High-intermediate Risk Patients Research Articles

Nodal staging in high and high-intermediate risk endometrial cancer surgery: Which role in the molecular classification era?

ObjectivesNodal staging contributes to risk group definition and the indication to adjuvant treatment in endometrial cancer (EC) patients. However, the role of nodal assessment evolved and requires redefinition.Primary outcome of the study was to assess the impact of surgical nodal staging in defining high-risk (HR) EC. Secondary outcome was to evaluate the contribution of nodal assessment to the decision for adjuvant treatment in both high-risk and high-intermediate risk (HIR) patients submitted to surgery. MethodsClinical stage I-II EC patients with postoperative diagnosis of HR and HIR disease were included. The contribution of nodal staging in prognostic groups allocation was assessed by reviewing HR patients to identify those without any other feature of such class (non-endometrioid histology, p53abn immunohistochemistry, post-operative T3-T4 disease) and HIR cases to assess how nodal staging affected adjuvant treatment indication. Descriptive statistics were conducted to describe the two populations. ResultsFifty-seven patients were included, 46 with HR and 11 with HIR disease. Chemotherapy and external-beam radiotherapy (EBRT) were proposed in 40 HR patients. Considering histology, immunohistochemical profile and FIGO stage, high risk classification was exclusively relied on nodal involvement in 2/46 cases (4.3 %). Omitting retroperitoneal staging, one of them would have been classified in the intermediate risk group and the other as HIR: without nodal staging, chemotherapy and EBRT would have been omitted in 1/40 (2.5 %) case.Among HIR patients, chemotherapy was proposed in 7/11 cases and EBRT in all cases. Adjuvant chemotherapy was indicated in 5/6 (83.3 %) and omitted in 1/6 (16.7 %) pN0 patient (stage Ib G2, substantial LVSI). In HIRpN0 patients, omitting nodal staging could have changed adjuvant treatment indication in 1/6 (16.7 %) case. In HIRpNx patients, adjuvant chemotherapy was omitted in one patient (stage II, grade 2 and LVSI negative): nodal staging unavailability might have changed indication to chemotherapy in 1/5 (20 %) case, without changing indication to EBRT.Unavailable nodal staging could globally be related to omission of chemotherapy in 2/57 (3.5 %) patients and of EBRT in 1/57 (1.8 %) patient. ConclusionsIn this series, nodal staging had limited impact on definition of HR class and on the choice of adjuvant treatment in HR and HIR EC patients.

Abstract 6416: Early stage endometrioid endometrial cancer recurrence risk stratification using a machine learning RNA-seq gene expression signature

Abstract Endometrioid endometrial cancer (EEC) adjuvant therapy decisions rely on risk stratification using histology, grade, stage, and lymphovascular space invasion (LVSI). Recently, molecular classification systems originating from TCGA, evaluated in GOG-210 and PORTEC-3 defined four prognostic subtypes based on POLE, MSI-H/MMR-D, and p53 alterations. Although valuable, this molecular approach still has significant limitations such as applicability to the majority of EEC patients categorized as no-specific molecular profile (NSMP) and the potential need to resolve pathogenic and prognostic heterogeneity within MMR-D, and TP53 subtypes. These unmet needs were key motivators for Tempus to develop a molecular classifier predicting distant recurrence risk in early-stage EEC with a focus on high intermediate-risk (HIR) patients. The RNA-seq-based gene expression profiler (GEP) was trained using a machine-learning pipeline with TCGA data which resulted in a 24 gene signature that classifies EEC patients as molecular risk (MR) high or low (MR-high, MR-low). The GEP MR test was then evaluated on a de-identified cohort of EEC patients (N=1037) from Tempus to test associations with known pathologic or molecular prognostic features. The GEP-MR risk predictor showed significant enrichment of MR high-risk in G3 versus G1/2 histology (p-value < 5e-8). A high correlation was found between the MR score and copy number alteration score (t-test p-value < 1e-5). Next, a clinical evaluation was performed in an early-stage EEC case-control cohort of patients with documented recurrence or no recurrence event at four years (N=109), from Stanford. In the entire cohort, the MR-high group had a significantly higher rate of distant recurrence in comparison to the MR-low group (HR=4.8, N=109). Next, we performed a subgroup analysis in the clinically important HIR patients. In this subgroup, the MR-high group had a significantly higher rate of distant recurrence in comparison to the MR-low group (HR=8.0, N=56). Lastly, given the significance of genomic biomarkers in the evolution of EEC FIGO staging, we stratified outcomes by the established TCGA subtypes as a reference standard and performed a subgroup analysis in patients classified as having no specific molecular profile (NSMP). Among patients who were NSMP, the MR-high group showed a significantly higher rate of distant recurrence in comparison to the MR-low group (HR=7.92, N=67). These evaluation studies demonstrate the performance of the GEP MR test in early-stage EEC distant recurrence risk stratification, specifically HIR patients, necessitating further studies to validate the test for clinical use in informing adjuvant clinical management. Citation Format: Rafi Pelossof, Talal Ahmed, Seung Won Hyun, Chithra Sangali, Ben Terdich, Calvin Chao, Michael Toboni, Casey Cosgrove, Elizabeth Kidd, Brook Howitt, Timothy Taxter. Early stage endometrioid endometrial cancer recurrence risk stratification using a machine learning RNA-seq gene expression signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6416.

Treatment outcomes of early-stage endometrial cancer patients: A propensity score matching of vaginal brachytherapy versus pelvic radiotherapy.

This study aimed to report the treatment outcomes of radiation therapy for early-stage endometrial cancer patients. In addition, this study intended to identify high-risk factors that require pelvic radiotherapy (PRT) in addition to vaginal brachytherapy (VBT) for intermediate-risk endometrial cancer patients. Patients with early-stage endometrial cancer receiving postoperative VBT alone or with PRT were included. Propensity score matching was used to balance the two study groups. The primary endpoint was locoregional recurrence (LRR). Age-adjusted Charlson comorbidity index and substantial lymphovascular space invasion were selected for subgroup analyses to identify the benefits of PRT over VBT alone. From 2005 to 2017, a total of 288 patients underwent analysis following propensity score matching. Of these, 144 received VBT and 144 received PRT. There was no significant difference in 5-year LRR between VBT and PRT for both intermediate (0% vs. 0%) and high-intermediate risk patients (3.5% VBT vs. 5.4% PRT; HR 0.54: 0.05-6.00; p = 0.616). The subgroup analyses revealed no significant factors favoring PRT over VBT. Patients with high comorbidities may have higher risks of non-cancer death after receiving PRT. Postoperative VBT alone is sufficient for early-stage intermediate-risk endometrial cancer patients.

