Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer.

BACKGROUND: Recurrent cervical cancer is a life-threatening disease, with limited treatment options available when disease progression occurs after first-line combination therapy. METHODS: We conducted a phase 3, multinational, open-label trial of tisotumab vedotin as second- or third-line therapy in patients with recurrent or metastatic cervical cancer. Patients were randomly assigned, in a 1:1 ratio, to receive tisotumab vedotin monotherapy (2.0 mg per kilogram of body weight every 3 weeks) or the investigator's choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed). The primary end point was overall survival. RESULTS: A total of 502 patients underwent randomization (253 were assigned to the tisotumab vedotin group and 249 to the chemotherapy group); the groups were similar with respect to demographic and disease characteristics. The median overall survival was significantly longer in the tisotumab vedotin group than in the chemotherapy group (11.5 months [95% confidence interval {CI}, 9.8 to 14.9] vs. 9.5 months [95% CI, 7.9 to 10.7]), results that represented a 30% lower risk of death with tisotumab vedotin than with chemotherapy (hazard ratio, 0.70; 95% CI, 0.54 to 0.89; two-sided P = 0.004). The median progression-free survival was 4.2 months (95% CI, 4.0 to 4.4) with tisotumab vedotin and 2.9 months (95% CI, 2.6 to 3.1) with chemotherapy (hazard ratio, 0.67; 95% CI, 0.54 to 0.82; two-sided P<0.001). The confirmed objective response rate was 17.8% in the tisotumab vedotin group and 5.2% in the chemotherapy group (odds ratio, 4.0; 95% CI, 2.1 to 7.6; two-sided P<0.001). A total of 98.4% of patients in the tisotumab vedotin group and 99.2% in the chemotherapy group had at least one adverse event that occurred during the treatment period (defined as the period from day 1 of dose 1 until 30 days after the last dose); grade 3 or greater events occurred in 52.0% and 62.3%, respectively. A total of 14.8% of patients stopped tisotumab vedotin treatment because of toxic effects. CONCLUSIONS: In patients with recurrent cervical cancer, second- or third-line treatment with tisotumab vedotin resulted in significantly greater efficacy than chemotherapy. (Funded by Genmab and Seagen [acquired by Pfizer]; innovaTV 301 ClinicalTrials.gov number, NCT04697628.).

The role of surgeon specialty in management and survival of malignant ovarian germ cell tumors: A population-based study.

OBJECTIVES: The aim of this study is to describe management and survival in adult patients with malignant ovarian germ cell tumors (MOGCT) undergoing surgery by general gynecologists (GG) versus gynecologic oncologists (GO). METHODS: This is a population-based retrospective cohort study, including patients (age ≥ 18 years old) with MOGCT identified in the provincial cancer registry of Ontario, (1996-2020). Baseline characteristics, surgical and chemotherapy treatment were compared between those with surgery by GG or GO. Cox proportional hazards (CPH) model was used to determine if surgeon specialty was associated with overall survival (OS). RESULTS: Overall, 363 patients were included. One-hundred and sixty (44%) underwent surgery by GO and 203 (56%) by GG. There were higher rates of stage II-IV in the GO group (27.5% vs 3.9%, p < 0.001, and higher proportion of chemotherapy (64.4% vs 37.4%, p < 0.0001). Five-year OS was 90% and 93% in the GO vs GG groups, respectively (p = 0.39). CPH model showed factors associated with increased risk of death were older age at diagnosis (HR 1.09, 95% CI 1.07-1.12) and chemotherapy (HR 3.12, 95% CI 1.44-6.75). Surgeon specialty was not independently associated with all-cause death (HR 1.04, 95% 0.51-2.15, p = 0.91). CONCLUSIONS: In this group of MOGCT, 5-year OS was not significantly different between patients having surgery by GO compared to GG. Nevertheless, survival rates were lower than expected in the GG group despite their low-risk features. Further exploration is warranted regarding the reasons for this and whether patients with suspected MOGCT may benefit from early assessment by GO for optimal management.

