Shifting incidence and survival of epithelial ovarian cancer (1995-2014): A SurvMark-2 study.

The aim of the study is to provide a comprehensive assessment of incidence and survival trends of epithelial ovarian cancer (EOC) by histological subtype across seven high income countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway and the United Kingdom). Data on invasive EOC diagnosed in women aged 15 to 99 years during 1995 to 2014 were obtained from 20 cancer registries. Age standardized incidence rates and average annual percentage change were calculated by subtype for all ages and age groups (15-64 and 65-99 years). Net survival (NS) was estimated by subtype, age group and 5-year period using Pohar-Perme estimator. Our findings showed marked increase in serous carcinoma incidence was observed between 1995 and 2014 among women aged 65 to 99 years with average annual increase ranging between 2.2% and 5.8%. We documented a marked decrease in the incidence of adenocarcinoma "not otherwise specified" with estimates ranging between 4.4% and 7.4% in women aged 15 to 64 years and between 2.0% and 3.7% among the older age group. Improved survival, combining all EOC subtypes, was observed for all ages combined over the 20-year study period in all countries with 5-year NS absolute percent change ranging between 5.0 in Canada and 12.6 in Denmark. Several factors such as changes in guidelines and advancement in diagnostic tools may potentially influence the observed shift in histological subtypes and temporal trends. Progress in clinical management and treatment over the past decades potentially plays a role in the observed improvements in EOC survival.

A comparison of synoptic reports and dictated reports to enhance and standardize surgical documentation and quality of care in epithelial ovarian cancer.

OBJECTIVE: The purpose of this study is to assess the degree to which synoptic reports (SRs) and dictated reports (DRs) document elements of the Ovarian Cancer Pan-Canadian Standards Data Elements (OCPCDE) checklist, and to compare their completeness. Analysis of dictated versus synoptic reporting has never been performed for suspected epithelial ovarian cancer (EOC) based on literature review at the time of data collection (1-12). METHODS: A retrospective chart review was performed including 254 charts of women 18 years or older, from 2012 to 2017, undergoing surgery for suspected EOC. Charts from five gynecologic oncologists, at a single tertiary care centre were used. The OCPCDE checklist was used to evaluate their completeness. Comparison of completeness between SRs and DRs was done using linear regression with a fixed effect of surgeon to account for intraclass correlation. RESULTS: The data showed that SRs included 20.1% more data elements than DRs. Data elements that may be perceived as being more critical were more likely to be documented in SRs. Residual disease data was documented in 51.7% DR versus 99.1% of SR. Descriptive data upon entering the abdomen was more frequently documented in DRs. CONCLUSION: This study shows that synoptic reporting includes more data elements deemed important by the OCPCDE checklist authors for suspected epithelial ovarian cancer surgery in our centre. We would recommend continuation of SRs in our department, and implementation of synoptic reporting in other gynecologic oncology centres where surgery for suspected epithelial ovarian cancer is performed.

Surgical margin status in relation to surgical approach in the management of early-stage cervical Cancer: A Canadian cervical Cancer collaborative (4C) study.

OBJECTIVE: Surgical margin status in women undergoing surgery for early-stage cervical cancer is an important prognostic factor. We sought to determine whether close (<3 mm) and positive surgical margins are associated with surgical approach and survival. METHODS: This is a national retrospective cohort study of cervical cancer patients treated with radical hysterectomy. Patients with stage IA1/LVSI-Ib2(FIGO 2018) with lesions up to 4 cm at 11 Canadian institutions from 2007 to 2019 were included. Surgical approach included robotic/laparoscopic (LRH), abdominal (ARH) or combined laparoscopic-assisted vaginal/vaginal (LVRH) radical hysterectomy. Recurrence free survival(RFS) and overall survival (OS) were estimated using Kaplan-Meier analysis. Chi-square and log-rank tests were used to compare groups. RESULTS: 956 patients met inclusion criteria. Surgical margins were as follows: negative (87.0%), positive (0.4%) or close <3 mm (6.8%), missing (5.8%). Most patients had squamous histology (46.9%); 34.6% had adenocarcinomas and 11.3% adenosquamous. Most were stage IB (75.1%) and 24.9% were IA. Mode of surgery included: LRH(51.8%), ARH (39.2%), LVRH (8.9%). Predictive factors for close/positive margins included stage, tumour diameter, vaginal involvement and parametrial extension. Surgical approach was not associated with margin status (p = 0.27). Close/positive margins were associated with a higher risk of death on univariate analysis (HR = non calculable for positive and HR = 1.83 for close margins, p = 0.017), but not significant for OS when adjusted for stage, histology, surgical approach and adjuvant treatment. There were 7 recurrences in patients with close margins (10.3%, p = 0.25). 71.5% with positive/close margins received adjuvant treatment. In addition, MIS was associated with a higher risk of death (OR = 2.39, p = 0.029). CONCLUSION: Surgical approach was not associated to close or positive margins. Close surgical margins were associated with a higher risk of death. MIS was associated with worse survival, suggesting that margin status may not be the driver of worse survival in these cases.

