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BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC. ispartof: CANCER vol:129 issue:5 pages:697-713 ispartof: location:United States status: published

OBJECTIVE: Lymph node metastases (pN+) in presumed early-stage cervical cancer negatively impact prognosis. Using federated learning, we aimed to develop a tool to identify a group of women at low risk of pN+, to guide the shared decision-making process concerning the extent of lymph node dissection.METHODS: Women with cervical cancer between 2005 and 2020 were identified retrospectively from population-based registries: the Danish Gynaecological Cancer Database, Swedish Quality Registry for Gynaecologic Cancer and Netherlands Cancer Registry. Inclusion criteria were: squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma; The International Federation of Gynecology and Obstetrics 2009 IA2, IB1 and IIA1; treatment with radical hysterectomy and pelvic lymph node assessment. We applied privacy-preserving federated logistic regression to identify risk factors of pN+. Significant factors were used to stratify the risk of pN+.RESULTS: We included 3606 women (pN+ 11%). The most important risk factors of pN+ were lymphovascular space invasion (LVSI) (odds ratio [OR] 5.16, 95% confidence interval [CI], 4.59-5.79), tumour size 21-40 mm (OR 2.14, 95% CI, 1.89-2.43) and depth of invasion>10 mm (OR 1.81, 95% CI, 1.59-2.08). A group of 1469 women (41%)-with tumours without LVSI, tumour size ≤20 mm, and depth of invasion ≤10 mm-had a very low risk of pN+ (2.4%, 95% CI, 1.7-3.3%).CONCLUSION: Early-stage cervical cancer without LVSI, a tumour size ≤20 mm and depth of invasion ≤10 mm, confers a low risk of pN+. Based on an international privacy-preserving analysis, we developed a useful tool to guide the shared decision-making process regarding lymph node dissection.

Ovarian cancer remains to have relatively poor prognosis particularly in low-resourced settings. It is therefore important to continually examine the burden of ovarian cancer to identify areas of disparities. Our study aims to provide an overview of the global burden of ovarian cancer using the GLOBOCAN 2020 estimates by country, world region, and Human Development Index (HDI) levels, as well as the predicted future burden by the year 2040 by HDI. Age-standardized incidence and mortality rates for ovarian cancer in 185 countries were calculated by country, world region, and for the four-tier HDI. The number of new cases and deaths were projected for the year 2040 based on demographic projections by HDI category. Approximately 314 000 new ovarian cancer cases and 207 000 deaths occurred in 2020. There were marked geographic variations in incidence rates, with the highest rates observed in European countries with very high HDI and low rates were found in African countries within the lowest HDI group. Comparable mortality rates were observed across the four-tier HDI. Relative to 2020 estimates, our projection for 2040 indicates approximately 96% and 100% increase in new ovarian cancer cases and deaths, respectively, among low HDI countries compared to 19% and 28% in very high HDI countries. Our study highlights the disproportionate current and future burden of ovarian cancer in countries with lower HDI levels, calling for global action to reduce the burden and inequality of ovarian cancer in access to quality cancer care and treatment.

How the tumor’s genetic make up (i.e. molecular profiles) is associated with changes in the tumor microenvironment (TME) in high-grade serous ovarian cancer (HGSOC) is incompletely understood, while these factors influence survival. To investigate this we analyzed the TME and molecular profiles (homologous recombination deficiency (HRD) and Cyclin E1 (CCNE1) amplification) of HGSOC and assessed their associations with each other and overall survival (OS). Patients with advanced-stage HGSOC treated in three Dutch hospitals between 2008-2015 were included. Patient, treatment, and outcome data were collected from medical records. BRCA1/2 mutation, BRCA1 promotor methylation analyses, and copy number variations were used to define five molecular profiles. Immunecell densites were assessed with immunohistochemical staining for T- (CD8 and CD103), B- cells (CD20) and macrophages (CD68). This resulted in the assessability of 348 patients who were categorized as; BRCA mutation or promotor methylation (BRCAm) (30%), non-BRCA mutated HRD (19%), CCNE1-amplification (13%), non-BRCAmut HRD and CCNE1-amplification (double classifier) (20%), and no specific molecular profile (NSMP) (18%). BRCAm tumors showed the highest immune cell densities and CCNE1-amplification the lowest. BRCAm showed the most favorable OS (52.5months), compared to non-BRCAmut HRD (41.0months), CCNE1-amplification (28.0months), double classifier (27.8months), and NSMP (35.4months). CCNE1-amplification and double classifier remained to have a significantly worse OS in multivariable analysis. Higher immune cell densities showed a favorable OS compared to lower densities, also within the molecular profiles. CD8+, CD20+, and CD103+ cells remained associated with OS in multivariable analysis. These results depict that both molecular profiles and TME are associated with OS. Immune composition for lymphocytes and macrophages differ per molecular profile, with higher immune cell densities showing a favorable OS, even within the profiles. HGSOC does not reflect one entity but comprises different variants based on molecular profiles and TME, which ideally is translated into tailored treatment approaches.

Correct identification of patients with lymph node metastasis from cervical cancer prior to treatment is of great importance, because it allows more tailored therapy. Patients may be spared unnecessary surgery or extended field radiotherapy if the nodal status can be predicted correctly. This review captures the existing knowledge on the identification of lymph node metastases in cervical cancer. The risk of nodal metastases increases per 2009 FIGO stage, with incidences in the pelvic region ranging from 2% (stage IA2) to 14-36% (IB), 38-51% (IIA) and 47% (IIB); and in the para-aortic region ranging from 2 to 5% (stage IB), 10-20% (IIA), 9% (IIB), 13-30% (III) and 50% (IV). In addition, age, tumor size, lymph vascular space invasion, parametrial invasion, depth of stromal invasion, histological type, and histological grade are reported to be independent prognostic factors for the risk of nodal metastases. Furthermore, biomarkers can contribute to predict a patient's nodal status, of which the squamous cell carcinoma antigen (SCC-Ag) is currently the most widely used in squamous cell cervical cancer. Still, pre-treatment lymph node assessment is primarily performed by imaging, of which diffusion-weighted magnetic resonance imaging has the highest sensitivity and 2-deoxy-2-[18F]fluoro-D-glucose positron emission computed tomography the highest specificity. Imaging results can be combined with clinical parameters in nomograms to increase the accuracy of predicting positives nodes. Despite all the progress regarding pre-treatment prediction of lymph node metastases in cervical cancer in recent years, prediction rates are not robust enough to safely abandon surgical staging of the pelvic or para-aortic region yet.