Prognostic significance of positive peritoneal cytology in endometrial carcinoma based on ESGO/ESTRO/ESP risk classification: A multicenter retrospective study

ObjectiveThis study aimed to determine the prognostic significance of positive peritoneal cytology (PC) on endometrial carcinoma (EC) patients under the ESGO/ESTRO/ESP risk classification. MethodsThis study retrospectively analyzed EC patients from 27 medical centers in China from 2000 to 2019. Patients were divided into three ESGO risk groups: low-risk, intermediate-risk and high-intermediate risk, and high-risk groups. The covariates were balanced by using the propensity score-based inverse probability of treatment weighting (PS-IPTW). The prognostic significance of PC was assessed by Kaplan-Meier curves and multivariate Cox regression analysis. ResultsA total of 6313 EC patients with PC results were included and positive PC was reported in 384 women (6.1%). The multivariate Cox analysis in all patients showed the positive PC was significantly associated with decreased PFS (hazard ratio [HR] 2.20, 95% confidence interval [CI] 1.55–3.13, P < 0.001) and OS (HR 2.25, 95% CI 1.49–3.40, P < 0.001),and the Kaplan-Meier curves also showed a poor survival in the intermediate and high-intermediate risk group (5-year PFS: 75.5% vs. 93.0%, P < 0.001; 5-year OS: 78.3% vs. 96.4%, P < 0.001); While in the low-risk group, there were no significant differences in PFS and OS between different PC status (5-year PFS: 93.1% vs. 97.3%, P = 0.124; 5-year OS: 98.6% vs. 98.2%, P = 0.823); in the high-risk group, significant difference was only found in PFS (5-year PFS: 62.5% vs. 77.9%, P = 0.033). ConclusionPositive PC was an adverse prognostic factor for EC, especially in the intermediate and high-intermediate risk patients. Gynecologic oncologists should reconsider the effect of positive PC on different ESGO risk groups.

It is not the time to abandon intraoperative frozen section in endometrioid adenocarcinoma: A large-scale, multi-center, and retrospective study.

Stage IB (deep myometrial invasion) high-grade endometrioid adenocarcinoma (EA), regardless of LVSI status, is classified into high-intermediate risk groups, requiring surgical lymph node staging. Intraoperative frozen section (IFS) is commonly used, but its adequacy and reliability vary between reports. Hence, we determined the utility of IFS in identification of high-risk factors, including deep myometrial invasion and high-grade. We retrospectively analyzed 9,985 cases operated with hysterectomy and diagnosed with FIGO stage I/II EA in postoperative paraffin section (PS) results at 30 Chinese hospitals from 2000 to 2019. We determined diagnostic performance of IFS and investigated whether the addition of IFS to preoperative biopsy and imaging could improve identification of high-risk factors. IFS and postoperative PS presented the highest concordance in assessing deep myometrial invasion (Kappa: 0.834), followed by intraoperative gross examination (IGE Kappa: 0.643), MRI (Kappa: 0.395), and CT (Kappa: 0.207). IFS and postoperative PS presented the highest concordance for high-grade EA (Kappa: 0.585) compared to diagnostic curettage (D&C 0.226) and hysteroscope (Hys 0.180). Sensitivity and specificity for detecting deep myometrial invasion were 86.21 and 97.20% for IFS versus 51.72 and 88.81% for MRI, 68.97 and 94.41% for IGE. These figures for detecting high-grade EA were 58.21 and 96.50% for IFS versus 16.42 and 98.83% for D&C, 13.43 and 98.64% for Hys. Parallel strategies, including MRI-IFS (Kappa: 0.626), D&C-IFS (Kappa: 0.595), and Hys-IFS (Kappa: 0.578) improved the diagnostic efficiencies of individual preoperative examinations. Based on the high sensitivity of IFS, parallel strategies improved the sensitivities of preoperative examinations to 89.66% (MRI), 64.18% (D&C), 62.69% (Hys), respectively, and these differences were statistically significant (p=0.000). IFS presented reasonable agreement rates predicting postoperative PS results, including deep myometrial invasion and high-grade. IFS helps identify high-intermediate risk patients in preoperative biopsy and MRI and guides intraoperative lymphadenectomy decisions in EA.

Prognostic Impact of Mismatch Repair Deficiency in High- and Low-Intermediate Risk, Early-Stage Endometrial Cancer Following Vaginal Brachytherapy

