Therapy For Endometrial Cancer Research Articles

Abstract IA004: Challenges for future adjuvant studies and the role of immunotherapy in endometrial cancer

Abstract Adjuvant therapy for endometrial cancer (EC) is recommended based on risk factors. In current clinical practice these are mainly based on classical pathological factors such as stage, grade and presence of LVSI. The Cancer Genome Atlas Group demonstrated that EC can be divided in four distinct subgroups with impact on prognosis. This has now been shown to be feasible using surrogate markers in multiple large cohorts. Analysis of the intratumoral immune infiltrate using a machine learning image-based algorithm, found that low intraepithelial density of CD8+ cells was an independent prognostic factor for recurrence free survival. Combining intraepithelial CD8+ cell density with molecular and pathological factors improved the risk stratification model. Exploratory analysis found a significant impact within the p53abnormal and no specific molecular profile subgroups. While in intermediate to high-intermediate risk the majority has no specific molecular profile, in high risk there are more patients with POLE hypermutated tumors, p53abnormal and mismatch repair deficient tumors. The question is how to bring these molecular factors to the clinic? Molecular stratification does present additional subgroups with a rationale for targeted approaches. It does however present a challenge for trial design and feasibility, An overview of current ongoing studies using targeted therapies is provided, with a focus on immune checkpoint inhibition. Citation Format: Remi A. Nout. Challenges for future adjuvant studies and the role of immunotherapy in endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA004.

Abstract PO041: Everolimus and MK-2206 reverse P4-resistant endometrial hyperplasia in Mig-6 mutant mice

Abstract Endometrial cancer is the most frequent type of gynecological tumor in the United States. Hysterectomy, the surgical removal of the uterus, is the main therapy for endometrial cancer, but this is not an option for women seeking to preserve their fertility. In cases of early-stage endometrial cancer and endometrial hyperplasia, hormonal therapy is a vital nonsurgical option. However, progesterone (P4) resistance robs women of the option to choose hormone therapy to preserve their uterus. Therefore, developing nonsurgical treatments for endometrial cancer remains an essential goal for women who wish to maintain endometrial functions and women in high-risk surgical conditions. Mitogen-inducible gene 6 (MIG-6) acts as a tumor suppressor during endometrial tumorigenesis and as a P4 target gene in humans and mice. We developed mice with the conditional knockout of Mig-6 in all uterine compartments (Pgrcre/+Mig-6f/f; Mig-6KO) and endometrial epithelial cell-specific Mig-6 knockout (Sprr2fcre/+Mig-6f/f; Mig-6Ep-KO) mice. P4 treatment abated the development of endometrial hyperplasia and restored morphological and histological characteristics of the uterus of Mig-6Ep-KO mice, but Mig-6Ep-KO mice showed P4 resistance. P4 treatment reduced cell proliferation which was accompanied by decreased AKT signaling. In order to investigate the inhibition effect of AKT/mTOR signaling as non-surgical treatment on P4-resistant endometrial hyperplasia, we treated Mig-6KO and Mig-6Ep-KO mice with either: 1) vehicle (PBS); 2) MK-2206 (360 mg/kg, once a week); or 3) everolimus (10mg/kg daily) at 10 weeks old (n=6/treatment/genotype) for 1 month. MK-2206 has completed phase II trials and inhibits AKT phosphorylation. Everolimus is FDA-approved mTOR inhibitor. The vehicle group of Mig-6KO and Mig-6Ep-KO mice manifested the endometrial hyperplasia phenotype. In contrast, IHC analysis showed that the groups receiving MK-2206 or everolimus experienced significantly decreased AKT phosphorylation and phosphorylated S6 levels, respectively, and decreased epithelial proliferation, resulting in restoration of normal uterine histology. These data suggest that everolimus and MK-2206 may be new non-surgical treatment options for P4-resistant endometrial hyperplasia. This information may help guide more effective non-surgical interventions in the future. The project described was supported by Grant Number P50CA098258 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. Citation Format: Tae Hoon Kim, Jae-Wook Jeong. Everolimus and MK-2206 reverse P4-resistant endometrial hyperplasia in Mig-6 mutant mice [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO041.