AIM: This study aims to report trends in primary treatment and survival in cervical cancer (CC) to identify opportunities to improve clinical practice and disease outcome.METHODS: Patients diagnosed with CC between 1989 and 2018 were identified from the Netherlands Cancer Registry (N = 21,644). Trends in primary treatment and 5-year relative survival were analysed with the Cochran-Armitage trend test and multivariable Poisson regression, respectively.RESULTS: In early CC, surgery remains the preferred treatment for ages 15-74. Overall, it was applied more often in younger than in older patients (92% in 15-44; 64% in 65-74). For 75+, surgery use was stable over time (38%-41%, p=0.368), while administration of radiotherapy decreased (57%-29%, p < 0.001). In locally advanced CC, chemoradiation use increased over time (5%-65%, p < 0.001). It was applied least often for 75+, in which radiotherapy remains most common (54% in 2014-2018). In metastatic CC, chemotherapy use increased over time (11%-28%, p < 0.001), but varied across age groups (6%-40% in 2014-2018). In patients treated with primary chemoradiation, regardless of stage, brachytherapy use increased over time (p ≤ 0.001). Full cohort 5-year survival increased from 68% to 74% (relative excess risk 0.55; 95% confidence interval [0.50-0.62]). Increases were most significant in locally advanced CC (38%-60%; 0.55 [0.47-0.65]). Survival remained stable in 75+ (38%-34%; 0.82 [0.66-1.02]).CONCLUSION: Relative survival for cervical cancer increased over the last three decades. The proportion of older patients receiving preferred treatment lags behind. Consequently, survival did not improve in the oldest patients.

Objective: Cervical cancer with ≤5 mm depth of invasion and >7 mm horizontal spread is classified FIGO IA instead of FIGO IB in the revised staging system, as horizontal spread is no longer considered. We aimed to determine the incidence of lymph node metastasis (LNM) and, consequently, the necessity of pelvic lymph node assessment. Methods: Patients diagnosed between January 2015 and May 2019 with cervical cancer FIGO (2009) stage IB with ≤5 mm depth of invasion and >7 mm horizontal spread, were identified from the Netherlands Cancer Registry. Associations between disease-characteristics and lymph node metastasis (LNM), and overall survival, were assessed. Results: Of 170 patients, six (3.5%) had LNM: 4/53 (7.6%) with adenocarcinoma and 2/117 (1.7%) with squamous cell carcinoma (p =.077). Four-year overall survival was 98.2%. LNM was observed more often in tumours with LVSI (4/43 patients, 9.3%) than without LVSI (2/117 patients, 1.7%) (p =.045). In adenocarcinoma with 3–5 mm depth of invasion LNM rate was 10% (4/40). None of the following tumours were observed with LNM: squamous cell carcinoma without LVSI (0/74); adenocarcinoma with

Upon discovery of lymph node metastasis during radical hysterectomy with pelvic lymphadenectomy in early-stage cervical cancer, the gynaecologist may pursue one of two treatment strategies: abandonment of surgery followed by primary (chemo)radiotherapy (PRT) or completion of radical hysterectomy, followed by adjuvant (chemo)radiotherapy (RHRT). Current guidelines recommend PRT over RHRT, as combined treatment is presumably associated with increased morbidity. However, this review of literature suggests there are no significant differences in survival and recurrence and total proportions of adverse events between treatment strategies. Additionally, both strategies are associated with varying types of adverse events, and affect quality of life and sexual functioning differently, both in the short and long term. Although total proportions of adverse events were comparable between treatment strategies, lower extremity lymphoedema was reported more often after RHRT and symptom experience (e.g. distress from bladder or bowel problems) and sexual dysfunction more often after PRT. As reporting of adverse events, quality of life and sexual functioning were not standardised across the articles included, and covariate adjustment was not conducted in most of the analyses, comparability of studies is hampered. Accumulating retrospective evidence suggests no major differences on oncological outcome and morbidity after PRT and RHRT for intraoperatively discovered lymph node metastasis in cervical cancer. However, conclusions should be considered cautiously, as all studies were of retrospective design with small sample sizes. Still, treatment strategies seem to affect adverse events, quality of life and sexual functioning in different ways, allowing room for shared decision-making and personalised treatment.

Contains fulltext : 220978.pdf (Publisher’s version ) (Open Access) AIM: Recently, the safety of laparoscopic radical hysterectomy (LRH) has been called into question in early-stage cervical cancer. This study aimed to evaluate overall survival (OS) and disease-free survival (DFS) in patients treated with abdominal radical hysterectomy (ARH) and LRH for early-stage cervical cancer and to provide a literature review. METHODS: Patients diagnosed between 2010 and 2017 with International Federation of Gynaecology and Obstetrics (2009) stage IA2 with lymphovascular space invasion, IB1 and IIA1, were identified from the Netherlands Cancer Registry. Cox regression with propensity score, based on inverse probability treatment weighting, was applied to examine the effect of surgical approach on 5-year survival and calculate hazard ratios (HR) and 95% confidence intervals (CIs). Literature review included observational studies with (i) analysis on tumours /=30 months (iii) >/=5 events per predictor parameter in multivariable analysis or a propensity score. RESULTS: Of the 1109 patients, LRH was performed in 33%. Higher mortality (9.4% vs. 4.6%) and recurrence (13.1% vs. 7.3%) were observed in ARH than LRH. However, adjusted analyses showed similar DFS (89.4% vs. 90.2%), HR 0.92 [95% CI: 0.52-1.60]) and OS (95.2% vs. 95.5%), HR 0.94 [95% CI: 0.43-2.04]). Analyses on tumour size (/=2 cm) also gave similar survival rates. Review of nine studies showed no distinct advantage of ARH, especially in tumours

