Randomized Trial of Radiation Therapy With or Without Chemotherapy for Endometrial Cancer

Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): 10-year clinical outcomes and post-hoc analysis by molecular classification from a randomised phase 3 trial

The PORTEC-3 trial investigated the benefit of chemoradiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We present the preplanned long-term analysis of the randomised PORTEC-3 trial with a post-hoc analysis including molecular classification of the tumours. PORTEC-3 was an open-label, multicentre, randomised, international phase 3 trial. Women were eligible if they had high-risk endometrial cancer (either International Federation of Gynecology and Obstetrics 2009 stage I, grade 3, with deep myometrial invasion and/or lymphovascular space invasion; stage II-III; or stage I-III with serous or clear-cell histology), were aged 18 years or older, and had a WHO performance score of 0-2. Participants were randomly assigned (1:1) to receive pelvic radiotherapy (48·6 Gy in 1·8 Gy fractions) or chemoradiotherapy (radiotherapy combined with two cycles of cisplatin 50 mg/m Between Nov 23, 2006, and Dec 20, 2013, 660 eligible and evaluable patients recruited at 103 centres in six clinical trial groups across seven countries were randomly assigned to chemoradiotherapy (n=330) or radiotherapy alone (n=330). Median follow-up was 10·1 years (IQR 9·8-11·0). Estimated 10-year overall survival was 74·4% (95% CI 69·8-79·4) in the chemoradiotherapy group and 67·3% (62·3-72·7) in the radiotherapy group (adjusted hazard ratio [HR] 0·73 [95% CI 0·54-0·97], p=0·032), and 10-year recurrence-free survival was 72·8% (67·2-77·6) versus 67·4% (61·7-72·4; adjusted HR 0·74 [95% CI 0·56-0·98], p=0·034). Molecular analysis was available for 411 (62%) patients (210 [64%] of 330 patients in the chemoradiotherapy group and 201 [61%] of 330 patients in the radiotherapy group), whose characteristics were similar to the overall trial population. Post-hoc analysis by molecular class showed that, for women with p53 abnormal tumours, 10-year overall survival was 52·7% (95% CI 40·8-68·1) with chemoradiotherapy versus 36·6% (25·0 to 53·7) with radiotherapy alone (adjusted HR 0·52 [95% CI 0·30-0·91], p=0·021); 10-year recurrence-free survival was 52·6% (95% CI 38·3 to 65·0) versus 37·0% (95% CI 23·7 to 50·2; HR 0·42 [95% CI 0·24 to 0·74], p=0·0027). MMRd and POLEmut cancers did not seem to benefit from chemoradiotherapy over radiotherapy alone, whereas the effects for NSMP cancers were modulated by oestrogen-receptor status. 10-year overall survival and recurrence-free survival were improved for patients with high-risk endometrial cancer treated with adjuvant chemoradiotherapy versus radiotherapy alone, with most clinically relevant benefit suggested for p53 abnormal cancers. Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council Australia, Cancer Australia, Italian Medicines Agency, and the Canadian Cancer Society Research Institute.

Long-Term Toxicity and Health-Related Quality of Life After Adjuvant Chemoradiation Therapy or Radiation Therapy Alone for High-Risk Endometrial Cancer in the Randomized PORTEC-3 Trial

The survival results of the PORTEC-3 trial showed a significant improvement in both overall and failure-free survival with chemoradiation therapy versus pelvic radiation therapy alone. The present analysis was performed to compare long-term adverse events (AE) and health-related quality of life (HRQOL). In the study, 660 women with high-risk endometrial cancer were randomly assigned to receive chemoradiation therapy (2 concurrent cycles of cisplatin followed by 4 cycles of carboplatin/paclitaxel) or radiation therapy alone. Toxicity was graded using Common Terminology Criteria for Adverse Events, version 3.0. HRQOL was measured using EORTC QLQ-C30 and CX24/OV28 subscales and compared with normative data. An as-treated analysis was performed. Median follow-up was 74.6 months; 574 (87%) patients were evaluable for HRQOL. At 5 years, grade ≥2 AE were scored for 78 (38%) patients who had received chemoradiation therapy versus 46 (24%) who had received radiation therapy alone (P = .008). Grade 3 AE did not differ significantly between the groups (8% vs 5%, P = .18) at 5 years, and only one new late grade 4 toxicity had been reported. At 3 and 5 years, sensory neuropathy toxicity grade ≥2 persisted after chemoradiation therapy in 6% (vs 0% after radiation therapy, P < .001) and more patients reported significant tingling or numbness at HRQOL (27% vs 8%, P < .001 at 3 years; 24% vs 9%, P = .002 at 5 years). Up to 3 years, more patients who had chemoradiation therapy reported limb weakness (21% vs 5%, P < .001) and lower physical (79 vs 87, P < .001) and role functioning (78 vs 88, P < .001) scores. Both treatment groups reported similar long-term global health/quality of life scores, which were better than those of the normative population. This study shows a long-lasting, clinically relevant, negative impact of chemoradiation therapy on toxicity and HRQOL, most importantly persistent peripheral sensory neuropathy. Physical and role functioning impairments were seen until 3 years. These long-term data are essential for patient information and shared decision-making regarding adjuvant chemotherapy for high-risk endometrial cancer.

Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy

PURPOSE The randomized Adjuvant Chemoradiotherapy Versus Radiotherapy Alone in Women With High-Risk Endometrial Cancer (PORTEC-3) trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy (CTRT) versus radiotherapy alone (RT) for women with high-risk endometrial cancer (EC). Because The Cancer Genome Atlas defined an EC molecular classification with strong prognostic value, we investigated prognosis and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants. METHODS Paraffin-embedded tissues of 423 consenting patients were collected. Immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE exonuclease domain were done to classify tumors as p53 abnormal (p53abn), POLE-ultramutated ( POLEmut), MMR-deficient (MMRd), or no specific molecular profile (NSMP). The primary end point was recurrence-free survival (RFS). Kaplan-Meier method, log-rank test, and Cox model were used for analysis. RESULTS Molecular analysis was successful in 410 high-risk EC (97%), identifying the 4 subgroups: p53abn EC (n = 93; 23%), POLEmut (n = 51; 12%), MMRd (n = 137; 33%), and NSMP (n = 129; 32%). Five-year RFS was 48% for patients with p53abn EC, 98% for POLEmut EC, 72% for MMRd EC, and 74% for NSMP EC ( P &lt; .001). The 5-year RFS with CTRT versus RT for p53abn EC was 59% versus 36% ( P = .019); 100% versus 97% for patients with POLEmut EC ( P = .637); 68% versus 76% ( P = .428) for MMRd EC; and 80% versus 68% ( P = .243) for NSMP EC. CONCLUSION Molecular classification has strong prognostic value in high-risk EC, with significantly improved RFS with adjuvant CTRT for p53abn tumors, regardless of histologic type. Patients with POLEmut EC had an excellent RFS in both trial arms. EC molecular classification should be incorporated in the risk stratification of these patients as well as in future trials to target specific subgroups of patients.

Prevalence and Prognosis of Lynch Syndrome and Sporadic Mismatch Repair Deficiency in Endometrial Cancer

Abstract Background Standard screening of endometrial cancer (EC) for Lynch syndrome (LS) is gaining traction; however, the prognostic impact of an underlying hereditary etiology is unknown. We established the prevalence, prognosis, and subsequent primary cancer incidence of patients with LS-associated EC in relation to sporadic mismatch repair deficient (MMRd)-EC in the large combined Post Operative Radiation Therapy in Endometrial Carcinoma-1, -2, and -3 trial cohort. Methods After MMR-immunohistochemistry, MLH1-promoter methylation testing, and next-generation sequencing, tumors were classified into 3 groups according to the molecular cause of their MMRd-EC. Kaplan-Meier method, log-rank test, and Cox model were used for survival analysis. Competing risk analysis was used to estimate the subsequent cancer probability. All statistical tests were 2-sided. Results Among the 1336 ECs, 410 (30.7%) were MMRd. A total of 380 (92.7%) were fully triaged: 275 (72.4%) were MLH1-hypermethylated MMRd-ECs; 36 (9.5%) LS MMRd-ECs, and 69 (18.2%) MMRd-ECs due to other causes. Limiting screening of EC patients to 60 years or younger or to 70 years or younger would have resulted in missing 18 (50.0%) and 6 (16.7%) LS diagnoses, respectively. Five-year recurrence-free survival was 91.7% (95% confidence interval [CI] = 83.1% to 100%; hazard ratio = 0.45, 95% CI = 0.16 to 1.24, P = .12) for LS, 95.5% (95% CI = 90.7% to 100%; hazard ratio = 0.17, 95% CI = 0.05 to 0.55, P = .003) for “other” vs 78.6% (95% CI = 73.8% to 83.7%) for MLH1-hypermethylated MMRd-EC. The probability of subsequent LS-associated cancer at 10 years was 11.6% (95% CI = 0.0% to 24.7%), 1.5% (95% CI = 0.0% to 4.3%), and 7.0% (95% CI = 3.0% to 10.9%) within the LS, “other,” and MLH1-hypermethylated MMRd-EC groups, respectively. Conclusions The LS prevalence in the Post Operative Radiation Therapy in Endometrial Carcinoma trial population was 2.8% and among MMRd-ECs was 9.5%. Patients with LS-associated ECs showed a trend towards better recurrence-free survival and higher risk for second cancers compared with patients with MLH1-hypermethylated MMRd-EC.

