Primary cytoreductive surgery compared with neoadjuvant chemotherapy in patients with BRCA mutated advanced high grade serous ovarian cancer: 10 year survival analysis.

OBJECTIVES: Given the high response to platinum based chemotherapy in BRCA 1/2 mutated high grade serous ovarian cancers, there is uncertainty about the relative benefits of primary cytoreductive surgery versus neoadjuvant chemotherapy in this population. We aimed to compare the survival outcomes for women with BRCA 1/2 mutated high grade serous ovarian cancers undergoing either primary cytoreductive surgery or neoadjuvant chemotherapy. METHODS: We conducted a retrospective cohort study of all stage III/IV BRCA mutated high grade serous ovarian cancers treated with primary cytoreductive surgery or neoadjuvant chemotherapy at a single tertiary cancer center between 1991 and 2020. Baseline demographics, initial disease burden, surgical complexity, and survival outcomes were examined. RESULTS: Of 314 women with germline or somatic BRCA mutations, 194 (62%) underwent primary cytoreductive surgery and 120 (38%) underwent neoadjuvant chemotherapy followed by interval cytoreductive surgery. Those undergoing primary cytoreductive surgery were younger (median age 53 years (range 47-59) vs 59 years (50-65), p<0.001), but there were no differences in functional status or underlying comorbidities. The initial disease burden was lower (disease score high (40% vs 44%; p<0.001) but surgical complexity was higher (surgical complexity score high (18% vs 3%; p<0.001) in the primary cytoreductive surgery cohort. The rate of optimal or complete cytoreduction was similar in both groups (89% vs 90%; p=0.23) as well as the rate of poly (ADP-ribose) polymerase inhibitor use (62% vs 68%; p=0.3). The 10 year overall survival and recurrence free survival were superior in the primary cytoreductive surgery cohort (overall survival 49% vs 25%, p<0.001 and progression free survival 25% vs 10%, p<0.001). After controlling for confounders, primary cytoreductive surgery remained a significant predictor of improved overall survival (hazard ratio (HR) 0.45; 95% confidence interval (CI) 0.27 to 0.74; p=0.002) and recurrence free survival (HR 0.55; 95% CI 0.37 to 0.80; p=0.002). CONCLUSIONS: Primary cytoreductive surgery was associated with improved survival in women with stage III/IV BRCA mutated high grade serous ovarian cancers compared with neoadjuvant chemotherapy.

Sustainability of an enhanced recovery pathway after minimally invasive gynecologic oncology surgery.

OBJECTIVE: Same day discharge is safe after minimally invasive gynecology oncology surgery. Our quality improvement peri-operative program based on enhanced recovery after surgery principles led to an increase in same day discharge from 30% to 75% over a 12 month period. Twelve months after program implementation, we assessed the sustainability of same day discharge rates, determined post-operative complication rates, and evaluated factors affecting same day discharge rates. METHODS: A retrospective chart review was conducted of 100 consecutive patients who underwent minimally invasive surgery at an academic cancer center from January to 2021 to December 2021. This cohort was compared with the active intervention cohort (n=102) from the implementation period (January 2020 to December 2020). Same day discharge rates and complications were compared. Multivariable analysis was performed to assess which factors remained associated with same day discharge post-intervention. RESULTS: Same day discharge post-intervention was 72% compared with 75% during active intervention (p=0.69). Both cohorts were similar in age (p=0.24) and body mass index (p=0.27), but the post-intervention cohort had longer operative times (p=0.001). There were no significant differences in 30-day complications, readmission, reoperation, or emergency room visits (p>0.05). There was a decrease in 30-day post-operative clinic visits from 18% to 5% in the post-intervention cohort (p=0.007), and unnecessary bowel prep use decreased from 35% to 14% (p<0.001). On multivariable analysis, start time (second case of the day) (OR 0.06; 95% CI 0.01 to 0.35), and ward narcotic use (OR 0.12; 95% CI 0.03 to 0.42) remained associated with overnight admission. CONCLUSION: Same day discharge rate was sustained at 72%, 12 months after the implementation of a quality improvement program to optimize same day discharge rate after minimally invasive surgery, while maintaining low post-operative complications and reducing unplanned clinic visits. To maximize same day discharge, minimally invasive gynecologic oncology surgery should be prioritized as the first case of the day, and post-operative narcotic use should be limited.

Computational modeling of ovarian cancer dynamics suggests optimal strategies for therapy and screening.

High-grade serous tubo-ovarian carcinoma (HGSC) is a major cause of cancer-related death. Treatment is not uniform, with some patients undergoing primary debulking surgery followed by chemotherapy (PDS) and others being treated directly with chemotherapy and only having surgery after three to four cycles (NACT). Which strategy is optimal remains controversial. We developed a mathematical framework that simulates hierarchical or stochastic models of tumor initiation and reproduces the clinical course of HGSC. After estimating parameter values, we infer that most patients harbor chemoresistant HGSC cells at diagnosis and that, if the tumor burden is not too large and complete debulking can be achieved, PDS is superior to NACT due to better depletion of resistant cells. We further predict that earlier diagnosis of primary HGSC, followed by complete debulking, could improve survival, but its benefit in relapsed patients is likely to be limited. These predictions are supported by primary clinical data from multiple cohorts. Our results have clear implications for these key issues in HGSC management.