Abstract PR001: Preclinical development of SHetA2 for endometrial cancer therapy

Abstract Introduction: SHetA2 (NSC 726189) is a novel drug that is entering first in human trials for gynecologic cancers. Upon binding to three related heat shock protein A chaperones proteins (HSPA5/Grp78, HSPA8/Hsc70, HSPA9/mortalin), SHetA2 causes release of their client proteins. Our objective was to evaluate the potential of SHetA2 for endometrial cancer therapy and to explore its mechanism of action. Methods: Endometrial cancer cell lines, Ishikawa, MFE280, MFE296, Hec1a, Hec1B and AN3CA were evaluated for SHetA2 effects on cell growth with a MTT assay. Ishikawa, Hec1B and AN3CA were also evaluated for SHetA2 effects on cell cycle progression by flow cytometry analysis of PI staining; apoptosis by flow cytometry analysis of annexin/PI staining, anchorage-independent growth using an agar colony formation, invasive potential with an matrigel invasion assay, and protein levels (in Ishikawa only) by mass spec analysis of protein extracts using a 5% false discovery rate. The in vivo efficacy of SHetA2 and paclitaxel alone and in combination were evaluated in athymic nude mice bearing Ishikawa xenografts treated with oral 60 mg/kg/day SHetA2, intraperitoneal injection of 10 mg/kg/week of paclitaxel, the combination or vehicle controls. Results: SHetA2 significantly reduced growth of all endometrial cancer cell lines in time- and dose- dependent manners. This inhibition occurred via G1 cell cycle arrest in Ishikawa and Hec-1b, and G2 arrest in AN3CA. SHetA2 inhibited anchorage-independent growth and invasive behaviors, and induced apoptosis in Ishikawa, Hec-1b and AN3CA. Proteomic analysis identified levels of 48 proteins to be significantly altered by SHetA2 in Ishikawa cells. Of these, 15, 10 and three are known to be bound by Hsc70, Grp78 and mortalin, respectively. Ingenuity analysis identified the top SHetA2-regulated canonical pathways to be EIF2 Signaling, Unfolded Protein Response, Glycolysis, ER Stress Pathway and Gluconeogenesis, and predicted the top upstream regulators of the proteomic changes to be three microtubule associated proteins (MAPT, PSEN1, APP), which also bind Hsc70. Since Hsc70 also binds paclitaxel, we predicted positive interaction between SHetA2 and paclitaxel on endometrial tumor growth. Both SHetA2 and paclitaxel significantly inhibited growth of Ishikawa xenografts, and the combination was more effective than either drug alone (Repeated Measures ANOVA p=0.0025). There were no significant effects of the treatments on mouse body weights. Conclusions: SHetA2 inhibits growth, migration and invasion of endometrial cancer cell lines in association with cell cycle arrest, apoptosis and regulation of its Grp78/Hsc70/mortalin target protein networks. Pathways regulated by SHetA2 are consistent with disruption of chaperone proteins. The in vivo efficacy of SHetA2 alone and in combination with paclitaxel justifies further development of this drug and combination with paclitaxel for treatment of endometrial cancer. Funding: Stephenson Cancer Center. Citation Format: Vishal Chandra, Rajani Rai, Doris M. Benbrook. Preclinical development of SHetA2 for endometrial cancer therapy [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PR001.

Risk Factors for Surgical Treatment of Endometrial Cancer Using Traditional and Laparoscopic Methods.