Mismatch repair deficiency (dMMR) is found in approximately 25% of endometrial cancers (EC), yet it remains unknown how this information should be incorporated into adjuvant treatment paradigms. Ongoing trials are investigating the potential use of immunotherapy in conjunction with radiotherapy for the adjuvant treatment of dMMR patients with high-intermediate risk (HIR) features. We hypothesized that dMMR status is associated with higher rates of recurrence in both low-intermediate risk (LIR) and HIR subgroups. We examined the impact of dMMR status on prognosis among patients with early-stage endometrioid EC treated with vaginal brachytherapy (VB).We performed a retrospective review of 198 patients who were treated with adjuvant VB for FIGO stage I or II endometrioid EC and had known MMR status. Both LIR and HIR patients (per GOG 249 criteria) were included. Patients with non-endometrioid and mixed histologies and patients treated with pelvic radiotherapy were excluded. Patient, tumor, and treatment characteristics were compared between patients with proficient mismatch repair (pMMR) and dMMR using c2 tests for categorical variables and t-tests for continuous variables. Recurrence free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards regression.Patients with dMMR compared to pMMR were more likely to have grade 2-3 tumors (75% vs. 57%, P = 0.012), lympho-vascular invasion (40% vs. 25%, P = 0.023), and HIR classification (65% vs. 49%, P = 0.038). There were no other differences in clinicopathologic or treatment characteristics. Median follow-up time for dMMR and pMMR patients was 37.5 and 37 months, respectively. Three-year RFS was inferior for dMMR compared to pMMR patients (75% vs. 96%, P = 0.001). dMMR patients compared to pMMR had similarly reduced 3-year RFS both within the LIR (74% vs. 100%, P = 0.026) and HIR (75% vs. 91%, P = 0.038) subgroups. Three-year OS was excellent across all categories and was not different between dMMR/pMMR patients (98% vs. 97%, P = 0.653) or HIR/LIR patients (97% vs. 97%, P = 0.999). On multivariable Cox regression, dMMR status was the only significant prognostic variable for RFS (HR 3.774, CI 1.495-9.526, P = 0.005), though it was not significant for OS. While failures were more likely in the dMMR cohort, salvage rates were high, and treatment included surgery (29.4%), pelvic RT (41.2%), chemotherapy (70.6%), and immunotherapy (47.1%).Following VB, patients with dMMR have poorer RFS compared to pMMR patients regardless of HIR/LIR risk classification. Increased monitoring for early salvage intervention and/or expansion of eligibility to clinical trials incorporating immune checkpoint inhibitors should be considered for both HIR and LIR patients with dMMR.

Efficacy of sentinel lymph node mapping in endometrial cancer with low‐ or high‐intermediate risk

This study was aimed to evaluate the efficacy of sentinel lymph node (SLN) mapping using indocyanine green (ICG) in Chinese women with endometrial cancer (EC). Consecutive EC patients undergoing SLN mapping at Obstetrics and Gynecology Hospital of Fudan University were retrospectively reviewed. Overall and bilateral SLN detection rates and SLN locations were presented. Sensitivity, negative predictive value (NPV), and agreement rate were calculated and were compared between patients with low-intermediate (LIR) or high-intermediate risk (HIR). There were 454 patients screened, with SLN mapping with ICG performed in 428 patients and systematic lymphadenectomy performed in 159 patients. Overall and bilateral SLN detection rates were 96.50% and 82.71%, respectively. The sensitivity of SLN mapping was 80.00%, and the NPV was 97.76%. SLNs were most commonly located in obturator and external iliac regions. Efficacy of SLN mapping was higher in LIR patients than in HIR patients, with sensitivities of 100.00% and 75.00% (p > 0.05), NPVs of 100.00% and 90.00% (p = 0.002), and agreement rates of 100.00% and 92.31% (p = 0.007), respectively. SLN mapping with ICG had acceptable diagnostic efficacy in Chinese women with EC, but may cause more missed diagnoses in patients with HIR due to relatively low NPV and agreement rate.

Effect of surgical approach on risk of recurrence after vaginal brachytherapy in early-stage high-intermediate risk endometrial cancer

Objectives: The objective was to determine if surgical approach affects time to recurrence in early-stage high-intermediate risk endometrial cancer (HIR-EC) treated with adjuvant vaginal brachytherapy (VBT). Methods: In this retrospective cohort study, HIR-EC patients treated with VBT between 2005-2017 were identified and those who received open or minimally invasive hysterectomies (MIS) were included. Clinical and surgical variables were analyzed and time to recurrence was compared between surgical groups. Results: We identified 494 patients, of which 363 had MIS hysterectomies, 92.5% had endometrioid histology, 45.7% were stage IA and 48.0% stage IB. Open hysterectomy patients had higher BMIs (p=0.007), lower rates of lymph node sampling (p<0.001) and lymphovascular space invasion (LVSI) (p=0.036), however in patients who recurred, no differences were noted between groups. Overall, 65 patients (13.2%) recurred, 14 in the open group (10.7%) and 51 in the MIS group (14.0%) (p=0.58), while vaginal recurrences were noted in 4.6% and 6.1% respectively. When compared to the open group, the MIS group had a significantly shorter time to any recurrence (p=0.022), to pelvic (p=0.05) and locoregional recurrence (p=0.021) and to death from any cause (p=0.039). After adjusting for age, BMI, grade, LVSI and surgery date, the MIS group had a higher risk of any recurrence (HR 2.29 (1.07-4.92), p=0.034) and locoregional recurrence (HR 4.18 (1.44-12.1), p=0.008). Conclusions: Patients with HIR-EC treated with VBT after MIS hysterectomy have a shorter time to recurrence and higher risk of recurrence when compared to open hysterectomy patients. Further studies into the safety of MIS in high-intermediate risk patients are required. The objective was to determine if surgical approach affects time to recurrence in early-stage high-intermediate risk endometrial cancer (HIR-EC) treated with adjuvant vaginal brachytherapy (VBT). In this retrospective cohort study, HIR-EC patients treated with VBT between 2005-2017 were identified and those who received open or minimally invasive hysterectomies (MIS) were included. Clinical and surgical variables were analyzed and time to recurrence was compared between surgical groups. We identified 494 patients, of which 363 had MIS hysterectomies, 92.5% had endometrioid histology, 45.7% were stage IA and 48.0% stage IB. Open hysterectomy patients had higher BMIs (p=0.007), lower rates of lymph node sampling (p<0.001) and lymphovascular space invasion (LVSI) (p=0.036), however in patients who recurred, no differences were noted between groups. Overall, 65 patients (13.2%) recurred, 14 in the open group (10.7%) and 51 in the MIS group (14.0%) (p=0.58), while vaginal recurrences were noted in 4.6% and 6.1% respectively. When compared to the open group, the MIS group had a significantly shorter time to any recurrence (p=0.022), to pelvic (p=0.05) and locoregional recurrence (p=0.021) and to death from any cause (p=0.039). After adjusting for age, BMI, grade, LVSI and surgery date, the MIS group had a higher risk of any recurrence (HR 2.29 (1.07-4.92), p=0.034) and locoregional recurrence (HR 4.18 (1.44-12.1), p=0.008). Patients with HIR-EC treated with VBT after MIS hysterectomy have a shorter time to recurrence and higher risk of recurrence when compared to open hysterectomy patients. Further studies into the safety of MIS in high-intermediate risk patients are required.