Background Tumor positivity and upstaging rates from various surgical staging steps performed in clinically early-stage epithelial ovarian carcinoma (EOC) vary widely in literature. Aim To quantify tumor positivity and upstaging rates for all staging surgery steps in EOC patients. Differences between subgroups based on their clinical and histological characteristics are explored. Methods A systematic search using synonyms of ‘ovarian cancer’, ‘neoplasm staging’, and ‘neoplasm metastasis' was conducted in PubMed, Embase, and the Cochrane Library. Meta-analysis was performed on 23 included studies, comprising 5194 clinical stage I or II EOC patients who underwent comprehensive surgical staging. Studies were assessed using the Newcastle-Ottawa Scale risk-of-bias tool. Pooled proportions and 95% confidence intervals were calculated using an inverse variance weighted random-effects model. Results Overall upstaging rate of clinically early-stage EOC patients was 18.7% (95%CI: 14.1–23.4%). Serous histology or high grade EOC showed the highest upstaging rate at 35.3% (95%CI: 21.8–48.7%) and 40.9% (95%CI: 35.6–46.2%). Lymph node involvement resulted in an upstaging rate of 8.7% (95%CI: 6.2–11.3%). Tumor was identified in uterus, cytology, peritoneal biopsies, omentum and appendix in 6.2% (95%CI: 1.8–10.7%), 18.4% (95%CI: 13.8–22.9%), 9.7% (95%CI: 3.8–15.6%), 5.2% (95%CI: 1.7–8.8%) and 3.6% (95%CI: 0.0–7.5%) of EOC patients. The corresponding upstaging rates were 5.9% (95%CI: 1.4–10.4%), 8.5% (95%CI: 1.8–15.2%), 3.5% (95%CI: 1.0–6.0%), 3.9% (95%CI: 1.4–6.3%) and 1.6% (95%CI: 0.0–3.4%), respectively. Conclusion The attributive value of comprehensive surgical staging in clinically early-stage EOC patients remains substantial, particularly in serous and high grade tumors.

The FIGO 2018 staging system was introduced to allow better prognostic differentiation in cervical cancer, causing considerable stage migration and affecting treatment options. We evaluated the accuracy of the FIGO 2018 staging in predicting recurrence free (RFS) and overall survival (OS) compared to FIGO 2009 staging in clinically early stage cervical cancer. We conducted a nationwide retrospective cohort study, including 2264 patients with preoperative FIGO (2009) IA1, IA2 and IB1 cervical cancer between 2007–2017. Kaplan–Meier analyses were used to assess survival outcomes. Logistic regression was used to assess risk factors for lymph node metastasis and parametrial invasion. Stage migration occurred in 48% (22% down-staged, 26% up-staged). Survival data of patients down-staged from IB to IA1/2 disease were comparable with FIGO 2009 IA1/2 and better than patients remaining stage IB1. LVSI, invasion depth and parametrial invasion were risk factors for lymph node metastases. LVSI, grade and age were associated with parametrial invasion. In conclusion, the FIGO 2018 staging system accurately reflects prognosis in early stage cervical cancer and is therefore more suitable than the FIGO 2009 staging. However subdivision in IA1 or IA2 based on presence or absence of LVSI instead of depth of invasion would have improved accuracy. For patients down-staged to IA1/2, less radical surgery seems appropriate, although LVSI and histology should be considered when determining the treatment plan.

Contradicting results regarding ovarian cancer prognosis in women with endometriosis have been reported in the literature. Owing to the small sample size of previous studies, larger studies are required to elucidate the role of endometriosis in ovarian cancer prognosis.This study aimed to evaluate the survival rate in women with ovarian cancer with or without histologically proven endometriosis in a Dutch population-based cohort.All women with ovarian cancer diagnosed between 1990 and 2015 were identified from the Netherlands Cancer Registry. We linked these women with the Dutch nationwide registry of histopathology and cytopathology (Pathologisch-Anatomisch Landelijk Geautomatiseerd Archief) to identify all women with histologically proven endometriosis. We compared the prognosis of patients with ovarian cancer with and without histologically proven endometriosis. Primary outcome was the overall survival with subgroup analyses stratified by histologic ovarian cancer subtype and stage. Multivariable Cox proportional hazard analysis was used to estimate hazard ratios with 95% confidence intervals.We included 32,419 patients with ovarian cancer, of whom 1979 (6.1%) had histologically proven endometriosis. The median age of histologic endometriosis diagnosis was 53 years (interquartile range, 46-62). Of all women with ovarian cancer and endometriosis, 81.2% received a diagnosis of synchronous endometriosis and ovarian cancer. The endometriosis cohort was younger at ovarian cancer diagnosis, had more favorable tumor characteristics, and more often had surgical treatment for ovarian cancer than the women without endometriosis. These variables were included in the multivariable model as confounders. Women with histologically proven endometriosis had a significantly better prognosis in both crude and adjusted analyses (hazard ratio, 0.46; 95% confidence interval, 0.43-0.49; P.0005, and adjusted hazard ratio, 0.89; 95% confidence interval, 0.83-0.95; P.05, respectively).Women with ovarian cancer and histologically proven endometriosis had longer overall survival than women with ovarian cancer without endometriosis, even after adjustment for confounders. Future studies on ovarian cancer treatment and prognosis should consider stratifying by endometriosis status to elucidate its role. Furthermore, women diagnosed as having ovarian cancer and concurrent endometriosis should be explained the role of endometriosis in ovarian cancer survival.

