Trends in incidence, treatment and survival of borderline ovarian tumors in the Netherlands: a nationwide analysis.

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 ratioadjusted 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.

Treatment patterns and associated factors in patients with advanced epithelial ovarian cancer: a population-based study.

OBJECTIVES: A 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. METHODS: All 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. RESULTS: A 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, p<0.001). Associated factors with no cancer-directed treatment were higher age, FIGO stage IV, lower socioeconomic status, co-morbidity, and more recent years of diagnosis (p<0.001). Main reasons for no cancer-directed treatment were patient's choice (40%) and poor condition of the patient (29%). CONCLUSIONS: The 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.

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.

Centralization of ovarian cancer in the Netherlands: Hospital of diagnosis no longer determines patients' probability of undergoing surgery.

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.

Quality improvement strategies for organizational change: a multiphase observational study to increase insight into nonparticipating organizations.

BACKGROUND: The scope of implementation research is often restricted to the analysis of organizations that participate voluntarily in implementation interventions. The recruitment of participants for a quality improvement collaborative increases awareness of the specific innovation. The objective of this multiphase observational study was to identify differences between organizations that participated in a large-scale implementation project aiming to improve perioperative care, functional recovery, and length of hospital stay after gynecologic surgery and organizations that did not participate. A secondary objective was to explore how perioperative practice changed among nonparticipants. METHODS: Of the seven gynecology departments of nonparticipating Dutch hospitals, five agreed to participate in a retrospective analysis. Baseline data of participating hospitals' (N = 19) characteristics, time to functional recovery, and length of hospital stay were compared. Outcome measures for the subsequent pre-post awareness study in the five nonparticipating hospitals were: (1) overall adherence to predefined evidence-based perioperative elements; and (2) change in functional recovery and length of hospital stay. Multivariable regression models, adjusted for baseline characteristics, were used for analysis. RESULTS: In retrospect, nonparticipating and participating hospitals did not differ in baseline characteristics, functional recovery, and length of hospital stay. In three of the five nonparticipating hospitals, adherence to the selected evidence-based perioperative elements increased significantly after awareness of the trial (overall mean difference 9.7%, 95% CI 6.9 to 12.5%, p <  0.001). Linear regression models revealed no statistically significant or clinically relevant differences in time to functional recovery (mean difference - 0.2 days, 95% CI -0.7 to 0.2, p = 0.319) or length of hospital stay (mean difference - 0.4 days, 95% CI -1.3 to 0.5, p = 0.419) in the nonparticipating hospitals. None of these hospitals managed to reduce time to functional recovery or length of hospital stay significantly. CONCLUSIONS: No differences in perioperative outcomes between the nonparticipating and participating hospitals were identified at baseline. Despite the statistically significant improvement in overall evidence-based perioperative care, the awareness raised by recruitment activities alone was not enough to reduce time to functional recovery and length of hospital stay in nonparticipating hospitals. Insight into the trends of nonparticipants is valuable to existing implementation effectiveness research.

Homologous Recombination Deficiency and Cyclin E1 Amplification Are Correlated with Immune Cell Infiltration and Survival in High-Grade Serous Ovarian Cancer.

BACKGROUND: How molecular profiles are associated with tumor microenvironment (TME) in high-grade serous ovarian cancer (HGSOC) is incompletely understood. Therefore, we analyzed the TME and molecular profiles of HGSOC and assessed their associations with overall survival (OS). METHODS: Patients with advanced-stage HGSOC treated in three Dutch hospitals between 2008-2015 were included. Patient data were collected from medical records. BRCA1/2 mutation, BRCA1 promotor methylation analyses, and copy number variations were used to define molecular profiles. Immune cells were assessed with immunohistochemical staining. RESULTS: 348 patients were categorized as BRCA mutation (BRCAm) (BRCAm or promotor methylation) (30%), non-BRCA mutated HRD (19%), Cyclin E1 (CCNE1)-amplification (13%), non-BRCAmut HRD and CCNE1-amplification (double classifier) (20%), and no specific molecular profile (NSMP) (18%). BRCAm showed highest immune cell densities and CCNE1-amplification lowest. BRCAm showed the most favorable OS (52.5 months), compared to non-BRCAmut HRD (41.0 months), CCNE1-amplification (28.0 months), double classifier (27.8 months), and NSMP (35.4 months). Higher immune cell densities showed a favorable OS compared to lower, also within the profiles. CD8+, CD20+, and CD103+ cells remained associated with OS in multivariable analysis. CONCLUSIONS: Molecular profiles and TME are associated with OS. TME differs per profile, with higher immune cell densities showing a favorable OS, even within the profiles. HGSOC does not reflect one entity but comprises different entities based on molecular profiles and TME.

Incidence and predictors of peritoneal metastases of gynecological origin: a population-based study in the Netherlands.

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.

Only complete tumour resection after neoadjuvant chemotherapy offers benefit over suboptimal debulking in advanced ovarian cancer.

OBJECTIVE: The aim of this study was to compare surgical results and survival outcome of advanced ovarian cancer patients who were treated with primary versus interval debulking surgery. STUDY DESIGN: In this retrospective study stage III and IV ovarian cancer patients who received debulking surgery from 2006 to 2015 were included. Surgical results were described as complete, optimal or suboptimal debulking and chi-square test was used to assess significant differences. Overall survival was measured using Kaplan-Meier curves, the log-rank test and uni- and multivariable Cox regression analyses. RESULTS: Of 146 patients included in the study, 55 patients were treated with primary debulking surgery (PDS) followed by adjuvant chemotherapy and 91 patients received neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS). Complete or optimal debulking (0-10mm of residual disease) was achieved in 76.4% (n=42) of the PDS group and in 79.1% (n=72) of the IDS group. Overall median survival was 38 months for PDS and 31 months for IDS, which was not significantly different (p=0.181). In the IDS group, a significant difference was found in OS between complete and optimal resection (p=0.013). Besides that, no difference in survival outcome was found in the IDS group between patients with optimal or suboptimal debulking (median survival were 20 and 19 months respectively). CONCLUSION: Complete debulking surgery is of utmost importance, both in case of PDS and IDS. Achieving optimal interval debulking of 1-10mm residual disease did not show any survival benefit over suboptimal interval debulking.