Phase II trial of pembrolizumab and epacadostat in recurrent clear cell carcinoma of the ovary: An NRG oncology study GY016.

INTRODUCTION: Early reports of PD-1 inhibition in ovarian clear cell carcinomas (OCCC) demonstrate promising response. We evaluated the combination of pembrolizumab and IDO-1 inhibitor epacadostat in patients with recurrent OCCC. METHODS: This single arm, two-stage, phase 2 trial included those with measurable disease and 1-3 prior regimens. Patients received intravenous pembrolizumab 200 mg every 3 weeks and oral epacadostat 100 mg twice a day. Primary endpoint was overall response rate (ORR), secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). The study was powered to detect an absolute 25% increase in response (15% to 40%). RESULTS: Between September 28, 2018 and April 10, 2019, 14 patients enrolled at first stage. Rate of accrual was 2.3 patients per month. Median age was 65 years (44-89), 10 (71.4%) had ≥2 prior regimens. ORR was 21% (95% CI 5-51%) within 7 months of study entry with 3 partial responses, and 4 had stable disease (disease control rate 50%). Median PFS was 4.8 months (95% CI: 1.9-9.6), OS 18.9 months (95% CI: 1.9-NR). Most common grade ≥ 3 adverse events were electrolyte abnormalities and gastrointestinal pain, nausea, vomiting, bowel obstruction. In July 2019, the study reached the pre-specified criteria to re-open to second stage; however, the study closed prematurely in February 2021 due to insufficient drug supply. CONCLUSIONS: Pembrolizumab and epacadostat demonstrated an ORR of 21% in this small cohort of recurrent OCCC. The rapid rate of accrual highlights the enthusiasm and need for therapeutic studies in patients with OCCC.

Consensus on surgical technique for sentinel lymph node dissection in cervical cancer.

OBJECTIVE: The purpose of this study was to establish a consensus on the surgical technique for sentinel lymph node (SLN) dissection in cervical cancer. METHODS: A 26 question survey was emailed to international expert gynecological oncology surgeons. A two-step modified Delphi method was used to establish consensus. After a first round of online survey, the questions were amended and a second round, along with semistructured interviews was performed. Consensus was defined using a 70% cut-off for agreement. RESULTS: Twenty-five of 38 (65.8%) experts responded to the first and second rounds of the online survey. Agreement ≥70% was reached for 13 (50.0%) questions in the first round and for 15 (57.7%) in the final round. Consensus agreement identified 15 recommended, three optional, and five not recommended steps. Experts agreed on the following recommended procedures: use of indocyanine green as a tracer; superficial (with or without deep) injection at 3 and 9 o'clock; injection at the margins of uninvolved mucosa avoiding vaginal fornices; grasping the cervix with forceps only in part of the cervix is free of tumor; use of a minimally invasive approach for SLN biopsy in the case of simple trachelectomy/conization; identification of the ureter, obliterated umbilical artery, and external iliac vessels before SLN excision; commencing the dissection at the level of the uterine artery and continuing laterally; and completing dissection in one hemi-pelvis before proceeding to the contralateral side. Consensus was also reached in recommending against injection at 6 and 12 o'clock, and injection directly into the tumor in cases of the tumor completely replacing the cervix; against removal of nodes through port without protective maneuvers; absence of an ultrastaging protocol; and against modifying tracer concentration at the time of re-injection after mapping failure. CONCLUSION: Recommended, optional, and not recommended steps of SLN dissection in cervical cancer have been identified based on consensus among international experts. These represent a surgical guide that may be used by surgeons in clinical trials and for quality assurance in routine practice.

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.

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.

Prognostic value of isolated tumor cells in sentinel lymph nodes in low risk endometrial cancer: results from an international multi-institutional study.