Contains fulltext : 244572.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To identify clinicopathologic factors predictive of early relapse (platinum-free interval (PFI) of ≤6 months) in advanced epithelial ovarian cancer (EOC) in first-line treatment, and to develop and internally validate risk prediction models for early relapse. METHODS: All consecutive patients diagnosed with advanced stage EOC between 01-01-2008 and 31-12-2015 were identified from the Netherlands Cancer Registry. Patients who underwent cytoreductive surgery and platinum-based chemotherapy as initial EOC treatment were selected. Two prediction models, i.e. pretreatment and postoperative, were developed. Candidate predictors of early relapse were fitted into multivariable logistic regression models. Model performance was assessed on calibration and discrimination. Internal validation was performed through bootstrapping to correct for model optimism. RESULTS: A total of 4,557 advanced EOC patients were identified, including 1,302 early relapsers and 3,171 late or non-relapsers. Early relapsers were more likely to have FIGO stage IV, mucinous or clear cell type EOC, ascites, >1 cm residual disease, and to have undergone NACT-ICS. The final pretreatment model demonstrated subpar model performance (AUC = 0.64 [95 %-CI 0.62-0.66]). The final postoperative model based on age, FIGO stage, pretreatment CA-125 level, histologic subtype, presence of ascites, treatment approach, and residual disease after debulking, demonstrated adequate model performance (AUC = 0.72 [95 %-CI 0.71-0.74]). Bootstrap validation revealed minimal optimism of the final postoperative model. CONCLUSION: A (postoperative) discriminative model has been developed and presented online that predicts the risk of early relapse in advanced EOC patients. Although external validation is still required, this prediction model can support patient counselling in daily clinical practice.

ObjectivesA significant proportion of women with advanced-stage ovarian cancer receive no cancer-directed treatment and limited research has been devoted to this group. This population-based study aimed to gain insight into treatment patterns and trends in patients with advanced epithelial ovarian cancer in the Netherlands and the main reasons for deciding for no cancer-directed treatment.MethodsAll patients diagnosed with advanced epithelial ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) classification IIB−IV, between 2008 and 2016 were identified from the Netherlands Cancer Registry. Trends in the number of patients receiving cancer-directed treatment were analyzed. Multivariable logistic regression analysis was used to identify factors associated with no cancer-directed treatment. The main reasons for no cancer-directed treatment were analyzed.ResultsA total of 9303 patients were included, of whom 14% (n=1270) received no cancer-directed treatment while 67% (n=6218) received a combination of cytoreductive surgery and chemotherapy. Some 15% (n=1399) received chemotherapy only, and 4.5% (n=416) surgical resection or hormonal therapy only. The proportion of patients receiving no cancer-directed treatment was higher in 2014–2016 (16%, n=496/3175) compared with 2008–2010 (11%, n=349/3057, pConclusionsThe proportion of patients with advanced epithelial ovarian cancer not receiving cancer-directed treatment has increased in the last decade in the Netherlands. Patient’s choice was the main reason for the decision to undergo no cancer-directed treatment, which indicates patient involvement in the decision-making process. The second most common reason for no cancer-directed treatment was poor condition of the patient, which might indicate careful selection of patients for treatment. Decision-making regarding treatment is well-considered, but more insight is needed, especially from the patient's perspective.

Objective: Peritoneal metastases (PM) are a challenge in gynecological cancers, but its appearance has never been described in a population-based study. Therefore, we describe the incidence of PM and identify predictors that increase the probability of peritoneal spread.Methods: All ovarian, endometrial and cervical cancer patients diagnosed in the Netherlands between 1989 and 2015 were identified from the Netherlands Cancer Registry and stratified for PM. Crude and age-adjusted incidence over time was calculated. Independent predictors for PM were identified using uni- and multivariable analyses.Results: The 94,981 patients were diagnosed with ovarian, endometrial or cervical cancer and respectively 61%, 2% and 1% presented with PM. Predictors for PM in ovarian cancer were: age between 50 and 74 years (odds ratio [OR]=1.19; 95% confidence interval [CI]=1.08-1.32), other distant metastases (OR=1.25; 95% CI=1.10-1.41), poor differentiation grade (OR=2.00; 95% CI=1.73-2.32) and serous histology. Predictors in endometrial cancer were lymph node metastases (OR=2.32; 95% CI=1.65-3.26), other distant metastases (OR=1.38; 95% CI=1.08-1.77), high-grade tumors (OR=1.95; 95% CI=1.38-2.76) and clear cell (OR=1.49; 95% CI=1.04-2.13) or serous histology (OR=2.71; 95% CI=2.15-3.42). In cervical cancer, the risk is higher in adenocarcinoma than in squamous cell carcinoma (OR=4.92; 95% CI=3.11-7.79).Conclusion: PM are frequently seen in patients with ovarian cancer. In endometrial and cervical cancer PM are rare. Histological subtype was the strongest predictive factor for PM in all 3 cancers. Better understanding of predictive factors for PM and thus the biological behavior is of paramount importance.

Objective: Uterine carcinosarcoma is a rare, aggressive subtype of endometrial cancer. Treatment consists of hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy (LND). The survival benefit of LND in relation to adjuvant radio- and/or chemotherapy is unclear. We evaluated the impact of LND on survival in relation to adjuvant therapy in uterine carcinosarcoma. Methods: Retrospective data on 1,140 cases were combined from the Netherlands Cancer Registry (NCR) and the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA). LND was defined as the removal of any nodes. Additionally, cases where 10 nodes or less (LND ≤10) or more than 10 nodes (LND > 10) were removed were analyzed separately. Adjuvant therapy was evaluated as radiotherapy, chemotherapy, or radiochemotherapy. Associations were analyzed by χ2 test, log-rank test, and Cox regression analysis. Results: Overall survival (OS) had improved after total abdominal hysterectomy with bilateral salpingo-oophorectomy with LND > 10 (HR 0.62, 95% CI 0.47–0.83). Adjuvant therapy was related to OS with an HR of 0.64 (95% CI 0.54–0.75) for radiotherapy, an HR of 0.65 (95% CI 0.48–0.88) for chemotherapy, and an HR of 0.25 (95% CI 0.13–0.46) for radiochemotherapy. Additionally, adjuvant treatment was related to OS when lymph nodes were positive (HR 0.22, 95% CI 0.11–0.42), but not when they were negative. Conclusion: LND is related to improved survival when more than 10 nodes are removed. Adjuvant therapy improves survival when LND is omitted, or when nodes are positive.

