Effect of surgical volume on short-term outcomes of cytoreductive surgery for advanced-stage ovarian cancer: A population-based study from the Dutch Gynecological Oncology Audit.

OBJECTIVE: Despite lacking clinical data, the Dutch government is considering increasing the minimum annual surgical volume per center from twenty to fifty cytoreductive surgeries (CRS) for advanced-stage ovarian cancer (OC). This study aims to evaluate whether this increase is warranted. METHODS: This population-based study included all CRS for FIGO-stage IIB-IVB OC registered in eighteen Dutch hospitals between 2019 and 2022. Short-term outcomes included result of CRS, length of stay, severe complications, 30-day mortality, time to adjuvant chemotherapy, and textbook outcome. Patients were stratified by annual volume: low-volume (nine hospitals, <25), medium-volume (four hospitals, 29-37), and high-volume (five hospitals, 54-84). Descriptive statistics and multilevel logistic regressions were used to assess the (case-mix adjusted) associations of surgical volume and outcomes. RESULTS: A total of 1646 interval CRS (iCRS) and 789 primary CRS (pCRS) were included. No associations were found between surgical volume and different outcomes in the iCRS cohort. In the pCRS cohort, high-volume was associated with increased complete CRS rates (aOR 1.9, 95%-CI 1.2-3.1, p = 0.010). Furthermore, high-volume was associated with increased severe complication rates (aOR 2.3, 1.1-4.6, 95%-CI 1.3-4.2, p = 0.022) and prolonged length of stay (aOR 2.3, 95%-CI 1.3-4.2, p = 0.005). 30-day mortality, time to adjuvant chemotherapy, and textbook outcome were not associated with surgical volume in the pCRS cohort. Subgroup analyses (FIGO-stage IIIC-IVB) showed similar results. Various case-mix factors significantly impacted outcomes, warranting case-mix adjustment. CONCLUSIONS: Our analyses do not support further centralization of iCRS for advanced-stage OC. High-volume was associated with higher complete pCRS, suggesting either a more accurate selection in these hospitals or a more aggressive approach. The higher completeness rates were at the expense of higher severe complications and prolonged admissions.

ESGO-ESMO-ESP consensus conference recommendations on ovarian cancer: pathology and molecular biology and early, advanced and recurrent disease.

The European Society of Gynaecological Oncology, the European Society for Medical Oncology (ESMO) and the European Society of Pathology held a consensus conference (CC) on ovarian cancer on 15-16 June 2022 in Valencia, Spain. The CC panel included 44 experts in the management of ovarian cancer and pathology, an ESMO scientific advisor and a methodologist. The aim was to discuss new or contentious topics and develop recommendations to improve and harmonise the management of patients with ovarian cancer. Eighteen questions were identified for discussion under four main topics: (i) pathology and molecular biology, (ii) early-stage disease and pelvic mass in pregnancy, (iii) advanced stage (including older/frail patients) and (iv) recurrent disease. The panel was divided into four working groups (WGs) to each address questions relating to one of the four topics outlined above, based on their expertise. Relevant scientific literature was reviewed in advance. Recommendations were developed by the WGs and then presented to the entire panel for further discussion and amendment before voting. This manuscript focuses on the recommendation statements that reached a consensus, their voting results and a summary of evidence supporting each recommendation.

Effects of a pre-visit online information tool about genetic counselling for ovarian cancer patients, a randomized controlled trial.

OBJECTIVE: In the Netherlands, patients with ovarian cancer are offered genetic testing. Pre-test preparation may help counseling patients. The aim of this study was to determine if use of a web-based intervention, leads to more effective genetic counseling of ovarian cancer patients. METHODS: Between 2016 and 2018, 127 ovarian cancer patients referred for genetic counseling in our hospital participated in this trial. 104 Patients were analyzed. All patients filled out questionnaires pre- and post-counseling. The intervention group also completed a questionnaire after visiting an online tool. Length of consultation, patients' satisfaction, knowledge, anxiety, depression and distress were compared before and after counselling. RESULTS: The intervention group had the same level of knowledge compared to the counseling group, but at an earlier point in time. They were satisfied with the intervention (86%) and better prepared for counseling (66%). The intervention did not lead to shorter consultations. No differences in levels of anxiety, depression, distress and satisfaction were observed. CONCLUSION: Although consultation length was unaffected, the improvements in knowledge after online education and patients satisfaction indicates that this tool can be an effective addition to genetic counseling. PRACTICE IMPLICATIONS: Use of an educational tool may lead to a more effective, personalized way of genetic counselling and enables shared decision making.