Surgical treatment is the most important part of therapy for endometrial cancer. The aim of the study was to define factors having the most significant impact on surgical treatment of endometrial cancer when using traditional and laparoscopic methods. In the study, we evaluated 75 females who were treated for endometrial cancer via laparoscopic surgery in 2019 and used a historical control of 70 patients treated by laparotomy in 2011. The evaluated risk factors included the method of surgery, type of lymphadenectomy, patient’s age, various obesity parameters, histological grading, cancer clinical staging, pelvic dimensions, previous abdominal surgeries, comorbidities, and number of deliveries. The duration of hospitalization, operation time, loss of hemoglobin, and procedure-related complications were used as parameters of perioperative outcomes. Multivariable linear regression analysis confirmed the following factors as being predictors of worse perioperative outcomes: laparotomy, abdominal obesity (waist circumstance and waist-to-hip ratio), range of lymphadenectomy, prior abdominal surgeries, and larger pelvic dimensions. Abdominal obesity is a significant risk factor in the treatment of endometrial cancer. Laparotomy continues to be utilized frequently in the management of endometrial cancer in Poland as well as elsewhere, and adopting a minimally invasive approach is likely to be beneficial for patient outcome.

Efficacy and Safety of Bevacizumab-Combined Chemotherapy for Advanced and Recurrent Endometrial Cancer: A Systematic Review and Meta-analysis.

Bevacizumab-combined chemotherapy is a new regimen for advanced/recurrent endometrial cancer. To evaluate the efficacy and safety of bevacizumab-combined chemotherapy in advanced/recurrent endometrial cancer. Systematic review and meta-analysis. Eligible studies were retrieved from Embase, PubMed, and Cochrane Library. The data of primary outcomes including progression-free survival and overall survival and secondary outcomes including overall survival, response rate, and adverse events (grade ≥2) were extracted, pooled, and used for the meta-analysis to compare the efficacy and safety of bevacizumab-combined chemotherapy with other treatments in patients with advanced/recurrent endometrial cancer. Notably, 2 randomized-controlled and 5 single-arm trials of bevacizumab-combined chemotherapy or bevacizumab single-agent therapy for endometrial cancer were included. Meta-analysis indicated that bevacizumab-combined chemotherapy significantly increased the progression-free survival rate (hazard ratio=0.82, 95% confidence interval=0.70, 0.97) and overall survival rate (hazard ratio=0.83, 95% confidence interval=0.70, 0.98) compared with chemotherapy alone. The rates of overall, complete, and partial response to bevacizumab-combined chemotherapy were 76%, 22%, and 21%, respectively. The 6 and 12-month disease-free progression rates after bevacizumab-combined chemotherapy were 79% and 62%, respectively. Anemia (23%), leukopenia (46%), neutropenia (51%), hypertension (16%), and fatigue (24%) were the general adverse events after bevacizumab-combined chemotherapy. Bevacizumab-combined chemotherapy may have a higher efficacy in improving the overall and progression-free survival in patients with advanced/recurrent endometrial cancers compared with chemotherapy alone.

LncRNA FOXCUT Stimulates the Progression of Endometrial Cancer.

Endometrial cancer (EC) is a common gynecological tumor and the third leading cause of cancer-related death in women. Previous research has proved that long noncoding RNA (lncRNA) FOXCUT acts as an oncogene in several cancers. This study ascertained that lncRNA FOXCUT was highly expressed in endometrial cancer cells. Overexpression of lncRNA FOXCUT promoted EC cell proliferation, invasion, and migration, as well as epithelial-mesenchymal transition (EMT). In addition, overexpression of lncRNA FOXCUT could inhibit the apoptosis of cancer cells and block EC cells in S phase, whereas silencing lncRNA FOXCUT had the opposite effect. Thus, lncRNA FOXCUT had a regulatory effect on promoting the progression of EC cells, which might provide novel potential targets for research on targeted therapy of EC.