OBJECTIVE: The prognostic significance of isolated tumor cells (≤0.2 mm) in sentinel lymph nodes (SLNs) of endometrial cancer patients is still unclear. Our aim was to assess the prognostic value of isolated tumor cells in patients with low risk endometrial cancer who underwent SLN biopsy and did not receive adjuvant therapy. Outcomes were compared with node negative patients. METHODS: Patients with SLNs-isolated tumor cells between 2013 and 2019 were identified from 15 centers worldwide, while SLN negative patients were identified from Mayo Clinic, Rochester, between 2013 and 2018. Only low risk patients (stage IA, endometrioid histology, grade 1 or 2) who did not receive any adjuvant therapy were included. Primary outcomes were recurrence free, non-vaginal recurrence free, and overall survival, evaluated with Kaplan-Meier methods. RESULTS: 494 patients (42 isolated tumor cells and 452 node negative) were included. There were 21 (4.3%) recurrences (5 SLNs-isolated tumor cells, 16 node negative); recurrence was vaginal in six patients (1 isolated tumor cells, 5 node negative), and non-vaginal in 15 (4 isolated tumor cells, 11 node negative). Median follow-up among those without recurrence was 2.3 years (interquartile range (IQR) 1.1-3.0) and 2.6 years (IQR 0.6-4.2) in the SLN-isolated tumor cell and node negative patients, respectively. The presence of SLNs-isolated tumor cells, lymphovascular space invasion, and International Federation of Obstetrics and Gynecology (FIGO) grade 2 were significant risk factors for recurrence on univariate analysis. SLN-isolated tumor cell patients had worse recurrence free survival (p<0.01) and non-vaginal recurrence free survival (p<0.01) compared with node negative patients. Similar results were observed in the subgroup of patients without lymphovascular space invasion (n=480). There was no difference in overall survival between the two cohorts in the full sample and the subset excluding patients with lymphovascular space invasion. CONCLUSIONS: Patients with SLNs-isolated tumor cells and low risk profile, without adjuvant therapy, had a significantly worse recurrence free survival compared with node negative patients with similar risk factors, after adjusting for grade and excluding patients with lymphovascular space invasion. However, the presence of SLNs-isolated tumor cells was not associated with worse overall survival.

Pre-operative wait times in high-grade non-endometrioid endometrial cancer: Do surgical delays impact patient survival?

OBJECTIVE: Practice guidelines advocating for regionalization of endometrial cancer surgery to gynecologic oncologists practicing in designated gynecologic oncology centres were published in Ontario in June 2013. Our objectives were to determine whether this policy affected surgical wait times, and whether longer wait time to surgery is a predictor of survival in high grade endometrial cancer patients. METHODS: This was a population-based retrospective cohort study, which included patients diagnosed with high-grade non-endometrioid endometrial cancer who had a hysterectomy between 2003 and 2017. Multivariable Cox proportional hazards regression with a spline function was used to model the relationship between surgical wait time and overall survival (OS). RESULTS: We identified 3518 patients who underwent hysterectomy for high-grade non-endometrioid endometrial cancer. Patients who had surgery with a gynecologic oncologist had a median surgical wait time from diagnosis to hysterectomy of 53 days compared to 57 days pre-regionalization (p = 0.0007), and from first gynecologic oncology consultation to hysterectomy of 29 days compared to 32 days pre-regionalization (p = 0.0006). Survival was inferior for patients who had surgery within 14 days of diagnosis (HR death 2.7 for 1-7 days, 95% CI 1.61-4.51, and HR death 1.96 for 8-14 days, 95% CI 1.50-2.57), reflective of disease severity. Decreased survival occurred with surgical wait times of more than 45 days from the patient's first gynecologic oncology appointment (HR death 1.19 for 46-60 days, 95% CI 1.04-1.36, and HR death 1.42 for 61-75 days, 95% CI 1.11-1.83). CONCLUSIONS: Regionalization of surgery for high-grade endometrial cancer has not had an impact on surgical wait times. Patients who have surgery more than 45 days after surgical consultation have reduced survival.

Small Cell and Other Rare Histologic Types of Cervical Cancer.