Safety of fertility sparing management in invasive mucinous ovarian carcinoma.

BACKGROUND: The aim of the study was to evaluate the safety of fertility-sparing surgery in invasive mucinous ovarian carcinomas (MOC). METHODS: Retrospective review was performed of MOCs diagnosed between 1999 and 2019 at two tertiary cancer centers. Pathology was reviewed to rule out metastasis from gastrointestinal tract. The demographics and survival outcomes were compared between women who underwent fertility-sparing surgery and those who underwent radical surgery (at least hysterectomy, bilateral salpingo-oophorectomy +/- staging). Cox proportional hazard models were constructed to evaluate the effect of fertility sparing surgery on survival. RESULTS: Of 134 with stage I disease, 42 (31%) underwent fertility-sparing surgery with unilateral salpingo-oophorectomy. Compared to women who underwent radical surgery, these women were younger with low grade, early-stage disease. Two patients (5%) in the fertility-sparing cohort experienced a recurrence and 1 of these 2 patients died due to disease progression. There was no difference in either OS or RFS between those that underwent fertility-sparing surgery and radical surgery. In a multivariable analysis adjusting for age and use of adjuvant chemotherapy, fertility-sparing surgery was not significantly associated with OS (HR 0.18; 95% CI 0.01-2.78) or RFS (HR 0.19; 95% CI 0.03-1.45). There were 4 patients (9%) with documented full-term delivery with median interval to conception of 11 months. CONCLUSIONS: Fertility-sparing surgery in stage I MOC is not associated with worse outcomes compared to radical surgery and is reasonable to offer to those with early stage disease who wish to retain fertility.

Using a machine learning algorithm to predict outcome of primary cytoreductive surgery in advanced ovarian cancer.

OBJECTIVE: To develop a machine learning (ML) algorithm to predict outcome of primary cytoreductive surgery (PCS) in patients with advanced ovarian cancer (AOC) METHODS: This retrospective cohort study included patients with AOC undergoing PCS between January 2017 and February 2021. Using radiologic criteria, patient factors (age, CA-125, performance status, BRCA) and surgical complexity scores, we trained a random forest model to predict the dichotomous outcome of optimal cytoreduction (<1 cm) and no gross residual (RD = 0 mm) using JMP-Pro 15 (SAS). This model is available at https://ipm-ml.ccm.sickkids.ca. RESULTS: One hundred and fifty-one patients underwent PCS and randomly assigned to train (n = 92), validate (n = 30), or test (n = 29) the model. The median age was 58 (27-83). Patients with suboptimal cytoreduction were more likely to have an Eastern Cooperative Oncology Group 3-4 (11% vs. 0.75%, p = 0.004), lower albumin (38 vs. 41, p = 0.02), and higher CA125 (1126 vs. 388, p = 0.012) than patients with optimal cytoreduction (n = 133). There were no significant differences in age, histology, stage, or BRCA status between groups. The bootstrap random forest model had AUCs of 99.8% (training), 89.6%(validation), and 89.0% (test). The top five contributors were CA125, albumin, diaphragmatic disease, age, and ascites. For RD = 0 mm, the AUCs were 94.4%, 52%, and 84%, respectively. CONCLUSION: Our ML algorithm demonstrated high accuracy in predicting optimal cytoreduction in patients with AOC selected for PCS and may assist decision-making.

Impact of lymphadenectomy and intra-operative tumor rupture on survival in early-stage mucinous ovarian cancers.

OBJECTIVE: Mucinous ovarian carcinoma is a rare subtype of epithelial ovarian cancer with scarce literature guiding its management. We aimed to investigate the optimal surgical management of clinical stage I mucinous ovarian carcinoma by examining the prognostic significance of lymphadenectomy and intra-operative rupture on patient survival. METHODS: We conducted a retrospective cohort study of all pathology-reviewed invasive mucinous ovarian carcinomas diagnosed between 1999 and 2019 at two tertiary care cancer centers. Baseline demographics, surgical management details, and outcomes were collected. Five-year overall survival, recurrence-free survival, and the association of lymphadenectomy and intra-operative rupture on survival were examined. RESULTS: Of 170 women with mucinous ovarian carcinoma, 149 (88%) had clinical stage I disease. Forty-eight (32%; n=149) patients had a pelvic and/or para-aortic lymphadenectomy, but only 1 patient with grade 2 disease was upstaged due to positive pelvic lymph nodes. Intra-operative tumor rupture was documented in 52 cases (35%). On multivariable analysis, after adjusting for age, final stage, and use of adjuvant chemotherapy, there was no significant association between intra-operative rupture with overall survival (HR 2.2 (0.6-8.0); p=0.3) or recurrence-free survival (HR 1.3 (0.5-3.3); p=0.6), or lymphadenectomy with overall survival (HR 0.9 (0.3-2.8); p=0.9) or recurrence-free survival (HR 1.2 (0.5-3.0); p=0.7). Advanced stage was the only factor that was significantly associated with survival. CONCLUSIONS: In clinical stage I mucinous ovarian carcinoma, systematic lymphadenectomy has low utility, as very few patients are upstaged and recurrence typically occurs in the peritoneum. Furthermore, intra-operative rupture does not appear to independently confer a worse survival, and therefore these women may not benefit from adjuvant treatment based on rupture alone.