Contains fulltext : 220441.pdf (Publisher’s version ) (Open Access) BACKGROUND: Patients with International Federation of Gynaecology and Obstetrics (FIGO) stage III endometrial cancer (EC) have a substantial risk of adverse outcomes. After surgery, adjuvant therapy is recommended with external beam radiotherapy (EBRT), chemotherapy (CT) or both EBRT and CT. Recent trials suggest that EBRT + CT is superior to EBRT or CT alone but also results in more toxicity. We have compared the outcome of different adjuvant treatments in a population-based cohort to identify subgroups that benefit most from EBRT + CT. METHODS: All patients diagnosed with FIGO stage III EC and treated with surgery in 2005-2016 were identified from the Netherlands Cancer Registry. The primary outcome was overall survival (OS); associations with adjuvant treatment were analysed using Cox regression analysis. RESULTS: Among 1241 eligible patients, EBRT + CT was associated with a better OS than CT (hazard ratio [HR] = 1.84, 95% confidence interval [CI] = 1.34-2.52) and EBRT alone (HR = 1.37, 95% CI = 1.05-1.79). In stage IIIC, there was a significant benefit of EBRT + CT compared with CT or EBRT alone. In stage IIIA-B, there was no difference between EBRT + CT or EBRT alone. In endometrioid EC (EEC) and carcinosarcomas, EBRT + CT was associated with a better OS than CT or EBRT alone. For uterine serous cancers, there was no survival benefit of EBRT + CT over CT. In all analysis by stage and histology, any adjuvant treatment was superior to no adjuvant therapy. CONCLUSIONS: In this population-based study, adjuvant EBRT + CT was associated with improved OS compared with CT or EBRT alone in FIGO stage IIIC EC, EEC and carcinosarcoma. This suggests that application of EBRT + CT in stage III should be further stratified according to these subgroups.

Background: Population-based data on borderline ovarian tumors (BOTs) are scarce and information regarding recent trends in incidence, treatment and survival is lacking. The purpose of this study was to analyze these trends in the Netherlands and to assess the risk of developing a subsequent invasive ovarian tumor. Material and methods: All consecutive patients diagnosed with BOTs between 1993 and 2016 (n = 7113) were identified from the Netherlands Cancer Registry (NCR). Annual age-adjusted incidence rates were calculated. Relative survival (RS) analyses and multivariable analyses estimating excess mortality were conducted. Patients with a subsequent invasive ovarian tumor were identified by the NCR. Results: Age-adjusted incidence increased from 2.1/100,000 person-years in 1993 to 4.2/100,000 in 2011, after 2011 the incidence declined. The proportion of bilateral tumors decreased over time from 16% in 1993-1998 to 11% in 2005-2010 and remained stable onwards. Survival improved over time (excess mortality ratio(adjusted) 2011-2016 versus 1993-1998: 0.25; 95%CI: 0.13-0.47). Five-year RS increased from 91% in 1993-1998 to 98% in 2011-2016 and 10-year RS from 88% in 1993-1998 to 96% in 2005-2010. Fewer patients were treated with chemotherapy (4.4% in 1993-1998 versus 0.7% in 2011-2016). During a median follow-up time of 8 years, 0.9% developed a subsequent invasive ovarian carcinoma. Conclusions: The incidence of BOTs increased over time from 1993 until 2010 but declined since 2011. This decline may be partly due to changes in the classification of gynecological tumors, as serous BOTs are now more often diagnosed as low grade serous ovarian cancers. Survival is high and has improved since 1993. The risk of a subsequent invasive ovarian carcinoma seems low.

IntroductionAccording to current guidelines, hormonal therapy may be applied in endometrioid type endometrial cancer as an alternative to surgery for fertility preservation and in medically unfit patients. Since it is unknown how often hormonal therapy is applied, the objective of this study was to investigate trends over time in hormonal therapy use in the background of the overall incidence of endometrial cancer.MethodsAll patients with endometrial cancer (n=48 222) registered in the Netherlands Cancer Registry in the period 1989–2018 were included. European age-standardized incidence rates with corresponding estimated annual percentage change were calculated to describe trends in the incidence of endometrial cancer. The use of hormonal therapy was analyzed in the three periods 1989–1998, 1999–2008, and 2009–2018 for the following sub-groups: primary and adjuvant therapy, International Federation of Gynecology and Oncology (FIGO) stage I–II and III–IV, and by age group.ResultsThe European age-standardized incidence rate of endometrioid endometrial cancer peaked in 2004 with a significant increase from 1989 to 2004 (annual percentage change 0.55; 95% CI 0.10 to 0.99, p=0.020) and a subsequent decrease from 2005 to 2018 (annual percentage change −1.79; 95% CI −2.28 to −1.31, pConclusionsThe use of primary hormonal therapy in endometrioid type endometrial cancer increased over time in patients aged ≤40 years and among elderly patients. The observed trends in the current use of hormonal therapy support the need to study the effect of hormonal treatment in elderly patients and as adjuvant treatment in advanced stage endometrial cancer.

Objective. Surgical care for advanced stage epithelial ovarian cancer (EOC) patients has been centralized in the Netherlands since 2012. We evaluated whether the likelihood for patients to undergo surgery depends on the hospital of initial diagnosis before and after centralization of surgical care. Methods. Patients with EOC FIGO stage IIB-IV, diagnosed in the Netherlands between 2000 and 2015, were identified from the Netherlands Cancer Registry. Multilevel multivariate logistic regression was used to study the association between hospital of diagnosis and patients' likelihood of undergoing surgery in subsequent time periods. Furthermore, changes in overall survival were analyzed by multivariable Cox regression models. Results. 15,314 EOC patients were selected from the NCR. Hospital of diagnosis was identified as a significant level for patients' likelihood of undergoing surgery in 2000-2005 (LR test p < 0.001), as well as in 2006-2011 (LR test p = 0.002) but not in 2012-2015 (LR test p = 0.127). Patients who underwent surgery in 2012-2015 had a better survival when compared to 2006-2011 (HR 0.90(0.84-0.96)). Conclusion. This study shows that centralization of surgical care resolved the variation between hospitals in the probability to undergo cytoreductive surgery for patients with advanced EOC. Since centralization was established in 2012, the decision to operate patients seems solely attributable to patient and tumor characteristics. This supports the growing evidence in favor of centralizing (surgical) treatment for complex and heterogeneous diseases such as EOC. (C) 2017 Elsevier Inc. All rights reserved.