Long-Term Metformin Effect on Endometrial Cancer Development Depending on Glucose Environment <i>In Vitro</i>

Objectives: Hyperinsulinemia as well as prolonged and elevated estrogen exposure are considered as risk factors for endometrial cancer (EC) development. Metformin, an anti-hyperglycemic and insulin-sensitizing biguanide, displayed anti-proliferative effects in recent studies. In the present study, the effects of long-term exposure of endometrial cancer cells to low and moderate concentrations of metformin on cell viability, proliferation, clonogenicity and migration were investigated under different metabolic conditions. Study Design: EC cell lines HEC-1A and Ishikawa were cultured under normo- (NG, 5.5 mM) or hyperglycemic (HG, 17.0 mM) conditions and treated with metformin (0.01 - 5.0 mM) in the presence of β-estradiol (E2) for 7 d. Results: A concentration-dependent decrease of cellular viability was observed in the MTT and ATP assays after metformin treatment. IC50 values were between 0.7 - 3.7 mM (NG) and 3.0 - 18.3 mM (HG), respectively. A protective effect of glucose on cellular viability was detected only in the ATP assay. Furthermore, metformin (0.5 - 5.0 mM) led to a significant decrease in proliferation by 12% - 55% (NG). However, a decreased proliferation rate was only induced at 5.0 mM metformin (40%) in the presence of high glucose levels in HEC-1A cells, indicating a glucose-related resistance to anti-proliferative metformin effects, which—to a lesser extent—was also observed in Ishikawa cells. Metformin treatment also caused concentration-dependent effects on clonogenicity and decreased the number and size of colonies. In HEC-1A cells, metformin (0.5 - 5.0 mM) reduced the colony formation by 44% - 80% (NG) and 29% - 81% (HG), respectively. Slightly higher metformin concentrations (1.0 - 5.0 mM) were necessary in Ishikawa cells to reduce clonogenicity by 36% - 86% independent of glucose levels. An investigation of migration in the wound healing assay revealed that the % wound closure decreased with increasing metformin concentrations, but independent of glucose levels. After treatment with 5.0 mM metformin, migration was significantly reduced in both cell lines. Conclusion: Our in vitro findings support the hypothesis that metformin has a direct effect on endometrial cancer cell lines and reflects the importance of the local glucose environment, suggesting that metformin may be considered as a potential adjuvant agent in endometrial cancer therapy due to its direct and indirect effects on endometrial development. However, further studies are necessary that confirm the relevance of our data for clinical applications.

Tribbles Pseudokinase 3 Contributes to Cancer Stemness of Endometrial Cancer Cells by Regulating β-Catenin Expression.

Simple SummaryEndometrial cancer (EC) is the second most common female malignancy worldwide, but the pathogenesis is not fully understood. Tribbles pseudokinase 3 (TRIB3) is a kind of scaffold protein that may regulate multiple cellular processes by organizing binding partner proteins involving signaling transduction pathways. The goal of this study is to investigate if TRIB3 is involved in the malignant features of EC. Our data demonstrate that TRIB3 positively regulates the cancer stem-cell activity and in vivo tumorigenicity of EC cells by modulating β-catenin signaling through directly interacting with the ELF4 transcription factor. Our results could lead to new insight for developing a novel therapeutic strategy for EC by targeting TRIB3.Endometrial cancer (EC) is the second most common gynecological malignancy worldwide. Tribbles pseudokinase 3 (TRIB3) is a scaffolding protein that regulates intracellular signal transduction, and its role in tumor development is controversial. Here, we investigated the biological function of TRIB3 in EC. We found that the messenger RNA (mRNA) expression level of TRIB3 was significantly and positively correlated with shorter overall survival of EC patients in The Cancer Genome Atlas database. The protein expression of TRIB3 was found to be significantly increased in EC cancer stem cells (CSCs) enriched by tumorsphere cultivation. Knockdown of TRIB3 in EC cells suppressed tumorsphere formation, the expression of cancer stemness genes, and the in vivo tumorigenesis. The expression of β-catenin at both the protein and the mRNA levels was downregulated upon TRIB3 silencing. TRIB3 was found to interact with E74 Like ETS transcription factor 4 (ELF4) in the nucleus and bound to ELF4 consensus sites within the catenin beta 1 (CTNNB1) promoter in EC cell lines. These data indicated that TRIB3 may regulate CTNNB1 transcription by enhancing the recruitment of ELF4 to the CTNNB1 promoter. In conclusion, our results suggest that TRIB3 plays an oncogenic role in EC and positively regulates the self-renewal and tumorigenicity of EC-CSCs. Targeting TRIB3 is considered as a potential therapeutic strategy in future EC therapy.