Textbook outcome as a composite outcome measure to compare hospital performances regarding cytoreductive surgery for ovarian cancer: A nationwide population-based study.

OBJECTIVE: Textbook outcome (TO) is a composite outcome measure used in surgical oncology to compare hospital outcomes using multiple quality indicators. This study aimed to develop TO as an outcome measure to assess healthcare quality for patients undergoing cytoreductive surgery (CRS) for advanced-stage ovarian cancer. METHODS: This population-based study included all CRS for FIGO IIIC-IVB primary ovarian cancer registered in the Netherlands between 2017 and 2020. The primary outcome was TO, defined as a complete CRS, combined with the absence of 30-day mortality, severe complications, and prolonged length of admission (≥ten days). Delayed start of adjuvant chemotherapy (≥six weeks) was not included in TO because of missing data. Logistic regressions were used to assess the association of case-mix factors with TO. Hospital variation was displayed using funnel plots. RESULTS: A total of 1909 CRS were included, of which 1434 were interval CRS and 475 were primary CRS. TO was achieved in 54% of the interval CRS cohort and 47% of the primary CRS cohort. Macroscopic residual disease after CRS was the most important factor for not achieving TO. Age ≥ 70 was associated with lower TO rates in multivariable logistic regressions. TO rates ranged from 40% to 69% between hospitals in the interval CRS cohort and 22% to 100% in the primary CRS cohort. In both analyses, one hospital had significantly lower TO rates (different hospitals). Case-mix adjustment significantly affected TO rates in the primary CRS analysis. CONCLUSIONS: TO is a suitable composite outcome measure to detect hospital variation in healthcare quality for patients with advanced-stage ovarian cancer undergoing CRS. Case-mix adjustment improves the accuracy of the hospital comparison.

Clinical outcomes of pelvic exenteration for gynecologic malignancies.

OBJECTIVES: The aim of this study was to analyze morbidity and survival after pelvic exenteration for gynecologic malignancies and evaluate prognostic factors influencing postoperative outcome. METHODS: We retrospectively reviewed all patients who underwent a pelvic exenteration at the departments of gynecologic oncology of three tertiary care centers in the Netherlands, the Leiden University Medical Centre, the Amsterdam University Medical Centre, and the Netherlands Cancer Institute, during a 20-year period. We determined postoperative morbidity, 2- and 5-year overall survival (OS) and 2- and 5-year progression free survival (PFS), and investigated parameters influencing these outcomes. RESULTS: A total of 90 patients were included. The most common primary tumor was cervical cancer (n = 39, 43.3%). We observed at least one complication in 83 patients (92%). Major complications were seen in 55 patients (61%). Irradiated patients had a higher risk of developing a major complication. Sixty-two (68.9%) required ≥1 readmission. Re-operation was required in 40 patients (44.4%). Median OS was 25 months and median PFS was 14 months. The 2-year OS rate was 51.1% and the 2-year PFS rate was 41.5%. Tumor size, resection margins and pelvic sidewall involvement had a negative impact on OS (HR = 2.159, HR = 2.376, and HR = 1.200, respectively). Positive resection margins and pelvic sidewall involvement resulted in decreased PFS (HR = 2.567 and HR = 3.969, respectively). CONCLUSION: Postoperative complications after pelvic exenteration for gynecologic malignancies are common, especially in irradiated patients. In this study, a 2-year OS rate of 51.1% was observed. Positive resections margins, tumor size, and pelvic sidewall involvement were related to poor survival outcomes. Adequate selection of patients who will benefit from pelvic exenteration is important.

Unilateral inguinofemoral lymphadenectomy in patients with early-stage vulvar squamous cell carcinoma and a unilateral metastatic sentinel lymph node is safe.

