Gretchen Glaser

2009 International Federation of Gynecology and Obstetrics (FIGO) stage IIIA endometrial cancer: oncologic outcomes based on involvement of adnexa, serosa, or both

To assess clinicopathologic features and survival outcomes of patients with endometrial carcinoma involving adnexal, full-thickness serosal, or combined involvement. This international, multi-institutional, retrospective study examined patients with 2009 International Federation of Gynecology and Obstetrics (FIGO) stage IIIA endometrial cancer and tumors involving the uterine serosa and/or adnexa, who were surgically staged between 2000 and 2019. Patients with sarcoma histology, concurrent endometrial/ovarian malignancy, neoadjuvant treatment, positive lymph nodes, or peritoneal disease were excluded. Of 185 patients identified, 139 had tumors with adnexal-only, 40 with serosal-only, and six with combined adnexal/serosal involvement. Median age at diagnosis was 60 years (range 23-89). Among tumors of endometrioid histology, 12 (48%) with serosal-only and 17 (19%) with adnexal-only involvement were FIGO grade 3 (p=0.007). Twenty-three tumors with serosal-only (64%) and 50 with adnexal-only (37%) involvement had lymphovascular invasion (p=0.004). Non-endometrioid histology was present in five tumors (83%) with combined adnexal/serosal, 15 (38%) with serosal-only, and 50 (36%) with adnexal-only involvement.Median follow-up was 77 months (range 0.6-254). Five-year progression-free survival and overall survival rates for all patients with stage IIIA disease were 73.8% (SE 3.5%) and 81.0% (SE 3.1%), respectively. For patients with adnexal-only, serosal-only, and combined adnexal/serosal involvement, 5-year progression-free survival rates were 80% (SE 3.8%), 61% (SE 8.3%), and 33% (SE 19.2%), respectively (p<0.01); 5-year overall survival rates were 85% (SE 3.3%), 70% (SE 7.8%), and 60% (SE 21.9%), respectively (p=0.09). On univariate analysis, tumors having serosal involvement with/without adnexal involvement, non-endometrioid histology, and lymphovascular invasion were significantly associated with progression. On multivariate analysis, tumors having serosal involvement with/without adnexal involvement remained significantly associated with recurrence (adjusted HR=2.2, 95% CI 1.2 to 4.3; p=0.01). Patients with 2009 FIGO stage IIIA endometrial cancer have distinct survival outcomes depending upon adnexal and/or serosal involvement. Progression-free survival was worse for patients with serosal involvement after adjusting for histology, adjuvant treatment, and lymphovascular space invasion.

A Phase I Trial of Nab-Paclitaxel/Bevacizumab (AB160) Nano-Immunoconjugate Therapy for Gynecologic Malignancies

Abstract Purpose: AB160 is a 160-nm nano-immunoconjugate consisting of nab-paclitaxel (ABX) nanoparticles noncovalently coated with bevacizumab (BEV) for targeted delivery into tissues expressing high levels of VEGF. Preclinical data showed that AB160 resulted in greater tumor targeting and tumor inhibition compared with sequential treatment with ABX then BEV. Given individual drug activity, we investigated the safety and toxicity of AB160 in patients with gynecologic cancers. Patients and Methods: A 3+3 phase I trial was conducted with three potential dose levels in patients with previously treated endometrial, cervical, and platinum-resistant ovarian cancer to ascertain the recommended phase II dose (RP2D). AB160 was administered intravenously on days 1, 8, and 15 of a 28-day cycle (ABX 75–175 mg/m2, BEV 30–70 mg/m2). Pharmacokinetic analyses were performed. Results: No dose-limiting toxicities (DLT) were seen among the three dose levels tested. Grade 3/4 toxicities included neutropenia, thromboembolic events, and leukopenia. DL2 (ABX 150 mg/m2, BEV 60 mg/m2) was chosen as the RP2D. Seven of the 19 patients with measurable disease (36.8%) had confirmed partial responses (95% confidence interval, 16.3%–61.6%). Pharmacokinetic analyses demonstrated that AB160 allowed 50% higher paclitaxel dosing and that paclitaxel clearance mirrored that of therapeutic antibodies. Conclusions: The safety profile and clinical activity of AB160 supports further clinical testing in patients with gynecologic cancers; the RP2D is DL2 (ABX 150 mg/m2, BEV 60 mg/m2).

Let go of the myth: safety of indocyanine green for sentinel lymph node mapping in endometrial cancer

