Learning to lead: The evolution of a pilot leadership curriculum for gynecologic oncology fellows at the Ohio State University.

•Leadership training is under-emphasized in traditional medical education.•An effective leadership curriculum must be dynamic and requires genuine investment from participants.•Through didactic education, self-reflection, and real-world perspective we can actively mold future leaders in gynecologic oncology.

Does the choice of platinum doublet matter? A study to evaluate the impact of platinum doublet choice for treatment of platinum-sensitive ovarian cancer recurrence on the development of future PARP inhibitor and platinum resistance.

OBJECTIVES: The use of a platinum doublet for the treatment of platinum-sensitive epithelial ovarian cancer (EOC) recurrence is well established. The impact of the non­platinum chemotherapy used as part of a platinum doublet on PARP inhibitor (PARPi) and platinum sensitivity it not known. We aimed to describe oncologic outcomes in cases of recurrent EOC receiving PARPi as maintenance therapy based on preceding platinum doublet. METHODS: Retrospective study of patients with platinum-sensitive recurrent ovarian, fallopian tube or primary peritoneal cancer treated with platinum doublet followed by maintenance PARPi from 1/1/2015 and 1/1/2022. Comparisons were made between patients receiving carboplatin + pegylated liposomal doxorubicin (CD) versus other platinum doublets (OPDs). Descriptive statistics, Kaplan-Meier and univariate survival analyses were performed. RESULTS: 100 patients received PARPi maintenance following a platinum doublet chemotherapy regimen for platinum-sensitive recurrence. 25/100 (25%) received CD and 75/100 (75%) received OPDs. Comparing CD and OPDs, median progression-free survival was 8 versus 7 months (p = 0.26), median time to platinum resistance was 15 versus 13 months (p = 0.54), median OS was 64 versus 90 months (p = 0.28), and median OS from starting PARPi was 25 versus 26 months (p = 0.90), respectively. CONCLUSIONS: Using pegylated liposomal doxorubicin as part of a platinum doublet preceding maintenance PARPi for platinum-sensitive recurrence does not seem to hasten PARPi resistance or platinum resistance compared to OPDs. Although there was a non-significant trend towards increased OS among patients who received a platinum doublet other than CD prior to PARPi, the OS from PARPi start was similar between groups. Given the retrospective nature of this study and small study population, further research is needed to evaluate if the choice of platinum doublet preceding PARPi maintenance impacts PARPi resistance, platinum resistance and survival.

Combination lenvatinib plus pembrolizumab in the treatment of ovarian clear cell carcinoma: A case series.

Effective second-line treatment options for patients with recurrent ovarian clear cell carcinoma (OCCC) are limited. This case series sought to report tumor characteristics and oncologic outcomes in a small group of patients treated with combination lenvatinib and pembrolizumab. A retrospective analysis of patients with ovarian clear cell carcinoma treated with combination lenvatinib and pembrolizumab at a single institution was performed. Patient and tumor characteristics were collected including demographics and germline/somatic testing. Clinical outcomes were also evaluated and reported. Three patients with recurrent OCCC were included in the study. The median age of patients was 48 years old. All patients had platinum-resistant disease and had received 1-3 prior lines of therapy. The overall response rate was 100% (3/3). Progression-free survival ranged from 10 months to not-yet-reached. One patient remains on treatment, while the other two died of disease with overall survival of 14 and 27 months. Combination lenvatinib-pembrolizumab demonstrated favorable clinical response in these patients with platinum-resistant, recurrent, ovarian clear cell carcinoma.

Glassy cell carcinoma of the cervix: Findings from a combined National Cancer Database analysis and single institution review of treatment patterns and outcomes.

OBJECTIVES: To describe stage, treatment patterns, and survival for glassy cell carcinoma of the cervix (GCCC), a poorly understood rare tumor. METHODS: Clinical data and survival were compared between GCCC and more common histologic types using the National Cancer Database (NCDB) from 2004 to 2017. A retrospective review of GCCC cases at our institution from 2012 to 2020 was simultaneously performed with staging updated according to 2018 FIGO staging. Descriptive statistics and survival analyses were performed, and outcomes compared to historical references. RESULTS: 143/89,001 (0.16%) NCDB cervical cancer cases were GCCC. Compared to other histologies, GCCC cases were younger, with 74.8% diagnosed before age 50. Stage distribution was similar. Stage I cases were less commonly treated with surgery alone (19/69, 27%). 79.4% of locally advanced (stage II-IVA) cases were treated with definitive chemoradiation. GCCC demonstrated worse OS for early-stage and locally-advanced disease. No survival differences were observed for patients with stage IVB disease. Our institutional review identified 14 GCCC cases. Median age at diagnosis was 34 years. All nine early-stage cases underwent radical hysterectomy. Adjuvant radiation was given for cases meeting Sedlis criteria (4/9, 44%). All five advanced stage cases were stage IIIC and received definitive chemoradiation. Recurrence rate was 0% (0/9) for early-stage and 60% (3/5) for advanced-stage cases. 3-year PFS was 100% for early-stage and 40% for advanced-stage. 3-year OS was 100% for early-stage and 60% for advanced-stage GCCC. CONCLUSIONS: GCCC presents at earlier ages than other cervical cancer histologic types. Although NCDB showed worse OS, our more contemporary institutional review, which incorporates updated staging and newer treatment modalities found outcomes more similar to historical references of more common histologic subtypes.

