Development and Internal Validation of Nomograms for Survival of Advanced Epithelial Ovarian Cancer Based on Established Prognostic Factors and Hematologic Parameters.

Objective: To assess the association between pretreatment thrombocytosis, anemia, and leukocytosis and overall survival (OS) of advanced-stage EOC. Furthermore, to develop nomograms using established prognostic factors and pretreatment hematologic parameters to predict the OS of advanced EOC patients. Methods: Advanced-stage EOC patients treated between January 1996 and January 2010 in eastern Netherlands were included. Survival outcomes were compared between patients with and without pretreatment thrombocytosis (≥450,000 platelets/µL), anemia (hemoglobin level of <7.5 mmol/L), or leukocytosis (≥11.0 × 109 leukocytes/L). Three nomograms (for ≤3-, ≥5-, and ≥10-year OS) were developed. Candidate predictors were fitted into multivariable logistic regression models. Multiple imputation was conducted. Model performance was assessed on calibration, discrimination, and Brier scores. Bootstrap validation was used to correct for model optimism. Results: A total of 773 advanced-stage (i.e., FIGO stages IIB-IV) EOC patients were included. The median [interquartile range, IQR] OS was 2.3 [1.3-4.2] and 3.0 [1.4-7.0] years for patients with and without pretreatment thrombocytosis (p < 0.01). The median OS was not notably different for patients with and without pretreatment leukocytosis (p = 0.58) or patients with and without pretreatment anemia (p = 0.07). The final nomograms comprised established predictors with either pretreatment leukocyte or platelet count. The ≥5- and ≥10-year OS models demonstrated good calibration and adequate discrimination with optimism-corrected c-indices [95%-CI] of 0.76 [0.72-0.80] and 0.78 [0.73-0.83], respectively. The ≤3-year OS model demonstrated suboptimal performance with an optimism-corrected c-index of 0.71 [0.66-0.75]. Conclusions: Pretreatment thrombocytosis is associated with poorer EOC survival. Two well-performing models predictive of ≥5-year and ≥10-year OS in advanced-stage EOC were developed and internally validated.

Survival of Women with Advanced Stage Cervical Cancer: Neo-Adjuvant Chemotherapy Followed by Radiotherapy and Hyperthermia versus Chemoradiotherapy.

AIM: To investigate and compare overall survival (OS), disease-free survival (DFS) and toxicity of women who underwent either chemoradiotherapy with or without prior lymph node debulking or upfront chemotherapy followed by radiotherapy and hyperthermia (triple therapy) for locally advanced cervical cancer (LACC) to identify a potential role for triple therapy. METHODS: Women with histologically proven LACC and with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB2 and IIA2 to IVA were included. Cox regression analyses were used for calculating hazard ratios and to adjust for confounding variables. A multivariable logistic regression analysis was used to examine the influence of covariates on toxicity. RESULTS: A total of 370 patients were included of whom 58% (n = 213) received chemoradiotherapy (CRT), 18% (n = 66) received node-debulking followed by chemoradiotherapy (LND-CRT) and 25% (n = 91) received triple therapy (TT). Five-year OS was comparable between the three treatment groups, with 53% (95% confidence interval 46-59%) in the CRT group, 45% (33-56%) in the LND-CRT group and 53% (40-64%) in the TT group (p = 0.472). In the adjusted analysis, 5-year OS and DFS were comparable between the three treatment groups. No chemotherapy-related differences in toxicity were observed. CONCLUSION: This study suggests that the toxicity and survival of TT is similar to CRT or LND-CRT.

Diagnostic accuracy of MRI, CT, and [18F]FDG-PET-CT in detecting lymph node metastases in clinically early-stage cervical cancer - a nationwide Dutch cohort study.

