The first joint European Society for Medical Oncology (ESMO), European SocieTy for Radiotherapy & Oncology (ESTRO) and European Society of Gynaecological Oncology (ESGO) consensus conference on endometrial cancer was held on 11-13 December 2014 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of endometrial cancer. Before the conference, the expert panel prepared three clinically-relevant questions about endometrial cancer relating to the following four areas: prevention and screening, surgery, adjuvant treatment and advanced and recurrent disease. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. Results of this consensus conference, together with a summary of evidence supporting each recommendation, are detailed in this article. All participants have approved this final article.

https://ijgc.bmj.com/content/ijgc/26/1/2.full.pdf

ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer: Diagnosis, Treatment and Follow-up.

PURPOSE To evaluate the very long-term results of the randomized Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 trial for patients with Stage I endometrial carcinoma (EC), focusing on the role of prognostic factors for treatment selection and the long-term risk of second cancers. PATIENTS AND METHODS The PORTEC trial (1990-1997) included 714 patients with Stage IC Grade 1-2 or Stage IB Grade 2-3 EC. After surgery, patients were randomly allocated to external-beam pelvic radiotherapy (EBRT) or no additional treatment (NAT). Analysis was by intention to treat. RESULTS 426 patients were alive at the date of analysis. The median follow-up time was 13.3 years. The 15-year actuarial locoregional recurrence (LRR) rates were 6% for EBRT vs. 15.5% for NAT (p 60 (HR 3.9, p = 0.002 for LRR and 2.7, p = 0.01 for EC death) and myometrial invasion >50% (HR 1.9, p = 0.03 and HR 1.9, p = 0.02). CONCLUSIONS The 15-year outcomes of PORTEC-1 confirm the relevance of HIR criteria for treatment selection, and a trend for long-term risk of second cancers. EBRT should be avoided in patients with low- and intermediate-risk EC.

Fifteen-year radiotherapy outcomes of the randomized PORTEC-1 trial for endometrial carcinoma.

BACKGROUND: Information about lymphatics and lymphangiogenesis in the human endometrium is limited. We investigated the distribution of endometrial lymphatic vessels during the normal menstrual cycle and in association with endometrial adenocarcinoma and investigated the expression of lymphangiogenic growth factors, vascular endothelial growth factor (VEGF)-C, VEGF-D and VEGF receptor-3 (VEGF-R3). METHODS AND RESULTS: Full thickness uterine samples (n 5 23 proliferative; n 5 23 secretory) and endometrial adenocarcinoma samples (n 5 7 grade I; n 5 10 grade III) were collected for the study and analysed by immunohistochemistry and western blotting. Lymphatic vessels of the functionalis were significantly reduced compared with basalis (P 5 0.001) across the menstrual cycle with lymphatics of the basalis sometimes intimately associated with spiral arterioles. Lymphatic vessels of endometrial adenocarinomas were located intra-tumoural and peri-tumoural with significant increases in the peri-tumoural lymphatic vessels compared with normal basalis (P 5 0.02). Interestingly, highgrade adenocarcinoma vessels containing tumour emboli demonstrated a mixed blood/lymphatic endothelial cell phenotype. VEGF-C and VEGF-D were immunolocalized in glandular epithelium and some stromal cells with the staining intensity of this localization increasing in endometrial adenocarcinoma. Protein analysis identified VEGF-C (58, 41, 31 and 21 kD) and VEGF-D (56, 41, 31 and 21 kD) and VEGF-R3 (148 and 65 kD) peptides in normal endometrium, with significant increases in several of these peptides for VEGF-C and VEGF-D and no changes in protein expression for VEGF-R3 in endometrial adenocarcinoma. CONCLUSION: Endometrial lymphatics are significantly reduced in the functionalis, and increases in endometrial adenocarcinoma peri-tumoural lymphatics are associated with increases in VEGF-C and VEGF-D peptides.