OBJECTIVE: Optimal management of the contralateral groin in patients with early-stage vulvar squamous cell carcinoma (VSCC) and a metastatic unilateral inguinal sentinel lymph node (SN) is unclear. We analyzed patients who participated in GROINSS-V I or II to determine whether treatment of the contralateral groin can safely be omitted in patients with a unilateral metastatic SN. METHODS: We selected the patients with a unilateral metastatic SN from the GROINSS-V I and II databases. We determined the incidence of contralateral additional non-SN metastases in patients with unilateral SN-metastasis who underwent bilateral inguinofemoral lymphadenectomy (IFL). In those who underwent only ipsilateral groin treatment or no further treatment, we determined the incidence of contralateral groin recurrences during follow-up. RESULTS: Of 1912 patients with early-stage VSCC, 366 had a unilateral metastatic SN. Subsequently, 244 had an IFL or no treatment of the contralateral groin. In seven patients (7/244; 2.9% [95% CI: 1.4%-5.8%]) disease was diagnosed in the contralateral groin: five had contralateral non-SN metastasis at IFL and two developed an isolated contralateral groin recurrence after no further treatment. Five of them had a primary tumor ≥30 mm. Bilateral radiotherapy was administered in 122 patients, of whom one (1/122; 0.8% [95% CI: 0.1%-4.5%]) had a contralateral groin recurrence. CONCLUSION: The risk of contralateral lymph node metastases in patients with early-stage VSCC and a unilateral metastatic SN is low. It appears safe to limit groin treatment to unilateral IFL or inguinofemoral radiotherapy in these cases.

Peroperative extent of peritoneal metastases affects the surgical outcome and survival in advanced ovarian cancer.

OBJECTIVE: Determining whether cytoreductive surgery (CRS) is feasible in patients with advanced ovarian cancer and whether extensive surgery is justified is challenging. Accurate patient selection for CRS based on pre- and peroperative parameters will be valuable. The aim of this study is to assess the association between the extent of peritoneal metastases as determined during surgery and completeness of interval CRS and survival. METHODS: This single-center observational cohort study included consecutive patients with newly diagnosed stage III-IV epithelial ovarian cancer who received neoadjuvant chemotherapy and underwent interval CRS. The 7 Region Count (7RC) was recorded during surgical exploration to systematically quantify the extent of peritoneal metastases. Logistic regression analysis was performed to predict surgical outcomes, and Cox regression analysis was done for survival outcomes. RESULTS: A total of 316 patients were included for analyses. The median 7RC was 4 (interquartile range: 2-6). Complete CRS was performed in 58%, optimal CRS in 30%, and incomplete CRS in 12% of patients. A higher 7RC was independently associated with lower odds of complete or optimal CRS in multivariable analysis (odds ratio [OR] = 0.45, 95% confidence interval [CI]: 0.33-0.63, p < 0.001). Similarly, a higher 7RC was independently associated with worse progression-free survival (hazard ratio [HR] = 1.17, 95% CI 1.08-1.26, p < 0.001) and overall survival (HR = 1.14, 95% CI 1.04-1.25, p = 0.007). CONCLUSION: The extent of peritoneal metastases, as expressed by the 7RC during surgery, is an independent predictor for completeness of CRS and has independent prognostic value for progression-free survival and overall survival in addition to completeness of CRS.

An overview of Clinical Quality Registries (CQRs) on gynecological oncology worldwide.

INTRODUCTION: Clinical Quality Registries (CQRs) were initiated in order to compare clinical outcomes between hospitals or regions within a country. To get an overview of these CQRs worldwide the aim of this study was to identify these CQRs for gynecological oncology and to summarize their characteristics, processes and QI's and to establish whether it is feasible to make an international comparison in the future. METHODS: To identify CQRs in gynecological oncology a literature search in Pubmed was performed. All papers describing the use of a CQR were included. Administrative, epidemiological and cancer registries were excluded as these registries do not primarily serve to measure quality of care through QI's. The taskforce or contact person of the included CQR were asked to participate and share information on registered items, processes and indicators. RESULTS: Five nations agreed to collaborate: Australia, Denmark, Italy, the Netherlands and Sweden. Denmark, Netherlands and Sweden established a nationwide registry, collecting data on multiple tumor types, and various QI's. Australia and Italy included patients with ovarian cancer only. All nations had a different process to report feedback results to participating hospitals. CONCLUSION: CQRs serve the same purpose to improve quality of care but vary on different aspects. Although similarities are observed in the topics measured by the QI's, an international comparison was not feasible as numerators or denominators differ between registries. In order to compare on an international level it would be useful to harmonize these registries and to set an international standard to measure the quality of care with similar indicators.

Adjuvant Use of PlasmaJet Device During Cytoreductive Surgery for Advanced-Stage Ovarian Cancer: Results of the PlaComOv-study, a Randomized Controlled Trial in The Netherlands.