Validation of the Integrated Prediction Model algorithm for outcome of cytoreduction in advanced ovarian cancer.

BACKGROUND: We previously developed the Integrated Prediction Model using a 4-step algorithm of unresectable stage IVB, patient factors, surgical resectability, and surgical complexity to predict outcome of <1 cm cytoreduction in advanced epithelial ovarian cancer, and triaged patients to neoadjuvant chemotherapy or primary cytoreductive surgery. OBJECTIVE: To validate the Integrated Prediction Model on a retrospective cohort of patients. METHODS: A retrospective cohort study of 107 patients with advanced ovarian cancer treated between January 2017 and September 2018 was carried out. The above mentioned 4-step algorithm determined cut-off points using the Youden Index. This validation study reports sensitivity, specificity, negative and positive predictive value on an external cohort. RESULTS: Among 107 patients, 61 had primary surgery and 46 had neoadjuvant chemotherapy. Compared with primary surgery, patients treated with neoadjuvant chemotherapy were significantly older (63.5 vs 61, p=0.037), more likely to have stage IV disease (52% vs 18%, p<0.001), Eastern Cooperative Oncology Group (ECOG) score >1 (30% vs 11%, 0.045), lower pre-operative albumin (37 vs 40, p<0.001), and higher CA-125 (970 vs 227.5, p<0.001). They also had higher patient factors (2 vs 0, p=0.013), surgical resectability (4 vs 1, p<0.001), and anticipated surgical complexity (8 vs 5, p<0.001). There was no significant difference in outcome of cytoreduction (<1 cm residual disease: 85% for primary surgery vs 87% interval surgery, p=0.12)In this validation cohort, triaging patients with patient factors ≤2, surgical resectability score ≤5, and surgical complexity score ≤9 to primary surgery had a sensitivity of 91% for optimal cytoreduction <1 cm and a specificity of 81%. The positive predictive value, negative predictive value, and accuracy were 83%, 90%, and 86%, respectively. Application of the Integrated Prediction Model would have prevented five patients from receiving suboptimal cytoreduction and triaged them to neoadjuvant chemotherapy. CONCLUSIONS: We validated the proposal that a triage algorithm integrating patient factors, surgical complexity, and surgical resectability in advanced ovarian cancer had high sensitivity and specificity to predict optimal cytoreduction <1 cm.

Integrated prediction model of patient factors, resectability scores and surgical complexity to predict cytoreductive outcome and guide treatment plan in advanced ovarian cancer.

OBJECTIVE: To report performance of an integrated predictive model (IPM) algorithm based on patient factors, surgical resectability and surgical complexity to predict outcome of primary cytoreductive surgery (PCS) and guide treatment plan in patients with advanced epithelial ovarian cancer (AEOC). METHODS: Patients with AEOC between October 2018 and October 2020 were enrolled into a dedicated AEOC program and decision for PCS or neoadjuvant chemotherapy (NACT) was based on multidisciplinary consensus. Data of unresectable stage IVb, patient factors (PF), surgical resectability scores (SRS) and surgical complexity scores (SCS) was prospectively documented. An integrated prediction model (IPM) was developed to predict outcome of optimal (RD < 1 cm) cytoreduction. Retrospective analysis was performed to assess the performance of the IPM. Cut-offs were selected using the Youden Index. RESULTS: Of 185 eligible patients, 81 underwent PCS and 104 were treated with NACT. Patients undergoing PCS had significantly lower median PF (0 vs 2, p < 0.01), SRS (2 vs 4, p < 0.01) and pre-operative SCS (6 vs 8.5, p = 0.01) compared to NACT. In patients undergoing PCS, 88% had optimal cytoreduction and 34.5% had grade 3-4 post-operative complications. A model triaging patients with unresectable Stage IVb, PF > 2, SRS > 5 and SCS > 9 to NACT had 85% sensitivity, 75% specificity and 85% accuracy for outcome of optimal cytoreduction. Our model would have improved triage of 3/10 sub-optimally cytoreduced patients to NACT. For outcome of no-gross residual disease (RD = 0 mm) using the same cut-offs sensitivity and specificity were 85% and 76% respectively. CONCLUSION: The 4-step IPM algorithm had high sensitivity and specificity for optimal cytoreduction with acceptable morbidity without delay to adjuvant therapy. This algorithm may be used to triage patients to PCS or NACT once it is further validated.