Sentinel lymph node mapping by intracervical indocyanine green injection is the preferred method for surgical staging in endometrial cancer. Adverse reactions to indocyanine green are extremely rare, and information about the safety of this tracer in patients with a history of other allergies, asthma, or comorbidities is limited. We aim to evaluate the rate of adverse reactions to indocyanine green injected during sentinel lymph node mapping in patients with endometrial cancer and review the etiology of such reactions. All patients with endometrial cancer undergoing sentinel lymph node mapping with indocyanine green cervical stroma injection at the Mayo Clinic in Rochester, Minnesota between June 2014 and December 2018 were retrospectively evaluated. Any adverse reaction occurring intra-operatively or within 7 days after surgery was identified. A thorough chart review was performed by an allergy specialist physician for any patient with an allergic-type reaction. We included 923 patients of which 565 (61.2%) had a history of allergy to antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), other medications, and/or environmental exposures. Of 490 patients who had previously received contrast media, 25 (5.1%) had a history of an adverse reaction. No immediate anaphylaxis or other allergic reactions were observed after indocyanine green injection. 10 (1.1%) patients developed a transient skin reaction within 7 days after surgery. None of these patients had a history of contrast media reaction. Based on timing and clinical/peri-operative history of affected patients, it was determined that skin reactions were likely induced by other newly prescribed medications or contact sensitivity, not administration of indocyanine green. Indocyanine green injection for sentinel lymph node mapping in patients with endometrial cancer caused no immediate/delayed anaphylactic or other severe allergic reactions. This included patients with a history of other allergies, asthma, and comorbidities. The myth of iodine's relationship to allergic reactions must be refuted to allow indocyanine green use in patients with a history of contrast media or shellfish allergy.

Endometrial carcinosarcoma without myoinvasion

Uterine carcinosarcoma without myoinvasion, limited to the endometrial lining/polyp or with no residual uterine disease at the time of hysterectomy, is extremely uncommon, with unknown oncologic outcomes. Thus, this study aimed to evaluate the long-term outcomes of patients with carcinosarcoma without myoinvasion. Patients with International Federation of Gynecology and Obstetrics 2009 stage IA carcinosarcoma without myoinvasion who underwent surgery from December 1998 to January 2023 were identified from 11 centers worldwide. Patients were classified by tumor status (limited to the endometrium, limited to polyp, no residual disease in the hysterectomy specimen) and by type of adjuvant therapy (chemotherapy vs no chemotherapy). Survival analysis follow-up was limited to the first 5 years after surgery. Of 97 patients included, 28 (28.9%) had disease confined to a polyp, 55 (56.7%) to the endometrium, and 14 (14.4%) had no residual disease in the hysterectomy specimen. Patients received observation only (n=16, 16.5%), vaginal brachytherapy alone (n=14, 14.4%), external beam radiation therapy ± vaginal brachytherapy (n=5, 5.2%), chemotherapy ± vaginal brachytherapy (n=51, 52.6%), and chemotherapy and external beam radiation therapy ± vaginal brachytherapy (n=7, 7.2%), whereas adjuvant therapy was unknown in 4 patients (4.1%). A total of 29 patients (29.9%) recurred, mostly with a distant pattern of relapse. The 5-year recurrence-free survival was 63.5% (95% CI 53.4% to 75.4%) and the overall survival was 72.0% (95% CI 62.6% to 82.9%). The median follow-up for patients without recurrence was 56.9 months (interquartile range; 21.8-72.9). No significant differences were observed in recurrence-free survival and overall survival based on status of the tumor (p=.99 and p=.43, respectively). The difference in recurrence-free survival and overall survival was not statistically significant based on the receipt of chemotherapy (p=.08 and p=.07, respectively). Patients with carcinosarcoma without myoinvasion have a poor prognosis, with a high recurrence rate with distant pattern. The use of chemotherapy did not achieve statistical significance but may be limited by our small series.

Rewinding the clock on positive peritoneal cytology in endometrial cancer: does it predict prognosis in low-risk disease?

Positive peritoneal cytology in endometrial cancer is a known risk factor for worse oncologic outcomes but is not used for staging purposes or to guide adjuvant treatment. Additionally, its prognostic impact on low-risk patients remains unclear. Therefore, we investigated the role of positive peritoneal cytology in patients with endometrial cancer and focused on low-risk disease. This is a retrospective cohort study including all consecutive patients undergoing primary surgery for endometrial cancer at Mayo Clinic from 1999 to 2021. The role of positive peritoneal cytology was investigated in the entire cohort and in 2 subgroups: the National Comprehensive Cancer Network (NCCN) low-risk group, including low-risk patients according to NCCN guidelines (endometrioid, grade 1-2, stage IA) and the European Society of Gynecologic Oncology/European Society of Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) low-risk group, including low-risk patients according to ESGO/ESTRO/ESP guidelines (as NCCN, plus no lymphovascular space invasion). Univariate and multivariable analyses were used to evaluate the association of positive peritoneal cytology with recurrence within 5 years after surgery, and Kaplan-Meier survival analyses were performed in all groups. A total of 3517 patients were included, 1911 in the NCCN low-risk group and 1832 in the ESGO/ESTRO/ESP low-risk group. Positive peritoneal cytology was found in 15.9% of the entire cohort (559/3517), 8.1% of the NCCN low-risk group (154/1911), and 7.9% of the ESGO/ESTRO/ESP low-risk group (145/1832). In both low-risk groups, 5-year recurrence-free survival was worse in patients with positive peritoneal cytology (p < .01 and p = .03, respectively), but there was no difference in overall survival. On univariate analysis, age, tumor grade, and positive peritoneal cytology were significant predictors of recurrence in both subgroups. After multivariable analysis, positive peritoneal cytology remained independently associated with recurrence (p < .01 and p = .03, respectively). Positive peritoneal cytology was an independent predictor of recurrence and was associated with worse recurrence-free survival in patients with low-risk endometrial cancer. However, overall survival was not impacted.