OBJECTIVE: Standard surgical treatment of advanced-stage ovarian carcinoma with electrosurgery cannot always result in complete cytoreductive surgery (CRS), especially when many small metastases are found on the mesentery and intestinal surface. We investigated whether adjuvant use of a neutral argon plasma device can help increase the complete cytoreduction rate. PATIENTS AND METHODS: 327 patients with FIGO stage IIIB-IV epithelial ovarian cancer (EOC) who underwent primary or interval CRS were randomized to either surgery with neutral argon plasma (PlasmaJet) (intervention) or without PlasmaJet (control group). The primary outcome was the percentage of complete CRS. The secondary outcomes were duration of surgery, blood loss, number of bowel resections and colostomies, hospitalization, 30-day morbidity, and quality of life (QoL). RESULTS: Complete CRS was achieved in 119 patients (75.8%) in the intervention group and 115 patients (67.6%) in the control group (risk difference (RD) 8.2%, 95% confidence interval (CI) -0.021 to 0.181; P = 0.131). In a per-protocol analysis excluding patients with unresectable disease, complete CRS was obtained in 85.6% in the intervention group and 71.5% in the control group (RD 14.1%, 95% CI 0.042 to 0.235; P = 0.005). Patient-reported QoL at 6 months after surgery differed between groups in favor of PlasmaJet surgery (95% CI 0.455-8.350; P = 0.029). Other secondary outcomes did not differ significantly. CONCLUSIONS: Adjuvant use of PlasmaJet during CRS for advanced-stage ovarian cancer resulted in a significantly higher proportion of complete CRS in patients with resectable disease and higher QoL at 6 months after surgery. (Funded by ZonMw, Trial Register NL62035.078.17.) TRIAL REGISTRATION: Approved by the Medical Ethics Review Board of the Erasmus University Medical Center Rotterdam, the Netherlands, NL62035.078.17 on 20-11-2017. Recruitment started on 30-1-2018.

Clinical implementation of routine diagnostic laparoscopy to guide initial treatment in patients with advanced-stage epithelial ovarian cancer in Dutch clinical practice: Evaluation of support and a budget impact analysis.

OBJECTIVE: In patients with advanced-stage epithelial ovarian cancer (EOC), a diagnostic laparoscopy (DLS) to determine treatment regime prevents futile laparotomies and seems cost-neutral. The uptake of DLS in current practice is unknown. We evaluated the clinical application of routine DLS in treatment planning in patients with advanced-stage EOC in the Netherlands. METHODS: The implementation was evaluated over the period 2017-2019, using a health technology assessment including clinical, organizational, and economic factors. Barriers for implementation were identified and DLS use was assessed using semi-structured surveys with healthcare professionals. Data from the Dutch Gynecological Oncology Audit were used to determine (un)successful CRS rates. To assess the economic impact, we performed a budget impact analysis (BIA) of the combined interventions of DLS and primary CRS. RESULTS: The DLS use to guide treatment planning increased from 16% to 20%. The majority of the centers did not support routine DLS implementation, mainly because of logistic barriers and its invasive nature. The primary CRS rate of all CRS decreased from 44% to 36%, in favor of interval CRS. The unsuccessful primary CRS rate decreased from 15% to 9% resulting in fewer patients needed a second interval CRS. Consequently, total health care costs decreased from €4.457.496 to €4.274.751. CONCLUSIONS: The implementation of routine DLS for guiding treatment planning in patients with advanced-stage EOC has limited support in the Netherlands. Over the years, total health care costs decreased. For current practice, it is advised that a DLS is useful in case it is uncertain whether a successful primary CRS is feasible based on conventional work-up.

Experiences, adherence and satisfaction with a combined exercise and dietary intervention for patients with ovarian cancer undergoing chemotherapy: A mixed-methods study.