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Lymphangiogensis of normal endometrium and endometrial adenocarcinoma

Background Postoperative radiation therapy for stage I endometrial cancer improves locoregional control but is without survival benefit. To facilitate treatment decision support for individual patients, accurate statistical models to predict locoregional relapse (LRR), distant relapse (DR), overall survival (OS), and disease-free survival (DFS) are required. Methods and Materials Clinical trial data from the randomized Post Operative Radiation Therapy for Endometrial Cancer (PORTEC-1; N=714 patients) and PORTEC-2 (N=427 patients) trials and registered group (grade 3 and deep invasion, n=99) were pooled for analysis (N=1240). For most patients (86%) pathology review data were available; otherwise original pathology data were used. Trial variables which were clinically relevant and eligible according to data constraints were age, stage, given treatment (pelvic external beam radiation therapy (EBRT), vaginal brachytherapy (VBT), or no adjuvant treatment, FIGO histological grade, depth of invasion, and lymph-vascular invasion (LVSI). Multivariate analyses were based on Cox proportional hazards regression model. Predictors were selected based on a backward elimination scheme. Model results were expressed by the c-index (0.5-1.0; random to perfect prediction). Two validation sets (n=244 and 291 patients) were used. Results Accuracy of the developed models was good, with training accuracies between 0.71 and 0.78. The nomograms validated well for DR (0.73), DFS (0.69), and OS (0.70), but validation was only fair for LRR (0.59). Ranking of variables as to their predictive power showed that age, tumor grade, and LVSI were highly predictive for all outcomes, and given treatment for LRR and DFS. The nomograms were able to significantly distinguish low- from high-probability patients for these outcomes. Conclusions The nomograms are internally validated and able to accurately predict long-term outcome for endometrial cancer patients with observation, pelvic EBRT, or VBT after surgery. These models facilitate decision support in daily clinical practice and can be used for patient counseling and shared decision making, selecting patients who benefit most from adjuvant treatment, and generating new hypotheses.

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Nomograms for Prediction of Outcome With or Without Adjuvant Radiation Therapy for Patients With Endometrial Cancer: A Pooled Analysis of PORTEC-1 and PORTEC-2 Trials

https://www.gynecologiconcology-online.net/article/S0090-8258(16)30002-6/pdf

Magnitude of risk for nodal metastasis associated with lymphvascular space invasion for endometrial cancer.

Purpose of investigation To evaluate whether lymphvascular space involvement (LVSI) is a risk factor for relapse of disease and lymph node metastasis in endometrial cancer Methods From 1978 till 2003, 609 patients with epithelial endometrial cancer were treated at the Groningen University Medical Center The association of LVSI and relapse of disease was evaluated in the total group of 609 patients and in a ‘ low' and ‘ high' risk stage I endometrial cancer group In 239 surgically staged patients, the relation of LVSI and lymph node metastasis was investigated Results The median age at diagnosis was 63 years (range 27- 92 years) with a median follow- up of 58 months (range 0- 236 months) More than half of the patients (56% ) received adjuvant radiotherapy LVSI was present in 123 patients (25,6% ), and a prognostic factor for relapse of disease (multivariate analysis, P 00001) In the ‘ low' and ‘ high' risk stage I endometrial cancer patients an increase of 26 times in relapse of disease was observed in the presence of LVSI LVSI positive tumors were more likely to have metastasized to the pelvic lymph nodes (multivariate analysis, P = 0001) In patients with proven negative nodes, LVSI was a prognostic factor for relapse of disease (univariate analysis, P = 002) Conclusion LVSI is a predictor of nodal disease and an independent prognostic factor for relapse of disease in all stages of endometrial cancer Patients with stage I endometrial cancer with positive LVSI are at risk for relapse of disease and might therefore benefit from adjuvant therapy Content The presence of lymphvascular space involvement (LVSI) in endometrial cancer is significantly and independently associated with an increased risk of pelvic lymph node metastases and/or relapse of disease

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Lymphvascular space involvement:An independent prognostic factor in endometrial cancer