Not all high-intermediate risk endometrial cancers are created equal: recurrence-free survival and cause-specific survival after observation or vaginal brachytherapy in all possible subgroups of early-stage high-intermediate risk endometrial cancer

<h3>Objectives:</h3> Historically, patients with early-stage high-intermediate risk (HIR) endometrioid endometrial cancer (EC) have been known to benefit from improved recurrence-free survival (RFS) with the use of adjuvant therapy. However, specific subgroups of HIR patients may benefit from observation ± vaginal brachytherapy (VB) only. We sought to evaluate RFS and cause-specific survival (CSS) after observation ± VB in the subgroups of early-stage HIR endometrioid EC. <h3>Methods:</h3> We identified patients with early-stage HIR endometrioid EC, who underwent a total hysterectomy, bilateral salpingo-oopho-rectomy, and sentinel lymph node biopsy or pelvic ± paraaortic lymphadenectomy at Mayo Clinic and Cleveland Clinic between 1999 and 2016. HIR group was defined based on revised GOG99 criteria used in the GOG249 trial: age ≥70 with 1 risk factor, age ≥50 with 2 risk factors, or all the 3 risk factors (grade 2-3, ≥50% myometrial invasion, or positive lymphovascular space invasion [LVSI]). HIR subgroups were determined by all possible combinations of risk factors, and 3-year RFS, site-specific RFS, and CSS were estimated. <h3>Results:</h3> Among 1,507 women with stage I or II EC, 447 stage I endometrioid EC patients were identified who fulfilled HIR criteria, and 349 (78.1%) were managed with observation ± VB. Eleven subgroups were defined and evaluated (Table). Among stage IA patients (1-5 subgroups), subgroup 5 (G3 ≥50y LVSI+) had the lowest RFS and CSS of 68.9% (46.6-100.0%) and 86.7% (71.1-100.0%), respectively, whereas the remaining 4 subgroups had 3-year RFS and CSS >90%. In all stage IA subgroups, 3-year lymphatic RFS was >90%; 3-year distant RFS was lowest in subgroup 5 (79.6% [56.9-100.0%] and 97.1% [91.8-100.0%] in subgroup 3 [G2 ≥50y LVSI+]). Additionally, 3-year CSS was <100% in these two subgroups (vs. 100% in subgroups 1, 2, and 4). Among the 6 stage IB subgroups (6-11), 3-year RFS ranged from 68.2% (48.6-95.7%) to 93.6% (87.7-99.9%) and 3-year CSS from 80.0% (58.7-100.0%) to 100.0% (100.0-100.0%). Lymphatic recurrence was observed in subgroup 8 (IB G2 ≥50y LVSI -), but site-specific RFS was >90%. Conversely, all stage IB subgroups experienced distant recurrence; 3-year distant RFS ranged from 73.1% (53.5-99.7%) to 96.5% (91.8-100.0%). 3-year distant RFS lower than 90% was observed in those subgroups with grade 3 or positive LVSI (7, 9, 10, and 11). <h3>Conclusions:</h3> Our results suggest that observation ± VB can be sufficient in some subgroups of stage I endometrioid HIR patients, specifically stage IA endometrioid HIR EC without the concomitant presence of grade 3 and LVSI. Among stage IB endometrioid HIR EC subgroups, particularly those with grade 3 or LVSI, observation ± VB is associated with lower RFS and CSS. Stratifying HIR patients into risk subgroups would alleviate the risk of overtreatment and undertreatment among patients with early-stage endometrioid EC; in this regard, the molecular characterization will provide a further instrument to achieve this objective.

Outcomes of sentinel lymph node mapping for patients with FIGO stage I endometrioid endometrial carcinoma

ObjectiveInvestigate the overall survival of patients with FIGO stage I endometrioid endometrial carcinoma who underwent sentinel lymph node biopsy (SLNBx). MethodsPatients diagnosed between 2012 and 2015 with pathological stage I endometrioid endometrial carcinoma who underwent minimally invasive hysterectomy and had at least one month of follow-up were identified in the National Cancer Database (NCDB). Patients who underwent SLNBx or systematic lymphadenectomy (LND) (defined as at least 20 lymph nodes removed) were selected. Overall survival (OS) was evaluated following generation of Kaplan-Meier curves and compared with the log-rank test. A Cox model was constructed to evaluate survival after controlling for confounders. ResultsA total of 13,010 patients with endometrioid endometrial carcinoma who met the inclusion criteria were identified; 9861 (75.8%) and 3149 (24.2%) patients had systematic LND and SLNBx, respectively. Patients who had LND were more likely to receive radiation therapy (27.4% vs 19.3%, p < 0.001) and chemotherapy (13% vs 8.7%, p < 0.001) compared to those who had SLNBx. After controlling for patient age, race, insurance status, depth of myometrial invasion, tumor grade, tumor size, presence of lymph-vascular invasion and receipt of radiation therapy, the performance of SLNBx was not associated with worse survival (HR: 0.99, 95% CI: 0.80, 1.21). For high-intermediate risk patients (based on GOG-99 criteria) after controlling for confounders, performance of SLNBx was not associated with worse survival (HR: 1.07, 95% CI: 0.80, 1.44). For intermediate risk patients who did not receive external beam radiation therapy or chemotherapy after controlling for confounders, performance of SLNBx was not associated with worse survival (HR: 1.58, 95% CI: 0.94, 2.65). ConclusionsSLNBx had no negative impact on the survival of patients with FIGO stage I endometrioid endometrial carcinoma who undergo hysterectomy.

