Adjuvant Therapy In Endometrial Cancer Research Articles

Molecular subtype stratified outcomes according to adjuvant therapy in endometrial cancer

ObjectivesRecent data support the predictive implications of molecular subtype assignment in endometrial cancer (EC). Our objective was to retrospectively assess clinical outcomes according to adjuvant treatment received within EC molecular subtypes. MethodsClinical outcomes (disease-specific and progression-free survival DSS/PFS) of EC patients from a single institution and population-based cohorts that had undergone molecular classification were assessed with respect to adjuvant therapy received and 2016 ESMO risk group. Results2472 ECs were assessed; 184 (7.4%) POLEmut, 638 (25.8%) MMRd, 1223 (49.5%) NSMP and 427 (17.3%) p53abn. N = 774 (34.6%) of the cohort were ESMO 2016 high risk and 109 (4.8%) were advanced or metastatic. In patients with MMRd EC, assessed across and within stage, there was no observed benefit in DSS or PFS with the addition of chemotherapy +/− radiation compared to radiation alone in ESMO high risk (p = 0.694) or ESMO high, advanced, metastatic risk groups combined (p = 0.852). In patients with p53abn EC, adjuvant chemotherapy given with radiation was associated with significantly longer DSS compared to radiation alone in ESMO high risk (p = 0.007) and ESMO high, advanced and metastatic risk groups combined (p = 0.015), even when restricted to stage I disease (p < 0.001) and when compared in serous vs. non-serous histotypes (p = 0.009). ConclusionsAdjuvant chemotherapy is associated with more favorable outcomes for patients with p53abn EC, including stage I disease and non-serous histotypes, but does not appear to add benefit within MMRd ECs for any stage of disease, consistent with PORTEC-3 molecular subanalysis. Prospective trials, assessing treatment efficacy within molecular subtype are needed, however these ‘real-world’ data should be considered when discussing adjuvant treatment with patients.

Heterogeneity of outcomes of endometrial cancer patients included in prospective clinical trials

ObjectiveTo assess heterogeneity in five-year overall survival of patients with endometrial cancer using a large retrospective database with cohorts defined by recent prospective clinical trials. MethodsThe National Cancer Database was used to identify patients with endometrial cancer who underwent hysterectomy from 2004 to 2016. The reported inclusion criteria for GOG-249, PORTEC-3, and GOG-258 were used to define the respective cohorts. Five-year overall survival for each cohort was stratified by tumor characteristics and adjuvant therapy regimens. ResultsA total of 89,133 patients were identified who would have fulfilled the entry criteria to GOG-249, PORTEC-3, or GOG-258. When stratified by tumor characteristics, irrespective of adjuvant therapy, five-year overall survival ranged from 59.9%–81.7% for patients meeting GOG-249 inclusion criteria, 40.2%–81.8% for patients meeting PORTEC-3 inclusion criteria, and 17.5%–75.0% for those meeting GOG-258 inclusion criteria. Analysis of subgroups by adjuvant therapy regimen revealed significant improvement in five-year overall survival for chemoradiotherapy compared to chemotherapy or radiotherapy alone for endometroid stage III and stage IVA disease and for some stages of serous and clear cell histology. ConclusionsRecent prospective trials of adjuvant therapy for endometrial cancer have included heterogeneous cohorts of patients based on five-year overall survival rates when the populations are stratified by tumor characteristics. The variation in expected five-year overall survival for subsets of patients may result in underpowered studies or misleading results.

Molecular subtype stratified response to adjuvant therapy in endometrial cancer (086)