Impact of comorbidities and extent of lymphadenectomy on quality of life in endometrial cancer patients treated with minimally invasive surgery in the era of sentinel lymph nodes

To identify predictors of quality of life (QoL) among patients who undergo surgical staging with sentinel lymph node (SLN) biopsy or lymphadenectomy for endometrial cancer. Patients who underwent minimally invasive surgery for primary endometrial cancer at the Mayo Clinic from October 2013 to June 2016 were mailed a 30-item QoL in Cancer survey (QLQ-C30) and a validated 13-item lower extremity lymphedema screening questionnaire. Patients who answered <50% of the items or had a pre-operative history of lymphedema were excluded. Multivariable linear regression models were fit to evaluate predictors of QoL using inverse-probability of treatment weighting to adjust for differences at the time of the surgery between the lymphadenectomy and SLN groups. The 221 patients included in the analysis were stratified into two groups: patients who underwent (1) bilateral lymphadenectomy as 'backup' after SLN mapping (lymphadenectomy group; n=101) or (2) SLN removal with or without side-specific lymphadenectomy (SLN group; n=120). On multivariable analysis, obesity, lower extremity lymphedema, and kidney disease had significant (p<0.05) and clinically meaningful negative impacts on global QoL. Declines in average adjusted global QoL scores were marked (19.7 points lower) in patients with BMI ≥40 kg/m Lower extremity lymphedema coupled with obesity predicts poorer QoL in patients who undergo surgical staging for endometrial cancer. In this population, reduction of lower extremity lymphedema by performing SLN instead of lymphadenectomy and earlier targeted interventions may improve patients' QoL. Future research focusing on targeted interventions is needed.

Prognostic factors in patients with endometrial cancer with isolated lymphatic recurrence

To analyze the clinicopathological features and outcomes in patients with endometrial cancer with isolated lymphatic recurrence after lymphadenectomy, stratified by different isolated lymphatic recurrence sites and treatment approaches. We retrospectively reviewed all surgically treated patients with endometrial cancer, identifying those with recurrence. We defined primary isolated lymphatic recurrence as the first and unique evidence of recurrence in lymph node-bearing areas, without concomitant vaginal, hematogenous, or peritoneal recurrence. Isolated lymphatic recurrences were classified as pelvic, para-aortic, distant, or multiple sites. Our primary outcome was cause-specific survival after diagnosis of the recurrence. Among 4216 patients with surgically staged endometrial cancer, we identified 66 (1.6%) women with isolated lymphatic recurrence. The overall median cause-specific survival for patients with isolated lymphatic recurrence was 24 months. Although cause-specific survival was not significantly different between the four isolated lymphatic recurrence groups (p=0.21), 7 of 15 (47%) patients with isolated lymphatic recurrence in the para-aortic area were long-term survivors. At multivariate Cox regression, the absence of lymphovascular space invasion and grade 1 histology in the primary tumor were significantly associated with improved cause-specific survival. In addition, patients with isolated lymphatic recurrence who underwent surgery for recurrence (with/without other associated therapies) had improved cause-specific survival compared with patients who did not undergo surgery, also after adjusting for age. Low-grade histology and absence of lymphovascular space invasion in the primary tumor were predictors of improved prognosis in patients with endometrial cancer with isolated lymphatic recurrence. In addition, in this retrospective cohort, patients with isolated lymphatic recurrence who were selected for eradicative surgical treatment had improved cause-specific survival.

The Quality of Life after Endometrial Cancer Study: Baseline Characteristics and Patient-Reported Outcomes

Endometrial cancer (EC) patients make up the second largest group of female cancer survivors. Patient-reported outcomes (PROs) including quality of life (QOL) and sexual function and satisfaction (SF and S) are critical facets of survivorship. This prospective, longitudinal study assesses associations between baseline characteristics and PROs after treatment. Herein, we report the baseline clinical characteristics and PROs prior to treatment initiation. Outcomes post-treatment over time will be reported separately. Patients with planned surgery for EC were prospectively enrolled in 2019–2021 and administered the European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire Core 30 (QLQ-C30), EORTC QLQ EC Module (EN24), Patient-Reported Outcomes Measurement Information System (PROMIS), and the Mayo Clinic lower extremity lymphedema (LEL) questionnaire. This study enrolled 198 patients with a mean (SD) age of 63.6 (9.8) years and body mass index of 35.5 (8.3) kg/m2. No significant differences in the PROs for the QOL were seen when compared to the reference means (SD) except for the lower interest in sexual activity (31.9 (9.8) vs. 47.5 (SE0.70)) and lower fatigue (21.3 (19.8) vs. 31.7 (25.9)). Increased obesity was associated with an increased likelihood of LEL (p &lt; 0.01) and multiple QOL scales, including poorer global health status (p &lt; 0.01) and physical functioning (p &lt; 0.01). Prior to treatment initiation for EC, the patients had a similar QOL compared to that of the general population. The patients with increasing obesity, a known risk factor for EC, had worse overall global health status and physical functioning. A better understanding of these QOL measures is imperative for earlier identification and intervention of patients at risk of chronic impairments from EC treatment.