Phase II trial of vaginal cuff brachytherapy followed by dose-dense chemotherapy in early stage endometrial cancer patients with enriched, high-intermediate risk factors for recurrence

ObjectiveTo determine the feasibility of vaginal cuff brachytherapy (VCB) followed by 3 cycles of dose dense paclitaxel and carboplatin chemotherapy (ddTC) in enriched, high-intermediate risk (H-IR) patients with early stage endometrial cancer following hysterectomy. MethodsA phase II trial of early stage endometrial cancer patients treated with VCB (2100 cGy) followed by three cycles of carboplatin (AUC 6) and dose dense paclitaxel (80 mg/m2) weekly within 12-weeks of surgery was conducted. The primary endpoint was the proportion of patients completing both VCB and ddTC. Secondary outcomes include short and long-term toxicities, recurrence rate and sites, and progression free survival. Toxicity assessments were patient reported as well as those resulting in delays or dose modifications. ResultsA total of 32 evaluable patients with median age of 64.5 years were included. Most patients were endometrioid histology (18/32, 56.3%) and fully staged (21/32, 65.6%) to stage Ib (18/32, 56.3%). In total, 27/32 (84.4%) patients completed treatment per protocol. Protocol non-completion included renal insufficiency, paclitaxel reaction, and treatment refusal. Median time to VCB completion was 11 days with all patients completing three fractions of VCB. Acute toxicities with VCB included grade 1 and 2 gastrointestinal, genitourinary and fatigue symptoms. Acute toxicities associated with ddTC included infusion reaction and neutropenia. Most reported long-term toxicities were grade 1 or 2 and resolved with time. ConclusionsTreatment with VCB followed by three cycles of ddTC is well-tolerated with promising utility for treatment in enriched high-intermediate risk endometrial cancer patients. Recurrence-free and overall survival outcomes are not yet mature.

Effect of surgical approach on risk of recurrence after vaginal brachytherapy in early-stage high-intermediate risk endometrial cancer

ObjectiveThe objective was to determine if surgical approach affects time to recurrence in early-stage high-intermediate risk endometrial cancer (HIR-EC) treated with adjuvant vaginal brachytherapy (VBT). MethodsIn this retrospective cohort study, HIR-EC patients treated with VBT between 2005 and 2017 were identified and those who received open or minimally invasive hysterectomies (MIS) were included. Clinical and surgical variables were analyzed and time to recurrence was compared between surgical groups. ResultsWe identified 494 patients, of which 363 had MIS hysterectomies, 92.5% had endometrioid histology, 45.7% were stage IA and 48.0% stage IB. Open hysterectomy patients had higher BMIs (p = 0.007), lower rates of lymph node sampling (p < 0.001) and lymphovascular space invasion (LVSI) (p = 0.036), however in patients who recurred, no differences were noted between groups. Overall, 65 patients (13.2%) recurred, 14 in the open group (10.7%) and 51 in the MIS group (14.0%) (p = 0.58), while vaginal recurrences were noted in 4.6% and 6.1% respectively. When compared to the open group, the MIS group had a significantly shorter time to any recurrence (p = 0.022), to pelvic (p = 0.05) and locoregional recurrence (p = 0.021) and to death from any cause (p = 0.039). After adjusting for age, BMI, grade, LVSI and surgery date, the MIS group had a higher risk of any recurrence (HR 2.29 (1.07–4.92), p = 0.034) and locoregional recurrence (HR 4.18 (1.44–12.1), p = 0.008). ConclusionsPatients with HIR-EC treated with VBT after MIS hysterectomy have a shorter time to recurrence and higher risk of recurrence when compared to open hysterectomy patients. Further studies into the safety of MIS in high-intermediate risk patients are required.

OUTCOMES SUTURELESS AORTIC VALVE REPLACEMENT VERSUS CONVENTIONAL AORTIC VALVE REPLACEMENT AND TRANSCATHETER AORTIC VALVE REPLACEMENT: A SYSTEMATIC REVIEW AND META-ANALYSIS

Sutureless aortic valve replacement (SuaVR) is a feasible alternative to conventional aortic replacement (SAVR) and transcatheter aortic valve replacement (TAVR). The aim of this study is to compare the effectiveness of the SuAVR versus SAVR, and SuAVR versus TAVR. We searched MEDLINE and EMBASE from inception to August 2018 for adjusted observational studies evaluating SuAVR, SAVR, and TAVR in adult patients with aortic stenosis. Independently and in duplicate, we performed screening, full-text assessment, risk of bias evaluation using the CLARITY tool. We pooled data using a random-effects model. We evaluated the quality of evidence using the GRADE framework. Of the references, 34 studies including 7979 participants (SuAVR versus SAVR= 6831; SuAVR versus TAVR= 1148) conducted between 2012 and 2018 were included. Overall, studies were judged to be at unclear risk of bias. Compared to SAVR and TAVR, SuAVR was associated with similar postoperative mean transvalvular gradients (mean difference]MD [: –1.00; 95% CI, -2.76 to 0.76; P=0.27) and (MD: 0.50; 95% CI, 0.27 to 1.28; P=0.20) respectively. Compared to TAVR, SuAVR showed a reduction in mortality at 30 days (odds ratio (OR): 0.36; 95% CI, 0.17 to 0.73; P=0.005) and 2 years (OR: 0.39, 95 CI, 0.17 to 0.88; P=0.003). Reduction in mortality did not reach statistical significance in high risk (OR:0.16, 95% CI, 0.02 to 1.35; P=0.09) or intermediate risk patients (OR: 0.76, 95% CI, 0.32 to 1.82, P=0.54). Compared to TAVR, SuAVR showed reduction in mild (OR: 0.09, 95% CI, 0.03 to 0.26, P=0.000) and moderate paravalvular leaks (OR: 0.11, 95% CI, 0.02 to 0.61, P=0.01). Moreover, SuAVR showed significant reduction in acute kidney injury compared to TAVR (OR: 0.50, 95 % CI, 0.27 to 0.91, P=0.02) and comparable reduction to SAVR (OR: 0.89, 95% CI, 0.45 to 1.76, P=0.47). Compared to SAVR, SuAVR showed a similar reduction in mortality at 30 days (OR: 1.01, 95 % CI, 0.72 to 1.42, P=0.93) and at 2 years (OR: 0.99, 95 % CI, 0.43 to 2.30, P= 0.30). These results were rated low-quality evidence using the GRADE framework. While the use of sutureless aortic valves is increasing with similar short and midterm outcomes compared to TAVR and SAVR, the quality of evidence supporting its utilization is low, even with matched patients. Comparative randomized data with long-term follow up is required to elucidate the role of SuAVR.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Clinical Practice Pattern Of Adjuvant Vaginal Brachytherapy In Early-stage Endometrial Carcinoma According To ESMO-ESGO-ESTRO Risk Classification: Long-term updated Data From A Multi-institutional Analysis In China