Exploring the role of a multidisciplinary hereditary gynecologic oncology clinic in epithelial ovarian cancer risk-reducing surgical decision-making practices: A mixed-methods study.

Individuals that have gynecologic reproductive organs with pathogenic variants in BRCA1 or BRCA2 ("BRCA-positive") have an increased risk of developing high-grade serous ovarian cancer (HGSOC). The majority of HGSOC develops in the fallopian tubes and later spreads to the ovaries and peritoneal cavity. Therefore, risk-reducing salpingo-oophorectomy (RRSO) is recommended for those who are BRCA-positive to preventatively remove their ovaries and fallopian tubes. The Hereditary Gynecology Clinic (HGC) is a provincial program in Winnipeg, Canada, that specifically targets care to the unique needs of such individuals through an interdisciplinary team of gynecological oncologists, menopause specialists, and registered nurses. A mixed-methods study design was used to explore the decision-making processes of these BRCA-positive individuals who have been recommended (or who completed) RRSO and experiences with healthcare providers at the HGC influenced this decision. Individuals who are BRCA-positive without a previous diagnosis of HGSOC and who had previously received genetic counselling were recruited from the HGC and the provincial cancer genetics program (Shared Health Program of Genetics & Metabolism). Forty-three people completed a survey and 15 participated in an in-depth interview about their experiences and decisions surrounding RRSO. Surveys were analyzed to compare scores on validated scales related to decision-making and cancer-related worry. Qualitative interviews were transcribed, coded, and analyzed using interpretive description. Participants described the complex decisions faced by those who are BRCA-positive, which are intertwined with life experiences and circumstances including age, marital status, and family disease history. Participants interpreted their HGSOC risk through a personalized "lens" of contextual factors that impacted perceptions about the practical and emotional implications of RRSO and the need for surgery. Mean scores on validated scales evaluating the HGC's impact on decisional outcomes and preparedness for decision-making about RRSO were not significant, indicating that the HGC played a supportive role, rather than helping with decision-making itself. Therefore, we present a novel framework that consolidates the various influences on decision-making and connects them to the psychological and practical implications of RRSO in the context of the HGC. Strategies for improving support, decisional outcomes, and the overall experiences of individuals who are BRCA-positive attending the HGC are also described.

Olaparib treatment for platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency status: Phase II LIGHT study primary analysis.

OBJECTIVE: Olaparib treatment resulted in significant improvement in objective response rates (ORRs) and progression-free survival (PFS) over non­platinum chemotherapy in patients with BRCA1/BRCA2-mutated (BRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) and ≥2 prior lines of platinum-based chemotherapy in the phase III SOLO3 study. LIGHT (NCT02983799) prospectively evaluated olaparib treatment for patients with PSROC and known BRCAm and homologous recombination deficiency (HRD) status. METHODS: In this phase II open-label multicenter study, patients with PSROC and ≥1 prior line of platinum-based chemotherapy were assigned to cohorts by presence of germline BRCAm (gBRCAm), somatic BRCAm (sBRCAm), HRD-positive tumors without BRCAm, or HRD-negative tumors. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR) and PFS. Tumors were analyzed using Myriad BRACAnalysis CDx and myChoice HRD assays; HRD-positive tumors were defined using a genomic instability score of ≥42. RESULTS: Of 272 enrolled patients, 271 received olaparib and 270 were included in efficacy analyses. At data cut-off, ORRs in the gBRCAm, sBRCAm, HRD-positive, and HRD-negative cohorts were 69.3%, 64.0%, 29.4%, and 10.1%, respectively. DCRs were 96.0%, 100.0%, 79.4%, and 75.3% in each cohort, respectively. Median PFS was 11.0, 10.8, 7.2, and 5.4 months, respectively. The most common (≥ 20%) treatment-emergent adverse events included nausea, fatigue/asthenia, vomiting, anemia, constipation, diarrhea, and decreased appetite. CONCLUSIONS: Olaparib treatment demonstrated activity across all cohorts. The greatest efficacy was observed in the BRCAm cohorts, regardless of gBRCAm/sBRCAm. For patients without a BRCAm, greater efficacy was observed in the HRD-positive than the HRD-negative cohorts. The safety profile was consistent with that established in previous olaparib studies.