OBJECTIVES: Imaging is increasingly used to assess lymph node involvement in clinically early-stage cervical cancer. This retrospective study aimed to evaluate the diagnostic accuracy of MRI, CT, and [18F]FDG-PET-CT. METHODS: Women with International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage IA2-IIA cervical cancer and pretreatment imaging between 2009 and 2017 were selected from the Netherlands Cancer Registry. Patient-based and region-based (i.e. pelvic and common iliac) nodal status was extracted from radiology reports. Pathology results were considered the reference standard for calculating accuracy indices. Multiple imputation was used for missing pathology to limit verification bias risk. RESULTS: Nodal assessment was performed in 1676 patients with MRI, 926 with CT, and 379 with [18F]FDG-PET-CT, with suspicious nodes detected in 17%, 16%, and 48%, respectively. [18F]FDG-PET-CT was used to confirm MRI/CT results in 95% of patients. Pathology results were imputed for 30% of patients. [18F]FDG-PET-CT outperformed MRI and CT in detecting patient-based nodal metastases with sensitivities of 80%, 48%, and 40%, and AUCs of 0.814, 0.706, and 0.667, respectively, but not in specificity: 79%, 92%, and 92%. Region-based analyses showed similar indices in the pelvic region, but worse performance in the common iliac region with AUCs of 0.575, 0.554, and 0.517, respectively. CONCLUSIONS: [18F]FDG-PET-CT outperformed MRI and CT in detecting nodal metastases, which may be related to its use as a verification modality. However, MRI and CT had the highest specificity. As MRI is generally performed routinely to assess local and regional spread of cervical cancer, [18F]FDG-PET-CT can be used to confirm suspicious nodes. CRITICAL RELEVANCE STATEMENT: Accurate assessment of the nodal status in clinically early-stage cervical cancer is essential for tumour staging, treatment decision making and prognosis. KEY POINTS: • The accuracy of MRI, CT or [18F]FDG-PET-CT for nodal staging in early cervical cancer is a subject of discussion. • Overall, [18F]FDG-PET-CT outperformed MRI, followed by CT, when used as a verification modality. • Staging with MRI and the addition of [18F]FDG-PET-CT to verify high-risk cases seems to be a good approach.

Treatment Strategies Guided by [18F]FDG-PET/CT in Patients with Locally Advanced Cervical Cancer and [18F]FDG-Positive Lymph Nodes.

BACKGROUND: Modern treatment guidelines for women with advanced cervical cancer recommend staging using 2-deoxy-2-[18F]fluoro-D-glucose positron emission computed tomography ([18F]FDG-PET/CT). However, the risk of false-positive nodes and therapy-related adverse events requires caution in treatment planning. Using data from the Netherlands Cancer Registry (NCR), we estimated the impact of [18F]FDG-PET/CT on treatment management in women with locally advanced cervical cancer, i.e., on nodal boosting, field extension, and/or debulking in cases of suspected lymph nodes. METHODS: Women diagnosed between 2009 and 2017, who received chemoradiotherapy for International Federation of Gynaecology and Obstetrics (2009) stage IB2, IIA2-IVB cervical cancer with an [18F]FDG-positive node, were retrospectively selected from the NCR database. Patients with pathological nodal examination before treatment were excluded. The frequency of nodal boosting, extended-field radiotherapy, and debulking procedures applied to patients with [18F]FDG-positive lymph nodes was evaluated. RESULTS: Among the 434 eligible patients with [18F]FDG-positive nodes, 380 (88%) received interventions targeting these lymph nodes: 84% of these 380 patients received nodal boosting, 78% extended-field radiotherapy, and 12% debulking surgery. [18F]FDG-positive nodes in patients receiving these treatments were more likely to be classified as suspicious than inconclusive (p = 0.009), located in the para-aortic region (p < 0.001), and larger (p < 0.001) than in patients who did not receive these treatments. CONCLUSION: While existing guidelines advocate [18F]FDG-PET/CT-guided treatment planning for the management of advanced cervical cancer, this study highlights that not all cases of [18F]FDG-positive nodes received an intervention, possibly due to the risk of false-positive results. Improvement of nodal staging may reduce suboptimal treatment planning.