To evaluate the clinical practice pattern of adjuvant vaginal brachytherapy (VBT) in early-stage endometrial carcinoma (EC) according to ESMO-ESGO-ESTRO risk classification in China from long-term updated data of a multi-institutional analysis. We retrospectively evaluated clinical data of patients with early-stage EC at 13 institutions in China between 2000 and 2015. Eligibility requirements included the primary hysterectomy/bilateral salpingo-oophorectomy and adjuvant radiotherapy, stage I and II disease (FIGO 2009 staging), and complete clinicopathologic and follow-up information. All patients were divided into low-risk (LR), intermediate-risk (IR), high-intermediate risk (HIR) and high-risk (HR) groups according to ESMO-ESGO-ESTRO risk classification. We evaluated clinical practice pattern and tendency of VBT in different risk groups during various periods. Proportions were compared by using the Chi square test for values of 5 or higher and with Fisher’s exact test for values of less than 5. All data were examined using statistical analysis software. A total of 1268 early-stage patients were reviewed and 1108 cases with intact data were included in the analysis. The median follow-up time was 53 months (range 6–207 months). The median age was 56 years (range 23–86 years). Stage Ia/b disease represented 86.0% of the cohort, HR patients 22.9%, HIR patients 20.0%, IR patients 29.2%. Patients received VBT alone (43.2%, n = 479), EBRT alone (14.3%, n = 158), EBRT+VBT (42.5%, n = 471), and chemotherapy (22.9%, n = 235). In HR and HIR groups, the proportion of VBT alone increased 33.3% (0 vs. 33.3%) and the proportion of VBT boost after EBRT decreased 10.5% (61.3% vs. 50.8%) from 2000 to 2015. In IR and LR groups, VBT alone increased 61.7% (4.7% vs. 66.4%) and VBT boost decreased 29.4% (51.6% vs. 22.2%) in the corresponding period. All institutions commonly use High-dose-rate(HDR) VBT. The commonly used applicators include the multichannel vaginal cylinder (77.7%), single channel vaginal cylinder (16.7%) and ovoids (5.6%). A fixed 3-4cm length of the proximal vagina was reported by 62.9%, a proximal 1/3-1/2 length of the vagina by 36.2%, and Entire vagina by 0.8%. Specify dose: 77.7% specify to 0.5-cm depth from the vaginal surface, and 22.3% specify elsewhere. There were 11 and 13 different dose-fractionation schedules for VBT alone and VBT boost, respectively. The most common fractionation for VBT alone and VBT boost is 5 Gy for six fractions and 5 Gy for two fractions, both to 0.5-cm depth. Our study provides an assessment of clinical practice pattern for adjuvant VBT management of early-stage EC in China. Historical data demonstrate that the clinical practice of adjuvant VBT alone increased significantly in different risk classification groups over the past 15 years, especially in IR to HR groups.

Lymph node dissection in endometrial cancer and clinical outcome: A population-based study in 5546 patients

BackgroundAccording to current treatment guidelines, comprehensive surgical staging procedures in endometrial cancer confined to the uterus depend on uterine risk factors: a systematic lymph node dissection (LND) is recommended in high risk patients and should be omitted in low risk patients. Its role in intermediate and high intermediate risk patients is inconclusive. The aim of this analysis was to review the implementation of this risk-adopted strategy. Materials and methodsData were provided by the population-based Munich Cancer Registry. Patients with endometrial cancer diagnosed between 1998 and 2016 were included. ResultsOf 5446 eligible patients, 58.5%, 30.1% and 11.4% belonged to the low risk, intermediate/high-intermediate and high risk group, respectively. Lymph node dissection was performed in 20.2%, 53.0% and 63.7% within these groups. Lymph node involvement was diagnosed in 1.7%, 9.6% and 19.3%, respectively. Within these risk groups, there was no significant difference in the time to local recurrence, lymph node recurrence or distant metastases between patients with and without LND. After adjusting for age and comorbidity-status, no significant difference in overall survival was found. ConclusionsThe application of a risk-adopted management of LND in early endometrial cancer in real-life is associated with a high rate of surgical under- and overtreatment. Corresponding survival data do not show a significant benefit of a systematic lymph node dissection. In order to improve the management and outcome of early endometrial cancer in the future, prospective trials, new surgical concepts and prognostic markers will be primary and necessary.

Prognostic value of echocardiographic parameters for right ventricular function in patients with acute non-massive pulmonary embolism.

A prognostic value of right ventricular (RV) systolic function assessed by echocardiography in patients with acute non-massive pulmonary embolism (PE) remains controversial. The hypothesis was RV free wall strain measured using speckle-tracking echocardiography might be a powerful prognostic factor in those patients. We aimed to evaluate the prognostic value of echocardiographic measurements of RV systolic function for clinical outcomes and to assess the correlation between the echocardiographic RV function parameters in patients with acute non-massive PE. Between November 2013 and September 2016, 144 consecutive patients diagnosed as acute non-massive pulmonary embolism were prospectively enrolled and echocardiographic evaluations were performed within 1week of diagnosis to measure various parameters of RV systolic function. The primary endpoint was in-hospital events, the composite of in-hospital PE-related death, need of additive treatments such as thrombolysis or pulmonary artery thromboembolectomy, and need of inotropics due to unstable vital sign. Among patients (mean age 60.3 ± 14.7years, 50% female) with acute non-massive PE, the in-hospital event rate was 11.1% (16 of 144 patients). In multivariate logistic regression analysis, after adjustment of confounding factors such as age, gender, and diabetes mellitus, RV free wall strain [odd ratio (OR) 1.12, 95% confidence interval (CI) 1.04-1.21, p = 0.002] and RV global wall strain (OR 1.20, 95% CI 1.07-1.35, p = 0.002) were independent predictors for in-hospital events. The event rates were significantly different between groups classified based on RV free wall strain with cut-off value of -15.85% (p < 0.001). RV strain assessed with speckle-tracking echocardiography is an independent prognostic marker for in-hospital events in patients with acute non-massive PE. Our results may help identify high-intermediate risk patients who need a closer monitoring.