Exosomal miR-499a-5p Inhibits Endometrial Cancer Growth and Metastasis via Targeting VAV3.

Background/AimThe current therapeutic strategies for endometrial cancer are limited and unsatisfactory. Accumulating evidence suggest that microRNAs (miRNAs) participate in tumor growth and metastasis. Mesenchymal stem cells (MSCs) derived exosomes (Exos) are considered as better miRNA delivery vehicles. Here, we investigated the therapeutic effect of exosomal miR-499a-5p (miR-499) in human endometrial cancer metastasis.MethodsMicroarray analysis and RT-PCR were performed to detect the relative expression of miR-499 in endometrial cancer tissues and cell lines. MSC-derived Exos were characterized by transmission electron microscope (TEM), Western blot (WB), and nanoparticle tracking analysis (NTA). miR-499 was loading into Exos using electroporation. Cell proliferation and angiogenesis capacity were tested by 5-ethynyl-29-deoxyuridine (EdU) assay and tube formation assay, respectively. Dual-luciferase reporter assay (DLR) was used to confirm the connection of miR-499 and VAV3.ResultsWe found that the expression of miR-499 was significantly downregulated in cancer tissues compared with adjacent tissues in endometrial cancer patients. Moreover, exosomal miR-499 not only dramatically suppressed endometrial cancer cells proliferation, endothelial cells tube formation in vitro, but also inhibited tumor growth and angiogenesis in vivo. In addition, we confirmed that miR-499 directly targets the 3′UTR sequence of VAV3.ConclusionThe novel identified exosomal miR-499 functions as a tumor suppressor in endometrial cancer though regulating VAV3, and these findings could be a valid molecular target for endometrial cancer therapy.

Efficacy and Safety of Bevacizumab-Combined Chemotherapy for Advanced and Recurrent Endometrial Cancer: A Systematic Review and Meta-Analysis.

Bevacizumab-combined chemotherapy is a new regimen for advanced/recurrent endometrial cancer. This study aimed to evaluate the efficacy and safety of bevacizumab-combined chemotherapy in advanced/recurrent endometrial cancer. This is a systematic review and meta-analysis of clinical trials. Eligible studies were retrieved form Embase, PubMed, and Cochrane Library. The data of primary outcomes including progression-free and overall survival and secondary outcomes including overall survival, response rate, and adverse events (grade ≥2) were extracted, pooled and used for the meta-analysis to compare the efficacy and safety of bevacizumab-combined chemotherapy versus other treatments in patients with advanced/recurrent endometrial cancer. Two randomized-controlled and five single arm trials of bevacizumab-combined chemotherapy or bevacizumab single-agent therapy for endometrial cancer were included. Meta-analysis indicated that bevacizumab-combined chemotherapy significantly increased the progression-free survival rate (Hazards ratio, HR=0.82, 95% CI 0.70, 0.97) and overall survival rate (HR=0.83, 95% CI 0.70, 0.98) as compared with chemotherapy alone. The rates of overall, complete, and partial response to bevacizumab-combined chemotherapy were 76%, 22%, and 21%, respectively. The six and 12-month disease-free progression rate after bevacizumab-combined chemotherapy were 79% and 62%, respectively. Anemia (23%), leukopenia (46%), neutropenia (51%), hypertension (16%), and fatigue (24%) were the general adverse events following bevacizumab-combined chemotherapy. This study suggested that bevacizumab-combined chemotherapy may have a higher efficacy in improving the overall and progression-free survival in patients with advanced/recurrent endometrial cancers as compared with chemotherapy alone.