Treatment outcomes and predictive factors in patients ≥70 years old with advanced ovarian cancer.

OBJECTIVE: To evaluate treatment outcomes, survival, and predictive factors in patients ≥70 with advanced epithelial ovarian cancer (AEOC). METHODS: A retrospective single institution cohort study of women ≥70 with Stage III-IV AEOC between 2010 and 2018. Patients had either primary cytoreductive surgery (PCS), neoadjuvant chemotherapy (NACT) with interval cytoreductive surgery (ICS), chemotherapy alone, or no treatment. Demographics, surgical outcome, complications, and survival outcome were compared between groups. RESULTS: Among 248 patients, 69 (27.7%) underwent PCS, 99 (39.9%) had ICS, 56 (22.5%) had chemotherapy alone. Twenty-four (9.6%) remained untreated. Optimal cytoreduction (≤1 cm) was achieved in 72.4% of PCS and 77.8% of NACT/ICS (p = 0.34), without difference in grade ≥3 postoperative complications (15.9% vs. 9.1%, p = 0.37). Progression-free survival (PFS) was 23.5 months in PCS and 15.0 months in ICS patients (hazard ratio [HR]: 1.4, p = 0.041). Patients in the surgical arms, PCS or ICS, had better 2-year overall survival (OS) compared to chemotherapy alone (79%, 68%, 41%, respectively, HR: 3.58, p < 0.001). In a subgroup analysis, patients ≥80 had improved 2-year OS when treated with NACT compared to PCS (82% vs. 57%) and a trend toward improved PFS. Age, stage, and CA-125 were determinants of undergoing PCS. CONCLUSION: In patients ≥70 with AEOC, surgery should not be deferred based on age alone. Fit, well selected patients ≥70 can benefit from PCS, while patients ≥80 might benefit from NACT over PCS.

Oncologic and pregnancy outcomes after fertility-sparing surgery for stage I, low-grade endometrioid ovarian cancer.

OBJECTIVE: To evaluate oncologic outcomes in patients with stage I endometrioid ovarian cancer treated with fertility-sparing compared with conventional surgery and to describe reproductive outcomes. METHODS: A retrospective cohort study was carried out of patients aged 18-45 with stage I, grade 1 and 2 (low-grade) endometrioid ovarian cancer treated at two cancer centers between July 2001 and December 2019. Clinical and pathologic characteristics were compared using Fisher's exact test for categorical and the Mann-Whitney U test for continuous variables. Recurrence-free and overall survival were calculated from Kaplan-Meier curves and compared for fertility-sparing and conventional surgery using the log rank test. Pregnancy outcomes are described. RESULTS: There were 230 patients with endometrioid ovarian cancer. After exclusion of patients with stage greater than I and those older than 45 years, there were 31 patients with stage I cancer aged 18-45. Of these patients, 11 (35.5%) underwent fertility-sparing surgery and 20 (64.5%) underwent conventional surgery. The median follow-up was 6.0 years (range 1.8-17.3). The median age was 36 years (range 26-42) in the fertility-sparing group and 42 years (range 35-45) in the conventional surgery group (p=0.001), with no difference in other clinical and pathologic characteristics. The 5-year recurrence-free survival was 90.9% (95% CI 73.9% to 100%) for the fertility-sparing group and 84.0% (95% CI 67.3% to 100%) for the conventional surgery group (p=0.65). The 5-year overall survival was 100% for patients in the fertility-sparing group and 92.6% (95% CI 78.7% to 100%) for patients treated with conventional surgery (p=0.49). Four (12.9%) patients had disease recurrence: three (15%) after conventional surgery and one (9.1%) in the contralateral ovary after fertility-sparing surgery and embryo cryopreservation. After fertility-sparing surgery, seven (63.6%) patients attempted pregnancy, of which five (71.4%) conceived with four (57.1%) using in vitro fertilization. Of the five patients who conceived, there were three spontaneous abortions and five live births. CONCLUSION: Fertility-sparing surgery appears safe and may be considered in young women with stage I, low-grade endometrioid ovarian cancer when fertility preservation is desired.

The effect of complete surgical staging and adjuvant chemotherapy on survival in stage I, grade 1 and 2 endometrioid ovarian carcinoma.