Comparison of outcomes between abdominal, minimally invasive and combined vaginal-laparoscopic hysterectomy in patients with stage IAI/IA2 cervical cancer: 4C (Canadian Cervical Cancer Collaborative) study.

OBJECTIVE: Although minimally invasive hysterectomy (MIS-H) has been associated with worse survival compared to abdominal hysterectomy (AH) for cervical cancer, only 8% of patients in the LACC trial had microinvasive disease (Stage IA1/IA2). We sought to determine differences in outcome among patients undergoing MIS-H, AH or combined vaginal-laparoscopic hysterectomy (CVLH) for microinvasive cervical cancer. METHODS: A retrospective cohort study of all patients undergoing hysterectomy (radical and non radical) for FIGO 2018, microinvasive cervical cancer across 10 Canadian centers between 2007 and 2019 was performed. Recurrence free survival (RFS) was estimated using Kaplan Meier Survival analysis. Chi-square and log-rank tests were used to compare outcomes. RESULTS: 423 patients with microinvasive cervical cancer were included; 259 (61.2%) Stage IA1 (22/8.5% with LVSI) and 164(38.8%) IA2. The median age was 44 years (range 24-81). The most frequent histology was squamous (59.4%). Surgical approach was: 50.1% MIS-H (robotic or laparoscopic), 35.0% AH and 14.9% CVLH. Overall, 70.9% underwent radical hysterectomy and 76.5% had pelvic lymph node assessment. There were 16 recurrences (MIS-H:4, AH:9, CVLH: 3). No significant difference in 5-year RFS was found (96.7% MIS-H, 93.7% AH, 90.0% CVLH, p = 0.34). In a sub-analysis of patients with IA1 LVSI+/IA2(n = 186), survival results were similar. Further, there was no significant difference in peri-operative complications (p = 0.19). Patients undergoing MIS-H had a shorter median length of stay(0 days vs 3 (AH) vs. 1.5 (CVLH), p < 0.001), but had more ER visits (16.0% vs 3.6% (AH), 3.5% (CVLH), p = 0.036). CONCLUSION: In this cohort, including only patients with microinvasive cervical cancer, no difference in recurrence was found by surgical approach. This may be due to the low rate of recurrence making differences hard to detect or due to a true lack of difference. Hence, this patient population may benefit from MIS without compromising oncologic outcomes.

A population-based study of outcomes in adjuvant radiotherapy for stage II endometrial carcinoma.