Confirmation of the utility of the CA-125 elimination rate (KELIM) as an indicator of the chemosensitivity in advanced-stage ovarian cancer in a "real-life setting".

OBJECTIVE: The modeled CA-125 ELIMination rate constant K (KELIM) has been validated as a marker of response to chemotherapy in >12,000 patients with advanced epithelial ovarian carcinoma (EOC) treated in first-line setting enrolled in >12 clinical trials. Patient KELIM is calculable online https://www.biomarker-kinetics.org/presentation. The objective was to investigate the prognostic value of KELIM in a large real-life national cancer registry with non-selected patients. METHODS: We investigated 4,025 EOC patients from the Netherlands Cancer Registry treated with neoadjuvant chemotherapy (NACT) ± followed by interval debulking surgery (IDS). Patient KELIM values were calculated in patients with ≥ 3 CA-125 measurements during NACT. KELIM was standardized with a pre-specified cut-off and scored as unfavorable/favorable (<1.0/≥1.0). KELIM's prognostic value regarding radiological response, completeness of IDS, progression-free survival (PFS), and overall survival (OS) was assessed using univariate/multivariate analyses. RESULTS: The data from 1,582 patients treated with heterogeneous chemotherapy regimens and sequences were assessable. KELIM was prognostic for radiological response and the likelihood of complete IDS after NACT (odds ratio=2.59; 95% confidence interval [CI]=2.04-3.29). Moreover, KELIM was independently associated with PFS (hazard ratio [HR]=0.76; 95% CI=0.66-0.87), and OS (HR=0.79; 95% CI=0.69-0.91). Combining KELIM with the completeness of the IDS resulted in 3 prognostic groups (satisfactory, intermediate, and poor) with significant OS differences, namely a good, intermediate, and poor survival respectively. CONCLUSION: The value of KELIM, as a pragmatic indicator of response to chemotherapy, was maintained in a large real-life population-based cohort, highlighting its applicability in routine conditions.

Vulvar squamous cell carcinoma in women 80 years and older: Treatment, survival and impact of comorbidities.

BACKGROUND: Despite being a disease of mainly older women, little is known about the clinical management of older women with vulvar squamous cell carcinoma (VSCC). We evaluated their daily clinical management compared with younger women, and established the prevalence of comorbidities and its impact on overall survival (OS). METHODS: All Dutch women diagnosed with VSCC from 2015 to 2020 (n = 2249) were selected from the Netherlands Cancer Registry. Women aged ≥80 years (n = 632, 28%) were defined as "older" patients, women <80 years were considered as "younger". Chi-square tests were performed to evaluate differences in treatment by age group and comorbidities. Differences in OS were evaluated using Kaplan-Meier Curves and log-rank test. RESULTS: The vast majority of both older (91%) and younger (99%) patients with FIGO IA VSCC received surgical treatment of the vulva. Older FIGO IB-IV VSCC patients were less likely to undergo groin surgery than younger patients (50% vs. 84%, p < 0.01). Performance of surgical treatment of the vulva and groin(s) was not associated with the number of comorbidities in older patients (p = 0.67 and p = 0.69). Older patients with ≥2 comorbidities did have poorer OS compared to women with one or no comorbidities (p < 0.01). CONCLUSION: The vast majority of older patients underwent vulvar/local surgery. Older patients less often received groin surgery compared to younger patients. The majority of older patients had at least one comorbidity, but this did not impact treatment choice. The poorer survival in older VSCC patients may therefore be due to death of competing risks instead of VSCC itself.

Impact of Sepsis on the Oncologic Outcomes of Advanced Epithelial Ovarian Cancer Patients: A Multicenter Observational Study.