Lymphovascular space invasion in node-negative endometrial cancer: what was old is new again

Impact of molecular classification on recurrence risk in endometrial cancer patients with lymph node metastasis: multicenter retrospective study

To assess the distribution of molecular classes and their impact on the risk of recurrence in endometrial cancer patients with lymph node metastasis at the time of primary surgery. Endometrial cancer patients with lymph node micrometastasis or macrometastasis (International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IIIC) after surgical staging at five referral centers worldwide from October 2013 to September 2022 who underwent molecular classification were identified. Endometrial cancers were categorized into four molecular classes: POLE mutated, mismatch repair deficient, p53 abnormal, and no specific molecular profile. Survival analyses using Kaplan-Meier and Cox models (univariate and multivariate) were conducted to evaluate the relationship between molecular class and 5-year recurrence free survival. 131 patients were included: 55 (42.0%) no specific molecular profile, 46 (35.1%) mismatch repair deficient, 1 (0.8%) POLE mutated, and 29 (22.1%) p53 abnormal. During a 5 year follow-up period, 50 (38.2%) patients experienced a recurrence with a median time of 1.2 years (interquartile range (IQR) 0.5-1.8). Median follow-up for the remaining 81 patients was 3.1 years (IQR 1.3-4.5). Survival analysis revealed a significant difference in recurrence-free survival between no specific molecular profile, mismatch repair deficient, and p53 abnormal classes (log rank p<0.01). In a model adjusted for type of lymph node metastasis and tumor grade, the molecular class did not retain significance (p=0.13), while in a model adjusted for type of lymph node metastasis and adjuvant therapy, the molecular class retained significance (p<0.01). Among patients with stage IIIC endometrial cancer, POLE mutated tumors exhibited an extremely low prevalence, with no specific molecular profile emerging as the largest molecular subgroup. Despite the significant difference in recurrence-free survival between molecular classes, conventional histopathologic parameters retained crucial prognostic value. Our findings highlight the necessity of integrating molecular classes with pathological characteristics, rather than considering them in isolation as crucial prognostic factors in stage IIIC endometrial cancer.

Artificial intelligence model for enhancing the accuracy of transvaginal ultrasound in detecting endometrial cancer and endometrial atypical hyperplasia

Transvaginal ultrasound is typically the initial diagnostic approach in patients with postmenopausal bleeding for detecting endometrial atypical hyperplasia/cancer. Although transvaginal ultrasound demonstrates notable sensitivity, its specificity remains limited. The objective of this study was to enhance the diagnostic accuracy of transvaginal ultrasound through the integration of artificial intelligence. By using transvaginal ultrasound images, we aimed to develop an artificial intelligence based automated segmentation model and an artificial intelligence based classifier model. Patients with postmenopausal bleeding undergoing transvaginal ultrasound and endometrial sampling at Mayo Clinic between 2016 and 2021 were retrospectively included. Manual segmentation of images was performed by four physicians (readers). Patients were classified into cohort A (atypical hyperplasia/cancer) and cohort B (benign) based on the pathologic report of endometrial sampling. A fully automated segmentation model was developed, and the performance of the model in correctly identifying the endometrium was compared with physician made segmentation using similarity metrics. To develop the classifier model, radiomic features were calculated from the manually segmented regions-of-interest. These features were used to train a wide range of machine learning based classifiers. The top performing machine learning classifier was evaluated using a threefold approach, and diagnostic accuracy was assessed through the F1 score and area under the receiver operating characteristic curve (AUC-ROC). 302 patients were included. Automated segmentation-reader agreement was 0.79±0.21 using the Dice coefficient. For the classification task, 92 radiomic features related to pixel texture/shape/intensity were found to be significantly different between cohort A and B. The threefold evaluation of the top performing classifier model showed an AUC-ROC of 0.90 (range 0.88-0.92) on the validation set and 0.88 (range 0.86-0.91) on the hold-out test set. Sensitivity and specificity were 0.87 (range 0.77-0.94) and 0.86 (range 0.81-0.94), respectively. We trained an artificial intelligence based algorithm to differentiate endometrial atypical hyperplasia/cancer from benign conditions on transvaginal ultrasound images in a population of patients with postmenopausal bleeding.

How deep is too deep? Assessing myometrial invasion as a predictor of distant recurrence in stage I endometrioid endometrial cancer