Clinical audit to determine efficacy of daily infusion of low dose of 20% albumin in combination with antibiotics in patients with spontaneous bacterial peritonitis.

Aim of the studyThe recommended high dose albumin treatment for spontaneous bacterial peritonitis (SBP) is not possible in the Indian setting due to financial constraints. Aim of the study was the retrospective audit to determine the outcome of patients with SBP on combination treatment of low dose albumin and appropriate antibiotics.Material and methodsPatients undergoing abdominal paracentesis in the period 2016-2018 were included. Patient details including age, gender, co-morbidity profile, details of previous hospitalisation and antibiotics, MELD score, and ascitic fluid analysis were noted. Details of albumin use and antibiotics were retrieved. SBP was classified based on mode of acquisition of infection and severity risk based on laboratory parameters. Statistics – χ2 test, Mann-Whitney U test, relative risk calculation. A p value of < 0.05 was considered as significant.Results24 (18.8%), 38 (29.7%) and 66 patients (51.5%) belonged to low, intermediate and high risk SBP groups, respectively. The median dose of albumin was 20 g/day for a median duration of 5 days (range 1-8). Between the 3 subgroups, there was no significant difference in the median age; the majority were men. Antibiotic escalation was necessary in intermediate and high risk cases (42.1% vs. 84.8%, p < 0.0001). The mortality rate in intermediate and high risk groups was 29% and 42%, respectively (p = 0.18). Between the 2 subgroups of intermediate risk, patients with serum bilirubin < 4 mg/dl and serum creatinine > 1 mg/dl were significantly older (54 vs. 49 years, p = 0.02), and had high mortality (40.7% vs. 0%). Cirrhosis-related complications (CRC; one or more in combinations) were more frequent in high risk and intermediate risk patients (p = 0.001) with a 7-8 times higher risk of mortality compared to those who had no CRC.ConclusionsOur protocol is associated with high mortality in intermediate and high risk SBP patients. Presence of one or more CRC increases the risk of mortality several fold.

Toxicity and Clinical Outcomes in Patients with Uterine Cancer Treated with Adjuvant Intensity Modulated Radiation Therapy and Vaginal Brachytherapy (IMRT+VB) “Sandwiched” between Combination Paclitaxel and Carboplatin

The IMRT technique for uterine cancer helps to lower dose to organs at risk, especially the bone marrow. PORTEC-2 also showed comparable outcomes of VB alone compared to external pelvic RT for high-intermediate risk patients. Few reports examine the combination of IMRT+VB, especially in the setting of chemotherapy for advanced patients. Here, we look at the long-term effects of adjuvant IMRT+VB “sandwiched” between carboplatin and paclitaxel chemotherapy (C-T Cx). We reviewed 206 patients treated with adjuvant IMRT+VB and sandwich chemotherapy for Stage I-III uterine cancer from 2009 - 2016. Patients were surgically staged with no visible residual disease. Chemotherapy regimen involved C-T Cx every 21 days for 3 cycles, followed by IMRT+VB, followed by 3 additional cycles of C-T Cx. Patients were to have received at least one cycle post-RT to be included. Toxicities were graded with CTCAE, version 4.03. Rates for local control (LC), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS) were examined using Kaplan-Meier survival curves. Median age and follow-up was 70 years (range: 36-94) and 39 months (range: 6.23-110.1 months), respectively. Ethnicity distribution was 48% African-American, 31% Hispanic, 17% White, 4% Asian, and 1% other. Histological type revealed 42% EAC, 40% UPSC, and 18% CS. FIGO stage distribution: IA-30%, IB-15%, II-16%, IIIA-7%, IIIB-15%, IIIC1-18%, and IIIC2-12%. Grade distribution: 1 – 9.7%, 2 – 8.7 %, 3 – 80.6%. LVSI was present in 51.5% of patients. Twenty-four (12%) patients underwent extended-field IMRT. Acute grade 2 and 3 GI toxicity was present in 17 (8.3%) and 4 (1.9%) patients, respectively. Two (1.0%) patients had acute grade 2, but none had grade ≥3 GU toxicity. Acute grade ≥3 neutropenia, anemia, and thrombocytopenia were present in 33.5%, 10.7%, and 11.7%, respectively. Late grade 2 and 3 GI toxicity was in 8 (3.9%) and 7 (3.4%) patients, respectively, including one with a colovesicular fistula. Five (2.4%) had late grade 2 but none had grade ≥3 GU toxicity. A large portion (21.4%) had grade 1 vaginal stenosis (VS), followed by grades 2 (9.2%) and 3 (1.0%). Stages I-II and III had similar five-year rate of LC (95.2% vs. 91.4%; logrank p=0.94) but significantly different DM rate (22.0% vs 49.6%; logrank p=0.002). Stages I-II and III had significantly different DFS (76.7% vs. 48.9%; logrank p=0.0012) but similar OS (86.0% vs. 85.7%; logrank p=0.79). Compared to EAC, CS was significantly more likely to have worse OS (HR: 7.65, 95% CI 1.53-38.4; p=0.013), DFS (HR: 3.83, 95% CI 1.80-8.15; p=0.0005), and DM rate (HR: 4.27, 95% CI 1.96-9.30; p=0.0003). Although not statistically significant, UPSC trended towards inferior OS (p=0.09) compared to EAC. This study represents the largest cohort of uterine cancer patients receiving adjuvant IMRT+VB “sandwiched” between chemotherapy. Patients have good long-term clinical outcomes and a low toxicity profile.