Gastritis as an immunotherapy-related toxicity in the treatment of endometrial cancer: A case report.

Gastritis related to immunotherapy use is a less commonly reported adverse effect. With increasing use of immunotherapy agents in the management of patients with endometrial cancer, even rare adverse effects are being seen more frequently in gynecologic oncology practice. A 66-year-old with recurrent mismatch repair deficient endometrial cancer was treated with single-agent pembrolizumab. She initially appeared to tolerate treatment well; however after 16 months of therapy she began to develop nausea, vomiting, and abdominal pain that resulted in 30-pound weight loss. Pembrolizumab was held out of concern for immunotherapy related toxicity. She underwent evaluation with gastroenterology including esophagogastroduodenoscopy (EGD) with biopsy that demonstrated severe lymphocytic gastritis. She was treated with IV methylprednisolone with improvement in symptoms over three days. She was then transitioned to oral prednisone at 60 mg daily with weekly taper by 10 mg, with a proton pump inhibitor (PPI) and carafate until resolution of symptoms. She subsequently had a follow up EGD with biopsy, which demonstrated resolving gastritis. She is presently doing well off of steroids with stable disease noted on her last scan after cessation of pembrolizumab.

Recurrence rate in early-stage epithelial ovarian cancer: Is there a role for upfront maintenance with PARP inhibitors in stages I and II?

Objective: To determine the recurrence rate and survival among early-stage epithelial ovarian cancer cases considering homologous recombination deficiency (HRD) status. Methods: Single institution retrospective study of stage I/II EOC patients from 2017 to 2020. HRD was defined as evidence of germline or somatic BRCA mutation, or loss of heterozygosity (LOH)/genomic instability (GIS) as determined by companion diagnostic tests. Kaplan-Meier analyses were performed. Results: 89 stage I/II cases were included. 4/89 (4.5%) had a germline BRCA1/2 mutation, 8 (9%) were germline negative but had a somatic BRCA mutation, and 8 (9%) were BRCA wild-type but had evidence of LOH/GIS on somatic testing; these 20/89 (22%) cases comprised the HRD group. The remaining tumors were confirmed homologous recombination proficient (HRP, 35/89, 39%) or homologous recombination unknown (HRU, 34/89, 38%). The overall recurrence rate was 33/89 (37%). There were more recurrences among HRD cases (14/20, 70%) compared to HRP/HRU cases (19/69, 27.5%, p = 0.0012). Median Recurrence-Free Survival (RFS) was 35 months for HRD cases and 225 months for HRP/HRU cases (p = 0.001). At 2 years, there were 60% HRD cases and 88% HRP/HRU cases recurrence-free. At 5 years there were 29% HRD and 69% HRP/HRU cases recurrence-free (p = 0.001). Conclusions: Despite a high rate of complete surgical staging and six cycles of adjuvant chemotherapy, recurrence rate was high in this early-stage cohort. Higher recurrence rates were seen in the HRD group, however these data are likely biased by the clinical practice of tumor testing primarily at the time of recurrence rather than the upfront setting. RFS was significantly lower for HRD cases.

Use of the Khorana score to predict venous thromboembolism in patients undergoing chemotherapy for uterine cancer.