Objectives: Molecular classification of endometrial cancer (EC) has been shown to have a strong prognostic value. Recent data support the predictive implications of molecular subtype assignment. Using combined EC cohorts that have undergone molecular classification, our objective was to assess the response to adjuvant therapy based on ESMO 2016 risk group criteria within the four molecular subtypes (MMRd, POLEmut, NSMP, and p53abn). Methods: Historical institutional (29%) and population-based cohorts of EC from 2016 (53%) and prior to 2016 (18%) that had undergone molecular classification were identified. We assessed outcomes (overall, disease-specific, or progression-free survival [OS, DSS, PFS]) based on the adjuvant treatment given, including none, vault brachytherapy (VB) only, external beam radiation (EBRT) ± VB, or chemotherapy (± any RT including EBRT or VB) across ESMO risk groups (low, intermediate, high-intermediate, high and advanced/metastatic) within the four molecular subtypes. Conclusions: Although retrospective data regarding where the treatment was given was not confined to clinical trial parameters and need to be interpreted with caution, these results are consistent with the PORTEC3 trial subgroup analysis showing chemotherapy does not appear to add benefit within MMRd EC but may improve outcomes for patients with p53abn EC. These findings support molecular subtype-directed trials, such as radiation alone ± investigational agent for MMRd, chemotherapy ± investigational agent for p53abn, and de-escalation of adjuvant therapy for POLEmut EC. Objectives: Molecular classification of endometrial cancer (EC) has been shown to have a strong prognostic value. Recent data support the predictive implications of molecular subtype assignment. Using combined EC cohorts that have undergone molecular classification, our objective was to assess the response to adjuvant therapy based on ESMO 2016 risk group criteria within the four molecular subtypes (MMRd, POLEmut, NSMP, and p53abn). Methods: Historical institutional (29%) and population-based cohorts of EC from 2016 (53%) and prior to 2016 (18%) that had undergone molecular classification were identified. We assessed outcomes (overall, disease-specific, or progression-free survival [OS, DSS, PFS]) based on the adjuvant treatment given, including none, vault brachytherapy (VB) only, external beam radiation (EBRT) ± VB, or chemotherapy (± any RT including EBRT or VB) across ESMO risk groups (low, intermediate, high-intermediate, high and advanced/metastatic) within the four molecular subtypes. Conclusions: Although retrospective data regarding where the treatment was given was not confined to clinical trial parameters and need to be interpreted with caution, these results are consistent with the PORTEC3 trial subgroup analysis showing chemotherapy does not appear to add benefit within MMRd EC but may improve outcomes for patients with p53abn EC. These findings support molecular subtype-directed trials, such as radiation alone ± investigational agent for MMRd, chemotherapy ± investigational agent for p53abn, and de-escalation of adjuvant therapy for POLEmut EC.

Effect of coexisting adenomyosis on patients with endometrioid adenocarcinoma: Determination of intraoperative risk factors for tumor metastasis and estimation of prognosis

We sought to clarify the impact of adenomyosis on the clinical and pathological prognosis of endometrial cancer to aid the selection of appropriate surgical intervention based on the diagnosis of adenomyosis. Our study aimed to report the frequency of adenomyosis in patients with endometrioid cancer and correlate its incidence rate with the survival and prognostic factors. This retrospective study included 357 patients. Patients with endometrioid adenocarcinoma were divided into two groups based on the presence of adenomyosis. The groups were compared in terms of tumor diameter, lymphovascular space invasion (LVSI), low-high risk pathologic status, stage of the disease, and survival outcome. Continuous variables were analyzed using the Student's t or Mann-Whitney U-test. Survival data were analyzed using the Kaplan-Meier test. The average age was similar between the two groups. In total, 47 (13.2%) of 357 patients had adenomyosis. A total of 43 (91.4%) cases with adenomyosis and 258 (83.2%) cases without adenomyosis had Stage I endometrioid adenocarcinoma (n = 301, 84.3%). Moreover, 32 (68.1%) cases with adenomyosis and 187 (60.3%) cases without adenomyosis were in the low-risk group. There was no statistically significant correlation between the risk groups (P = 0.309) and overall survival between the two groups (P = 0.416). No correlation was seen between the characteristics of endometrioid type endometrial cancer and survival rates in patients with or without adenomyosis. The impact of adenomyosis as a factor in evaluating the perioperative prognosis and planning postoperative adjuvant therapy for endometrial cancer should be assessed by further studies.

Refining Adjuvant Therapy for Endometrial Cancer: New Standards and Perspectives.

Simple SummaryIn recent years, the adjuvant treatment of endometrial carcinoma has changed due to the integration of the molecular features in the clinical–pathological classification. The new ESGO/ESTRO/ESP guidelines (2021) proposed the evaluation of the adjuvant treatment of endometrial carcinoma using a prognostic-risk group stratification based on pathogenetic, clinical, and molecular features. Moreover, the adjuvant therapy of endometrial carcinoma is currently being re-defined in ongoing studies. This review provides a comprehensive overview of endometrial carcinoma adjuvant therapy, analyzing the “new standards” and “new perspectives”.Endometrial carcinoma is the most frequent cancer of the reproductive female organs. Most endometrial cancers are diagnosed at early stage (75%). Treatment options depend on pathogenetic, histopathologic and clinical characteristic at the diagnosis. To improve patient management in the near future, recent research has focused on new molecular features; evidence has shown that these give a better definition of patient prognosis and can help in tailoring adjuvant treatments by identifying specific subgroups of patients whose tumors may benefit from specific therapeutic approaches. In this review, we will focus on current knowledge of adjuvant treatment of endometrial carcinoma, using a prognostic-risk group stratification based on pathogenetic, clinical and molecular features, and will take a look at the ongoing trials that will further change the therapeutic approach in coming years.