OBJECTIVE: Our study aimed to analyze recurrence and survival outcomes in stage II endometrial cancer patients treated with adjuvant radiotherapy at CancerCare Manitoba, a Canadian provincial cancer program. METHODS: This retrospective population-based cohort study identified all International Federation of Gynecology and Obstetrics (FIGO) 2009 stage II endometrioid type endometrial carcinoma diagnosed between January 1995 and December 2019. All patients underwent surgery followed by vaginal vault brachytherapy alone or external beam pelvic radiotherapy plus vaginal vault brachytherapy. We used Kaplan-Meier curves to describe overall survival and recurrence-free survival, and cumulative incidence to describe recurrence. Cox regression was used to predict overall survival and recurrence-free survival competing risk regression to predict recurrence. RESULTS: A total of 121 patients were included (78 vaginal brachytherapy alone and 43 external beam pelvic radiotherapy plus vaginal brachytherapy) with a median age of 62 (range 24-85). The median follow-up was 55.2 months (range 7.1-147.9) in the vaginal brachytherapy group and 41.9 months (range 7.4-127.0) in the pelvic radiotherapy group. Lymph node dissection was performed in 79 (65.3%) patients. There were 14 (17.9%) recurrences (8 vaginal vault, 3 pelvic, 3 distant) with vaginal brachytherapy and 7 (16.3%) recurrences (3 vaginal vault, 2 pelvic, 2 distant) with external beam pelvic radiotherapy. The 5 year overall survival was 73.1% with vaginal vault brachytherapy vs 73.7% with external beam pelvic radiotherapy plus vaginal brachytherapy (p=0.31), the 5 year recurrence-free survival was 65.0% vs 68.2% (p=0.61), and the 5 year recurrence risk was 20.3% vs 19.4% (p=0.94). On univariable and multivariable analysis, only age was a statistically significant predictor for overall survival and recurrence-free survival (p<0.05), but not lymphovascular space invasion (HR, 2.97; 95% CI, 0.99 to 8.93 for overall survival, p=0.15). The type of adjuvant radiotherapy did not predict for recurrence (p=0.94). CONCLUSIONS: There was no significant difference in overall survival, recurrence-free survival, and recurrence risk between vaginal vault brachytherapy vs external beam pelvic radiotherapy plus vaginal vault brachytherapy in patients with stage II endometrial cancer.

The Canadian Gynecologic Oncology Peri-operative Management Survey: re-examining Enhanced Recovery After Surgery (ERAS) recommendations.

OBJECTIVE: Enhanced Recovery After Surgery (ERAS) is a global surgery quality improvement program associated with improved clinical outcomes across the spectrum of disciplines, including gynecologic oncology. The objective of this study was to re-survey the practice of ERAS Gynecologic Oncology guidelines across Canada, after the initial guidelines publication (2016), subsequent guidelines update (2019), and Society of Gynecologic Oncology of Canada (GOC) education events. METHODS: A survey was created and developed through the GOC Communities of Practice ERAS section and distributed to all members between March and November 2021. The results of this survey were compared with the survey performed in 2015 RESULTS: The initial GOC survey in 2015 included 77/92 active gynecologic oncologists (84%) representing all provinces in Canada. The current updated survey had responses from 59/118 active gynecologic oncologists (51%) also from every province. Compared with the original survey there was a statistically significant improvement in uptake of 10 ERAS recommendations: smoking/alcohol cessation, modern fasting guidelines (allowance of clear fluids and solid food pre-operatively), carbohydrate loading, pre-operative warming, early feeding, post-operative laxative use, avoidance of nasogastric tubes and abdominal drains, foley catheter removal at 6 hours, and active mobilization (all p<0.003). Only two fields (stopping oral contraceptive medications pre-operatively and foley catheter removal post-operative day 1) showed worsening uptake across the two surveys (p<0.01). The ERAS recommendations that did not change in the examined time frame included routine use of mechanical bowel preparation, venous thromboembolism prophylaxis, pre-operative antibiotics, and additional antibiotic dosing for prolonged surgery. CONCLUSIONS: This survey demonstrates increased uptake of 10 of the ERAS guideline recommendations among Canadian gynecologic oncology providers. These findings may translate to improvements in clinical outcomes and healthcare system-level benefits including increased hospital capacity and cost savings.

Canadian Enhanced Recovery After Surgery (ERAS) Cesarean Delivery Perioperative Management Survey.

Enhanced Recovery After Surgery (ERAS) is a global surgical quality improvement initiative that has spread across numerous surgical disciplines. The uptake of ERAS in cesarean delivery in Canada is presently unknown. This study surveyed the current practices of Society of Obstetricians and Gynaecologists of Canada (SOGC) members with regards to ERAS guidelines for preoperative, intraoperative, and postoperative cesarean delivery care. Survey responses highlight perioperative practice variations across Canada. Active implementation of ERAS cesarean delivery guidelines could potentially lessen variations in perioperative care, improve patient outcomes, and minimize health care costs.

Perioperative Incidence of Venous Thromboembolism in Patients With Ovarian Cancer Using Four Different Data Collection Methods: A Manitoba Ovarian Cancer Outcomes (MOCO) Group Study.