The goal of this study was to evaluate the depth of myometrial invasion as a predictor of distant recurrence in patients with node-negative stage IB endometrioid endometrial cancer. A retrospective multicenter study, including surgically staged endometrial cancer patients at Mayo Clinic, Rochester (MN, USA) between January 1999 and December 2017, and Fondazione Policlinico Universitario A. Gemelli (Rome, Italy) between March 2002 and March 2017, was conducted. Patients without lymph node assessment were excluded. The follow-up was restricted to the first 5 years following surgery. Recurrence-free survival was estimated using the Kaplan-Meier method. Cox proportional hazards models were fit to evaluate the association of clinical and pathologic characteristics with the risk of recurrence. Of 386 patients, the mean (SD) depth of myometrial invasion was 70.4 (13.2)%. We identified 51 recurrences (14 isolated vaginal, 37 non-vaginal); the median follow-up of the remaining patients was 4.5 (IQR 2.3-7.0) years. At univariate analysis, the risk of non-vaginal recurrence increased by 64% (95% CI 1.28 to 2.12) for every 10-unit increase in the depth of myometrial invasion. International Federation of Gynecology and Obstetrics (FIGO) grade and myometrial invasion were independent predictors of non-vaginal recurrence. The 5-year non-vaginal recurrence-free survival was 95.2% (95% CI 92.0% to 98.6%), 84.0% (95% CI 76.6% to 92.1%), and 67.1% (95% CI 54.2% to 83.0%) for subsets of patients with myometrial invasion <71% (n=207), myometrial invasion ≥71% and grade 1-2 (n=132), and myometrial invasion ≥71% and grade 3 (n=47), respectively. A total of 256 (66.3%) patients received either vaginal brachytherapy only or no adjuvant therapy. Patients who received adjuvant chemotherapy, regardless of receipt of external beam radiotherapy or vaginal brachytherapy, had an approximately 70% lower risk of any recurrence (HR adjusted for age, grade, myometrial invasion 0.31, 95% CI 0.12 to 0.85) and of non-vaginal recurrence (adjusted HR 0.32, 95% CI 0.10 to 0.99). The invasion of the outer third of the myometrium and histologic grade were found to be independent predictors of distant recurrence among patients with endometrioid, node-negative stage IB endometrial cancer. Future studies should investigate if systemic adjuvant therapy for patients with myometrial invasion of the outer third would improve outcomes.

Endometrial cancer with positive sentinel lymph nodes: pathologic characteristics of metastases as predictors of extent of lymphatic dissemination and prognosis

To assess predictors of extensive lymph node dissemination and non-vaginal recurrence in patients with endometrial cancer with positive sentinel lymph nodes (SLNs). Patients with endometrial cancer who underwent primary surgery with SLN mapping and had at least one positive node between October 2013 and May 2019 were included. Positive SLNs were reviewed, and cases were classified according to the location of the metastasis (extracapsular vs intracapsular), and the size of the largest SLN metastasis (isolated tumor cells, micrometastasis, macrometastasis). Associations were assessed based on fitting logistic regression models and Cox proportional hazards models. A total of 103 patients met the inclusion criteria: including 36 (34.9%) with isolated tumor cells, 27 (26.2%) with micrometastasis, and 40 (38.8%) with macrometastasis. Notably, 71.4% of patients exhibiting extracapsular SLN metastases had multiple positive SLNs (p=0.008). Extracapsular invasion (adjusted odds ratio (aOR) 5.81, 95% CI 1.4 to 23.6) and age (aOR=1.8, 95% CI 1.1 to 3.0) emerged as independent predictors of multiple positive SLNs. Among the 38 patients who underwent a backup pelvic lymphadenectomy, 18 (47.4%) presented with positive pelvic non-SLNs, a phenomenon more prevalent in patients with macrometastasis (p=0.004).Independent predictors of non-vaginal recurrence included SLN macrometastasis (adjusted hazard ratio (aHR) 3.3, 95% CI 1.3 to 8.3), non-endometrioid histology (aHR=3.7, 95% CI 1.5 to 9.3), and cervical stromal invasion (aHR=5.5, 95% CI 2.0 to 14.9). Among the 34 patients with isolated tumor cells and endometrioid histology, 3 (9%) experienced a recurrence, all of whom had not received any adjuvant chemotherapy or external beam radiotherapy. Patients with positive SLN macrometastasis are independently associated with extensive lymphatic dissemination and distant recurrences. The risk of multiple positive SLNs increases with the extracapsular location of the SLN metastasis and with age. Independent uterine pathologic predictors of non-vaginal recurrence are non-endometrioid histology and cervical stromal invasion.

Incidence of sentinel lymph node metastases in apparent early-stage endometrial cancer: a multicenter observational study

Ultrastaging is accurate in detecting nodal metastases, but increases costs and may not be necessary in certain low-risk subgroups. In this study we examined the risk of nodal involvement detected by sentinel lymph node (SLN) biopsy in a large population of apparent early-stage endometrial cancer and stratified by histopathologic characteristics. Furthermore, we aimed to identify a subgroup in which ultrastaging may be omitted. We retrospectively included patients who underwent SLN (with bilateral mapping and no empty nodal packets on final pathology) ± systematic lymphadenectomy for apparent early-stage endometrial cancer at two referral cancer centers. Lymph node status was determined by SLN only, regardless of non-SLN findings. The incidence of macrometastasis, micrometastasis, and isolated tumor cells (ITC) was measured in the overall population and after stratification by histotype (endometrioid vs serous), myometrial invasion (none, <50%, ≥50%), and grade (G1, G2, G3). Bilateral SLN mapping was accomplished in 1570 patients: 1359 endometrioid and 211 non-endometrioid, of which 117 were serous. The incidence of macrometastasis, micrometastasis, and ITC was 3.8%, 3.4%, and 4.8%, respectively. In patients with endometrioid histology (n=1359) there were 2.9% macrometastases, 3.2% micrometastases, and 5.3% ITC. No macro/micrometastases and only one ITC were found in a subset of 274 patients with low-grade (G1-G2) endometrioid endometrial cancer without myometrial invasion (all <1%). The incidence of micro/macrometastasis was higher, 2.8%, in 708 patients with low-grade endometrioid endometrial cancer invading <50% of the myometrium. In patients with serous histology (n=117), the incidence of macrometastases, micrometastasis, and ITC was 11.1%, 6.0%, and 1.7%, respectively. For serous carcinoma without myometrial invasion (n=36), two patients had micrometastases for an incidence of 5.6%. Ultrastaging may be safely omitted in patients with low-grade endometrioid endometrial cancer without myometrial invasion. No other subgroups with a risk of nodal metastasis of less than 1% have been identified.