The aim of this study is to assess time trends of the risk of melanoma as a second primary cancer (MSPC) among cancer patients in the Netherlands during 1989-2008. Data from the population-based Netherlands Cancer Registry (NCR) were used for an analysis of time trends in the risk of MSPC in a fixed inception cohorts design (1989-1990, 1996-1997, and 2003), with similar lengths of follow-up. Standardized incidence ratios and absolute excess risks (AERs) were calculated to estimate the relative risks and excess absolute risks of MSPC. Differential time trends of risk in MSPC were observed, that is, decreasing for standardized incidence ratios and increasing for AERs in both sexes, but not reaching significance. Over time, AER changed from 24 to 72 per 10 000 person years (P for trend=0.01) in male patients with a previous melanoma during 2-5 years of follow-up, whereas among women with a first squamous cell carcinoma of skin, AER increased markedly (P for trend=0.3) over time during the first year of follow-up, coinciding with a decrease during the 2-5 years of the follow-up period (P for trend=0.1). MSPCs diagnosed later during follow-up were thicker than those diagnosed earlier, this difference being only statistically significant among male patients with a previous melanoma. The observed favorable risk trend among female patients coincided with thicker MSPCs than male patients. Differential risk trends were observed for MSPC among cancer patients during the past two decades in the Netherlands that did not seem to be affected by greater awareness of the disease. As the stage distribution of MSPCs worsened during follow-up, efforts should be made towards an earlier diagnosis of MSPC.

The influence of socioeconomic inequalities in pancreatic cancer patients and especially its effect in patients who had a resection is not known. Hospital type in which resection is performed might also influence outcome. Patients diagnosed with pancreatic cancer from 1989 to 2011 (n = 34,757) were selected from the population-based Netherlands Cancer Registry. Postal code was used to determine SES. Multivariable survival analyses using Cox regression were conducted to discriminate independent risk factors for death. Patients living in a high SES neighborhood more often underwent resection and more often were operated in a university hospital. After adjustment for clinicopathological factors, risk of dying was increased independently for patients with intermediate and low SES compared to patients with high SES. After resection, no survival difference was found among patients in the three SES groups. However, survival was better for patients treated in university hospitals compared to patients treated in non-university hospitals. Low SES was an independent risk factor for poor survival in patients with pancreatic cancer. SES was not an adverse risk factor after resection. Resection in non-university hospitals was associated with a worse prognosis.

Introduction To establish the impact of lymph node dissection and chemotherapy on survival in patients with early-stage epithelial ovarian cancer (EOC). Methods All Dutch patients with International Federation of Gynaecology and Obstetrics (FIGO) stage I–IIA and IIIA1 EOC between 2000 and 2012 were included. Data concerning age, stage, tumour grade, histological subtype, hospital type, lymph node dissection, adjuvant chemotherapy and survival were extracted from the Netherlands Cancer Registry. Results Of 3658 patients included, 1813 (49.6%) had lymph nodes removed. Relative survival of patients with lymph node dissection (including those with lymph node metastases) was significantly better than that of patients without, also after correcting for stage, tumour grade, histology and age (89% and 82%, respectively; relative excess risk [RER], 0.64; 95% confidence interval [CI]: 0.52–0.78). There was a positive correlation between the number of removed lymph nodes and overall survival (after excluding patients with lymph node metastases). Of patients with stage I–IIA EOC who had ≥10 lymph nodes removed, there was no difference in relative survival between those who received chemotherapy and those who did not (RER, 0.51; 95% CI: 0.15–1.64). This was also true for a subgroup of patients with high-risk features (stage IC and IIA and/or tumour grade 3 and/or clear cell histology [RER, 0.90; 95% CI: 0.46–1.99]). Conclusion Adequate dissection of at least 10 but preferably ≥20 lymph nodes should be standard procedure for the staging of early-stage EOC. Adjuvant chemotherapy after an adequate lymph node dissection does not seem to contribute to a better relative survival.

Migrant populations experience a health transition that influences their cancer risk, determined by environmental changes and acculturation processes. In this retrospective cohort study, we investigated differences in breast and stomach cancer risk and survival in migrants to the Netherlands. Invasive breast and stomach cancer cases diagnosed between 1996 and 2006 were selected from the Netherlands Cancer Registry. Standardized incidence ratios (SIR) were computed as the ratio of observed and expected cancers. Differences in the survival were expressed as hazard ratio (HR) using Cox regression and relative survival rates (RSR). All migrant women exhibited a significantly lower risk for breast cancer compared with Dutch natives. However, 5-year RSR was lower in all migrants (range 68-73%) compared with Dutch natives (85%). Death rates were increased in Moroccan [HR = 1.2 (1.0-1.5)] and reduced in Indonesian [HR = 0.8 (0.8-0.9)] patients with breast cancer. The incidence of noncardia stomach cancer was significantly elevated in all migrants, being highest in Turkish males [SIR = 1.9 (1.6-2.3)]. Cardia stomach cancer was less frequent in all migrants, being lowest in Surinamese males [SIR = 0.3 (0.2-0.6)]. Death rates for stomach cancer were lower in patients from Morocco [HR = 0.6 (0.4-0.9)], whereas 1-year RSR for stomach cancer was better in all migrant groups. Both lower breast cancer rates and higher stomach cancer rates point to a strong link between environmental exposures, behavioural patterns and cancer risk during the life course. Favourable risks in migrants should be sustained as long as possible whereas survival disparities require careful monitoring and counteraction with preventive means as well as improved access to healthcare. European Journal of Cancer Prevention 20:150-156 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Background: The clinical and prognostic evaluation of cervical and vaginal tumors other than squamous cell and adenocarcinomas is hampered by the low incidence, and clinical and epidemiological studies on these uncommon tumors are scarce. Having close affinity with the pathology laboratories, the Netherlands Cancer Registry offers a great opportunity to study frequency, stage, treatment, and survival of uncommon tumors in the cervix and vagina and separately, the clear cell adenocarcinoma of the vagina and cervix. Methods: All invasive cervical tumors (n = 10,570) and all in situ and invasive vaginal tumors (n = 778) diagnosed in the Netherlands during 1989-2003 were selected from the Netherlands Cancer Registry. Age, stage at diagnosis, and treatment were described for each histological subgroup to find differences between common and uncommon tumors, including 5-year relative survival rates. Results: Twenty-five patients (3%) with cervical cancer subsequently developed a vaginal tumor (during 1989-2003), and 19 of these patients underwent hysterectomy for their cervical cancer. A significantly worse prognosis was found for patients with small cell neuroendocrine cervical tumors and for patients with vaginal melanomas. Patients with clear cell adenocarcinoma of the vagina and cervix were found across all age categories. Conclusions: The less common histological types of cervical and vaginal cancers were clearly different from squamous cell carcinomas, especially with respect to age at diagnosis and survival rates. Spreading population-based knowledge of effects of treatment of these uncommon tumors should help clinical decision making and therefore improve prognosis.