OBJECTIVES: To assess the effect of complete surgical staging and adjuvant chemotherapy on survival in stage I, low grade endometrioid ovarian cancer. METHODS: This retrospective study was conducted at two cancer centers from July 2001 to December 2019. Inclusion criteria were all stage I, grade 1 and 2 endometrioid ovarian cancer patients. Patients with mixed histology, concurrent endometrial cancer, neoadjuvant chemotherapy, and patients who did not undergo follow-up at our centers were excluded. Clinical, pathologic, recurrence, and follow-up data were collected. Cox proportional hazard model evaluated predictive factors. Recurrence-free survival and overall survival were calculated using the Kaplan-Meier method. RESULTS: There were 131 eligible stage I patients: 83 patients (63.4%) were stage IA, 5 (3.8%) were stage IB, and 43 (32.8%) were stage IC, with 80 patients (61.1%) having grade 1 and 51 (38.9%) patients having grade 2 disease. Complete lymphadenectomy was performed in 34 patients (26.0%), whereas 97 patients (74.0%) had either partial (n=22, 16.8%) or no (n=75, 57.2%) lymphadenectomy. Thirty patients (22.9%) received adjuvant chemotherapy. Median follow-up was 51.5 (95% CI 44.3 to 57.2) months. Five-year recurrence-free survival was 88.0% (95% CI 81.6% to 94.9%) and 5 year overall survival was 95.1% (95% CI 90.5% to 99.9%). In a multivariable analysis, only grade 2 histology had a significantly higher recurrence rate (HR 3.42, 95% CI 1.03 to 11.38; p=0.04). There was no difference in recurrence-free survival (p=0.57) and overall survival (p=0.30) in patients with complete lymphadenectomy. In stage IA/IB, grade 2 there was no benefit of adjuvant chemotherapy (p=0.19), and in stage IA/IB, low grade without complete surgical staging there was no benefit of adjuvant chemotherapy (p=0.16). Twelve patients (9.2%) had recurrence; 3 (25%) were salvageable at recurrence and are alive with no disease. CONCLUSIONS: Patients with stage I, low grade endometrioid ovarian cancer have a favorable prognosis, and adjuvant chemotherapy and staging lymphadenectomy did not improve survival.

Enhanced recovery after minimally invasive gynecologic oncology surgery to improve same day discharge: a quality improvement project.

OBJECTIVES: Same day discharge after minimally invasive hysterectomy has been shown to be safe and feasible. We designed and implemented a quality improvement perioperative program based on early recovery after surgery principles to improve the rate of same day discharge from 30% to 75% after minimally invasive gynecologic oncology surgery over a 12 month period. METHODS: We enrolled 102 consecutive patients undergoing minimally invasive hysterectomy at a single cancer center during a 12 month period. A pre-intervention cohort of 100 consecutive patients was identified for comparison of clinicodemographic variables and perioperative outcomes. A multidisciplinary team developed a comprehensive perioperative care program and followed quality improvement methodology. Patients were followed up for 30 days after discharge. A statistical process chart was used to monitor the effects of our interventions, and a multivariate analysis was conducted to determine factors associated with same day discharge. RESULTS: Same day discharge rate increased from 29% to 75% after implementation (p<0.001). The post-intervention cohort was significantly younger (59 vs 62 years; p=0.038) and had shorter operative times (180 vs 211 min; p<0.001) but the two groups were similar in body mass index, comorbidity, stage, and intraoperative complications. There was no difference in 30 day perioperative complications, readmissions, reoperations, emergency department visits, or mortality. Overnight admissions were secondary to nausea and vomiting (16%), complications of pre-existing comorbidities (12%), and urinary retention (8%). On multivariate analysis, longer surgery, timing of surgery, and narcotic use on the ward were significantly associated with overnight admission. Overall, 89% of patients rated their experience as 'very good' or 'excellent', and 87% felt that their length of stay was adequate. CONCLUSIONS: Following implementation of a perioperative quality improvement program targeted towards minimally invasive gynecologic oncology surgery, our intervention significantly improved same day discharge rates while maintaining a low 30 day perioperative complication rate and excellent patient experience.

The correlation between BRCA status and surgical cytoreduction in high-grade serous ovarian carcinoma.

OBJECTIVE: BRCA-associated ovarian cancers are biologically unique; it is unclear if this translates to favorable outcomes at the time of primary cytoreduction (PCS). The aim of this study was to compare the amount of residual disease after PCS in BRCA mutated (BRCAm) and wild-type (BRCAwt) high-grade serous ovarian cancers (HGSC), and to assess whether BRCA status was an independent predictor of complete cytoreduction. METHODS: We conducted a retrospective analysis of patients with stage III/IV HGSC with known germline and somatic BRCA status, treated with PCS from 2000 to 2017. We compared the complete, optimal and suboptimal cytoreduction rates between the BRCAm and BRCAwt cohorts and built a predictive model to assess whether BRCA status was predictive of complete cytoreduction. RESULTS: Of 303 treated with PCS, 120 were germline/somatic BRCAm (40%) and 183 were BRCAwt (60%). BRCAm women tended to be younger, but there were no differences between the two groups in preoperative CA-125, disease burden, surgical complexity, length of surgery, or perioperative complications. BRCAm group had a higher rate of complete cytoreduction to no residual disease (0 mm) [72% vs. 48%] (p < 0.001). In a multivariate model, after accounting for age, length of surgery, CA-125 level, stage, disease burden and surgical complexity, BRCAm status was predictive of 0 mm residual disease with odds ratio of 5.3 (95% CI 2.45-11.5; p < 0.001). CONCLUSIONS: BRCAm status is predictive of complete cytoreduction at the time of PCS. Despite similar disease burden and surgical efforts, one is more likely to achieve complete resection in BRCAm HGSC.