Reduced lymphedema after sentinel lymph node biopsy versus lymphadenectomy for endometrial cancer

Endometrial cancer surgical staging includes lymph node assessment which can lead to lower extremity lymphedema. The aim of this study was to estimate prevalence after sentinel lymph node biopsy versus lymphadenectomy. Consecutive patients who underwent minimally invasive surgery at the Mayo Clinic, Rochester, Minnesota, USA, between January 2009 and June 2016 for newly diagnosed endometrial cancer were mailed our validated 13 item lower extremity lymphedema screening questionnaire. We also ascertained via questionnaire whether the patient was ever diagnosed with lower extremity lymphedema. Among 378 patients included in the analysis, 127 (33.5%) had sentinel lymph node biopsy with or without side specific lymphadenectomy (sentinel lymph node cohort) and 251 (66.4%) underwent bilateral lymphadenectomy prior to sentinel lymph node biopsy implementation at our institution or as 'backup' after sentinel lymph node mapping (lymphadenectomy cohort). The prevalence of lower extremity lymphedema was 41.5% (157/378), with 69 patients (18.3%) self-reporting a lower extremity lymphedema diagnosis after their endometrial cancer surgery at a median of 54.3 months (interquartile range 31.2-70.1 months), and an additional 88 patients (23.3%) identified by the screening questionnaire. The prevalence of lower extremity lymphedema was significantly higher in the lymphadenectomy cohort compared with the sentinel lymph node group (49.4% (124/251) vs 26.0% (33/127); p<0.001). When the cohorts were restricted to patients surgically managed after the introduction of sentinel lymph node, the prevalence of lower extremity lymphedema was still significantly higher in the lymphadenectomy cohort compared with the sentinel lymph node cohort (39.0% (41/105) vs 26.0% (33/127); p=0.03). In a multivariable analysis adjusted for body mass index, receipt of adjuvant external beam radiation, diabetes, congestive heart failure, and International Federation of Gynecology and Obstetrics grade, the adjusted odds ratio for the association between type of nodal sampling (lymphadenectomy cohort vs sentinel lymph node cohort) and lower extremity lymphedema was 2.75 (95% confidence interval 1.69 to 4.47, p<0.001). Sentinel lymph node biopsy was associated with a decreased risk of post-treatment lymphedema compared with lymphadenectomy in patients who underwent surgical staging for endometrial carcinoma.

Overall survival after surgical staging by lymph node dissection versus sentinel lymph node biopsy in endometrial cancer: a national cancer database study

Substituting lymphadenectomy with sentinel lymph node biopsy for staging purposes in endometrial cancer has raised concerns about incomplete nodal resection and detrimental oncological outcomes. Therefore, this study aimed to investigate the association between the type of lymph node assessment and overall survival in endometrial cancer accounting for node status and histology. Women with stage I-III endometrial cancer who underwent hysterectomy and lymph node assessment from January 2012 to December 2015 were identified in the National Cancer Database. Patients who underwent neoadjuvant therapy, had previous cancer, and whose follow-up was less than 90 days were excluded. Multivariable Cox proportional hazards regression analyses were performed to assess factors associated with overall survival. Of 68 614 patients, 64 796 (94.4%) underwent lymphadenectomy, 1777 (2.6%) underwent sentinel node biopsy only, and 2041 (3.0%) underwent both procedures. On multivariable analysis, neither sentinel lymph node biopsy alone nor sentinel node biopsy followed by lymphadenectomy was associated with significantly different overall survival compared with lymphadenectomy alone (HR 0.92, 95% CI 0.73 to 1.17, and HR 0.91, 95% CI 0.77 to 1.08, respectively). When stratified by lymph node status, sentinel node biopsy alone or followed by lymphadenectomy was not associated with different overall survival, both in patients with negative (HR 0.95, 95% CI 0.73 to 1.24, and HR 1.04, 95% CI 0.85 to 1.27, respectively) or positive (HR 0.91, 95% CI 0.54 to 1.52, and HR 0.77, 95% CI 0.57 to 1.04, respectively) lymph nodes. These findings held true when sentinel node biopsy alone and sentinel node biopsy plus lymphadenectomy groups were merged, and on stratification by histotype (type one vs type 2) or inclusion of only complete lymphadenectomy (at least 10 pelvic nodes and at least one para-aortic node removed). In all analyses, age, Charlson-Deyo score, black race, AJCC pathological T stage, grade, lymphovascular invasion, brachytherapy, and adjuvant chemotherapy were independently associated with overall survival. No difference in overall survival was found in patients with endometrial cancer who underwent sentinel node biopsy alone, sentinel node biopsy followed by lymphadenectomy, or lymphadenectomy alone. This observation remained regardless of node status, histotype, and lymphadenectomy extent.