PURPOSE OF REVIEW: The goal of this paper was to summarize the recent evidence on rare subtypes of cervical cancer including small-cell carcinoma of the cervix (SCCC), gastric-type adenocarcinoma, and carcinosarcoma. RECENT FINDINGS: All three cervical cancer subtypes are aggressive with poor treatment response and high recurrence rates. Molecular studies have identified various actionable mutations in both SCCC (PIK3CA, MYC, TP53, PTEN, ARID1A, KRAS, BRCA2) and gastric-type adenocarcinoma (KRAS, ARID1A, PTEN). While there are a limited number of case reports demonstrating a favorable response for recurrent SCCC to immune checkpoint inhibitors, a larger case series failed to show benefit. The checkpoint inhibitors role in gastric-type adenocarcinoma and carcinosarcoma is yet to be determined. Ninety-one percent of SCCC cases show PARP expression, suggesting a possible role for PARP inhibitors; however, this has yet to be examined in future clinical trials. More studies are needed, with a focus on targeted therapies. The role of PARP inhibitors in SCCC is potentially promising, but significant collaboration between centers/groups will be required to achieve this.

Immune Checkpoint Inhibitors for the Treatment of Gestational Trophoblastic Neoplasia: Rationale, Effectiveness, and Future Fertility.

OPINION STATEMENT: Most individuals with gestational trophoblastic neoplasia (GTN) are cured with chemotherapy; however, about 5% of them will develop chemotherapy-resistant disease and will die of disease progression. Most GTN tissues express programmed death ligand-1 (PDL-1), making immune checkpoint inhibitors (ICIs) targeting this pathway an attractive treatment option for individuals with GTN. There is increasing evidence to support the use of ICIs for individuals with recurrent or resistant GTN, but available data are derived from case reports and small single arm trials. As promising as it seems, not all individuals with GTN respond to ICIs, and there is lack of evidence toward which factors mediate the effect of ICIs on GTN. In addition, treatment-related adverse events and impact on future fertility are not negligible and should be considered before initiating this treatment. Therefore, additional research is needed to evaluate treatment outcome of ICIs in GTN compared to standard treatment, and to identify molecular and clinical predictors for treatment response, before this treatment is incorporated into the standard of care.

The role of oophoropexy in patients with gynecological cancer who need radiation therapy.

Pelvic radiotherapy is an essential component of cancer therapy for patients with cervical and other gynecological malignancies. The ovaries are particularly radiosensitive, and even low radiotherapy doses may result in impaired or complete loss of ovarian function, causing hormonal disturbances and infertility. Recent advances in both surgery and radiotherapy have facilitated the ability of some patients to maintain ovarian function through ovarian transposition and careful radiotherapy planning. Multidisciplinary discussions should be undertaken to consider which candidates are appropriate for transposition. Generally, patients under age 35 should be considered due to ovarian reserve, likelihood of oophoropexy success, and radioresistance of ovaries. Those patients with small squamous cell tumors, minimal extra-uterine extension, and no lymphovascular invasion or lymph node involvement are ideal candidates to minimize risk of ovarian metastasis. Patients should be assessed and counseled about the risks of ovarian metastasis and the likelihood of successful ovarian preservation before undergoing oophoropexy and starting treatment. Oophoropexy should be bilateral if possible, and ovaries should be placed superior and lateral to the radiotherapy field. Studies limiting the mean ovarian dose to less than 2-3 Gray have demonstrated excellent preservation of ovarian function. Intensity modulated radiotherapy and volumetric modulated arc therapy techniques have the potential to further minimize the dose to the ovary with excellent outcomes. The addition of brachytherapy to the treatment regimen will probably cause minimal risk to transposed ovaries. Oophoropexy before radiotherapy may preserve the hormonal function of ovaries for a duration, and fertility might be possible through surrogate pregnancy. Successful ovarian transposition has the potential to improve the overall health and wellbeing, reproductive options, and potentially quality of life in patients with cervical and other gynecological cancers.

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.

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.

Dual mechanical and pharmacological thromboprophylaxis decreases risk of pulmonary embolus after laparotomy for gynecologic malignancies.

