patients with EC that underwent primary surgical treatment between 2002 and 2010 were included. Primary outcome was defined as the contribution of abnormal cervical cytology in the preoperative identification of high-grade EC. As secondary outcome, recurrence-free survival (RFS) and disease-specific survival were determined based on preoperative cervical cytology, and compared to the currently established risk factors: myometrial invasion, high-grade and lymph vascular space invasion. RESULTS: Abnormal cervical cytology was present in 45.1%. For patients with preoperative inconclusive and high-grade histology, the presence of abnormal cervical cytology contributed to an improved identification of high-grade EC in final histology (odds ratio [OR] 6.40 [95% confidence interval {CI}: 1.92-21.26]; OR 2.86 [95% CI: 1.14-7.14]), respectively. Patients with abnormal cervical cytology had a significant worse 5-year median RFS. Abnormal cervical cytology was independently related to RFS (hazard ratio 1.67 [95% CI: 1.04-2.68]) and disease-specific survival (hazard ratio 3.15 [95% CI: 1.74-5.71]). CONCLUSIONS: Abnormal cytology contributes to the preoperative identification of patients with high-grade EC, and is associated with compromised outcome. Future studies are warranted to determine whether cervical cytology could be incorporated into preoperative prediction models for lymph node metastasis.

Compliance with adjuvant treatment guidelines in endometrial cancer: room for improvement in high risk patients.

OBJECTIVES: Compliance of physicians with guidelines has emerged as an important indicator for quality of care. We evaluated compliance of physicians with adjuvant therapy guidelines for endometrial cancer patients in the Netherlands in a population-based cohort over a period of 10years. METHODS: Data from all patients diagnosed with endometrial cancer between 2005 and 2014, without residual tumor after surgical treatment, were extracted from the Netherlands Cancer Registry (N=14,564). FIGO stage, grade, tumor type and age were used to stratify patients into risk groups. Possible changes in compliance over time and impact of compliance on survival were assessed. RESULTS: Patients were stratified into low/low-intermediate (52%), high-intermediate (21%) and high (20%) risk groups. Overall compliance with adjuvant therapy guidelines was 85%. Compliance was highest in patients with low/low-intermediate risk (98%, no adjuvant therapy indicated). The lowest compliance was determined in patients with high risk (61%, external beam radiotherapy with/without chemotherapy indicated). Within this group compliance decreased from 64% in 2005-2009 to 57% in 2010-2014. In high risk patients with FIGO stage III serous disease compliance was 55% (chemotherapy with/without radiotherapy indicated) and increased from 41% in 2005-2009 to 66% in 2010-2014. CONCLUSION: While compliance of physicians with adjuvant therapy guidelines is excellent in patients with low and low-intermediate risk, there is room for improvement in high risk endometrial cancer patients. Eagerly awaited results of ongoing randomized clinical trials may provide more definitive guidance regarding adjuvant therapy for high risk endometrial cancer patients.

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.

The influence of sarcopenia on survival and surgical complications in ovarian cancer patients undergoing primary debulking surgery.

BACKGROUND: Sarcopenia, severe skeletal muscle loss, has been identified as a prognostic factor in various malignancies. This study aims to investigate whether sarcopenia is associated with overall survival (OS) and surgical complications in patients with advanced ovarian cancer undergoing primary debulking surgery (PDS). METHODS: Ovarian cancer patients (n = 216) treated with PDS were enrolled retrospectively. Total skeletal muscle surface area was measured on axial computed tomography at the level of the third lumbar vertebra. Optimum stratification was used to find the optimal skeletal muscle index cut-off to define sarcopenia (≤38.73 cm2/m2). Cox-regression and Kaplan-Meier analysis were used to analyse the relationship between sarcopenia and OS. The effect of sarcopenia on the development of major surgical complications was studied with logistic regression. RESULTS: Kaplan-Meier analysis showed a significant survival disadvantage for patients with sarcopenia compared to patients without sarcopenia (p = 0.010). Sarcopenia univariably predicted OS (HR 1.536 (95% CI 1.105-2.134), p = 0.011) but was not significant in multivariable Cox-regression analysis (HR 1.362 (95% CI 0.968-1.916), p = 0.076). Significant predictors for OS in multivariable Cox-regression analysis were complete PDS, treatment in a specialised centre and the development of major complications. Sarcopenia was not predictive of major complications. CONCLUSION: Sarcopenia was not predictive of OS or major complications in ovarian cancer patients undergoing primary debulking surgery. However a strong trend towards a survival disadvantage for patients with sarcopenia was seen. Future prospective studies should focus on interventions to prevent or reverse sarcopenia and possibly increase ovarian cancer survival. Complete cytoreduction remains the strongest predictor of ovarian cancer survival.

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.