OBJECTIVE: The sepsis-induced inflammatory response may potentially affect malignant cells. Recently, a case of spontaneous regression of a histologically confirmed International Federation of Gynecology and Obstetrics (FIGO) stage IIIC epithelial ovarian cancer (EOC) following sepsis was reported. The aim of our study was to assess the impact of sepsis on the oncologic outcomes of advanced-stage EOC patients. METHODS: Gynecologic oncologic patients admitted to the Intensive Care Unit of three oncologic centers between 2006 and 2019 were identified and patients who experienced sepsis following advanced-stage EOC diagnosis were selected. Survival outcomes were compared with advanced-stage EOC patients from the Netherlands Cancer Registry (NCR). To correct for case-mix differences, propensity score matching using 1:3 nearest neighbor matching was conducted after which survival analyses were repeated. RESULTS: A total of 18 of 215 patients with advanced-stage EOC experienced sepsis. Sepsis patients had similar distributions of patient, tumor, and treatment characteristics to 3988 patients from the NCR cohort. A total of 3 of 18 patients died from the complications of sepsis. While the remaining patients initially responded to treatment, 14/15 patients relapsed. The median (IQR) overall survival was 31 (24-44) and 35 (20-60) months for the sepsis and unmatched NCR cohort (p = 0.56), respectively. The median (IQR) progression-free survival was 16 (11-21) and 16 (11-27) months (p = 0.90), respectively. Survival outcomes did not differ following propensity matching (overall survival of 31 (24-44) vs. 36 (20-56) months, p = 0.40; progression-free survival of 16 (11-21) and 16 (12-21) months, p = 0.72). CONCLUSION: In this observational study, the occurrence of sepsis did not affect the oncologic and survival outcomes of advanced-stage EOC patients.

Incidence of gynaecological cancer during the COVID-19 pandemic: A population-based study in the Netherlands.

OBJECTIVE: To study the impact of the COVID-19 pandemic and consequent lockdown on the number of diagnoses of gynaecological malignancies in the Netherlands. METHODS: We performed a retrospective cohort study using data from the Netherlands Cancer Registry (NCR) on women of 18 years and older diagnosed with invasive endometrial, ovarian, cervical or vulvar cancer in the period 2017-2021. Analyses were stratified for age, socioeconomical status (SES) and region. RESULTS: The incidence rate of gynaecological cancer was 67/100.000 (n = 4832) before (2017-2019) and 68/100.000 (n = 4833) during (2020) the COVID-19 pandemic. Comparing the number of diagnoses of the two periods for the four types of cancer separately showed no significant difference. During the first wave of COVID-19 (March-June 2020), a clear decrease in number of gynaecological cancer diagnoses was visible (20-34 %). Subsequently, large increases in number of diagnoses were visible (11-29 %). No significant differences in incidence were found between different age groups, SES and regions. In 2021 an increase of 5.9 % in number of diagnoses was seen. CONCLUSION: In the Netherlands, a clear drop in number of diagnoses was visible for all four types of gynaecological cancers during the first wave, with a subsequent increase in number of diagnoses in the second part of 2020 and in 2021. No differences between SES groups were found. This illustrates good organisation of and access to health care in the Netherlands.

A federated approach to identify women with early-stage cervical cancer at low risk of lymph node metastases.

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.

Stage, treatment and survival of low-grade serous ovarian carcinoma in the Netherlands: A nationwide study.