OBJECTIVE: To evaluate the incidence of venous thromboembolism (VTE) in 90-day pre-operative period and at 30 and 90 days post surgery in patients who underwent debulking for ovarian cancer, analyze the impact of extended prophylaxis that was initiated in 2012, and examine the influence of data collection technique on reported rates of VTE. METHODS: This retrospective database and records study examined rates of VTE in epithelial ovarian cancer patients in Manitoba, Canada between 2004 and 2016. Cases of VTE were identified using ICD codes, drug prescriptions, and records reviews; 4 different data collection methods were used. Analysis was performed with analysis of variance, Kruskal-Wallis and χ2 tests, and interrupted time series models. RESULTS: Data collection identified 823 debulking surgeries, with a final cohort of 779 patients; data were analyzed before and after extended prophylaxis intervention. Overall rates of VTE varied by collection method and were 1.82%-5.47%, 0.36%-3.16%, 0.85%-1.46%, and 1.46%-2.79%, respectively. During this timeframe, we noted a significant increase in the use of neoadjuvant chemotherapy (P = 0.010) and stage migration to stage 3 (P < 0.001). CONCLUSION: We report the rates of VTE utilizing 4 different data collection methods. We found a low overall rate, with some trends requiring further investigation. This study highlights the importance of data collection method on the reported rates of VTE in research.

Chromosome instability is prevalent and dynamic in high-grade serous ovarian cancer patient samples.

OBJECTIVE: High-grade serous ovarian cancer (HGSOC) is the most lethal gynaecological malignancy in women with a high level of mortality, metastatic disease, disease recurrence and multi-drug resistance. Many previous studies have focused on characterising genome instability in recurrent resistant HGSOC and while this has advanced our understanding of HGSOC, our fundamental knowledge of the mechanisms driving genome instability remains limited. Chromosome instability (CIN; an increased rate of chromosome gains and losses) is a form of genome instability that is commonly associated with recurrence and multi-drug resistance in many cancer types but has just begun to be characterised in HGSOC. METHOD: To examine the relationship between CIN and HGSOC, we employed single-cell quantitative imaging microscopy approaches capable of capturing the cell-to-cell heterogeneity associated with CIN, to assess the prevalence and dynamics of CIN within individual and patient-matched HGSOC ascites and solid tumour samples. RESULTS: CIN occurs in 90.9% of ascites samples and 100% of solid tumours, while in-depth analyses identified statistically significant temporal dynamics within the serial ascites samples. In general, aneuploidy and CIN increase with disease progression and frequently decrease following chemotherapy treatments in responsive disease. Finally, our work identified higher levels of CIN in solid tumours relative to ascites samples isolated from the same individual, which identifies a novel difference existing between solid tumours and ascites samples. CONCLUSIONS: Our findings provide novel insight into the relationship between CIN and HGSOC, and uncover a previously unknown relationship existing between CIN in solid tumours and metastatic disease (ascites).

Development of a surgical competency assessment tool for sentinel lymph node dissection by minimally invasive surgery for endometrial cancer.

INTRODUCTION: Sentinel lymph node dissection is widely used in the staging of endometrial cancer. Variation in surgical techniques potentially impacts diagnostic accuracy and oncologic outcomes, and poses barriers to the comparison of outcomes across institutions or clinical trial sites. Standardization of surgical technique and surgical quality assessment tools are critical to the conduct of clinical trials. By identifying mandatory and prohibited steps of sentinel lymph node (SLN) dissection in endometrial cancer, the purpose of this study was to develop and validate a competency assessment tool for use in surgical quality assurance. METHODS: A Delphi methodology was applied, included 35 expert gynecological oncology surgeons from 16 countries. Interviews identified key steps and tasks which were rated mandatory, optional, or prohibited using questionnaires. Using the surgical steps for which consensus was achieved, a competency assessment tool was developed and subjected to assessments of validity and reliability. RESULTS: Seventy percent consensus agreement standardized the specific mandatory, optional, and prohibited steps of SLN dissection for endometrial cancer and informed the development of a competency assessment tool. Consensus agreement identified 21 mandatory and three prohibited steps to complete a SLN dissection. The competency assessment tool was used to rate surgical quality in three preselected videos, demonstrating clear separation in the rating of the skill level displayed with mean skills summary scores differing significantly between the three videos (F score=89.4; P<0.001). Internal consistency of the items was high (Cronbach α=0.88). CONCLUSION: Specific mandatory and prohibited steps of SLN dissection in endometrial cancer have been identified and validated based on consensus among a large number of international experts. A competency assessment tool is now available and can be used for surgeon selection in clinical trials and for ongoing, prospective quality assurance in routine clinical care.