OBJECTIVE: This study examined experiences, adherence and satisfaction with a combined exercise and dietary intervention in patients with ovarian cancer and their healthcare professionals (HCPs) as part of the randomized PADOVA trial. METHODS: A mixed-methods approach was used in 24 patients with ovarian cancer receiving first-line chemotherapy who were randomly allocated to a combined exercise and dietary intervention or usual care with counseling sessions post-treatment. Qualitative data on intervention experiences, adherence and satisfaction was collected using semi-structured interviews with patients and their HCPs (n = 18 physical therapists; n = 5 dietitians). Quantitative data on adherence and satisfaction was collected to provide context to qualitative data. RESULTS: Exercise relative dose intensity ranged from 36 to 100% (median 72%) and patients attended 33-133% (median 100%) of the prescribed dietary counseling sessions. Patients appreciated guidance on exercise and nutrition and perceived benefits including improved physical fitness, quality of life, peer support and recovery after surgery and/or chemotherapy cycles. Both patients and HCPs were satisfied with the intervention and perceived that participation exceeded prior expectations. Median patient satisfaction score with the intervention was 8.5 out of 10. Suggestions for improving the intervention included further personalization of the number, content and scheduling of the sessions to preferences of patients and HCPs. Patients in the usual care group reported counseling sessions post-chemotherapy to be too little too late. CONCLUSIONS: Patients with ovarian cancer adhered well to the intervention. Numerous perceived benefits of the intervention were reported by patients and HCPs. Good adherence and positive experiences support successful implementation in clinical practice.

Impact of the COVID-19-pandemic on patients with gynecological malignancies undergoing surgery: A Dutch population-based study using data from the 'Dutch Gynecological Oncology Audit'.

OBJECTIVE: The COVID-19-pandemic caused drastic healthcare changes worldwide. To date, the impact of these changes on gynecological cancer healthcare is relatively unknown. This study aimed to assess the impact of the COVID-19-pandemic on surgical gynecological-oncology healthcare. METHODS: This population-based cohort study included all surgical procedures with curative intent for gynecological malignancies, registered in the Dutch Gynecological Oncology Audit, in 2018-2020. Four periods were identified based on COVID-19 hospital admission rates: 'Pre-COVID-19', 'First wave', 'Interim period', and 'Second wave'. Surgical volume, perioperative care processes, and postoperative outcomes from 2020 were compared with 2018-2019. RESULTS: A total of 11,488 surgical procedures were analyzed. For cervical cancer, surgical volume decreased by 17.2% in 2020 compared to 2018-2019 (mean 2018-2019: n = 542.5, 2020: n = 449). At nadir (interim period), only 51% of the expected cervical cancer procedures were performed. For ovarian, vulvar, and endometrial cancer, volumes remained stable. Patients with advanced-stage ovarian cancer more frequently received neoadjuvant chemotherapy in 2020 compared to 2018-2019 (67.7% (n = 432) vs. 61.8% (n = 783), p = 0.011). Median time to first treatment was significantly shorter in all four malignancies in 2020. For vulvar and endometrial cancer, the length of hospital stay was significantly shorter in 2020. No significant differences in complicated course and 30-day-mortality were observed. CONCLUSIONS: The COVID-19-pandemic impacted surgical gynecological-oncology healthcare: in 2020, surgical volume for cervical cancer dropped considerably, waiting time was significantly shorter for all malignancies, while neoadjuvant chemotherapy administration for advanced-stage ovarian cancer increased. The safety of perioperative healthcare was not negatively impacted by the pandemic, as complications and 30-day-mortality remained stable.

Postoperative outcomes of primary and interval cytoreductive surgery for advanced ovarian cancer registered in the Dutch Gynecological Oncology Audit (DGOA).

OBJECTIVES: The challenge when performing cytoreductive surgery (CRS) is to balance the benefits and risks. The aim of this study was to report short term postoperative morbidity and mortality in relation to surgical outcome in patients undergoing primary debulking surgery (PDS) or interval debulking (IDS) surgery in the Netherlands. METHODS: The Dutch Gynecological Oncology Audit (DGOA) was used for retrospective analysis. Patients undergoing PDS or IDS between January 1st, 2015 - December 31st, 2018 were included. Outcome was frequency of postoperative complications. Median time to adjuvant chemotherapy and severity of complications were related to outcome of CRS. Complications with Clavien-Dindo ≥3 were analyzed per region and case mix corrected. Statistical analysis was performed with R.Studio. RESULTS: 1027 patients with PDS and 1355 patients with IDS were included. Complications with re-invention were significantly higher in PDS compared to IDS (5.7% vs. 3.6%, p = 0.048). Complete cytoreduction was 69.7% in PDS and 62.1% IDS, p < 0.001. Time to adjuvant chemotherapy was 49 days in patients with complete CRS and a complication with re-intervention. Regional variation for severe complications showed one region outside confidence intervals. CONCLUSIONS: Higher complete cytoreduction rate in the PDS group indicates that the correct patients have been selected, but is associated with a higher percentage of complication with re-intervention. As result, time to start adjuvant chemotherapy is longer in this group. Maintaining a balance in aggressiveness of surgery and outcome of the surgical procedure with respect to severe complications is underlined. Bench marked data should be discussed nationally to improve this balance.