Sequencing chemotherapy before radiotherapy for women with stage IIIC endometrial cancer

It is unclear how to best sequence adjuvant chemotherapy and radiotherapy for advanced endometrial cancer. We studied the outcomes for women treated with chemotherapy before radiotherapy in a chemotherapy-first (chemotherapy for 6 cycles followed radiotherapy) or 'sandwich' approach (chemotherapy for 3 cycles followed by radiotherapy and subsequently chemotherapy for 3 cycles). Women with stage IIIC endometrial cancer and no gross residual disease treated with chemotherapy before radiotherapy between April 2003 and April 2016 were included. The Kaplan-Meier method was used to estimate recurrence and survival. We performed a meta-analysis of endometrial cancer trials comparing chemotherapy and radiotherapy versus radiotherapy alone. A total of 102 patients were included. The mean (SD) age was 63.8 (10.6) years; 84 patients received the chemotherapy-first approach and 18 patients received the 'sandwich' approach. Pelvic and para-aortic nodes were removed in 99% and 88.2%, respectively. Among all the patients, we observed 1 pelvic (1%), 1 para-aortic (1%), and 5 vaginal (4.9%) recurrences. At 3 years, for the 'sandwich' and chemotherapy-first approaches, the vaginal recurrence was 11.8% and 4.2%, pelvic recurrence was 0% and 1.5%, para-aortic recurrence was 0% and 1.2%, distant recurrence was 42.9% and 24.4%, and overall survival was 70.3% and 81.7%, respectively. With 'chemotherapy before radiotherapy' 94.9% completed 4+ chemotherapy cycles (vs 71-90% reported in the literature for 'radiotherapy before chemotherapy'). In a meta-analysis of endometrial cancer trials, distant recurrence rates were reduced with 4+ chemotherapy cycles but not with 3 cycles (p=0.01). Chemotherapy before radiation sequencing for stage IIIC endometrial cancer was associated with a high proportion of patients completing 4+ chemotherapy cycles and low locoregional lymphatic recurrence rate, despite delaying radiotherapy until after 3-6 cycles of chemotherapy and not administering concurrent cisplatin.

The shift from inpatient to outpatient hysterectomy for endometrial cancer in the United States: trends, enabling factors, cost, and safety

To evaluate trends in outpatient versus inpatient hysterectomy for endometrial cancer and assess enabling factors, cost and safety. In this retrospective cohort study, patients aged 18 years or older who underwent hysterectomy for endometrial cancer between January 2008 and September 2015 were identified in the Premier Healthcare Database. The surgical approach for hysterectomy was classified as open/abdominal, vaginal, laparoscopic or robotic assisted. We described trends in surgical setting, perioperative costs and safety. The impact of patient, provider and hospital characteristics on outpatient migration was assessed using multivariate logistic regression. We identified 41 246 patients who met inclusion criteria. During the time period studied, we observed a 41.3% shift from inpatient to outpatient hysterectomy (p<0.0001), an increase in robotic hysterectomy, and a decrease in abdominal hysterectomy. The robotic hysterectomy approach, more recent procedure (year), and mid-sized hospital were factors that enabled outpatient hysterectomies; while abdominal hysterectomy, older age, Medicare insurance, black ethnicity, higher number of comorbidities, and concomitant procedures were associated with an inpatient setting. The shift towards outpatient hysterectomy led to a $2500 savings per case during the study period, in parallel to the increased robotic hysterectomy rates (p<0.001). The post-discharge 30-day readmission and complications rate after outpatient hysterectomy remained stable at around 2%. A significant shift from inpatient to outpatient setting was observed for hysterectomies performed for endometrial cancer over time. Minimally invasive surgery, particularly the robotic approach, facilitated this migration, preserving clinical outcomes and leading to reduction in costs.

Multi-center, international endometrial cancer consortium highlights

The multi-center, international consortium on endometrial cancer held in January 2025 at Mayo Clinic in Rochester, Minnesota brought together leading experts in gynecologic oncology to explore the latest advancements in the understanding, diagnosis, and treatment of endometrial cancer. Discussions centered on key topics, including updates in molecular testing and disease staging, emerging treatment strategies for advanced and recurrent disease, fertility-sparing management, and critical pathology challenges, particularly, the assessment of lympho-vascular space invasion. Each topic was examined in dedicated working group sessions, fostering in-depth exchanges to identify research priorities and develop actionable strategies. This summary highlights the central themes and insights from the meeting, outlining a roadmap for future advancements in the field. By promoting inter-disciplinary collaboration, the meeting laid the foundation for future research, policy recommendations, and clinical innovations aimed at improving patient outcomes.

Quality of Life and Adverse Events: Prognostic Relationships in Long-Term Ovarian Cancer Survival