The Risk of Postoperative Infectious Complications Following Massive Intraoperative Blood Loss During Gynaecologic Laparotomy: Retrospective Cohort Study.

PURPOSE: To determine whether massive intraoperative blood loss (MIBL) was independently associated with postoperative infectious complications after gynaecologic laparotomy. METHODS: We conducted a retrospective cohort study of patients undergoing gynaecologic laparotomy who were exposed or not exposed to MIBL. The outcome of interest was composite postoperative febrile morbidity. Multiple logistic regression was used to determine the association between exposure and outcome while controlling for measured covariates. RESULTS: The primary outcome was identified to have occurred in 48% (144 of 298) of surgeries with MIBL compared with 12% (51 of 413) of surgeries without MIBL (P < 0.0001). MIBL was found to be strongly and independently associated with primary outcome (adjusted odds ratio 7.04; 95% confidence interval 4.62-10.74; P < 0.0001) after adjusting for age, body mass index, diabetes, immunosuppression, type of procedure, incision type, drains left in situ, and bowel complications. CONCLUSION: MIBL is strongly and independently associated with postoperative febrile morbidity after gynaecologic laparotomy.

Exploring variations in ovarian cancer survival by age and stage (ICBP SurvMark-2): A population-based study.

OBJECTIVE: The study aims to evaluate the differences in ovarian cancer survival by age and stage at diagnosis within and across seven high-income countries. METHODS: We analyzed data from 58,161 women diagnosed with ovarian cancer during 2010-2014, followed until 31 December 2015, from 21 population-based cancer registries in Australia, Canada, Denmark, Ireland, New Zealand, Norway, and United Kingdom. Comparisons of 1-year and 3-year age- and stage-specific net survival (NS) between countries were performed using the period analysis approach. RESULTS: Minor variation in the stage distribution was observed between countries, with most women being diagnosed with 'distant' stage (ranging between 64% in Canada and 71% in Norway). The 3-year all-ages NS ranged from 45 to 57% with Australia (56%) and Norway (57%) demonstrating the highest survival. The proportion of women with 'distant' stage was highest for those aged 65-74 and 75-99 years and varied markedly between countries (range:72-80% and 77-87%, respectively). The oldest age group had the lowest 3-year age-specific survival (20-34%), and women aged 65-74 exhibited the widest variation across countries (3-year NS range: 40-60%). Differences in survival between countries were particularly stark for the oldest age group with 'distant' stage (3-year NS range: 12% in Ireland to 24% in Norway). CONCLUSIONS: International variations in ovarian cancer survival by stage exist with the largest differences observed in the oldest age group with advanced disease. This finding endorses further research investigating international differences in access to and quality of treatment, and prevalence of comorbid conditions particularly in older women with advanced disease.

Guidelines for vulvar and vaginal surgery: Enhanced Recovery After Surgery Society recommendations.

This is the first collaborative Enhanced Recovery After Surgery Society guideline for optimal perioperative care for vulvar and vaginal surgeries. An Embase and PubMed database search of publications was performed. Studies on each topic within the Enhanced Recovery After Surgery vulvar and vaginal outline were selected, with emphasis on meta-analyses, randomized controlled trials, and prospective cohort studies. All studies were reviewed and graded according to the Grading of Recommendations, Assessment, Development and Evaluation system. All recommendations on the Enhanced Recovery After Surgery topics are based on the best available evidence. The level of evidence for each item is presented.

Exploring international differences in ovarian cancer treatment: a comparison of clinical practice guidelines and patterns of care.