Sentinel lymph node mapping best approach to guide adjuvant therapy in endometrial cancer

Sentinel lymph node mapping best approach to guide adjuvant therapy in endometrial cancer

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.

Japan Society of Gynecologic Oncology 2018 guidelines for treatment of uterine body neoplasms.

The Fourth Edition of the Guidelines for Treatment of Uterine Body Neoplasm was published in 2018. These guidelines include 9 chapters: 1. Overview of the guidelines, 2. Initial treatment for endometrial cancer, 3. Postoperative adjuvant therapy for endometrial cancer, 4. Post-treatment surveillance for endometrial cancer, 5. Treatment for advanced or recurrent endometrial cancer, 6. Fertility-sparing therapy, 7. Treatment of uterine carcinosarcoma and uterine sarcoma, 8. Treatment of trophoblastic disease, 9. Document collection; and nine algorithms: 1-3. Initial treatment of endometrial cancer, 4. Postoperative adjuvant treatment for endometrial cancer, 5. Treatment of recurrent endometrial cancer, 6. Fertility-sparing therapy, 7. Treatment for uterine carcinosarcoma, 8. Treatment for uterine sarcoma, 9. Treatment for choriocarcinoma. Each chapter includes overviews and clinical questions, and recommendations, objectives, explanation, and references are provided for each clinical question. This revision has no major changes compared to the 3rd edition, but does have some differences: 1) an explanation of the recommendation decision process and conflict of interest considerations have been added in the overview, 2) nurses, pharmacists and patients participated in creation of the guidelines, in addition to physicians, 3) the approach to evidence collection is listed at the end of the guidelines, and 4) for clinical questions that lack evidence or clinical validation, the opinion of the Guidelines Committee is given as a “Recommendations for tomorrow”.

Adjuvant Therapy in Endometrial Cancer with Special Emphasis and Reference to Indian Setting

The incidence of endometrial cancer (EC) is on the rise in India. The median age at presentation is lesser than the Western population. Majority of the patients present in early stages with excellent overall survival rates after surgery. Adjuvant therapy is essential in high-risk stages I–III for improving outcomes. The quality and extent of surgery, and complete histopathological information are important factors for outcome and tailoring adjuvant therapy. Depending on patients and histopathological factors, various risk groups have been defined for prognostication and defining adjuvant therapy. Adjuvant therapy including external radiation, vaginal brachytherapy, chemotherapy and combined chemoradiotherapy has been tried depending on various risk groups. The purpose of this article is to review and interpret and update the results of existing literature on adjuvant therapy in EC with a special focus on Indian reports and standards.

Targeting Endometrial Cancer Stem Cell Activity with Metformin Is Inhibited by Patient-Derived Adipocyte-Secreted Factors.

Advanced endometrial cancer continues to have a poor prognosis, due to limited treatment options, which may be further adversely impacted by obesity. Endometrial cancer stem cells have been reported to drive metastasis, chemotherapy resistance and disease relapse, but have yet to be fully characterised and no specific targeted therapies have been identified. Here, we describe the phenotype and genotype of aldehyde dehydrogenase high (ALDHhigh) and CD133+ve endometrial cancer stem cells and how adipocyte secreted mediators block the inhibitory effect of metformin on endometrial cancer stem cell activity. Ishikawa and Hec-1a cell lines were used to characterise ALDHhigh and CD133+ve endometrial cancer cells using flow cytometry, functional sphere assays and quantitative-Polymerase Chain Reaction. The comparative effect of metformin on endometrial cancer stem cell activity and bulk tumour cell proliferation was determined using an Aldefluor and cytotoxicity assay. The impact of adipocyte secreted mediators on metformin response was established using patient-derived conditioned media. ALDHhigh cells demonstrated greater endometrial cancer stem cell activity than CD133+ve cells and had increased expression of stem cell and epithelial-mesenchymal transition genes. Treatment with 0.5–1 mM metformin reduced the proportion and activity of both endometrial cancer stem cell populations (p ≤ 0.05), without affecting cell viability. This effect was, however, inhibited by exposure to patient-derived adipocyte conditioned media. These results indicate a selective and specific effect of metformin on endometrial cancer stem cell activity, which is blocked by adipocyte secreted mediators. Future studies of metformin as an adjuvant therapy in endometrial cancer should be adequately powered to investigate the influence of body mass on treatment response.