Objective: Gynecologic cancers are associated with a high risk of venous thromboembolism (VTE). The Khorana score is a validated tool to assess risk of VTE in cancer patients. The purpose of this study is to determine if the Khorana score can be used as a risk stratification tool for VTE in patients with uterine cancer undergoing chemotherapy. Methods: A retrospective cohort study of patients with newly diagnosed uterine cancer receiving chemotherapy over a 4-year period was conducted. The patients were stratified based on their Khorana score as well as their chemotherapy sequence, neoadjuvant or definitive versus adjuvant. Results: A total of 276 patients were included: 40 received neoadjuvant or definitive, 236 adjuvant chemotherapy. Most patients had advanced stage disease (64.5%). 18 (6.5%) patients developed VTE within 180 days of initiating chemotherapy. High Khorana score was associated with a non-significant increase in VTE (K ≥ 2 OR 1.17, CI 0.40-3.39, K ≥ 3 OR 1.69, CI 0.61-4.69) but had poor predictive accuracy based on area under the curve (K ≥ 2 0.51, K ≥ 3 0.55). The VTE rate was higher in the neoadjuvant/definitive chemotherapy group to adjuvant (12.5% vs 5.5%, p = 0.11). While the former group had a higher average Khorana score (2.35 vs 1.93, p = 0.0048), this was not predictive of VTE. Conclusions: While validated in other cancer types, the Khorana score was found to be a poor predictor of VTE in patients with uterine cancer. The use of the Khorana score to guide routine thromboprophylaxis in these patients should be used with caution and further investigation is warranted.

The modified 5-item frailty index is a predictor of post-operative complications in vulvar cancer: a National Surgical Quality Improvement Program (NSQIP) analysis.

OBJECTIVE: To determine whether frailty is associated with post-operative complications following surgery for vulvar cancer. METHODS: This retrospective study used a multi-institutional dataset from the National Surgical Quality Improvement Program (NSQIP) database (2014-2020) to analyze the relationship between frailty, procedure type, and post-operative complications. Frailty was determined using the modified frailty index-5 (mFI-5). Univariate and multivariable-adjusted logistic regression analyses were performed. RESULTS: Of 886 women, 49.9% underwent radical vulvectomy alone, and 19.5% and 30.6% underwent concurrent unilateral or bilateral inguinofemoral lymphadenectomy, respectively; 24.5% had mFI ≥2 and were considered frail. Compared with non-frail women, those with an mFI ≥2 were more likely to have an unplanned readmission (12.9% vs 7.8%, p=0.02), wound disruption (8.3% vs 4.2%, p=0.02), and deep surgical site infection (3.7% vs 1.4%, p=0.04). On multivariable-adjusted models, frailty was a significant predictor for minor (OR 1.58, 95% CI 1.09 to 2.30) and any complications (OR 1.46, 95% CI 1.02 to 2.08). Specifically, for radical vulvectomy with bilateral inguinofemoral lymphadenectomy, frailty was significantly associated with major (OR 2.13, 95% CI 1.03 to 4.40) and any complications (OR 2.10, 95% CI 1.14 to 3.87). CONCLUSION: In this analysis of the NSQIP database, nearly 25% of women undergoing radical vulvectomy were considered frail. Frailty was associated with increased post-operative complications, especially in women concurrently undergoing bilateral inguinofemoral lymphadenectomy. Frailty screening prior to radical vulvectomy may assist in patient counseling and improve post-operative outcomes.

Postoperative venous thromboembolism risk stratification in patients with uterine cancer.

BACKGROUND: Uterine cancers are associated with a high risk for venous thromboembolisms. The American Society of Clinical Oncology practice guidelines recommend that all patients undergoing pelvic surgery for cancer should receive extended pharmacologic thromboprophylaxis with the duration being dependent on risk. However, risk stratification for patients with uterine cancer is not clearly defined. The Caprini score is the most widely used risk assessment model but it has been found to have limited use in the gynecologic oncology population. A modified Caprini score has been explored in other populations. The Khorana score is an additional risk assessment model that has not been studied in this context. OBJECTIVE: Our objective was to evaluate the ability of a modified Caprini model and the Khorana score to risk stratify patients with uterine cancer for postoperative venous thromboembolisms within 90 days of surgery. STUDY DESIGN: Following institutional review board approval, a retrospective cohort study was performed, and all patients with uterine cancer who underwent a hysterectomy over a 4-year period were included. The Caprini and Khorana scores were calculated for each patient. The Caprini score cutoff for highest risk was evaluated at ≥7, ≥8, and ≥9 (modified Caprini) and the Khorana score cutoff was evaluated at ≥2 and ≥3. To determine the prognostic use of each score and other clinico-pathologic criteria related to the development of a venous thromboembolism, univariate analyses were performed using independent t tests, chi-square tests, or Fisher's exact tests; a multivariate analysis was performed using logistic regression. RESULTS: A total of 954 patients were included. The rate of venous thromboembolism development was 1.7% (16/954). A minimally invasive surgical approach was used in 90.5% (863/954) of patients. The mean Caprini score for patients with a venous thromboembolism was 10.3 compared with 8.1 for patients without a venous thromboembolism (95% confidence interval, 1.17-3.33; P<.0001). The mean Khorana score for the venous thromboembolism group was 2.4 vs 1.9 for those without (95% confidence interval, 0.04-0.82; P=.03). Both the Caprini and Khorana scores were found to be associated with venous thromboembolisms, but only a Caprini score with a cutoff of ≥8 or ≥9 was statistically significant (risk ratio, 31.25; 95% confidence interval, 1.88-519.49; risk ratio, 4.59; 95% confidence interval, 1.49-14.13, respectively), with high accuracy based on the area under the curve (0.75 and 0.68, respectively). Of the minimally invasive subgroup, 11.7% (101/863) of patients had same-day discharge with no postoperative thromboprophylaxis; none of these patients developed venous thromboembolisms. Despite extended prophylaxis among the laparotomy patients (30 days), the rate of venous thromboembolisms was more than 3 times that of the minimally invasive group (5.49% vs 1.7%). Advanced tumor stage and leukocytosis were noted to be independent risk factors for venous thromboembolisms. CONCLUSION: Our study suggests that using a modified Caprini score could help to identify the highest-risk patients who would benefit from prolonged thromboprophylaxis, could reduce the incidence of postoperative venous thromboembolisms, and could minimize the cost and harm of overtreatment. These findings need to be validated in a prospective manner, and further research is needed to determine the optimal duration of therapy.