Peroperative scoring systems for predicting the outcome of cytoreductive surgery in advanced-stage ovarian cancer - A systematic review.

The extent of peritoneal metastases (PM) largely determines the possibility of complete or optimal cytoreductive surgery in advanced ovarian cancer. An objective scoring system to quantify the extent of PM can help clinicians to decide whether or not to embark on CRS. Therefore several scoring systems have been developed by different research teams and this review summarizes their performance in predicting a complete or optimal cytoreduction in patients with advanced ovarian cancer. A systematic search in the MEDLINE database revealed 19 articles that described a total of five main scoring systems to predict the completeness of CRS in patients with FIGO stage III-IV ovarian cancer based on the surgical exploration of the abdominal cavity; PCI, PIV, Eisenkop, Espada, and Kasper. The Peritoneal Cancer Index (PCI) and the Predictive Index Value (PIV) were mentioned most frequently and showed AUCs of 0.69-0.92 and 0.66-0.98, respectively. Due to the use of different cut-offs sensitivities and specificities greatly varied. Therefore with the current data, no scoring system could be identified as best. An objective measure of the extent of disease can be of great clinical use for identifying ovarian cancer patients for which a complete (or optimal) CRS is achievable, however due to local differences in treatment strategies and surgical policy a widely adopted objective scoring system with a standard cut-off value is not feasible. Nevertheless, objective scoring systems can play an important role to guide treatment decisions.

Clinical auditing as an instrument to improve care for patients with ovarian cancer: The Dutch Gynecological Oncology Audit (DGOA).

INTRODUCTION: The Dutch Gynecological Oncology Audit (DGOA) was initiated in 2014 to serve as a nationwide audit, which registers the four most prevalent gynecological malignancies. This study presents the first results of clinical auditing for ovarian cancer in the Netherlands. METHODS: The Dutch Gynecological Oncology Audit is facilitated by the Dutch Institute of Clinical Auditing (DICA) and run by a scientific committee. Items are collected through a web-based registration based on a set of predefined quality indicators. Results of quality indicators are shown, and benchmarked information is given back to the user. Data verification was done in 2016. RESULTS: Between January 01, 2014 and December 31, 2018, 6535 patients with ovarian cancer were registered. The case ascertainment was 98.3% in 2016. The number of patients with ovarian cancer who start therapy within 28 days decreased over time from 68.7% in 2014 to 62.7% in 2018 (p < 0.001). The percentage of patients with primary cytoreductive surgery decreased over time (57.8%-39.7%, P < 0.001). However, patients with complete primary cytoreductive surgery improved over time (53.5%-69.1%, P < 0.001). Other quality indicators did not significantly change over time. CONCLUSION: The Dutch Gynecological Oncology Audit provides valuable data on the quality of care on patients with ovarian cancer in the Netherlands. Data show variation between hospitals with regard to pre-determined quality indicators. Results of 'best practices' will be shared with all participants of the clinical audit with the aim of improving quality of care nationwide.

Health-related quality of life after interval cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with stage III ovarian cancer.

INTRODUCTION: The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery (CRS) improves recurrence-free (RFS) and overall survival (OS) in patients with FIGO stage III ovarian cancer. We evaluated the effect of HIPEC on patient's health-related quality of life (HRQoL) in the OVHIPEC trial. MATERIALS AND METHODS: OVHIPEC was a multicentre, open-label, randomized phase III trial for patients with stage III ovarian cancer. Patients were randomly assigned (1:1) to receive interval CRS with or without HIPEC with cisplatin. HRQoL was assessed using the EORTC QLQ-C30, and the ovarian (QLQ-OV28) and colorectal cancer (QLQ-CR38) modules. HRQoL questionnaires were administered at baseline, after surgery, after end of treatment, and every three months thereafter. HRQoL was a secondary endpoint, with the prespecified focus on the QLQ-C30 summary score and symptom scores on fatigue, neuropathy and gastro-intestinal symptoms. HRQoL was analysed using linear and non-linear mixed effect models. RESULTS: In total, 245 patients were randomized. One-hundred-ninety-seven patients (80%) completed at least one questionnaire. No significant difference over time in the QLQ-C30 summary scores was observed between the study arms (p-values for linear and non-linear growth: p > 0.133). The pattern over time for fatigue, neuropathy and gastro-intestinal symptoms did not significantly differ between treatment arms. CONCLUSION: The addition of HIPEC to interval CRS does not negatively impact HRQoL in patients with stage III ovarian cancer who are treated with interval CRS due to the extent of disease. These HRQoL results, together with the improvement in RFS and OS, support the viability of HIPEC as an important treatment option in this patient population. CLINICALTRIALS. GOV NUMBER: NCT00426257. EUDRACT NUMBER: 2006-003466-34.