Gynecologic oncology treatment modifications or delays in response to the COVID-19 pandemic in a publicly funded versus privately funded North American tertiary cancer center.

OBJECTIVE: To compare gynecologic oncology surgical treatment modifications and delays during the first wave of the COVID-19 pandemic between a publicly funded Canadian versus a privately funded American cancer center. METHODS: This is a retrospective cohort study of all planned gynecologic oncology surgeries at University Health Network (UHN) in Toronto, Canada and Brigham and Women's Hospital (BWH) in Boston, USA, between March 22,020 and July 302,020. Surgical treatment delays and modifications at both centers were compared to standard recommendations. Multivariable logistic regression was performed to adjust for confounders. RESULTS: A total of 450 surgical gynecologic oncology patients were included; 215 at UHN and 235 at BWH. There was a significant difference in median time from decision-to-treat to treatment (23 vs 15 days, p < 0.01) between UHN and BWH and a significant difference in treatment delays (32.56% vs 18.29%; p < 0.01) and modifications (8.37% vs 0.85%; p < 0.01), respectively. On multivariable analysis adjusting for age, race, treatment site and surgical priority status, treatment at UHN was an independent predictor of treatment modification (OR = 9.43,95% CI 1.81-49.05, p < 0.01). Treatment delays were higher at UHN (OR = 1.96,95% CI 1.14-3.36 p = 0.03) and for uterine disease (OR = 2.43, 95% CI 1.11-5.33, p = 0.03). CONCLUSION: During the first wave of COVID-19 pandemic, gynecologic oncology patients treated at a publicly funded Canadian center were 9.43 times more likely to have a surgical treatment modification and 1.96 times more likely to have a surgical delay compared to an equal volume privately funded center in the United States.

Risk of second malignancy in patients with ovarian clear cell carcinoma.

OBJECTIVE: Ovarian clear cell carcinoma has unique clinical and molecular features compared with other epithelial ovarian cancer histologies. Our objective was to describe the incidence of second primary malignancy in patients with ovarian clear cell carcinoma. METHODS: Retrospective cohort study of patients with ovarian clear cell carcinoma at two tertiary academic centers in Toronto, Canada between May 1995 and June 2017. Demographic, histopathologic, treatment, and survival details were obtained from chart review and a provincial cancer registry. We excluded patients with histologies other than pure ovarian clear cell carcinoma (such as mixed clear cell histology), and those who did not have their post-operative follow-up at these institutions. RESULTS: Of 209 patients with ovarian clear cell carcinoma, 54 patients developed a second primary malignancy (25.8%), of whom six developed two second primary malignancies. Second primary malignancies included: breast (13), skin (9), gastrointestinal tract (9), other gynecologic malignancies (8), thyroid (6), lymphoma (3), head and neck (4), urologic (4), and lung (4). Eighteen second primary malignancies occurred before the index ovarian clear cell carcinoma, 35 after ovarian clear cell carcinoma, and 7 were diagnosed concurrently. Two patients with second primary malignancies were diagnosed with Lynch syndrome. Smoking and radiation therapy were associated with an increased risk of second primary malignancy on multivariable analysis (OR 3.69, 95% CI 1.54 to 9.07, p=0.004; OR 4.39, 95% CI 1.88 to 10.6, p=0.0008, respectively). However, for patients developing second primary malignancies after ovarian clear cell carcinoma, radiation therapy was not found to be a significant risk factor (p=0.17). There was no significant difference in progression-free survival (p=0.85) or overall survival (p=0.38) between those with second primary malignancy and those without. CONCLUSION: Patients with ovarian clear cell carcinoma are at increased risk of second primary malignancies, most frequently non-Lynch related. A subset of patients with ovarian clear cell carcinoma may harbor mutations rendering them susceptible to second primary malignancies. Our results may have implications for counseling and consideration for second primary malignancy screening.

Implementation of a restrictive opioid prescription protocol after minimally invasive gynecologic oncology surgery.

OBJECTIVES: Opioids are routinely prescribed after minimally invasive gynecologic oncology surgery, with minimal data to inform the ideal dose. The aim of this study was to evaluate the impact of a restrictive opioid prescription protocol on the median morphine milligram equivalents prescribed and pain control in patients undergoing minimally invasive surgery. METHODS: A restrictive opioid prescription protocol was implemented from January through December 2020 at a single tertiary cancer center in Ontario, Canada. Consecutive patients undergoing minimally invasive hysterectomy for suspected malignancy were included. Simultaneously, we implemented use of multimodal analgesia, patient and provider education, pre-printed standardized prescriptions, and tracking of opioid prescriptions. Total median morphine milligram equivalents prescribed were compared between pre- and post-intervention cohorts. Patients were surveyed regarding opioid use and pain control at 30 days post-surgery. RESULTS: A total of 101 women in the post-intervention cohort were compared with 92 consecutive pre-intervention controls. Following protocol implementation, median morphine milligram equivalents prescribed decreased from 50 (range 9-100) to 25 (range 8-75) (p<0.001). In the post-intervention cohort, 75% (76/101) used 10 median morphine milligram equivalents or less and 55 patients (54%) used 0 median morphine milligram equivalent. There was no additional increase in opioid refill requests after implementation of our strategy. Overall, patients reported a median pain score of 3/10 at 30 days post-surgery; the highest pain scores and most of the pain occurred in the first week after surgery. CONCLUSIONS: Implementation of a restrictive opioid prescription protocol led to a significant reduction in opioid use after minimally invasive gynecologic oncology surgery, with over 50% of patients requiring no opioids postoperatively.