The MEMORY Study: MulticentEr study of Minimally invasive surgery versus Open Radical hYsterectomy in the management of early-stage cervical cancer: Survival outcomes.

OBJECTIVE: The Laparoscopic Approach to Cervical Cancer (LACC) trial found that minimally invasive radical hysterectomy compared to open radical hysterectomy compromised oncologic outcomes and was associated with worse progression-free survival (PFS) and overall survival (OS) in early-stage cervical carcinoma. We sought to assess oncologic outcomes at multiple centers between minimally invasive (MIS) radical hysterectomy and OPEN radical hysterectomy. METHODS: This is a multi-institutional, retrospective cohort study of patients with 2009 FIGO stage IA1 (with lymphovascular space invasion) to IB1 cervical carcinoma from 1/2007-12/2016. Patients who underwent preoperative therapy were excluded. Squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinomas were included. Appropriate statistical tests were used. RESULTS: We identified 1093 cases for analysis-715 MIS (558 robotic [78%]) and 378. OPEN procedures. The OPEN cohort had more patients with tumors >2 cm, residual disease in the hysterectomy specimen, and more likely to have had adjuvant therapy. Median follow-up for the MIS and OPEN cohorts were 38.5 months (range, 0.03-149.51) and 54.98 months (range, 0.03-145.20), respectively. Three-year PFS rates were 87.9% (95% CI: 84.9-90.4%) and 89% (95% CI: 84.9-92%), respectively (P = 0.6). On multivariate analysis, the adjusted HR for recurrence/death was 0.70 (95% CI: 0.47-1.03; P = 0.07). Three-year OS rates were 95.8% (95% CI: 93.6-97.2%) and 96.6% (95% CI: 93.8-98.2%), respectively (P = 0.8). On multivariate analysis, the adjusted HR for death was 0.81 (95% CI: 0.43-1.52; P = 0.5). CONCLUSION: This multi-institutional analysis showed that an MIS compared to OPEN radical hysterectomy for cervical cancer did not appear to compromise oncologic outcomes, with similar PFS and OS.

Implementing universal upfront multi-gene panel testing in endometrial cancer: From cost to practical considerations.

OBJECTIVES: The routine use of upfront universal germline genetic testing among patients with newly diagnosed endometrial cancer (EC) has been proposed to improve diagnosis of Lynch syndrome (LS) and discover pathogenic variants (PVs) in other cancer susceptibility genes. We propose an algorithm prioritizing upfront multi-gene panel testing (MGPT) for newly diagnosed EC patients. METHODS: A decision analysis compared the cost of the current algorithm of universal mismatch repair (MMR) immunohistochemistry (IHC) for all EC cases to a new MGPT algorithm that employs upfront MGPT for all EC cases and reserves MMR IHC for the recurrent setting. The increase in the number of LS diagnoses using upfront MGPT, and the number of patients with PVs in BRCA1 and BRCA2 are also estimated. RESULTS: The MGPT algorithm demonstrated a cost savings of $259 per patient. Assuming 66,950 new cases of EC per year, this would represent $17.1 M of cost savings per year. When applied to all new diagnoses of EC in one year, the MGPT algorithm identified 660 (1%) additional cases of LS that would have been missed with the current algorithm. An additional 660 (1%) EC patients with BRCA1 or BRCA2 PVs would be diagnosed only through implementation of universal MGPT. CONCLUSIONS: The use of universal upfront MGPT is a practical consideration for patients with newly diagnosed EC for cost savings and improved diagnosis of highly penetrant cancer syndromes. Incorporation of germline genetic testing in the upfront setting represents an opportunity to improve access to genetic counseling and testing, and ultimately an avenue to achieve equity and improve the lives of our patients with EC and their families.