OBJECTIVES: Patients with gynecologic malignancies have high rates of post-operative venous thromboembolism. Currently, there is no consensus for peri-operative thromboprophylaxis specific to gynecologic oncology. We aimed to compare rates of symptomatic pulmonary embolus within 30 days post-operatively, and to identify risk factors for pulmonary embolus. METHODS: The Division of Gynecologic Oncology at Sunnybrook Health Sciences Centre implemented dual thromboprophylaxis for laparotomies in December 2017. We conducted a prospective study of laparotomies for gynecologic malignancies from December 2017 to October 2018, with comparison to historical cohort from January 2016 to November 2017 using the institutional National Surgical Quality Improvement Program database (NSQIP). Pre-intervention, patients received low molecular weight heparin during admission and extended 28-day prophylaxis was continued at the surgeon's discretion. Post-intervention, all patients received both mechanical thromboprophylaxis with sequential compression devices during admission and 28-day prophylaxis with low molecular weight heparin. RESULTS: There were 371 and 163 laparotomies pre- and post-intervention, respectively. Patient characteristics (age, body mass index, diabetes, smoking, tumor stage), rate of malignant cases, operative blood loss and duration, and length of stay were similar between groups. After implementation, pulmonary emboli rates decreased from 5.1% to 0% (p=0.001). There were more cytoreductive procedures pre-intervention (p≤0.0001) but surgical complexity scores were similar (p=0.82). Univariate analysis revealed that surgery pre-intervention (OR 4.25, 95% CI 1.04 to 17.43, p=0.04), length of stay ≥5 days (OR 11.94, 95% CI 2.65 to 53.92, p=0.002), and operative blood loss ≥500 mL (OR 2.85, 95% CI 1.05 to 7.8, p=0.04) increased risk of pulmonary embolus. On multivariable analysis, surgery pre-intervention remained associated with more pulmonary emboli (OR 4.16, 95% CI 1.03 to 16.79, p=0.045), when adjusting for operative blood loss. CONCLUSION: Dual thromboprophylaxis after laparotomy significantly reduced rates of pulmonary embolus in this high-risk patient population.

Oncologic outcomes of endometrial cancer in patients with low-volume metastasis in the sentinel lymph nodes: An international multi-institutional study.

OBJECTIVE: To assess oncologic outcomes in endometrial cancer patients with low-volume metastasis (LVM) in the sentinel lymph nodes (SLNs). METHODS: Patients with endometrial cancer and SLN-LVM (≤2 mm) from December 3, 2009, to December 31, 2018, were retrospectively identified from 22 centers worldwide. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IV, adnexal involvement, or unknown adjuvant therapy (ATx) were excluded. RESULTS: Of 247 patients included, 132 had isolated tumor cell (ITC) and 115 had micrometastasis (MM). Overall 4-year recurrence-free survival (RFS) was 77.6% (95% CI, 70.2%-85.9%); median follow-up for patients without recurrence was 29.6 (interquartile range, 19.2-41.5) months. At multivariate analysis, Non-endometrioid (NE) (HR, 5.00; 95% CI, 2.50-9.99; P < .001), lymphovascular space invasion (LVSI) (HR, 3.26; 95% CI, 1.45-7.31; P = .004), and uterine serosal invasion (USI) (HR, 3.70; 95% CI, 1.44-9.54; P = .007) were independent predictors of recurrence. Among 47 endometrioid ITC patients without ATx, 4-year RFS was 82.6% (95% CI, 70.1%-97.2). Considering 18 ITC patients with endometrioid grade 1 disease, without LVSI, USI, or ATx, only 1 had recurrence (median follow-up, 24.8 months). CONCLUSIONS: In patients with SLN-LVM, NE, LVSI, and USI were independent risk factors for recurrence. Patients with any risk factor had poor prognosis, even when receiving ATx. Patients with ITC and grade 1 endometrioid disease (no LVSI/USI) had favorable prognosis, even without ATx. Further analysis (with more patients and longer follow-up) is needed to assess whether ATx can be withheld in this low-risk subgroup.

Standardization of lower extremity quantitative lymphedema measurements and associated patient-reported outcomes in gynecologic cancers.

