Outcome of Endometrial Cancer Stage IIIA with Adnexa or Serosal Involvement Only

Objective. The aim of this study is to look at possible differences in outcome between serosa and adnexal involvement stage IIIA endometrial carcinoma. Methods. 67 patients with stage IIIA endometrial carcinoma were included, 46 with adnexal involvement and 21 with serosa. A central histopathological review was performed. Results. The 7-year locoregional failure rate was (LRFR) 2.2% for adnexal involvement and 16.0% for involvement of the serosa (P = .0522). The 7-year distant metastasis-free survival was 72.7% for adnexal involvement and 58.7% for serosa (P = .3994). The 7-year disease-specific survival (DSS) was 71.8% for patients with adnexal involvement and 75.4% for patients with serosa. Conclusion. Endometrial carcinoma stage IIIA with involvement of the adnexa or serosa showed to have a comparable disease-specific survival. Locoregional control was worse for serosa involvement compared to adnexa

Automated causal inference in application to randomized controlled clinical trials

Randomized controlled trials (RCTs) are considered the gold standard for testing causal hypotheses in the clinical domain; however, the investigation of prognostic variables of patient outcome in a hypothesized cause–effect route is not feasible using standard statistical methods. Here we propose a new automated causal inference method (AutoCI) built on the invariant causal prediction (ICP) framework for the causal reinterpretation of clinical trial data. Compared with existing methods, we show that the proposed AutoCI allows one to clearly determine the causal variables of two real-world RCTs of patients with endometrial cancer with mature outcome and extensive clinicopathological and molecular data. This is achieved via suppressing the causal probability of non-causal variables by a wide margin. In ablation studies, we further demonstrate that the assignment of causal probabilities by AutoCI remains consistent in the presence of confounders. In conclusion, these results confirm the robustness and feasibility of AutoCI for future applications in real-world clinical analysis

Short Androgen Suppression and Radiation Dose Escalation in Prostate Cancer:12-Year Results of EORTC Trial 22991 in Patients With Localized Intermediate-Risk Disease

The European Organisation for Research and Treatment of Cancer (EORTC) trial 22991 (NCT00021450) showed that 6 months of concomitant and adjuvant androgen suppression (AS) improves event- (EFS, Phoenix) and clinical disease-free survival (DFS) of intermediate- and high-risk localized prostatic carcinoma, treated by external-beam radiotherapy (EBRT) at 70-78 Gy. We report the long-term results in intermediate-risk patients treated with 74 or 78 Gy EBRT, as per current guidelines. Of 819 patients randomly assigned between EBRT or EBRT plus AS started on day 1 of EBRT, 481 entered with intermediate risk (International Union Against Cancer TNM 1997 cT1b-c or T2a with prostate-specific antigen (PSA) ≥ 10 ng/mL or Gleason ≤ 7 and PSA ≤ 20 ng/mL, N0M0) and had EBRT planned at 74 (342 patients, 71.1%) or 78 Gy (139 patients, 28.9%). We report the trial primary end point EFS, DFS, distant metastasis-free survival (DMFS), and overall survival (OS) by intention-to-treat stratified by EBRT dose at two-sided α = 5%. At a median follow-up of 12.2 years, 92 of 245 patients and 132 of 236 had EFS events in the EBRT plus AS and EBRT arm, respectively, mostly PSA relapse (48.7%) or death (45.1%). EBRT plus AS improved EFS and DFS (hazard ratio [HR] = 0.53; CI, 0.41 to 0.70; P < .001 and HR = 0.67; CI, 0.49 to 0.90; P = .008). At 10 years, DMFS was 79.3% (CI, 73.4 to 84.0) with EBRT plus AS and 72.7% (CI, 66.2 to 78.2) with EBRT (HR = 0.74; CI, 0.53 to 1.02; P = .065). With 140 deaths (EBRT plus AS: 64; EBRT: 76), 10-year OS was 80.0% (CI, 74.1 to 84.7) with EBRT plus AS and 74.3% (CI, 67.8 to 79.7) with EBRT, but not statistically significantly different (HR = 0.74; CI, 0.53 to 1.04; P = .082). Six months of concomitant and adjuvant AS statistically significantly improves EFS and DFS in intermediate-risk prostatic carcinoma, treated by irradiation at 74 or 78 Gy. The effects on OS and DMFS did not reach statistical significance

Role of Brachytherapy in the Postoperative Management of Endometrial Cancer: Decision-Making Analysis among Experienced European Radiation Oncologists.

