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Objective: In the first part of this phase II study (NCT01164995), the combination of carboplatin and adavosertib (AZD1775) was shown to be safe and effective in patients with TP53 mutated platinum-resistant ovarian cancer (PROC). Here, we present the results of an additional safety and efficacy cohort and explore predictive biomarkers for resistance and response to this combination treatment., Methods: This is a phase II, open-label, non-randomized study. Patients with TP53 mutated PROC received carboplatin AUC 5 mg/ ml·min intravenously and adavosertib 225 mg BID orally for 2.5 days in a 21-day cycle. The primary objective is to determine the efficacy and safety of carboplatin and adavosertib. Secondary objectives include progression-free survival (PFS), changes in circulating tumor cells (CTC) and exploration of genomic alterations., Results: Thirty-two patients with a median age of 63 years (39-77 years) were enrolled and received treatment. Twenty-nine patients were evaluable for efficacy. Bone marrow toxicity, nausea and vomiting were the most common adverse events. Twelve patients showed partial response (PR) as best response, resulting in an objective ORR of 41% in the evaluable patients (95% CI: 23%-61%). The median PFS was 5.6 months (95% CI: 3.8-10.3). In patients with tumors harboring CCNE1 amplification, treatment efficacy was slightly but not significantly better., Conclusions: Adavosertib 225 mg BID for 2.5 days and carboplatin AUC 5 could be safely combined and showed anti-tumor efficacy in patients with PROC. However, bone marrow toxicity remains a point of concern, since this is the most common reason for dose reductions and dose delays., Competing Interests: Declaration of Competing Interest A list with conflicts of interest of all authors will be provided., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To evaluate feasibility of chemoradiation as alternative for extensive surgery in patients with locally advanced vulvar cancer and to report on locoregional control, toxicity and survival., Methods: In a multicenter, prospective phase II trial patients with locally advanced vulvar cancer were treated with locoregional radiotherapy combined with sensitizing chemotherapy (capecitabine). Treatment feasibility, percentage locoregional control, survival and toxicity were evaluated., Results: 52 patients with mainly T2/T3 disease were treated according to the study protocol in 10 centers in the Netherlands from 2007 to 2019. Full dose radiotherapy (tumor dose of 64.8Gy) was delivered in 92% and full dose capecitabine in 69% of patients. Most prevalent acute ≥ grade 3 toxicities were regarding skin/mucosa and pain (54% and 37%). Late ≥grade 3 toxicity was reported for skin/mucosa (10%), fibrosis (4%), GI incontinence (4%) and stress fracture or osteoradionecrosis (4%). Twelve weeks after treatment, local clinical complete response (cCR) and regional control (RC) rates were 62% and 75%, respectively. After 2 years, local cCR persisted in 22 patients (42%) and RC was 58%. Thirty patients (58%) had no evidence of disease at end of follow-up (median 35 months). In 9 patients (17%) extensive surgery with stoma formation was needed. Progression free survival was 58%, 51% and 45% and overall survival was 76%, 66%, 52% at 1,2, and 5 years., Conclusions: Definitive capecitabine-based chemoradiation as alternative for extensive surgery is feasible in locally advanced vulvar cancer and results in considerable locoregional control with acceptable survival rates with manageable acute and late toxicity., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The hospital type affects the surgical outcomes of ovarian cancer patients. In the present study, we wanted to investigate the effect of hospital type on chemotherapy efficacy., Methods: Data were collected from 1077 ovarian cancer patients treated from 1996 to 2003 in a random sample of 18 Dutch hospitals. Hospitals were categorized by the number of medical oncologists working in a hospital and additionally by chemotherapy volume (< or =100, 101-200, or >200 patients yearly) and ovarian cancer patient-volume (< or =6, 7-12, >12 yearly). The outcomes were the proportions of patients achieving complete remission, recurrence rates, and disease-free and overall survival. Data were analyzed using multivariable logistic regression (complete remission and recurrence) and Cox regression (survival)., Results: Data of 761 of the 777 patients who received chemotherapy could be analyzed. Hospital type did not affect the complete remission rates, recurrence rates, or the disease-free survival. Overall survival was better in hospitals with 2 or more medical oncologists and in hospitals with a high ovarian cancer patient-volume (hazard ratios both 0.8 (95% confidence interval=0.7-1.0))., Conclusions: Thus, hospital type did not influence the outcomes of first-line chemotherapy in ovarian cancer patients. However, overall survival was better in hospitals with 2 or more medical oncologists and in hospitals with a high ovarian cancer patient-volume, suggesting differences in second-line chemotherapy.

Objective: We investigated the influence of hospital and gynecologist level of specialization and volume on surgical results and on survival of ovarian cancer patients., Methods: Data were collected from 1077 ovarian cancer patients treated from 1996 to 2003 in a random sample of 18 Dutch hospitals. Hospitals and gynecologists were classified according to specialization (general, semi-specialized or specialized) and by volume (12 cases/year). Outcomes were percentage of adequately staged and optimally debulked patients and length of overall survival. Data were analyzed using multivariable logistic regression (surgical results) and Cox regression (survival)., Results: The level of specialization and the volume of hospitals and of gynecologists were strongly related to the proportion of adequately staged patients (adjusted odds ratio (OR) specialized hospitals 3.9 (95% confidence interval (CI) 2.0-7.6); specialized gynecologists 9.5 (95% CI 4.7-19)). Patients with stage III disease had a higher chance of optimal debulking when treated in specialized hospitals (adjusted OR 1.7 (95% CI 1.1-2.7)) or by high volume gynecologists (adjusted OR 2.8 (95% CI 1.4-5.7)). Overall survival was best in patients treated in specialized hospitals and by high-volume gynecologists., Conclusion: The specialization level of hospitals and the surgical volume of gynecologists positively influence outcomes of surgery and survival. Concentration of ovarian cancer care thus seems warranted.