Hans H. B. Wenzel

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

AbstractIntroductionSerous 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 MethodsPatients 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.ResultsOver 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.ConclusionsOver 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.

Survival of patients with early-stage cervical cancer after abdominal or laparoscopic radical hysterectomy: a nationwide cohort study and literature review

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. 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 ≤4 cm (ii) median follow-up ≥30 months (iii) ≥5 events per predictor parameter in multivariable analysis or a propensity score. 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/≥2 cm) also gave similar survival rates. Review of nine studies showed no distinct advantage of ARH, especially in tumours <2 cm. After adjustment, our retrospective study showed equal oncological outcomes between ARH and LRH for early-stage cervical cancer - also in tumours <2 cm. This is in correspondence with results from our literature review.

Short‐term surgical complications after radical hysterectomy—A nationwide cohort study

AbstractIntroductionCentralization has, among other aspects, been argued to have an impact on quality of care in terms of surgical morbidity. Next, monitoring quality of care is essential in identifying areas of improvement. This nationwide cohort study was conducted to determine the rate of short‐term surgical complications and to evaluate its possible predictors in women with early‐stage cervical cancer.Material and methodsWomen diagnosed with early‐stage cervical cancer, 2009 FIGO stages IB1 and IIA1, between 2015 and 2017 who underwent radical hysterectomy with pelvic lymphadenectomy in 1 of the 9 specialized medical centers in the Netherlands, were identified from the Netherlands Cancer Registry. Women were excluded if primary treatment consisted of hysterectomy without parametrial dissection or radical trachelectomy. Women in whom radical hysterectomy was aborted during the procedure, were also excluded. Occurrence of intraoperative and postoperative complications and type of complications, developing within 30 days after surgery, were prospectively registered. Multivariable logistic regression analysis was used to identify predictors of surgical complications.ResultsA total of 472 women were selected, of whom 166 (35%) developed surgical complications within 30 days after radical hysterectomy. The most frequent complications were urinary retention with catheterization in 73 women (15%) and excessive perioperative blood loss &gt;1000 mL in 50 women (11%). Open surgery (odds ratio [OR] 3.42; 95% CI 1.73‐6.76), chronic pulmonary disease (OR 3.14; 95% CI 1.45‐6.79), vascular disease (OR 1.90; 95% CI 1.07‐3.38), and medical center (OR 2.83; 95% CI 1.18‐6.77) emerged as independent predictors of the occurrence of complications. Body mass index (OR 0.94; 95% CI 0.89‐1.00) was found as a negative predictor of urinary retention. Open surgery (OR 36.65; 95% CI 7.10‐189.12) and body mass index (OR 1.15; 95% CI 1.08‐1.22) were found to be independent predictors of excessive perioperative blood loss.ConclusionsShort‐term surgical complications developed in 35% of the women after radical hysterectomy for early‐stage cervical cancer in the Netherlands, a nation with centralized surgical care. Comorbidities predict surgical complications, and open surgery is associated with excessive perioperative blood loss.

No improvement in survival of older women with cervical cancer—A nationwide study

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. 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. 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]). 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.

Treatment of bulky lymph nodes in locally advanced cervical cancer: boosting versus debulking

Treatment strategies for bulky lymph nodes in patients with locally advanced cervical cancer scheduled for definitive chemoradiation include nodal boosting with radiotherapy, surgical debulking, or both. The aim of this retrospective cohort study was to compare survival and toxicity in patients receiving these treatments and to compare them with a group that received neither form of treatment. Women diagnosed between January 2009 and January 2017 with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB2, IIA2-IVA cervical cancer with lymph nodes ≥1.5 cm without upper limit on pretreatment imaging and treated with definitive chemoradiation were selected from the Netherlands Cancer Registry. Patients were categorized by intention-to-treat strategy: boosting, debulking, or neither treatment, with subgroup analysis for patients receiving both treatments, that is, debulking with boosting. Overall and relapse-free survival outcomes were compared by Kaplan-Meier and Cox regression analyses and toxicity by logistic regression analysis. Of 190 patients, 101 (53%) received only nodal boosting, 31 (16%) debulking alone, 29 (15%) debulking combined with boosting, and 29 (15%) received neither treatment. The 5 year overall and relapse-free survival for the treatment groups were 58%, 45% and 45% (p=0.19), and 47%, 44% and 46% (p=0.87), respectively. Multivariable Cox regression analyses demonstrated no differences in overall and relapse-free survival. Combination of debulking with boosting was associated with decreased overall and relapse-free survival compared with debulking alone (HR 2.47, 95% CI 1.22 to 5.00; and HR 2.37, 95% CI 1.14 to 4.93). Nodal boosting was independently associated with a decreased toxicity risk compared with debulking strategy (OR 0.37, 95% CI 0.16 to 0.83). This study showed no survival benefit from either nodal boosting or debulking strategy in patients with suspicious bulky nodes. Nodal boosting might, however, be associated with less toxicity. Dual treatment with debulking and boosting showed a worse survival outcome because this group probably represents patients with poor prognostic factors.

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

AbstractIntroductionTo 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 methodsIn 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.ResultsThe 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 &lt; 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.ConclusionsPresenting 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.