With respect to cervical cancer management, Finland and the Netherlands are comparable in relevant characteristics, e.g., fertility rate, age-of-mother at first birth and a national screening programme for several years. The aim of this study is to compare trends in incidence of and mortality from cervical cancer in Finland and the Netherlands in relation to the introduction and intensity of the screening programmes. Therefore, incidence and mortality rates were calculated using the Cancer Registries of Finland and the Netherlands. Data on screening intensity were obtained from the Finnish Cancer Registry and the Dutch evaluation centre at ErasmusMC-Rotterdam. Women aged 30-60 have been screened every 5 years, in Finland since 1992 and in the Netherlands since 1996. Screening protocols for smear taking and referral to the gynaecologist are comparable. Incidence and mortality rates have declined more in Finland. In 2003, age-adjusted incidence and mortality in Finland were 4.0 and 0.9 and in the Netherlands 4.9 and 1.4 per 100,000 woman-years, respectively. Excess smear use in the Netherlands was estimated to be 24 per 1,000 women during a 5-year interval compared to 121 in Finland. The decline in mortality in Finland seems to be almost completely related to the screening programme whereas in the Netherlands it was initially considered to be a natural decline. Differences in risk factors might also play a role: the Netherlands has higher population density and higher percentages of immigrants and (female) smokers. The greater excess smear use in Finland might also have affected incidence. (c) 2007 Wiley-Liss, Inc.

Incidence of cancer may vary within a country and over time because of previous differences in exposure to risk factors or interventions for early detection (screening). This study describes time-space trends of incidence of common cancer sites across the Netherlands during the period 1989-2003 and speculates on the reasons for the observations. From the Netherlands Cancer Registry, World standardized incidence rates per municipality were smoothed calculating weighted averages for each 2 km by 2 km grid of the population mid-points of neighbouring municipalities and presented as map animations. Spatial relative changes in incidence were estimated by comparing the periods 1989-1994 and 1998-2003. Complete time-space trends can be found as map animations on http://maps.ikcnet.nl. The incidence of cervical and stomach cancer (for both sexes) decreased, being higher in the cities than in the rural areas during all periods and contrasting the trends in colorectal and breast cancer. The relative increase in incidence of lung cancer among females was highest in the rural north, but the incidence remained higher in the cities of the mid-west Netherlands. For males, there was a marked decrease in lung cancer incidence across the country since 1991. Incidence of melanoma increased, rates being twice as high in the coastal area than in the cities. Prostate cancer maps largely replicated the known history of PSA-testing in the Netherlands. Time-space cancer incidence patterns gave insight into effects of changes in exposure to risk determinants and early detection. The maps illustrate marked potential for cancer prevention at the national and regional level. (C) 2008 Wiley-Liss, Inc.

Background. Migrant populations usually experience a health transition with respect to their cancer risk as a result from environmental changes and acculturation processes. We investigated potentially contrasting experiences with breast and stomach cancer risk and survival in migrants to the Netherlands in a retrospective cohort study. Methods. Invasive breast (n = 96 126) and stomach cancer cases (n = 24 496) diagnosed 1996–2009 were selected from the population-based Netherlands Cancer Registry. Standardized Incidence Ratios (SIRs) were computed as the ratio of observed and expected cancers. Differences in survival were expressed as relative excess risk of mortality (RER). Results. Women from Morocco, Suriname and Turkey exhibited a significantly lower risk for breast cancer than native Dutch women (SIR range 0.5–0.9). Relative excess mortality was significantly increased in Surinamese (RER = 1.2, 95% CI 1.0–1.5) patients. The incidence of non-cardia stomach cancer was significantly elevated in all migrants, except in Indonesians, being highest in Turkish males (SIR = 2.2, 1.9–2.6). Cardia stomach cancer appeared to be less frequent in all migrants, being lowest in Surinamese males (SIR = 0.3, 0.2–0.5). Relative excess mortality was significantly lower in patients from the Antilles (RER = 0.7, 0.5–1.0), Suriname (0.8, 0.6–0.9) and Turkey (0.7, 0.6–0.9). Conclusion. The lower incidence rates of breast and cardia stomach cancer in migrants as well as their higher non-cardia stomach cancer rates reflect most likely early life exposures including pregnancy and/or dietary patterns during life-course. While higher relative excess mortality from breast cancer in migrant women might point toward inadequate access and treatment in this group, lower excess mortality from (especially non-cardia) stomach cancer remains to be explained