BACKGROUND There are various society-specific guidelines addressing adjuvant brachytherapy (BT) after surgery for endometrial cancer (EC). However, these recommendations are not uniform. Against this background, clinicians need to make decisions despite gaps between best scientific evidence and clinical practice. We explored factors influencing decision-making for adjuvant BT in clinical routine among experienced European radiation oncologists in the field of gynaecological radiotherapy (RT). We also investigated the dose and technique of BT. METHODS Nineteen European experts for gynaecological BT selected by the Groupe Européen de Curiethérapie and the European Society for Radiotherapy & Oncology provided their decision criteria and technique for postoperative RT in EC. The decision criteria were captured and converted into decision trees, and consensus and dissent were evaluated based on the objective consensus methodology. RESULTS The decision criteria used by the experts were tumour extension, grading, nodal status, lymphovascular invasion, and cervical stroma/vaginal invasion (yes/no). No expert recommended adjuvant BT for pT1a G1-2 EC without substantial LVSI. Eighty-four percent of experts recommended BT for pT1a G3 EC without substantial LVSI. Up to 74% of experts used adjuvant BT for pT1b LVSI-negative and pT2 G1-2 LVSI-negative disease. For 74-84% of experts, EBRT + BT was the treatment of choice for nodal-positive pT2 disease and for pT3 EC with cervical/vaginal invasion. For all other tumour stages, there was no clear consensus for adjuvant treatment. Four experts already used molecular markers for decision-making. Sixty-five percent of experts recommended fractionation regimens of 3 × 7 Gy or 4 × 5 Gy for BT as monotherapy and 2 × 5 Gy for combination with EBRT. The most commonly used applicator for BT was a vaginal cylinder; 82% recommended image-guided BT. CONCLUSIONS There was a clear trend towards adjuvant BT for stage IA G3, stage IB, and stage II G1-2 LVSI-negative EC. Likewise, there was a non-uniform pattern for BT dose prescription but a clear trend towards 3D image-based BT. Finally, molecular characteristics were already used in daily decision-making by some experts under the pretext that upcoming trials will bring more clarity to this topic

The number of metastatic sites for stage IIIA endometrial carcinoma, endometrioid cell type, is a strong negative prognostic factor

The aim of this study was to look at the impact of the number of sites with tumour involvement on outcome for patients with stage IIIA endometrioid-type endometrial carcinoma.\ud \ud Patients and methods: 141 patients stage IIIA were included. A central histopathological review was performed. Patients staged solely on the presence of a positive peritoneal washing were excluded. Follow-up ranged from 2 to 217 months with a median of 43 months. Endpoints of the study were locoregional recurrence rates, distant metastasis-free survival (DMFS), disease-free survival (DFS) and disease-specific survival (DSS).\ud \ud Results: In multivariate analyses the number of involved sites showed to be the only independent significant variable for DMFS, DFS, and DSS with a Hazard Ratio of 2.1, 2.2, and 2.2, respectively. The DSS was significantly related to the number of involved sites, with a 5-year DSS of 70.4% for one site, 42.8% for two sites, and 43.9% for three sites, respectively (p = 0.001).\ud \ud Conclusion: The number of involved sites outside the corpus uterine for stage IIIA seems to be a strong negative prognostic factor for stage IIIA endometrial carcinoma

Radiation therapy combined with hyperthermia versus cisplatin for locally advanced cervical cancer: Results of the randomized RADCHOC trial

Background: Chemoradiation (RT-CT) is standard treatment for locally advanced cervical cancer (LACC). This study tried to establish if radiotherapy combined with hyperthermia (RT-HT) should be preferred in bulky and/or FIGO-stage >= III. Methods: In this open-label, multicenter randomized trial, patients with LACC were randomly assigned by a computer-generated, biased coin minimization technique to RT-CT or RT-HT. Central randomization was done with stratification by FIGO-stage, tumour diameter and nodal status. Primary endpoint was event free survival (EFS). Secondary endpoints were pelvic recurrence free survival (PRFS), overall survival (OS) and treatment related toxicity. Analysis was done by intention to treat. Results: The trial was closed prematurely (87 of 376 planned patients enrolled: 43 RT-CT; 44 RT-HT). Median follow-up time was 7.1 years. The cumulative incidence of an event was 33% in the RT-CT group and 35% in the RT-HT group. The corresponding hazard rate (HR) for EFS was 1.15 (CI: 0.56-2.36, p = 0.7). Also the hazards for PRFS (0.94; CI 0.36-2.44) and OS (1.04; CI 0.48-2.23) at 5 years were comparable between both treatment arms as was grade >= 3 radiation related late toxicity (6 RT-CT and 5 RT-HT patients). Conclusion: After 25% of intended accrual, data suggest comparable outcome for RT-CT and RT-HT

Substantial lymph-vascular space invasion (LVSI) is a significant risk factor for recurrence in endometrial cancer - A pooled analysis of PORTEC 1 and 2 trials