Intraperitoneal treatment for advanced ovarian cancer, the Dutch experience. What did we learn?

BACKGROUND: Combined administration of intravenous (iv) and intraperitoneal (ip) (iv/ip) chemotherapy is an effective adjuvant treatment option after primary debulking surgery (PDS) for advanced ovarian cancer (OC). Increased toxicityand patient burden limit its use in daily practice. OBJECTIVE: To assess toxicity and survival outcomes of iv/ip chemotherapy in daily practice in the Netherlands. METHODS: This retrospective cohort study included 81 women who underwent at least an optimal PDS for FIGO stage III OC followed by iv/ip chemotherapy according to the Armstrong regimen, in four hospitals in the Netherlands between January 2007 and May 2016. We collected information on surgical procedure, abdominal port implantation, toxicity, and recurrence-free and overall survival. RESULTS: All participants underwent PDS, of whom 60 (74%) had their ip catheter implanted during PDS. Most frequently reported all grade toxicity was haematological n = 44 (54%). Forty-four patients (54%) completed all six cycles of iv/ip chemotherapy. The most frequent causes of discontinuation of iv/ip administration were renal dysfunction (12/37 = 32%) and catheter problems (7/37 = 19%). Median recurrence-free survival and overall survival were 24 months (range 0 - 108) and 80 months (range 4-115), respectively. Surgical outcome, completion of more than three courses of treatment and intra-abdominal localisation of recurrent disease were associated with better survival outcomes. CONCLUSION: In daily practice, 54% of patients with advanced OC could complete all scheduled cycles of iv/ ip chemotherapy with acceptable morbidity and toxicity, leading to outcomes comparable with the results of published trials on iv/ip chemotherapy.

The effect of the peritoneal tumor microenvironment on invasion of peritoneal metastases of high-grade serous ovarian cancer and the impact of NEOADJUVANT chemotherapy.

Peritoneal metastases of high-grade serous ovarian cancer (HGSOC) are small-sized deposits with superficial growth toward the peritoneal cavity. It is unknown whether integrity of the peritoneal elastic lamina (PEL) correlates with the peritoneal tumor microenvironment (pTME) and whether neoadjuvant chemotherapy (NACT) affects the pTME. We explored integrity of PEL, composition of pTME, effects of NACT, and the prognostic implications in patients with extensive peritoneal metastases of HGSOC. Peritoneal samples (n = 69) were collected during cytoreductive surgery between 2003 and 2016. Clinical data were collected from medical charts. Integrity of PEL was evaluated with elastic stains. T cell (CD3, CD8) and M2-macrophage markers (CD163) were scored using algorithms created in definiens tissue studio. Patients with a disrupted PEL (n = 39; 57%), more often had residual disease after surgery (p = 0.050), compared to intact PEL. An intact PEL was associated with increased intraepithelial (ie) CD8+ cells (p = 0.032), but was not correlated with improved survival. After NACT, increased ieCD3+ cells were shown, compared to no-NACT (p = 0.044). Abundance of total CD3+ and CD8+ cells were associated with PFS (multivariate HR 0.40; 95%CI 0.23-0.69 and HR 0.49; 95%CI 0.29-0.83) and OS (HR 0.33; 95%CI 0.18-0.62 and HR 0.36; 95%CI 0.20-0.64). M2-macrophage infiltration was not correlated with survival. NACT increases abundance of ieCD3+ cells in peritoneal metastases of HGSOC. Increase of CD3+ and CD8+ cells is associated with improved PFS and OS. This suggests that CD3+ and CD8+ cells may function as prognostic biomarkers. Their role as predictive biomarker for chemotherapy or immunotherapy response in HGSOC warrants further research.