Up-Front Multigene Panel Testing for Cancer Susceptibility in Patients With Newly Diagnosed Endometrial Cancer: A Multicenter Prospective Study.

PURPOSE: Clinical utility of up-front multigene panel testing (MGPT) is directly related to the frequency of pathogenic variants (PVs) in the population screened and how genetic findings can be used to guide treatment decision making and cancer prevention efforts. The benefit of MGPT for many common malignancies remains to be determined. In this study, we evaluated up-front MGPT in unselected patients with endometrial cancer (EC) to determine the frequency of PVs in cancer susceptibility genes. METHODS: Patients with EC were prospectively enrolled at nine Ohio institutions from October 1, 2017, to December 31, 2020. Nine hundred and sixty-one patients with newly diagnosed EC underwent clinical germline MGPT for 47 cancer susceptibility genes. In addition to estimating the prevalence of germline PVs, the number of individuals identified with Lynch syndrome (LS) was compared between MGPT and tumor-based screening. RESULTS: Likely pathogenic variants or PVs were identified in 97 of 961 women (10.1%). LS was diagnosed in 29 of 961 patients (3%; 95% CI, 2.1 to 4.3), with PVs in PMS2 most frequent. MGPT revealed nine patients with LS in addition to the 20 identified through routine tumor-based screening. BRCA1 and BRCA2 PVs were found in 1% (10 of 961; 95% CI, 0.6 to 1.9) of patients and that group was significantly enriched for type II ECs. CONCLUSION: This prospective, multicenter study revealed potentially actionable germline variants in 10% of unselected women with newly diagnosed EC, supporting the use of up-front MGPT for all EC patients. The discovery that BRCA1 or BRCA2 heterozygotes frequently had type II cancers points to therapeutic opportunities for women with aggressive histologic EC subtypes.

Outcomes of Minimally Invasive versus Open Radical Hysterectomy for Early Stage Cervical Cancer Incorporating 2018 FIGO Staging.

STUDY OBJECTIVE: To compare outcomes after minimally invasive surgery (MIS) vs open radical hysterectomy for early stage cervical cancer incorporating 2018 Federation of Gynecology and Obstetrics (FIGO) staging. DESIGN: A retrospective analysis. SETTING: A single teaching hospital. PATIENTS: Patients after radical hysterectomy for stage IA1 with lymphovascular invasion, IA2, or IB1 squamous, adenosquamous, or adenocarcinoma of the cervix between 2007 and 2018, mirroring the Laparoscopic Approach to Cervical Cancer trial criteria. INTERVENTIONS: The use of MIS surgery for performing radical hysterectomy. MEASUREMENTS AND MAIN RESULTS: The outcomes were compared between patients undergoing MIS vs open approaches. A total of 126 patients met the inclusion criteria. The approach was open in 44 patients (35%) and MIS in 82 patients (65%); 49% were laparoscopic and 51% were robotic. Distribution based on the 2009 FIGO staging showed 1 stage IA1 with lymphovascular invasion, 15 stage IA2, and 110 stage IB1 patients. Although not statistically significant, the 3-year disease-free survival (DFS) was higher in the open compared to the MIS group (95% vs 87%; p = .17), and the overall survival was higher in the open compared to the MIS group (97% vs 92%; p = .25). Fourteen patients whose disease recurred were Stage IB1 by FIGO 2009 staging; 11/14 were reclassified to a higher stage by 2018 FIGO staging (5/5 open, 6/9 MIS). Adjuvant therapy was recommended for all these patients based on the Sedlis criteria (10/14) or other risk factors (4/14). Despite this, only 1/9 of MIS patients whose disease recurred received adjuvant therapy compared with 3/5 patients whose disease recurred in the open group (p = .05). CONCLUSION: In a cohort of patients similar to that of the Laparoscopic Approach to Cervical Cancer trial, 2018 FIGO staging may be useful to refine indications for MIS radical hysterectomy in early stage cervical cancer. However, disparate outcomes between MIS and open approaches may be explained by differences in compliance with National Comprehensive Cancer Network guidelines for adjuvant therapy.