INTRODUCTION: The International Cancer Benchmarking Partnership demonstrated international differences in ovarian cancer survival, particularly for women aged 65-74 with advanced disease. These findings suggest differences in treatment could be contributing to survival disparities. OBJECTIVE: To compare clinical practice guidelines and patterns of care across seven high-income countries. METHODS: A comparison of guidelines was performed and validated by a clinical working group. To explore clinical practice, a patterns of care survey was developed. A questionnaire regarding management and potential health system-related barriers to providing treatment was emailed to gynecological specialists. Guideline and survey results were crudely compared with 3-year survival by 'distant' stage using Spearman's rho. RESULTS: Twenty-seven guidelines were compared, and 119 clinicians completed the survey. Guideline-related measures varied between countries but did not correlate with survival internationally. Guidelines were consistent for surgical recommendations of either primary debulking surgery or neoadjuvant chemotherapy followed by interval debulking surgery with the aim of complete cytoreduction. Reported patterns of surgical care varied internationally, including for rates of primary versus interval debulking, extensive/'ultra-radical' surgery, and perceived barriers to optimal cytoreduction. Comparison showed that willingness to undertake extensive surgery correlated with survival across countries (rs=0.94, p=0.017). For systemic/radiation therapies, guideline differences were more pronounced, particularly for bevacizumab and PARP (poly (ADP-ribose) polymerase) inhibitors. Reported health system-related barriers also varied internationally and included a lack of adequate hospital staffing and treatment monitoring via local and national audits. DISCUSSION: Findings suggest international variations in ovarian cancer treatment. Characteristics relating to countries with higher stage-specific survival included higher reported rates of primary surgery; willingness to undertake extensive/ultra-radical procedures; greater access to high-cost drugs; and auditing.

Response to Multi-Line Chemotherapy in Non-Serous Epithelial Ovarian Cancer.

OBJECTIVES: To describe the response rate to chemotherapy, rates of recurrence, and overall survival in patients with non-serous epithelial ovarian cancers. METHODS: This retrospective cohort study used the Manitoba Cancer Registry to identify all women with non-serous epithelial ovarian, fallopian, or peritoneal cancer treated between 1995 and 2010. Chart review entailed extracting information regarding therapy and outcomes. All patients with recurrence were identified and response to chemotherapy was assessed. RESULTS: We identified 392 patients with non-serous ovarian cancers, 192 of whom received chemotherapy in the first-line setting. Optimal debulking resulted in improvements in rates of recurrence and overall survival (P < 0.001). Histology did not have an effect on recurrence or overall survival. Forty-eight patients (25%) had a recurrence and received second-line therapy, and 21 (11%) received third-line therapy. Response rates were similar regardless of histology. In the second-line setting, 40.9%-83.3% of patients (other > mucinous > clear cell > endometrioid) and in the third-line setting, 33.3%-75.0% of patients (other > mucinous > clear cell > endometrioid) received >6 lines of chemotherapy. Twenty-three percent of patients experienced a recurrence within 2 years of first-line therapy. Two-year survival was 79.4% after first-line treatment, 27.6% after second-line treatment, and 19.5% after third-line treatment. CONCLUSION: Patients with clear cell ovarian cancer had chemotherapy continuation rates similar to those of previously reported studies. This is one of the first studies reporting response rates for mucinous and endometrioid subtypes. Recurrent disease responds to treatment with second- and third-line therapy, emphasizing the importance of offering patients subsequent lines of chemotherapy for disease management. Further studies are needed to determine the optimal regimen.

The temporal dynamics of chromosome instability in ovarian cancer cell lines and primary patient samples.

Epithelial ovarian cancer (EOC) is the most prevalent form of ovarian cancer and has the highest mortality rate. Novel insight into EOC is required to minimize the morbidity and mortality rates caused by recurrent, drug resistant disease. Although numerous studies have evaluated genome instability in EOC, none have addressed the putative role chromosome instability (CIN) has in disease progression and drug resistance. CIN is defined as an increase in the rate at which whole chromosomes or large parts thereof are gained or lost, and can only be evaluated using approaches capable of characterizing genetic or chromosomal heterogeneity within populations of cells. Although CIN is associated with numerous cancer types, its prevalence and dynamics in EOC is unknown. In this study, we assessed CIN within serial samples collected from the ascites of five EOC patients, and in two well-established ovarian cancer cell models of drug resistance (PEO1/4 and A2780s/cp). We quantified and compared CIN (as measured by nuclear areas and CIN Score (CS) values) within and between serial samples to glean insight into the association and dynamics of CIN within EOC, with a particular focus on resistant and recurrent disease. Using quantitative, single cell analyses we determined that CIN is associated with every sample evaluated and further show that many EOC samples exhibit a large degree of nuclear size and CS value heterogeneity. We also show that CIN is dynamic and generally increases within resistant disease. Finally, we show that both drug resistance models (PEO1/4 and A2780s/cp) exhibit heterogeneity, albeit to a much lesser extent. Surprisingly, the two cell line models exhibit remarkably similar levels of CIN, as the nuclear areas and CS values are largely overlapping between the corresponding paired lines. Accordingly, these data suggest CIN may represent a novel biomarker capable of monitoring changes in EOC progression associated with drug resistance.