Combined modality adjuvant therapy for high-risk endometrial cancer

Combined modality adjuvant therapy for high-risk endometrial cancer

Early-Stage Endometrial Cancer: Recurrence Pattern and Survival Analysis from a Tertiary Cancer Centre in South India

The incidence of endometrial cancer is rising in India possibly due to the change in lifestyle and urbanization. Recent years have also shown a change in the adjuvant therapy for endometrial cancer. We evaluated the pattern of recurrence and survival of stage I and II carcinoma endometrium treated at our institution during a 5-year period. This was a single-institution retrospective analysis where all patients with early (Stage I and II) endometrial cancers treated from January 2004 to December 2008 were included. Data were retrieved from the hospital electronic medical records and hospital-based cancer registry. Details regarding the disease, initial treatment, follow-up, recurrence, and present status of the patient were collected. During the study period, 103 women with early endometrial cancer were identified. Patients were classified into low-risk, low-intermediate risk (LIR), high-intermediate risk (HIR), and high-risk (HR) groups according to the risk stratification used by the PORTEC study group. There were no recurrences in the low-risk group, whereas 9 % of LIR, 13.7 % of HIR, and 66 % of high-risk group recurred. The recurrence pattern was also distinctive between the groups with LIR having more vault recurrences, HIR and HR groups having distant recurrences. The local recurrences were salvageable whereas the distant recurrences were not. Overall and disease-free survival were 96.35 and 86.6 %, respectively. Endometrial carcinoma is mostly detected in early stages and has an excellent prognosis. Risk stratification is a prognostic indicator and also deciding factor in offering adjuvant therapy. Majority of uterus confined disease falls under intermediate risk group. Recurrences in LIR are locoregional and are salvageable with RT, while recurrences in HIR and HR are distant and not salvageable. EBRT with VBT improved DFS in both LIR and HIR groups when compared with no adjuvant treatment.

Efficacy of raloxifene hydrochloride for the prevention of health care problems in patients who undergo surgery for endometrial cancer: a multicenter randomized clinical trial.

Removal of the ovaries is common during surgery for endometrial cancer. However, because loss of the ovaries can cause several health problems in patients, strategies for the prevention of such problems need to be established. Hence, we decided to conduct a multicenter randomized clinical trial to assess the effect of raloxifene on bone mineral density (BMD), bone metabolism, and the lipid profile of patients who had undergone surgery for patients with endometrial cancer. Patients with endometrial cancer were enrolled after treatment. The participants were randomized into 2 groups: group 1 included 39 women who received alfacalcidol (1 μg/d) alone and group 2 included 37 women who received alfacalcidol and the test drug, raloxifene hydrochloride, at a dose of 60 mg/d. The BMD of lumbar spine and femoral neck, serum bone markers, as well as lipid profile parameters were evaluated at enrollment as well as 6, 12, and 24 months after the enrollment. The primary efficacy end point was the percentage change from baseline to 24 months in lumbar spine (L2-L4) and femoral neck BMD. Sixty-four women completed the 24-month study. At 24 months, the lumbar and femoral neck BMDs were significantly increased in group 2 compared with group 1 (3.5% vs -0.8% and 2.3% vs -2.8%, respectively). In group 2, low-density lipoprotein-cholesterol levels were significantly reduced by 13.6% and serum N-terminal telopeptide of type I collagen as well as bone-specific alkaline phosphatase values were significantly reduced by 16.7% and 25.7%, respectively. The patients who received adjuvant therapy for endometrial cancer showed a significantly higher response to raloxifene (5.8% vs 1.9%). Recurrence was detected in 2 (2.6%) patients in group 1. No severe adverse events were noted in any patient during the study period. Raloxifene exerts positive effects on BMD, bone metabolism, and lipid profile parameters and could provide an improved therapeutic option for patients with endometrial cancer.

Absence of occult micrometastases in histologically negative lymph nodes among patients with distant recurrent endometrial cancer.

5606 Background: Lymph node metastasis is a criterion for adjuvant therapy in endometrial cancer (EC). The incidence of immunohistochemical (IHC) stain-positive micrometastases in H&E-negative lymp...