The use of indocyanine green fluorescence angiography to assess anastomotic perfusion following bowel resection in surgery for gynecologic malignancies - A report of 100 consecutive anastomoses.

OBJECTIVE: Real-time intraoperative assessment of anastomotic perfusion with indocyanine green fluorescence angiography (ICG-FA) is a recent technique that is found to assist intraoperative decision-making and decrease risk of anastomotic leak in the General Surgery literature. No studies to date evaluate its use in Gynecologic Oncology. Our objectives were to assess the safety and feasibility of ICG-FA use and to describe the intraoperative assessment of anastomotic perfusion with ICG-FA. METHODS: A retrospective study of a prospectively-collected database of patients with a gynecologic malignancy who underwent a bowel resection at Princess Margaret Cancer Centre in Toronto, Canada, between November 1, 2017 and December 15, 2019 was conducted. ICG-FA was administered intravenously, and a near infrared imaging system (Pinpoint, Novadaq, Canada; SPY-PHI, Stryker, USA) was used to objectively assess bowel perfusion. RESULTS: ICG-FA was used to assess a total of 100 bowel anastomoses in 82 consecutive surgeries: 56 low anterior resections, 19 small bowel resections, 15 right hemi-colectomies, 6 left hemi-colectomies, 3 transverse colectomies, and 1 total colectomy. Fifty-five end-to end, 44 side-to-side and 1 end-to-side anastomoses were assessed. ICG angiography was successful in all patients, allowing complete visualization of anastomotic perfusion in all cases. Hypoperfusion detected by ICG-FA resulted in change in operative plan for three patients (two anastomotic revisions and one diverting ileostomy). There were no adverse reactions to ICG. In this cohort, there was one postoperative anastomotic leak. CONCLUSIONS: ICG-FA enables objective and accurate intraoperative evaluation of anastomotic perfusion in surgeries for gynecologic malignancies. Its implementation and routine use were found to be safe and well-tolerated without side effects in our study cohort. ICG-FA can be used with other risk-assessment strategies to guide operative decision-making in Gynecologic Oncology.

Preoperative neutrophil-to-lymphocyte ratio predicts 30 day postoperative morbidity and survival after primary surgery for ovarian cancer.

OBJECTIVE: The preoperative neutrophil-to-lymphocyte ratio has been found to be an independent prognostic indicator for perioperative complications and survival outcomes in patients undergoing oncologic surgery for several malignancies. The objective of this study was to evaluate the role of the preoperative neutrophil-to-lymphocyte ratio in predicting 30-day postoperative morbidity and overall survival in advanced-stage high-grade serous ovarian cancer patients after primary surgery. METHODS: A retrospective study was conducted on consecutive patients who underwent primary surgery for high-grade serous ovarian cancer between January 2008 and December 2016 at a single tertiary academic institution in Toronto, Canada. Optimal thresholds for preoperative neutrophil-to-lymphocyte ratio were determined using receiver-operator characteristic curve analysis. Cox-proportional hazard models, Kaplan-Meier, and logistic regression analyses were performed. RESULTS: Of 505 patients with ovarian cancer during the study period, 199 met the inclusion criteria. Receiver-operator characteristic curve analysis generated optimal preoperative neutrophil-to-lymphocyte ratio thresholds of 2.3 and 2.9 for 30-day postoperative morbidity and survival outcomes, respectively. A neutrophil-to-lymphocyte ratio ≥2.3 was predictive of a composite outcome of 30-day postoperative complications (odds ratio 7.3, 95% confidence interval 2.44 to 21.81; p=0.0004), after adjusting for longer operative time and intraoperative complications. Postoperative complications included superficial surgical site infections (p=0.007) and urinary tract infections (p=0.004). A neutrophil-to-lymphocyte ratio ≥29 was associated with worse 5-year overall survival (57.8% vs 77.7%, p=0.003), and suggested no statistically significant difference in progression-free survival (33.8% vs 40.7%, p=0.054). On multivariable analysis, the neutrophil-to-lymphocyte ratio remained an independent predictor for overall survival (p=0.02) when adjusting for suboptimal cytoreduction (p≤0.0001). DISCUSSION: A preoperative neutrophil-to-lymphocyte ratio ≥2.3 and ≥2.9 is associated with greater risk of 30-day postoperative morbidity and worse overall survival, respectively. This marker may be used in conjunction with other risk assessment strategies to preoperatively identify high-risk patients. Further prospective study is required to investigate its role in clinical decision-making.