Abstract Background There is a critical need to identify patient characteristics associated with long-term ovarian cancer survival. Methods Quality of life (QOL), measured by the Functional Assessment of Cancer Therapy-Ovarian-Trial Outcome Index (FACT-O-TOI), including physical, functional, and ovarian-specific subscales, was compared between long-term survivors (LTS) (8+ years) and short-term survivors (STS) (&amp;lt;5 years) of GOG 218 at baseline; before cycles 4, 7, 13, 21; and 6 months post-treatment using linear and longitudinal mixed models adjusted for covariates. Adverse events (AEs) were compared between survivor groups at each assessment using generalized linear models. All P values are 2-sided. Results QOL differed statistically significantly between STS (N = 1115) and LTS (N = 260) (P &amp;lt; .001). Baseline FACT-O-TOI and FACT-O-TOI change were independently associated with long-term survival (odds ratio = 1.05, 95% confidence interval = 1.03 to 1.06 and odds ratio = 1.06, 95% confidence interval = 1.05 to 1.07, respectively). A 7-point increase in baseline QOL was associated with a 38.0% increase in probability of LTS, and a 9-point increase in QOL change was associated with a 67.0% increase in odds for LTS. QOL decreased statistically significantly with increasing AE quartiles (cycle 4 quartiles: 0-5 vs 6-8 vs 9-11 vs ≥12 AEs, P = .01; cycle 21 quartiles: 0-2 vs 3 vs 4-5 vs ≥6 AEs, P = .001). Further, LTS reported statistically significantly better QOL compared with STS (P = .03 and P = .01, cycles 4 and 21, respectively), with similar findings across higher AE grades. Conclusions Baseline and longitudinal QOL change scores distinguished LTS vs STS and are robust prognosticators for long-term survival. Results have trial design and supportive care implications, providing meaningful prognostic value in this understudied population.

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

This study assessed oncologic outcomes of patients with intermediate-risk endometrioid endometrial cancer and isolated tumor cells (ITC) (≤0.2 mm or ≤200 cells) in sentinel lymph nodes (SLNs). Patients with SLN-ITC diagnosed between 2012 and 2019 were identified from 19 centers worldwide, while SLN-negative patients were identified at Mayo Clinic, Rochester between 2014 and 2018. Only patients with endometrioid endometrial cancer and intermediate-risk factors (low-grade endometrioid histology and myometrial invasion ≥50%; high-grade endometrioid histology and myometrial invasion <50%) were included. Oncologic outcomes were evaluated by grouping patients according to prognostic factors: SLN-ITC and lymphovascular space invasion (LVSI). SLN-ITC patients with post-operative observation or vaginal brachytherapy (VB) alone were compared with similar node-negative patients. Of the 166 patients included, those with simultaneous presence of SLN-ITC and LVSI were at higher risk of non-vaginal recurrence (HR 3.73 [95% CI 1.17 to 11.84], p = .01) compared with patients who were node-negative with no LVSI. Among the 122 patients (28 SLN-ITC, 94 node-negative) who underwent post-operative observation or VB alone, 1 isolated vaginal recurrence was documented in a node-negative patient, while non-vaginal recurrence occurred in 3 of 28 (10.7%) SLN-ITC and 7 of 94 (7.4%) node-negative patients. The median follow-up was 2.4 years (interquartile range; 1.8-3.0) among the remaining 25 ITC patients and 2.8 years (interquartile range; 0.8-4.2) among the remaining 87 node-negative patients. There was no difference in non-vaginal recurrence-free survival (SLN-ITC: 87.3% [95% CI 74.7% to 100.0%] vs node-negative: 82.2% [95% CI 69.1% to 97.9%], p = .46) or overall survival (SLN-ITC: 76.4% [95% CI 54.3 to 100.0] vs node-negative: 84.5% [95% CI 75.0 to 95.2], p = .28) between the 2 cohorts. In patients with endometrioid endometrial cancer and intermediate-risk factors (including patients who received chemotherapy/external beam radiotherapy), the combination of SLN-ITC and LVSI was associated with worse prognosis compared with patients with no risk factors or only 1 risk factor. In the sub-group of patients who received post-operative observation or VB alone, SLN-ITC did not worsen prognosis relative to node-negative patients.

Outcomes of low-risk endometrial cancer with isolated tumor cells in the sentinel lymph nodes: a prospective, multi-center, single-arm, observational study (ENDO-ITC study)

It is unclear whether isolated tumor cells (ITCs) in sentinel lymph nodes (SLNs) adversely affect prognosis, especially in low-risk endometrial cancer. In a retrospective study, we showed a worse recurrence-free survival for low-risk endometrial cancer with ITCs than the node-negative group. Our aim is to evaluate whether the likelihood of disease recurrence differs between a prospective cohort of patients with low-risk endometrial cancer with ITCs and an historical cohort with negative SLNs. We hypothesize that patients with low-risk endometrial cancer and ITCs will have a worse recurrence-free survival than patients who are node-negative. This is a prospective, multi-center, single-arm observational study. Consecutive patients with low-risk endometrial cancer with ITCs in the SLNs will be accrued. Observation only will be suggested after surgery. We will include patients with endometrial cancer undergoing pelvic SLN biopsy and ultra-staging with the following characteristics: endometrioid histology, grades 1 to 2, <50% myometrial invasion, without substantial/extensive lympho-vascular space invasion. ITCs in SLNs are defined as tumor cell aggregates ≤0.2 mm or <200 cells. The primary end point is recurrence-free survival, measured from the date of surgery to the date of recurrence, death, or last disease evaluation. With a sample size of 132 women with low-risk endometrial cancer and ITCs, a 1-sided log-rank test achieves 85% power at a 0.05 significance level to detect an HR of 2.1. The expected number of events during the study is 17.3. The study duration will be 60 months: 24 for enrollment and 36 for follow-up. The results are expected in 2029. ClinicalTrials.gov: NCT06689956.

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

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. 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. 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. 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.