Introduction: Corpus uteri cancer is the most common malignancy of the female reproductive tract in industrialized countries, and its incidence is increasing. Although most of these tumors are of the common endometrial type, there are also many uncommon tumors of the corpus uteri. We examined the incidence and survival of patients with uncommon epithelial tumors, carcinosarcomas, and sarcomas of the corpus uteri diagnosed since 1989. Methods: All common and uncommon malignancies of the corpus uteri registered in the nationwide population-based Netherlands Cancer Registry (NCR) during 1989-2008 were included (n = 30,960). The histological subtypes were described according to the Blaustein classification system. Age-standardized incidence for 1989-2008 was calculated per 1,000,000 person-years (p-y), and relative survival was calculated according to the type of uncommon tumor. Results: The incidence of corpus uteri malignancies increased from 159 to 177 per 1,000,000 p-y, mainly owing to the rise in endometrioid adenocarcinomas from 106 to 144 per 1,000,000 p-y. In contrast, the incidence of uncommon epithelial endometrial carcinomas (UEECs) decreased from 30 to 13 per 1,000,000 p-y, although carcinosarcomas increased slightly from 5.1 to 6.9 per 1,000,000 p-y. Furthermore, a remarkable shift in incidence of endometrial stromal cell sarcomas (ESS) was observed from high-grade ESSs to low-grade ESSs after 2003. Five-year relative survival for patients with UEEC decreased from 72% to 54% and for patients with serous adenocarcinoma from 73% to 51%. Coinciding with an increase in the incidence of common adenocarcinoma of the corpus uteri, there was a decline in uncommon adenocarcinomas and more or less a stable incidence of sarcomas and carcinosarcomas. Conclusion: The decrease in UEEC tumors consisted largely of fewer serous carcinomas, possibly and likely reflecting a more precise histopathological classification of villoglandular tumors. Unfortunately, relative survival for patients with UEEC, sarcomas, and carcinosarcomas did not improve over the study period, indicating a need for more research on treatment strategies for this group of patients.

We explored trends in incidence and mortality of cervical cancer by age, stage and morphology, and linked the observed trends to screening activities. Data was retrieved from the Netherlands Cancer Registry during 1989-2007 (incidence) and Statistics Netherlands during 1970-2007 (mortality). Trends were evaluated by calculating the estimated annual percentage change (EAPC). Joinpoint regression analysis was used to detect changes in trends. Cervical intraepithelial neoplasia (CIN) detection rates were calculated by data from "the nationwide network and registry of histo- and cytopathology" during 1990-2006. Total age-adjusted incidence rate (European standardized rate (ESR)) was 7.9 per 100,000 woman years in 2007. During 1989-1998, incidence rates decreased with an EAPC of -1.3% (95% confidence interval (CI) -2.2 to -0.3), during 1998-2001 with -6.7% (95% CI: -16.4 to 4.1), and increased during 2001-2007 with 2.3% (95% CI: 0.4 to 4.2). Total mortality ESR was 1.9 per 100,000 woman years in 2007. Mortality rates decreased during 1970-1994 annually with -4.1% (95% CI: -4.6% to -3.7%), and with -2.6% (95% CI: -3.8% to -1.5%) during 1994-2007. The observed trend in total incidence is similar to the trend in squamous cell carcinomas in age group 35-54 years, suggesting that the observed trends are likely to be associated to changes in the screening program. This is supported by the trend in CINIII detection rates. In conclusion, incidence and mortality overall decreased and leveled off. On top of that there was an extra decrease that was compensated by a following recent increase in incidence, probably resulting from reorganization of the Dutch screening program.

Background: Survival differences in stomach cancer are depended on patient, tumour and treatment factors. Some populations are more prone to develop stomach cancer, such as people with low socioeconomic status (SES). The aim of this population based study was to assess whether differences in socioeconomic status (SES) alone, after adjusting for confounding factors, also influence survival. Methods: From 1989 to 2007 all patients with stomach cancer were selected from the cancer registry of the Comprehensive Cancer Centre North-East. Postal code at diagnosis was used to determine SES, dividing patients in three groups; low, intermediate and high SES. Associations between age, localization, grade, stage, and treatment were determined using Chi-square analysis. Relative survival analysis was used to estimate relative excess risk (RER) of dying according to SES. Results: In low SES neighbourhoods diagnosis was established at older age. More distal tumours were detected in patients with low SES, whereas pathology showed more poorly differentiated tumours in patients with high SES. Overall, more resections were performed in, and more chemotherapy was administrated to patients in high SES neighbourhoods. After adjusting for confounding factors, the risk of dying was lower for patients with high SES (RER 0.89,95% Confidence Interval 0.81-0.98) compared to patients with low SES. Conclusion: SES proved to be an independent prognostic factor for survival in patients with stomach cancer. (C) 2011 Elsevier Ltd. All rights reserved.

Recommendations for the age to initiate cervical cancer screening should be directed towards maximum detection of early cervical cancer. However, the screening programme should do more good than harm. The aim of this analysis was to determine whether the target age for cervical cancer screening should be lowered in view or apparent increases in new cases of invasive cancer below age 30 and in age group 30-44 years in The Netherlands. Therefore, all cervical cancer cases diagnosed between January 1, 1989 and December 31, 2003 were selected from the nationwide population-based Netherlands Cancer Registry. For age group 25-39 years, incidence data were also available for 2004 and 2005. To describe trends, the estimated annual percentage of change and joinpoint analysis were used. Between ages 25 and 28 years, the absolute number of new cases of cervical cancer annually has varied between 0 and 9 per age. Significantly decreasing trends in incidence were observed for age groups 35-39 and 45-49 (p < 0.0001 and p = 0.01, respectively). The annual number of deaths fluctuated with a decreasing trend for age groups 30-34 and 35-39 years (p = 0.01 and p = 0.03, respectively). Because the incidence and mortality rates for cervical cancer among women younger than 30 are low and not increasing, lowering the age for cervical cancer screening is not useful at this time. Although the number of years of life gained is high for every case of cervical cancer prevented, the disadvantages of lowering the screening age would be very large and even become disproportionate compared to the potential advantages. (C) 2008 Wiley-Liss, Inc.