Oncological outcomes after radical hysterectomy followed by adjuvant (chemo)radiation or no further treatment in women with cervical cancer FIGO 2018 IB2-IIA2 – A multinational population-based cohort study

The role of adjuvant treatment after radical hysterectomy for early-stage cervical cancer with intermediate-risk factors remains uncertain. In this international population-based cohort study, we investigated the potential benefit of adjuvant treatment on overall survival (OS) and recurrence-free survival (RFS). Utilizing population-based registers from Sweden, Denmark, and the Netherlands, we included women with early-stage cervical cancer FIGO 2018 stages IB2-IIA2 with tumor size >20 mm and negative lymph nodes. All women underwent radical hysterectomy followed by either adjuvant radiotherapy or chemoradiotherapy (AT) or no further treatment (NFT). Survival outcomes were analyzed to assess the impact of AT. A total of 976 women with early-stage cervical cancer, treated between 2010 and 2017, were analyzed. At five years, there were no significant differences in OS (87.7 % vs. 91.9 %) or RFS (79.8 % vs. 82.6 %) between the AT (309 women, 32 %) and NFT (667 women, 68 %) groups. Selecting women with the intermediate risk factors: tumor size > =4cm or tumor size 2-3,9 cm with the presence of lymphovascular space invasion, no significant differences in OS or RFS were observed between AT and NFT. In addition, a multivariable analysis found that tumor size and lymphovascular space invasion predicted adverse survival outcomes. In this population-based cohort study, adjuvant therapy after radical hysterectomy was not associated with a survival benefit in women with FIGO 2018 IB2-IIA2 cervical cancer. These findings corroborate earlier findings on the role of adjuvant therapy for cervical cancer with intermediate-risk factors and support de-escalation to avoid radiation harm for this patient population.

Impact of patient characteristics on primary treatment approach of endometrial cancer: a population-based study in the Netherlands

The incidence of endometrial cancer is rising worldwide, with increasing numbers of elderly patients with substantial comorbidity. We aimed to provide insight into the primary treatment strategies, trends, and outcomes for patients with endometrial cancer in the Netherlands across different periods, and to evaluate the influence of patient characteristics on treatment approaches within these periods. All patients diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage I to III endometrial cancer between 1995 and 2022 were identified in the Netherlands Cancer Registry. Data on histology, FIGO stage, primary treatment, Charlson comorbidity index, body mass index, and outcome were collected and analyzed. Patients were evaluated in 6 5-year cohorts to observe possible trends in treatment choices and outcomes over time, based on patient and tumor characteristics. A total of 43,443 patients were included. Most patients were diagnosed with endometrioid histology (89%, n = 38,751) and early-stage disease (FIGO I-II, 87%, n = 38,077). An increase in endometrial cancer incidence and survival was observed over time, along with a shift toward more non-endometrioid endometrial cases. A primary surgical approach was performed in 95% (n = 41,107) of patients. Among those receiving non-surgical management, curative treatment was reported in only 4% (n = 88). Most patients unfit for surgery either received no treatment (n = 1053, 2%) or were treated with hormonal therapy (n = 840, 2%). Over time, we observed increased use of hormonal therapy as a non-surgical treatment. Patients who did not undergo surgery were older, more often had a body mass index >30 kg/m Incidence and survival in patients with endometrial cancer increased between 1999 and 2022. Patients unfit for surgery most often received no treatment or palliative hormonal therapy. Curative radiotherapy is not often used in patients unfit for surgery and should be considered for this group of patients.

Radical hysterectomy or chemoradiotherapy for clinically early-stage cervical cancer with suspicious lymph nodes on imaging: a retrospective cohort study

The optimal treatment of clinically early-stage cervical cancer with suspicious lymph nodes on pretreatment imaging is unclear. Therefore, we aimed to compare surgery (i.e., radical hysterectomy and pelvic lymphadenectomy±adjuvant therapy) with primary chemoradiotherapy as treatment strategies in this patient group regarding recurrence-free, overall survival and toxicity. Women diagnosed between 2009-2017 with the International Federation of Gynecology and Obstetrics (2009) stage IA-IIA and suspicious nodes based on radiologic assessment of pretreatment imaging were retrospectively selected from the Netherlands Cancer Registry. Cox proportional hazard was used to estimate survival and logistic regression for toxicity. Inverse probability weighting was used to correct for confounding. Grade ≥2 surgery-related (≤30 days) and grade ≥3 chemotherapy or radiotherapy-related (≤6 months) toxicity were collected. Missing data were imputed. Of 330 patients included, 131 (40%) received surgery (followed by adjuvant therapy in 54%) and 199 (60%) chemoradiotherapy. Pathological nodal status was known in 100% of the surgery group and 32% (n=63) of the chemoradiotherapy group, of whom 43% (56/131) and 89% (56/63), respectively, had metastases. After adjustment for confounders, the recurrence-free survival (hazard ratio [HR]=0.67; 95% confidence interval [CI]=0.34-1.31) and overall survival (HR=0.75; 95% CI=0.38-1.47) were not significantly different between both groups, while surgery was associated with more toxicity (odds ratio=2.82; 95% CI=1.42-5.60), mainly surgery-related. In patients with clinically early-stage cervical cancer and suspicious nodes on imaging, surgery and primary chemoradiotherapy yielded comparable results in terms of survival, whereas surgery might be associated with more (surgery-related) short-term toxicity.