Practice changing standardization of lower extremity lymphedema quantitative measurements with integrated patient reported outcomes will likely refine and redefine the optimal risk-reduction strategies to diminish the devastating limb-related dysfunction and morbidity associated with treatment of gynecologic cancers. The National Cancer Institute (NCI), Division of Cancer Prevention brought together a diverse group of cancer treatment, therapy and patient reported outcomes experts to discuss the current state-of-the-science in lymphedema evaluation with the potential goal of incorporating new strategies for optimal evaluation of lymphedema in future developing gynecologic clinical trials.

Outcomes after the regionalization of care for high-grade endometrial cancers: a population-based study.

BACKGROUND: In June 2013, Ontario Health (Cancer Care Ontario), the agency responsible for advancing cancer care in Ontario, Canada, published practice guidelines recommending that gynecologic oncologists at tertiary care centers manage the treatment of patients with high-grade endometrial cancers. This study examines the effects of this regionalization of care on patient outcomes. OBJECTIVE: This study aimed to evaluate the impact of the regionalization of surgery for high-grade endometrial cancer on patient and treatment outcomes. STUDY DESIGN: In this retrospective cohort study, patients diagnosed with nonendometrioid high-grade endometrial cancer from 2003 to 2017 were identified using province-wide administrative databases. To allow 6 months for knowledge translation, 2 periods were defined, with January 1, 2014, as the cutoff. Methods for segmented regression were used to test the effect of the guidelines. Multivariable Cox proportional hazards regression was used to evaluate whether regionalization of care had an impact on patient survival. RESULTS: There were 3518 patients with nonendometrioid high-grade endometrial cancer identified. The case mix as represented by patient comorbidities and the disease stage distribution did not differ significantly between the 2 regionalization periods. There was a significant increase (69%-85%; P<.001) in the proportion of primary surgeries performed by gynecologic oncologists after regionalization, which was not explained by secular trends. After regionalization, the proportion of patients who had surgical staging (50%-63%; P<.001) and the proportion of patients who received adjuvant treatment (65%-71%; P<.001) increased significantly. After adjusting for age, stage, and comorbidities, there was a decrease in the hazard of mortality (hazard ratio, 0.85 [95% confidence interval, 0.73-0.99]; P=.04) after regionalization. CONCLUSION: The publication of a regionalization policy for the treatment of high-grade endometrial cancers in Ontario led to an increase in the proportion of surgeries performed by gynecologic oncologists. This also translated into a significant improvement in patient survival.

Cervical conization and lymph node assessment for early stage low-risk cervical cancer.

OBJECTIVE: There has been a contemporary shift in clinical practice towards tailoring treatment in patients with early cervical cancer and low-risk features to non-radical surgery. The objective of this study was to evaluate the oncologic, fertility, and obstetric outcomes after cervical conization and sentinel lymph node (SLN) biopsy in patients with early stage low-risk cervical cancer. METHODS: We conducted a retrospective review in patients with early cervical cancer treated with cervical conization and lymph node assessment between November 2008 and February 2020. Eligibility criteria included patients with a histologic diagnosis of invasive squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma, International Federation of Gynecology and Obstetrics 2009 stage IA1 with positive lymphovascular space invasion (LVSI), stage IA2, or stage IB1 (≤2 cm) with less than two-thirds (<10 mm) cervical stromal invasion. RESULTS: A total of 44 patients were included in the analysis. The median age was 31 years (range 19-61) and 20 patients (45%) were nulliparous. One patient had a 25 mm tumor while the remaining patients had tumors smaller than 20 mm. Eighteen (41%) patients had LVSI. Median follow-up was 44 months (range 6-137). A total of 17 (39%) patients had negative margins on the diagnostic excisional procedure, and none had residual disease on the repeat cone biopsy. Three (6.8%) patients had micrometastases detected in the SLNs and underwent ipsilateral lymphadenectomy; all remaining non-SLN lymph nodes were negative. Six (13.6%) patients required more definitive surgical or adjuvant treatment due to high-risk pathologic features. There were no recurrences documented. Three patients developed cervical stenosis. The live birth rate was 85% and 16 (94%) of 17 patients had live births at term. CONCLUSION: Cervical conization with SLN biopsy appears to be a safe treatment option in selected patients with early cervical cancer. Future results of prospective trials may shed definitive light on fertility-sparing options in this group of patients.