INTRODUCTION: Serous ovarian carcinomas constitute the largest group of epithelial ovarian cancer (60%-75%) and are further classified into high- and low-grade serous carcinoma. Low-grade serous carcinoma (LGSC) is a relatively rare subtype (approximately 5% of serous carcinomas) and epidemiologic studies of large cohorts are scarce. With the present study we aimed to report trends in stage, primary treatment and relative survival of LGSC of the ovary in a large cohort of patients in an effort to identify opportunities to improve clinical practice and outcome of this relatively rare disease. MATERIAL AND METHODS: Patients diagnosed with LGSC between 2000 and 2019 were identified from the Netherlands Cancer Registry (n = 855). Trends in FIGO stages and primary treatment were analyzed with the Cochran-Armitage trend test, and differences in and trends of 5-year relative survival were analyzed using multivariable Poisson regression. RESULTS: Over time, LGSC was increasingly diagnosed as stage III (39.9%-59.0%) and IV disease (5.7%-14.4%) and less often as stage I (34.6%-13.5%; p < 0.001). Primary debulking surgery was the most common strategy (76.2%), although interval debulking surgery was preferred more often over the years (10.6%-31.1%; p < 0.001). Following primary surgery, there was >1 cm residual disease in only 15/252 patients (6%), compared with 17/95 patients (17.9%) after interval surgery. Full cohort 5-year survival was 61% and survival after primary debulking surgery was superior to the outcome following interval debulking surgery (60% vs 34%). Survival following primary debulking surgery without macroscopic residual disease (73%) was better compared with ≤1 cm (47%) and >1 cm residual disease (22%). Survival following interval debulking surgery without macroscopic residual disease (51%) was significantly higher than after >1 cm residual disease (24%). Except FIGO stage II (85%-92%), survival did not change significantly over time. CONCLUSIONS: Over the years, LGSC has been diagnosed as FIGO stage III and stage IV disease more often and interval debulking surgery has been increasingly preferred over primary debulking in these patients. Relative survival did not change over time (except for stage II) and worse survival outcomes after interval debulking surgery were observed. The results support the common recommendation to perform primary debulking surgery in patients eligible for primary surgery.

Evaluation of external validity of the OVHIPEC-1 trial in a real-world population.

OBJECTIVE: The OVHIPEC-1 trial (Phase III randomised clinical trial for stage III ovarian carcinoma randomising between interval cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy) showed improved survival when interval cytoreductive surgery (CRS) was combined with hyperthermic intraperitoneal chemotherapy in patients with stage III epithelial ovarian cancer (EOC). The authors compared the control arm of the trial with a real-world population treated in the Netherlands during the same period to explore generalizability of the trial results. METHODS: For this nationwide comparative cohort study, all patients with EOC undergoing interval CRS between 2007 and 2016 were identified from the Netherlands Cancer Registry if they fulfilled the eligibility criteria of OVHIPEC-1 (n = 1376). Patient and treatment characteristics, and overall survival (OS) were compared between trial and real-world populations. RESULTS: Age, comorbidity, BRCA status, histologic subtype, and residual disease were similar in trial and real-world patients. Trial patients had a better performance status, higher socioeconomic status, and underwent bowel surgery more often. In a real-world setting, patients more often received more than six cycles. The difference in OS between the trial and the real-world populations was not statistically significant (unadjusted hazard ratio, 1.09 [95% confidence interval, 0.87-1.37]; P = 0.44). CONCLUSION: Despite differences in patient characteristics, OS of patients treated in the control arm of OVHIPEC-1 was similar to patients treated outside the trial. The trial population accurately represents real-world patients with stage III EOC undergoing interval CRS in terms of outcome.

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.

Establishment of the Dutch Nationwide, Interdisciplinary Infrastructure and Biobank for Fundamental and Translational Ovarian Cancer Research: Archipelago of Ovarian Cancer Research.