Stigmasterol sensitizes endometrial cancer cells to chemotherapy by repressing Nrf2 signal pathway

BackgroundChemoresistance reduces the 5-year survival rate of endometrial cancer patient, which is the current major obstacle for cancer therapy. Increasing evidence state that Nrf2 contributes to chemoresistance in several kinds of cancer. However, its role in endometrial cancer cells remains unclarified.MethodsImmunohistochemistry staining was used to detect the expression of Nrf2 in normal patient and endometrial cancer patient. Stable transfection Ishikawa cell line with high level of Nrf2 was established to evaluate its role in chemoresistance. Dot blot assays were used to assess global hydroxymethylation level after stigmasterol treatment. Cellular growth profile was detected by CCK8 assay. Western blot was used to evaluate the changes of the target molecules after various treatments.ResultsNrf2 is overexpressed in endometrial cancer tissues compared with the normal endometrium. Overexpression of Nrf2 resulted in decrease sensitivity to cisplatin. In addition, stigmasterol has been identified as a novel Nrf2 inhibitor. It enhanced the sensitivity of endometrial cancer cells to cisplatin, and the underlying mechanism is that stigmasterol declines the Nrf2 protein level.ConclusionsOur findings identified stigmasterol as a new potential inhibitor of Nrf2 and highlight a critical role of stigmasterol in overcoming chemoresistance in endometrial cancer therapy.

Outcomes after chemotherapy, radiation or combination therapy for high-intermediate and high-risk early-stage endometrial cancer

Objective: The adjuvant therapy for high-intermediate and high-risk endometrial cancer remains controversial. A recent randomized trial (PORTEC-3) reported that survival was improved with combination chemotherapy and radiotherapy, although the survival benefit was most pronounced in women with stage III tumors. We analyzed the association between multimodal therapy and survival for women with stage I–II high- and high-intermediate risk endometrial cancer.

A randomized phase II/III study of paclitaxel/carboplatin/metformin versus paclitaxel/carboplatin/placebo as initial therapy for measurable stage III or IVA, stage IVB, or recurrent endometrial cancer: An NRG Oncology/GOG study

Objective: Obesity and diabetes are associated with increased risk and worse outcomes for endometrial cancer. Paclitaxel and carboplatin is the standard initial therapy for advanced and recurrent endometrial cancer. Thus, we evaluated the efficacy and tolerability of the addition of the antidiabetic drug metformin to paclitaxel and carboplatin in endometrial cancer patients.

5P Hormonal biomarkers can improve prediction of response to hormonal therapy in advanced and recurrent endometrial cancer: Results of the PROMOTE-R study

5P Hormonal biomarkers can improve prediction of response to hormonal therapy in advanced and recurrent endometrial cancer: Results of the PROMOTE-R study

Heterogeneity of patients with high-intermediate and high-risk endometrial cancer included in prospective trials

Objective: Adjuvant therapy for endometrial cancer remains controversial. Clinical and pathologic characteristics have been used to stratify women based on risk of recurrence. Recently, several prospective trials have examined the use of various combinations of adjuvant chemotherapy and radiation for women classified as high-intermediate and high risk. These trials included a wide spectrum of tumor types and stages. We assessed the long-term survival of women with high-intermediate and high-risk endometrial cancer as classified by GOG 249 and PORTEC-3.

Using machine learning to create a precision prognostication system for endometrial cancer

Objective: A variety of risk stratification systems have been developed to predict prognosis and tailor adjuvant therapy for endometrial cancer. These systems rely on a variety of variables including stage, histology, and age but often classify patients with widely variable risks into similar categories. We used a novel machine learning algorithm to develop a precision prognostic system for high-intermediate and high-risk endometrial cancer.