Addition of Rituximab to CHOP-like Chemotherapy Improves Survival in Patients with Primary Mediastinal B-Cell Lymphoma Independent of IPI Risk Category

IntroductionThe optimal management of primary mediastinal B-cell lymphoma (PMBCL) is not fully established. The addition of rituximab (R) to CHOP-like (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone) induction therapy has improved survival in PMBCL patients. However, these results were obtained in young preselected patients with a favorable prognosis and a reevaluation in unselected patient cohort is warranted.MethodsIn the current study we retrospectively analyzed the therapy response, progression free and overall survival (PFS, OS) of 80 PMBCL patients treated with a CHOP-based regimen with (N=35, standard treatment since 2001) and without rituximab (N=45). Advanced stage disease was present in 20 patients (25%). Low and low-intermediate or higher risk IPI were found in 50 (66%) and 26 (34%) patients, respectively. Seven patients (16%) in the rituximab cohort and 17 patients (49%) in the non-rituximab cohort received a consolidation high-dose (HD) chemotherapy and autologous blood stem cell transplantation (ABSCT). Radiation therapy was performed in 70 patients (88%). 24 (53%) patients who had received a rituximab-containing induction therapy (overall N=45) received rituximab maintenance therapy. A subgroup analysis with regard to International Prognostic Index (IPI) risk category and consolidation HD chemotherapy and ABSCT was performed.ResultsIn the cohort treated without rituximab 3 patients (9%) did not respond to therapy, 17 (49%) and 15 (43%) patients reached complete and partial remission (CR, PR). Projected 10-year PFS rate was 67% and projected 10-year OS rate were 72%. In the rituximab cohort no primary induction failures were observed, 15 (34%) and 28 (64%) patients reached CR and PR. Projected 10-year PFS rate was 95% and projected 10-year OS rate was 92%. The differences in PFS and OS between the rituximab and non rituximab cohort were highly significant (PFS P=0.001, HR=0.123, CI95 0.041 - 0.374, OS P=0.023, HR=0.248, CI95 0.079 - 0.778). In the rituximab cohort HD chemotherapy and ABSCT had no significant influence on PFS and OS. Contrary, in not rituximab treated patients a favorable result was observed for patients who received HD chemotherapy and ABSCT with regard to PFS (P=0.043) but not to OS. A subgroup PFS analysis by IPI risk (low versus low-intermediate, high-intermediate, and high) revealed that both low risk and other than low risk PMBCL patients benefit from addition of rituximab to induction chemotherapy (low risk subgroup: P=0.036, HR=7.308, CI95 1.168 - 45.703; other than low risk subgroup: P=0.027, HR=7.442, CI95 1.677 - 33.028, Figure 1A). In addition, the OS probability was significantly higher in the group of low-intermediate, high-intermediate and high IPI risk patients who were treated with rituximab compared to those patients who did not receive rituximab (P=0.035, HR=6.909, CI95 1.564 - 30.511). However, no OS benefit was observed in the low IPI risk subgroup between those patients who received rituximab and those who did not (P=0.065, Figure 1B). No statistically significant differences in PFS (P=0.167) and OS (P=0.585) were observed between patients with and without rituximab maintenance. In multivariate analysis, only addition of rituximab to induction chemotherapy and reaching CR after first line therapy had a beneficial effect on both PFS and OS, whereas IPI, age, upfront HD/ABSCT and rituximab maintenance had no impact on survival.ConclusionOur data demonstrate a survival benefit in unselected PMBCL patients treated with CHOP-like induction regimen and additional rituximab compared to CHOP-like treatment without rituximab independently of the IPI risk score. Moreover, if rituximab is added to induction therapy HD chemotherapy and ABSCT as part of the first line therapy do not improve PFS or OS. The role of rituximab maintenance therapy should be further evaluated in larger patient cohorts. [Display omitted] DisclosuresWitzens-Harig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Prognostic Value of NCCN-IPI and Interim PET/CT Based on Visual Assessment in the Treatment of Peripheral T Cell Lymphomas

BackgroundIt has been well known that peripheral T cell lymphoma (PTCL) has undergone poor prognosis compared with other non-Hodgkin lymphomas (NHL). Although the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) has been proposed to determining prognosis for patients with diffuse large B-cell lymphoma (DLBCL) at 2014, there is no study examines whether NCCN-IPI could apply to the T-cell NHLs. In addition, a few studies suggest prognostic utility of interim PET/CT in PTCL, but the role of interim PET/CT is not clear.PurposeWe evaluate the predictive efficacy of the NCCN-IPI and interim PET/CT based on visual assessment in patients with newly diagnosed PTCLs.MethodsThis study included 153 patients with de novo peripheral PTCLs, diagnosed from January 2010 to August 2015. The NCCN-IPI was calculated as following the original references. Survival outcomes were compared with a matched result of IPI and/or Prognostic Index for peripheral T cell lymphoma, unspecified (PIT). Visual assessment of interim PET/CT based on Deauville five point scales was performed at the time of diagnosis, mid-treatment and completion of CHOP/CHOP-like or other non-anthracycline chemotherapy.ResultsThe subtypes of PTCLs included PTCL, not otherwise specified (PTCL-NOS) (26%), angioimmunoblastic T cell lymphoma (20%), anaplastic large cell lymphoma (13%), extranodal NK/T cell lymphoma, nasal type (35%), and the others (6%). The NCCN-IPI showed better risk-based prognostic discrimination than IPI and PIT, especially between high-intermediate and high risk subgroups (3-year overall survival 40% vs. 27% vs. 26% among the high-intermediate risk group, respectively; 3-year overall survival 15% vs. 33% vs. 32% among the high risk group, respectively) with a median follow-up of 25.1 months (Figure 1). The absolute difference of survival rates between the low and high risk groups was 75% based on the NCCN-IPI stratification compared with 45% on the IPI stratification or 54% on the PIT stratification, respectively. When divided into two histologic subgroups (nodal vs. extra-nodal type), the NCCN-IPI showed considerable discriminatory capacity in both histologic groups. However, the IPI or PIT classification could not have discrimination in extra-nodal PTCLs. The interim PET-CT was significantly predicting for progression free survival in all PTCL patients, however, it also showed no predictive value in the patients with extranodal PTCLs, especially NK/T cell lymphoma.ConclusionsThe NCCN-IPI is a powerful prognostic model in PTCLs predicting overall survival among high-intermediate and high risk patients. Also, interim PET/CT response based on visual assessment could be a valuable prediction tool in nodal PTCLs, however, it should be carefully interpreted in the treatment of extranodal subtypes. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.