OBJECTIVES: Ovarian cancer has the worst overall survival rate of all gynecologic malignancies. For the majority of patients, the 5-year overall survival rate of less than 50% has hardly improved over the last decades. To improve the outcome of patients with all subtypes of ovarian cancer, large-scale fundamental and translational research is needed. To accommodate these types of ovarian cancer research, we have established a Dutch nationwide, interdisciplinary infrastructure and biobank: the Archipelago of Ovarian Cancer Research (AOCR). The AOCR will facilitate fundamental and translational ovarian cancer research and enhance interdisciplinary, national, and international collaboration. DESIGN: The AOCR biobank is a prospective ovarian cancer biobank in which biomaterials are collected, processed, and stored in a uniform matter for future (genetic) scientific research. All 19 Dutch hospitals in which ovarian cancer surgery is performed participate and collaborate in the AOCR biobank. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients of 16 years and older with suspected or diagnosed ovarian, fallopian tube, or primary peritoneal cancer are recruited for participation. Patients who agree to participate give written informed consent for collection, storage, and issue of their biomaterials for future studies. After inclusion, different blood samples are taken at various predefined time points both before and during treatment. In case of a diagnostic paracentesis or biopsy, the residual biomaterials of these procedures are stored in the biobank. During surgery, primary tumor tissue and, if applicable, tissue from metastatic sites are collected and stored. From each patient, a representative histological hematoxylin and eosin stained slide is digitalized for research purposes, including reassessment by a panel of gynecologic pathologists. Clinical and pathological data are obtained on a per-study basis from Dutch registries. Research proposals for the issue of biomaterials and data are evaluated by both the Archipelago Scientific Committee and the Steering Committee. Researchers using the biomaterials from the AOCR biobank are encouraged to enrich the biobank with data and materials resulting from their analyses and experiments. LIMITATIONS: The implementation and first 4 years of collection are financed by an infrastructural grant from the Dutch Cancer Society. Therefore, the main limitation is that the costs for sustaining the biobank after the funding period will have to be covered. This coverage will come from incorporation of budget for biobanking in future grant applications and from fees from external researchers and commercial parties using the biomaterials stored in the AOCR biobank. Moreover, we will apply for grants aimed at sustaining and improving research infrastructures and biobanks. CONCLUSIONS: With the establishment of the Dutch nationwide, interdisciplinary Archipelago of Ovarian Cancer Research infrastructure and biobank, fundamental and translational research on ovarian cancer can be greatly improved. The ultimate aim of this infrastructure is that it will lead to improved diagnostics, treatment, and survival of patients with ovarian cancer.

Does the New FIGO 2018 Staging System Allow Better Prognostic Differentiation in Early Stage Cervical Cancer? A Dutch Nationwide Cohort Study.

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.

End-of-life care for patients with advanced ovarian cancer in the Netherlands: A retrospective registry-based analysis.

OBJECTIVE: Patients with advanced ovarian cancer have a poor prognosis and can experience debilitating symptoms in the last phase of life. Several analyses, mainly performed in the United States (US), show high rates of chemotherapy administration and hospital visits near the end-of-life in this patient category. No large European studies are available, while the organisation of palliative care differs between the US and Europe. We aimed to analyse the intensity of inpatient care near the end-of-life in the Netherlands and perform a cross-study comparison with previous reports. METHODS: All patients with ovarian cancer that died in 2016 and 2017 were identified from the Vektis database, a data warehouse including all insurance declarations in the Netherlands. For the last 6 months of life the following parameters of aggressive care were extracted: administration of chemotherapy, emergency room (ER) visits, surgical procedures, hospital and intensive care unit (ICU) admissions. The intensity of inpatient care was compared to previously reported European and US data. RESULTS: Data on medical care use was available for 1775 patients. During the last 6 months of life, half of the ovarian cancer patients were admitted to hospital. Chemotherapy administration near the end-of-life was infrequent: 12% in the last month of life. Surgery and ICU admissions in the final 6 months of life were rare (<10%). Our cohort showed the lowest percentages of all five indicators of aggressive care reported thus far. CONCLUSION: Aggressive medical care use in the final 6 months of life in this Dutch cohort of ovarian cancer patients was lower than in other previously reported cohorts.

Ovarian cancer today and tomorrow: A global assessment by world region and Human Development Index using GLOBOCAN 2020.

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.

The prognostic value of the number of positive lymph nodes and the lymph node ratio in early-stage cervical cancer.