Evaluation of Changes in the Expression Profile of mRNA and Proteinencoding Adiponectin in Ishikawa Cell Line under the Influence of Cisplatin - Preliminary Report.

Background A reduced concentration of adiponectin is considered as an independent factor of the risk of inducing endometrial cancer. Cisplatin is a drug used in the therapy of this type of neoplasm. However, knowledge of the effects of cisplatin on the adiponectin level is still limited.Objective The purpose of this study was to assess the impact of cisplatin depending on the concentration and time of exposition of the cells to the drug on the adiponectin level in the endometrial cancer cell line.Methods Cells of endometrial cancer cell line Ishikawa were exposed for 12,24 and 48 hour periods to cisplatin with the following concentrations: 2.5µM, 5µM, 10µM. The changes in the expression profile of adiponectin were compared to the RtqPCR reaction and ELISA test. The STATISTICA 13.0 PL program was used for statistical analysis (p<0.05).Results In the culture without the drug, the concentration of adiponectin was statistically lower than in the cell culture incubated with the drug. Changes on the mRNA level seem to be more specific than on the protein level, although in both cases, the same trend in the expression changes was noted.DiscussionThe longer the time of exposition of the cells to the drug, the expression of mRNA, and the adiponectin protein increased. Changes in the expression profile were characterized statistically (p<0.05).Conclusion Cisplatin, in a noticeable way, changes the expression profile of adiponectin. Molecular analysis indicated that in the case of endometrial cancer therapy should be implemented with a concentration of no less than 5 µM.

Efficacy and Toxicity of Adjuvant Therapies for High-Risk Endometrial Cancer in Stage I-III: A Systematic Review and Network Meta-Analysis.

BackgroundThe use of adjuvant therapy for high-risk endometrial cancer patients (HREC) in International Federation of Gynecology and Obstetrics (FIGO) stage I–III remains debatable. This network meta-analysis was conducted to compare and rank adjuvant therapies based on efficacies and toxicities to facilitate clinical decision-making and further research.Material/MethodsWe searched 3 databases – PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials – from inception to December 9, 2019. Only randomized controlled trials that compared any of these adjuvant therapies (pelvic radiotherapy, vaginal brachytherapy, chemotherapy, and chemoradiotherapy) with each other or surgery alone were included. The network meta-analysis was performed in a frequentist framework using Stata software 15.0.ResultsFourteen RCTs with 5872 participants were eligible. No significant difference between treatments was observed in 5-year overall survival (OS) or distant metastasis. Compared with surgery alone, adjuvant pelvic radiotherapy plus chemotherapy (pelvic RT-CT) prolonged 5-year progression-free survival (PFS) and pelvic radiotherapy (pelvic RT) (RR=0.61, 95% CI 0.39–0.96; RR=0.779, 95% CI 0.63–0.95). Compared with surgery alone, pelvic RT, the combination of pelvic RT and vaginal brachytherapy (pelvic RT-VBT), chemotherapy (CT), and pelvic RT-CT led to fewer local recurrences (RR=0.33, 95% CI 0.21–0.50; RR=0.15, 95% CI 0.03–0.74; RR=0.39, 95% CI 0.21–0.73; RR=0.17, 95% CI 0.06–0.46). Adjuvant CT was found to result in more grade III/IV late toxicities than surgery alone (RR=11.8, 95% CI 1.02–137.14). Pelvic RT-CT ranked first for OS, PFS, distant metastasis, and local recurrence.ConclusionsPelvic RT-CT is superior to other treatments for PFS and local recurrence rate, and associated related toxicities are tolerable, suggesting it may be an ideal adjuvant therapy for HREC patients.