International validation of Enhanced Recovery After Surgery Society guidelines on enhanced recovery for gynecologic surgery.

BACKGROUND: Enhanced Recovery After Surgery Society publishes guidelines on perioperative care, but these guidelines should be validated prospectively. OBJECTIVE: To evaluate the association between compliance with Enhanced Recovery After Surgery Gynecologic/Oncology guideline elements and postoperative outcomes in an international cohort. STUDY DESIGN: The study comprised 2101 patients undergoing elective gynecologic/oncology surgery between January 2011 and November 2017 in 10 hospitals across Canada, the United States, and Europe. Patient demographics, surgical/anesthesia details, and Enhanced Recovery After Surgery protocol compliance elements (pre-, intra-, and postoperative phases) were entered into the Enhanced Recovery After Surgery Interactive Audit System. Surgical complexity was stratified according to the Aletti scoring system (low vs medium/high). The following covariates were accounted for in the analysis: age, body mass index, smoking status, presence of diabetes, American Society of Anesthesiologists class, International Federation of Gynecology and Obstetrics stage, preoperative chemotherapy, radiotherapy, operating time, surgical approach (open vs minimally invasive), intraoperative blood loss, hospital, and Enhanced Recovery After Surgery implementation status. The primary end points were primary hospital length of stay and complications. Negative binomial regression was used to model length of stay, and logistic regression to model complications, as a function of compliance score and covariates. RESULTS: Patient demographics included a median age 56 years, 35.5% obese, 15% smokers, and 26.7% American Society of Anesthesiologists Class III-IV. Final diagnosis was malignant in 49% of patients. Laparotomy was used in 75.9% of cases, and the remainder minimally invasive surgery. The majority of cases (86%) were of low complexity (Aletti score ≤3). In patients with ovarian cancer, 69.5% had a medium/high complexity surgery (Aletti score 4-11). Median length of stay was 2 days in the low- and 5 days in the medium/high-complexity group. Every unit increase in Enhanced Recovery After Surgery guideline score was associated with 8% (IRR, 0.92; 95% confidence interval, 0.90-0.95; P<.001) decrease in days in hospital among low-complexity, and 12% (IRR, 0.88; 95% confidence interval, 0.82-0.93; P<.001) decrease among patients with medium/high-complexity scores. For every unit increase in Enhanced Recovery After Surgery guideline score, the odds of total complications were estimated to be 12% lower (P<.05) among low-complexity patients. CONCLUSION: Audit of surgical practices demonstrates that improved compliance with Enhanced Recovery After Surgery Gynecologic/Oncology guidelines is associated with an improvement in clinical outcomes, including length of stay, highlighting the importance of Enhanced Recovery After Surgery implementation.

Guidelines for perioperative care in gynecologic/oncology: Enhanced Recovery After Surgery (ERAS) Society recommendations-2019 update.

BACKGROUND: This is the first updated Enhanced Recovery After Surgery (ERAS) Society guideline presenting a consensus for optimal perioperative care in gynecologic/oncology surgery. METHODS: A database search of publications using Embase and PubMed was performed. Studies on each item within the ERAS gynecologic/oncology protocol were selected with emphasis on meta-analyses, randomized controlled trials, and large prospective cohort studies. These studies were then reviewed and graded according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. RESULTS: All recommendations on ERAS protocol items are based on best available evidence. The level of evidence for each item is presented accordingly. CONCLUSIONS: The updated evidence base and recommendation for items within the ERAS gynecologic/oncology perioperative care pathway are presented by the ERAS® Society in this consensus review.