INTRODUCTION: To establish the impact of the number of lymph node metastases (nLNM) and the lymph node ratio (LNR) on survival in patients with early-stage cervical cancer after surgery. MATERIAL AND METHODS: In this nationwide historical cohort study, all women diagnosed between 1995 and 2020 with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IA2-IIA1 cervical cancer and nodal metastases after radical hysterectomy and pelvic lymphadenectomy from the Netherlands Cancer Registry were selected. Optimal cut-offs for prognostic stratification by nLNM and LNR were calculated to categorize patients into low-risk or high-risk groups. Kaplan-Meier overall survival analysis and flexible parametric relative survival analysis were used to determine the impact of nLNM and LNR on survival. Missing data were imputed. RESULTS: The optimal cut-off point was ≥4 for nLNM and ≥0.177 for LNR. Of the 593 women included, 500 and 501 (both 84%) were categorized into the low-risk and 93 and 92 (both 16%) into the high-risk groups for nLNM and LNR, respectively. Both high-risk groups had a worse 5-year overall survival (p < 0.001) compared with the low-risk groups. Being classified into the high-risk groups is an independent risk factor for relative survival, with excess hazard ratios of 2.4 (95% confidence interval 1.6-3.5) for nLNM and 2.5 (95% confidence interval 1.7-3.8) for LNR. CONCLUSIONS: Presenting a patient's nodal status postoperatively by the number of positive nodes, or by the nodal ratio, can support further risk stratification regarding survival in the case of node-positive early-stage cervical cancer.

Oncologic outcomes after splenectomy during initial cytoreductive surgery in advanced epithelial ovarian cancer: a nationwide population-based cohort study.

INTRODUCTION: Epithelial ovarian cancer (EOC) patients undergoing splenectomy during cytoreductive surgery represent a small subgroup of patients. Splenic metastases or technical reasons due to extensive upper abdominal disease may require a splenectomy. It has been hypothesized that as the spleen's antitumor immunologic functions may inhibit cancer growth, splenectomy may promote the growth of residual disease as observed in other cancer types of murine studies. The few studies assessing the impact of splenectomy on the oncologic outcomes of advanced stage EOC patients have reported inconsistent results. It remains unclear whether splenectomy during cytoreductive surgery is justified to achieve complete cytoreduction. The aim of this study was to assess the impact of a splenectomy on perioperative outcomes and survival of advanced stage EOC patients. MATERIAL AND METHODS: In this nationwide population-based study, all consecutive patients diagnosed with FIGO stage IIIC and IV EOC between 1 January 2008 and 31 December 2015 were identified from the Netherlands Cancer Registry. Patients who underwent cytoreductive surgery combined with platinum-based chemotherapy as primary treatment were selected. Differences in clinicopathologic characteristics between splenectomy and non-splenectomy patients were assessed. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier survival curves and log-rank tests. Cox proportional hazards models were used to adjust for covariates that influence survival. RESULTS: A total of 3911 patients were identified: 99 splenectomy and 3812 non-splenectomy patients. Splenectomy patients were more likely to undergo extensive surgery or surgical reintervention, to receive intraperitoneal chemotherapy, intraoperative and postoperative blood transfusion, to experience postoperative infections, and to be admitted to an intensive care unit (all p < 0.002). No significant differences in PFS or OS were observed between splenectomy vs non-splenectomy patients after adjusting for covariates. CONCLUSIONS: Although advanced stage EOC patients who undergo splenectomy during cytoreductive surgery have less favorable perioperative outcomes, no adverse impact of splenectomy on the survival of advanced stage EOC patients was observed. Splenectomy during cytoreductive surgery seems to be justified to achieve complete cytoreduction in advanced stage EOC patients.

Primary or adjuvant chemoradiotherapy for cervical cancer with intraoperative lymph node metastasis - A review.

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.

Clinicopathologic predictors of early relapse in advanced epithelial ovarian cancer: development of prediction models using nationwide data.

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.