Outcomes After Salvage Radiation Therapy for Recurrent Endometrial Cancer in Patients With No Prior Adjuvant Therapy: An Institutional Review

PurposeAfter definitive surgery, women with early-stage, low-risk endometrial cancer are observed. However, some will require salvage radiation therapy for recurrence. The purpose of this study was to evaluate our experience using salvage radiation for recurrent endometrial cancer in patients who did not receive upfront adjuvant therapy. Methods and MaterialsTwenty-eight women with endometrial cancer who had undergone initial definitive hysterectomy without adjuvant therapy developed isolated local or regional recurrence and were treated with salvage radiation in our department from 2004 to 2018. Salvage radiation included whole pelvic radiation, vaginal brachytherapy, or both. Patient and tumor characteristics, treatment details, and toxicities were recorded and analyzed. ResultsThe median time to first recurrence was 1.7 years. First recurrences consisted of local recurrence in 23 patients, regional recurrence in 4, and both in 1. The median times from hysterectomy to first recurrence, local and regional, were 1.2 and 4.0 years, respectively. All patients underwent salvage radiation for management of their first recurrence. The median total equivalent dose in 2 Gy fractions for this treatment was 67.6 Gy (37.5–81.8 Gy). Two second recurrences occurred following salvage treatment, both local recurrence, at 6.5 and 13.5 months after radiation. The 2-year rates of local control, disease-free survival, and overall survival were 93%, 80%, and 88%, respectively. Treatment was well-tolerated, with low rates of gastrointestinal and genitourinary toxicity. ConclusionsIn this group of patients, salvage radiation therapy for local or regional recurrence of endometrial cancer resulted in excellent control with low rates of acute and chronic toxicities.

Definitive Radiation Therapy for Medically Inoperable Endometrial Cancer

The standard of care for patients with endometrial cancer typically involves upfront surgery. External beam radiotherapy, brachytherapy, and/or chemotherapy are implemented in the adjuvant setting based on individual risk factors. In the subset of women who are unable to receive surgery due to medical comorbidities or tumor-related factors, external beam radiation and/or uterine brachytherapy can be employed in the definitive setting. To evaluate the clinical outcomes from definitive radiation therapy in women with newly diagnosed, medically inoperable, endometrial cancer. We used an institutional endometrial cancer database to identify medically inoperable patients who received definitive radiation therapy from 1999-2018. Kaplan-Meier method was used to calculate overall survival, cause-specific survival, and locoregional recurrence free survival. Cox regression analysis was used to assess variables associated with these outcomes. Forty-four patients were identified, with a median follow up of 29.1 months. Median age was 68 years (R: 40-90) and the median body mass index (BMI) was 43 (R:23-88). Ten patients (22.7%) had FIGO grade 3 disease. One patient received external beam radiation to the pelvis alone, twenty-seven patients underwent brachytherapy alone, and sixteen patients received combined external beam radiation to the pelvis followed by consolidative uterine brachytherapy. Chemotherapy was delivered in the neoadjuvant setting in two patients, adjuvant in one patient, and concurrently in two patients. 55% of patients had PET/CT and/or MRI based treatment planning. Four patients were unable to complete their intended treatment course due to exacerbation of medical comorbidities (2), progression of disease during treatment (1), or uterine perforation (1). Locoregional recurrence free survival was 92% (95% C.I. 83.7-100%) at 2 years. Cause-specific survival and overall survival were 79.3% (95% C.I. 65.8-95.7%) and 62% (95% C.I. 48.8-78.7%) respectively at 2 years. On univariate analysis, Grade 3 disease, age, and the presence of lymphadenopathy were associated with decreased overall survival, while surprisingly, BMI was associated with improved OS. KPS less than 80, radiotherapy technique, and smoking status were not associated with OS. On multivariate analysis, only the presence of lymphadenopathy remained significant. No variables were significantly associated with locoregional recurrence. There were no acute grade 3 toxicities observed in this cohort. Grade 3 toxicity was seen in 7.8% of patients with sufficient long term follow up. Definitive radiation therapy for endometrial cancer in medically inoperable patients is associated with excellent locoregional control and cause-specific survival. Cause-specific survival was considerably longer than overall survival in this cohort, suggesting that these patients frequently succumb to other medical conditions.