Abstract Background Lymph-vascular space invasion (LVSI) is an important adverse prognostic factor in endometrial cancer (EC). However, its role in relation to type of recurrence and adjuvant treatment is not well defined, and there is significant interobserver variation. This study aimed to quantify LVSI and correlate this to risk and type of recurrence. Methods In the post operative radiation therapy in endometrial carcinoma (PORTEC)-trials stage I EC patients were randomised to receive external beam radiotherapy (EBRT) versus no additional treatment after surgery (PORTEC-1, n = 714), or to EBRT versus vaginal brachytherapy (PORTEC-2, n = 427). In tumour samples of 926 (81.2%) patients with endometrioid tumours LVSI was quantified using 2-, 3- and 4-tiered scoring systems. Cox proportional hazard models were used for time-to-event analysis. Results Any degree of LVSI was identified in 129 cases (13.9%). Substantial LVSI (n = 44, 4.8%) using the 3-tiered approach had the strongest impact on the risk of distant metastasis (hazard ratio (HR) 4.5 confidence interval (CI) 2.4-8.5). In multivariate analysis (including: age, depth of myometrial invasion, grade, treatment) substantial LVSI remained the strongest independent prognostic factor for pelvic regional recurrence (HR 6.2 CI 2.4-16), distant metastasis (HR 3.6 CI 1.9-6.8) and overall survival (HR 2.0 CI 1.3-3.1). Only EBRT (HR 0.3 CI 0.1-0.8) reduced the risk of pelvic regional recurrence. Conclusions Substantial LVSI, in contrast to focal or no LVSI, was the strongest independent prognostic factor for pelvic regional recurrence, distant metastasis and overall survival. Therapeutic decisions should be based on the presence of substantial, not 'any' LVSI. Adjuvant EBRT and/or chemotherapy should be considered for stage I EC with substantial LVSI

Substantial lymph-vascular space invasion (LVSI) is a significant risk factor for recurrence in endometrial cancer - A pooled analysis of PORTEC 1 and 2 trials

Abstract Background Lymph-vascular space invasion (LVSI) is an important adverse prognostic factor in endometrial cancer (EC). However, its role in relation to type of recurrence and adjuvant treatment is not well defined, and there is significant interobserver variation. This study aimed to quantify LVSI and correlate this to risk and type of recurrence. Methods In the post operative radiation therapy in endometrial carcinoma (PORTEC)-trials stage I EC patients were randomised to receive external beam radiotherapy (EBRT) versus no additional treatment after surgery (PORTEC-1, n = 714), or to EBRT versus vaginal brachytherapy (PORTEC-2, n = 427). In tumour samples of 926 (81.2%) patients with endometrioid tumours LVSI was quantified using 2-, 3- and 4-tiered scoring systems. Cox proportional hazard models were used for time-to-event analysis. Results Any degree of LVSI was identified in 129 cases (13.9%). Substantial LVSI (n = 44, 4.8%) using the 3-tiered approach had the strongest impact on the risk of distant metastasis (hazard ratio (HR) 4.5 confidence interval (CI) 2.4-8.5). In multivariate analysis (including: age, depth of myometrial invasion, grade, treatment) substantial LVSI remained the strongest independent prognostic factor for pelvic regional recurrence (HR 6.2 CI 2.4-16), distant metastasis (HR 3.6 CI 1.9-6.8) and overall survival (HR 2.0 CI 1.3-3.1). Only EBRT (HR 0.3 CI 0.1-0.8) reduced the risk of pelvic regional recurrence. Conclusions Substantial LVSI, in contrast to focal or no LVSI, was the strongest independent prognostic factor for pelvic regional recurrence, distant metastasis and overall survival. Therapeutic decisions should be based on the presence of substantial, not 'any' LVSI. Adjuvant EBRT and/or chemotherapy should be considered for stage I EC with substantial LVSI

Improved Risk Assessment by Integrating Molecular and Clinicopathological Factors in Early-stage Endometrial Cancer-Combined Analysis of the PORTEC Cohorts

Purpose: Recommendations for adjuvant treatment for women with early-stage endometrial carcinoma are based on clinicopathologic features. Comprehensive genomic characterization defined four subgroups: p53-mutant, microsatellite instability (MSI), POLE-mutant, and no specific molecular profile (NSMP). We aimed to confirm the prognostic capacity of these subgroups in large randomized trial populations, investigate potential other prognostic classifiers, and integrate these into an integrated molecular risk assessment guiding adjuvant therapy. Experimental Design: Analysis of MSI, hotspot mutations in 14 genes including POLE, protein expression of p53, ARID1a, P-catenin, LICAM, PI EN, ER, and PR was undertaken on 947 available early-stage endometrioid endometrial carcinomas from the PORTEC-1 and -2 trials, mostly high-intermediate risk (n = 614). Prognostic value was determined using univariable and multivariable Cox proportional hazard models. AUCs of different risk stratification models were compared. Results: Molecular analyses were feasible in >96% of the patients and confirmed the four molecular subgroups: p53 mutant (9%), MSI (26%), POLE-mutant (6%), and NSMP (59%). Integration of prognostic molecular alterations with established clinicopathologic factors resulted in a stronger model with improved risk prognostication. Approximately 15% of high intermediate risk patients had unfavorable features (substantial lymphovascular space invasion, p53-mutant, and/or >10% LICAM), 50% favorable features (POLE-mutant, NSMP being microsatellite stable, and CTN NB 1 wild-type), and 35% intermediate features (MSI or CTNNB1-mutant). Conclusions: Integrating clinicopathologic and molecular factors improves the risk assessment of patients with early-stage endometrial carcinoma. Assessment of this integrated risk profile is feasible in daily practice, and holds promise to reduce both overtreatment and undertreatment. (C) 2016 AACR