The role of postoperative radiation therapy for endometrial cancer: Executive Summary of an American Society for Radiation Oncology evidence-based guideline

PurposeTo present evidence-based guidelines for adjuvant radiation in the treatment of endometrial cancer. Methods and materialsKey clinical questions to be addressed in this evidence-based guideline on endometrial cancer were identified. A comprehensive literature review was performed to identify studies that included no adjuvant therapy, or pelvic radiation or vaginal brachytherapy with or without systemic chemotherapy. Outcomes included local control, survival rates, and overall assessment of quality of life. ResultsPatients with grade 1 or 2 cancers with either no invasion or <50% myometrial invasion (MI), especially when no other high risk features are present, can be safely observed after hysterectomy. Vaginal cuff brachytherapy is as effective as pelvic radiation therapy at preventing vaginal recurrence for patients with grade 1 or 2 cancers with ≥50% MI or grade 3 tumors with <50% MI. Patients with grade 3 cancer with ≥50% MI or cervical stroma invasion may benefit from pelvic radiation to reduce the risk of pelvic recurrence. There is limited evidence for a benefit to vaginal cuff brachytherapy following pelvic radiation. Multimodality treatment is recommended for patients with positive nodes or involved uterine serosa, ovaries or fallopian tubes, vagina, bladder, or rectum. ConclusionsExternal beam and vaginal brachytherapy remain integral aspects of adjuvant therapy for endometrial cancer.

Adjuvant therapy for endometrial cancer.

Endometrial cancer is a common gynecologic malignancy typically diagnosed at early stage and cured with surgery alone. Adjuvant therapy is tailored according to the risk of recurrence, estimated based on the International Federation of Gynecology and Obstetrics (FIGO) stage and other histological factors. The objective of this manuscript is to review the evidence guiding adjuvant therapy for early stage and locally advanced uterine cancer. For patients with early stage disease, minimizing toxicity, while preserving outstanding cure rates remains the major goal. For patients with locally advanced endometrial cancer optimal combined regimens are being defined. Risk stratification based on molecular traits is under development and may aid refine the current risk prediction model and permit personalized approaches for women with endometrial cancer.

RETIRED: The Role of Adjuvant Therapy in Endometrial Cancer

This document has been archived because it contains outdated information. It should not be consulted for clinical use, but for historical research only. Please visit the journal website for the most recent guidelines.

Antiproliferative and apoptotic effect of epigallocatechin-3-gallate on Ishikawa cells is accompanied by sex steroid receptor downregulation

Endometrial cancer is a significant malignancy in developed countries. Unopposed estrogen stimulation is considered as an important risk factor for endometrial cancer. Epigallocathechin-3-gallate (EGCG), biological active component of green tea, inhibits cancer cell proliferation. However, it is unknown whether EGCG has anticancer effects on endometrial cancer and what the molecular mechanism(s) are. We investigated the anticancer effects of EGCG on a human endometrial adenocarcinoma cell line (Ishikawa cells) with or without 17β-estradiol (E2) treatment. Cell proliferation assay was performed using 3-(4,5-dimethylthiaxol-2-yi)-2,5-diphenyltetraxolium bromide (MTT). The cell cycle was determined by flow cytometry and real-time analysis of cyclin and cdk genes. The apoptosis was measured by Annexin V-PI staining and real-time analysis of bcl-2, Bax and caspase genes. The MAPK signal, Akt and caspase-3 were determined by immunoblotting. Decreased estrogen and progesterone receptor expression was observed in EGCG-treated Ishikawa cells, and decreased MAPK signals and phospho-Akt were observed as well. EGCG caused the arrest of cells in the G0/G1 phase of the cell cycle. This compound interfered with Akt activation and MAPK signals, and increased apoptosis signals leading to a controlled caspases, Bcl-2, Bax genes and protein expression. Taken together, EGCG inhibits cell proliferation and induces apoptosis through Akt and MAPK signals. These findings suggest that EGCG may exert growth-inhibitory and apoptosis-inducing effects on endometrial cancer cells, accompanied by decreased estrogen and progesterone receptor. EGCG may have future clinical implications with respect to the development of novel approaches as an adjuvant therapy in endometrial cancer.

Controversies in the Adjuvant Therapy of Endometrial Cancer

Endometrial cancer is the most common malignancy of the female genital tract. Surgical treatment includes hysterectomy, bilateral salpingo-oophorectomy, and an appropriate staging procedure. Relapse of endometrial cancer may occur in patients with high risk factors, such as old age, grade 3 cancer, deep myometrial invasion, and papillary serous and clear cell types. In recent years, several randomized trials reported the results of adjuvant therapy for patients with high risk factors. Nonetheless, some controversies still exist. This paper presents and discusses the results of important randomized trials of adjuvant therapy for endometrial cancer with risk factors.