Survival after minimally invasive surgery in early cervical cancer: is the intra-uterine manipulator to blame?

OBJECTIVES: Minimally invasive radical hysterectomy is associated with decreased survival in patients with early cervical cancer. The objective of this study was to determine whether the use of an intra-uterine manipulator at the time of laparoscopic or robotic radical hysterectomy is associated with inferior oncologic outcomes. METHODS: A retrospective cohort study was carried out of all patients with cervical cancer (squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma) International Federation of Gynecology and Obstetrics 2009 stages IA1 (with positive lymphovascular space invasion) to IIA who underwent minimally invasive radical hysterectomy at two academic centers between January 2007 and December 2017. Treatment, tumor characteristics, and survival data were retrieved from hospital records. RESULTS: A total of 224 patients were identified at the two centers; 115 had surgery with the use of an intra-uterine manipulator while 109 did not; 53 were robotic and 171 were laparoscopic. Median age was 44 years (range 38-54) and median body mass index was 25.8 kg/m2 (range 16.6-51.5). Patients in whom an intra-uterine manipulator was not used at the time of minimally invasive radical hysterectomy were more likely to have residual disease at hysterectomy (p<0.001), positive lymphovascular space invasion (p=0.02), positive margins (p=0.008), and positive lymph node metastasis (p=0.003). Recurrence-free survival at 5 years was 80% in the no intra-uterine manipulator group and 94% in the intra-uterine manipulator group. After controlling for the presence of residual cancer at hysterectomy, tumor size and high-risk pathologic criteria (positive margins, parametria or lymph nodes), the use of an intra-uterine manipulator was no longer significantly associated with worse recurrence-free survival (HR 0.4, 95% CI 0.2 to 1.0, p=0.05). The only factor which was consistently associated with recurrence-free survival was tumor size (HR 2.1, 95% CI 1.5 to 3.0, for every 10 mm increase, p<0.001). CONCLUSION: After controlling for adverse pathological factors, the use of an intra-uterine manipulator in patients with early cervical cancer who underwent minimally invasive radical hysterectomy was not an independent factor associated with rate of recurrence.

Patterns of recurrence and impact on survival in patients with clear cell ovarian carcinoma.

BACKGROUND: Patients with recurrent clear cell ovarian cancer have poor prognosis and limited effective systemic treatment options. OBJECTIVES: To characterize patterns of recurrence and compare overall survival and post-recurrence survival parameters in patients with recurrent ovarian clear cell carcinoma. METHODS: Clinical data on patients with ovarian clear cell carcinoma between June 1995 and August 2014 were collected. Patients with clear cell ovarian cancer recurrence were included in this study. Patients with different histologic sub-type, persistent or progressive disease on completion of the initial treatment were excluded. Descriptive statistics, univariate and multivariable analyses, and Kaplan-Meier survival probability estimates were completed. The log-rank test was used to quantify survival differences on univariable analysis. To search for significant covariates related to the overall survival and post-recurrence survival, a univariable Cox proportional hazard model was performed. RESULTS: A total of 209 patients met inclusion criteria. Of these, 61 (29%) patients who were free of disease at completion of the initial treatment had recurrence. Patterns of recurrence were as follows: 38 (62%) patients had multiple-site recurrence, 12 (20%) had single-site recurrence, and 11 (18%) had nodal recurrence only. The median overall survival was 44.7 months (95% CI 33.4 to 64.2) and was significantly associated with pattern of recurrence (p=0.005). The median post-recurrence survival was 18.4 months (95% CI 12.5 to 26.7): 54.4 months (95% CI 11 to 125.5) in single-site recurrence, 13.7 months (95% CI 6.8 to 16.5) in multiple-site recurrence, and 30.1 (95% CI 7.2 to 89) months in nodal recurrence (p=0.0002). In the multivariable analysis, pattern of recurrence was a predictor of post-recurrence survival.Six patients (9.8%) had a prolonged disease-free interval after recurrence (disease-free for more than 30 months after completion of treatment for recurrence). Prolonged recurrences were noted in 4 (33%) of 12 patients with single-site recurrence, 1 (9%) of 11 patients with nodal recurrence, and in 1 (2.7%) of 38 patients with multiple-site recurrence. Three of the six patients with a prolonged disease-free interval after recurrence were treated surgically at the time of recurrence. CONCLUSION: Ovarian clear cell carcinoma predominantly recurs in multiple sites and it is associated with a high mortality rate and short post-recurrence survival. When recurrences are limited to a single site, or only to lymph nodes, the median post-recurrence survival is longer. Disease-free interval after recurrence is longer in patients with single-site recurrence who are treated surgically at the time of recurrence.