Spheroid-Based Approach to Assess the Tissue Relevance of Analysis of Dispersed-Settled Tissue Cells by Cytometry of the Reaction Rate Constant.

Cytometry of Reaction Rate Constant (CRRC) uses time-lapse fluorescence microscopy to measure a rate constant of a catalytic reaction in individual cells and, thus, facilitate accurate size determination for cell subpopulations with distinct efficiencies of this reaction. Reliable CRRC requires uniform exposure of cells to the reaction substrate followed by their uniform imaging, which in turn, requires that a tissue sample be disintegrated into a suspension of dispersed cells, and these cells settle on the support surface before being analyzed by CRRC. We call such cells "dispersed-settled" to distinguish them from cells cultured as a monolayer. Studies of the dispersed-settled cells can be tissue-relevant only if the cells maintain their 3D tissue state during the multi-hour CRRC procedure. Here, we propose an approach for assessing tissue relevance of the CRRC-based analysis of the dispersed-settled cells. Our approach utilizes cultured multicellular spheroids as a 3D cell model and cultured cell monolayers as a 2D cell model. The CRRC results of the dispersed-settled cells derived from spheroids are compared to those of spheroids and monolayers in order to find if the dispersed-settled cells are representative of the spheroids. To demonstrate its practical use, we applied this approach to a cellular reaction of multidrug resistance (MDR) transport, which was followed by extrusion of a fluorescent substrate from the cells. The approach proved to be reliable and revealed long-term maintenance of MDR transport in the dispersed-settled cells obtained from cultured ovarian cancer spheroids. Accordingly, CRRC can be used to determine accurately the size of a cell subpopulation with an elevated level of MDR transport in tumor samples, which makes CRRC a suitable method for the development of MDR-based predictors of chemoresistance. The proposed spheroid-based approach for validation of CRRC is applicable to other types of cellular reactions and, thus, will be an indispensable tool for transforming CRRC from an experimental technique into a practical analytical tool.

Does timing of intraperitoneal chemotherapy initiation following primary cytoreductive surgery with bowel resection impact outcomes in patients with advanced ovarian cancer?

OBJECTIVES: The primary objective of this study is to determine if early administration of intraperitoneal (IP) chemotherapy and intra-operative insertion of an IP port are associated with increased complications in patients who undergo a bowel resection procedure as part of primary cytoreductive surgery for ovarian cancer. METHODS: This was a multi-centre retrospective cohort study, at 2 high volume cancer centers. For our primary outcomes, univariate logistic regression was completed to assess the impact of timing of IP chemotherapy administration and IP port insertion on perioperative complications. Kaplan Meier survival curves were compared using the Log-Rank test. RESULTS: We identified 131 patients treated with IP chemotherapy after bowel resection during primary cytoreduction for advanced ovarian cancer; 75 patients started IP treatment at the first adjuvant chemotherapy, while 56 patients received intravenous (IV) chemotherapy and later transitioned to IP chemotherapy. The majority of patients had stage III/IV disease (87%) and high-grade serous histology (91.6%). Compared to patients who received their first cycle of chemotherapy IV, patients who started with IP chemotherapy were not at increased risk of intra-abdominal infections (8% vs 16% (p = 0.15)), IP port related complications (20% vs 19.6% (p = 0.96)), or anastomotic leak (2.7% vs 3.6% (p = 0.8)). There was a non-statistically significant trend for increased rates of anastomotic leak (5.6% vs 3.3% (p = 0.62)), intra-abdominal infection (16.7% vs 6.7% (p = 0.17)) and IP port related complications (24.1% vs 13.3% (p = 0.21)) in patients who had intra-operative IP port insertion compared to delayed post-operative port insertion. CONCLUSIONS: Administration of IP chemotherapy in the first post-operative cycle after bowel resection is not associated with increased post-operative complications in women with advanced ovarian carcinoma undergoing primary cytoreductive surgery. Intra-operative IP port insertion may be associated with a small increase in major complications in this population.