Alexandra Leary

Carien Creutzberg

Carien Creutzberg is Professor of Radiation Oncology, specialised in Radiation Therapy for Gynecological Cancers, at the Department of Radiation Oncology at Leiden University Medical Center, the Netherlands. She has completed clinical training in Radiation Oncology at the Daniel den Hoed Cancer Center in Rotterdam in 1993, and has defended her PhD thesis at the Erasmus University Rotterdam in 1998. She started as associate professor at Leiden University Medical Centre in 2000, and continued to combine patient care with clinical research and teaching of students and residents. She was appointed full professor as of August 2012. Her scientific and educational activities are consistent with her specialisation in Gynecologic Oncology. She has been initiator and principal investigator of the PORTEC-1 (1990-97), PORTEC-2 (2002-06), PORTEC-3 (2006-2013) and PORTEC-4 (ongoing) trials, and has been awarded Dutch Cancer Society Grants for all of the PORTEC trials, a translational research project and two patient rehabilitation projects. She has been one of the initiators of the Dutch Gynecologic Oncology Group, of which she is board member. She has been Council member of the European Society of Gynaecological Oncology from 2013-2017, and is currently co-chair of the GCIG Endometrial Cancer Committee, ESMO Faculty Member for the Gynaecological Cancer Track and member of the Dutch Cancer Society Scientific Board. She has been member of the Uterine Corpus Cancer Task Force of the National Cancer Institute USA (2007-2013), Council member of the International Gynecologic Cancer Society (2008-2012), and Senior Editor of Int J Gynecol Cancer. She has been supervising PhD theses on clinical and translational research based on the PORTEC-trials and related studies since 2008. She has been invited speaker at numerous national and international scientific meetings on Gynecologic Oncology and Radiation Oncology, and has written over 120 scientific articles, book chapters and commentaries. Her research in radiation therapy for endometrial cancer has had clear impact on treatment guidelines and research programs for Endometrial Cancer worldwide

Cathelijne Post

Dina Ruano

Emma J Crosbie

Lisa Vermij

Maartje Nielsen

Maartje started her clinical genetics training at the LUMC and received this degree in December 2012. In 2011, she received a PhD in medicine with a thesis on MUTYH- and APC-associated polyposis. She is a clinical geneticist at the LUMC's Department of Clinical Genetics. In 2012, she was rewarded with a personal grant from the Dutch Cancer Society (KWF). After that, she received more grants (in cooperation with other research groups) from the Dutch Digestive Disease Foundation and KWF, which enabled her to do research besides clinical work. She has received several awards for her research, such as the Marie Parijs Prize for upcoming researchers in the LUMC, the Dick-Held Thesis Prize 2012, the LUMC Thesis Award 2011, and the Janssen Gastrointestinal Research Prize 2012. Her main research interests include analyzing cancer risk in genetically predisposed families and estimating associations between risk factors, genetic and external, and cancer incidence. She successfully set up (inter) national large clinical databases of families with a specific genetic background. For example, starting in 2004, she generated a clinical database of MUTYH associated in the Netherlands, and in collaboration with the universities of Cardiff and Bonn, we gathered the largest patient group of this disease in the world (over 300 MAP patients). With this large amount of clinical data, she could describe the clinical phenotype, cancer risks, extracolonic manifestations, geno-phenotype correlations, molecular and histological characteristics of cancer tissue, and construct surveillance guidelines for MAP patients. Outcomes have been implemented in the genetic and gastroenterology practice. From 2011, the same procedure was used to assemble the world's largest cohorts of PMS2 patients, including Dutch patients and their families, as well as several families from other European countries. In 2014 and 2018, PMS2 cancer risk studies were published in the Journal of Clinical Oncology. Furthermore, over 400 patients with unexplained polyposis were assembled to analyze whether APC mosaic mutations were present. With this strategy, we have already discovered mosaic in over 50 patients; we are now analyzing the phenotype and will recommend screening guidelines for this group of patients. Also, we discovered that one-third of the patients with unexplained polyposis likely have a somatic APC DNA defect due to a genotoxin colibactin produced by Escherichia coli, which explains a major part of the adenoma development in these cases. The LUMC holds the expertise center for BAP1 tumor predisposition syndrome in the Netherlands. Research focuses on analyzing cancer risk in patients with BAP1-TPDS, determining the diagnostic yield and false-positive surveillance rate, and studying molecular aspects of BAP1-TPDS tumors compared to sporadic tumors. Lastly, Maartje is involved in the infrastructure for The Netherlands Genetic Tumour Risk Registry (NESTOR) to accelerate research on hereditary cancer; an ICT infrastructure project started in June 2024 that aims to build a central data registry and portal for patients, professionals, and scientists.

Nanda Horeweg

Assistant professor @ Department of Radiation Oncology - Leiden University Medical Center - the Netherlands. Clinical Epidemiologist. Methodological lead and contributions to clinical trials, such as PORTEC 4a, RAINBO platform trials and PROQEM, and international research consortia such as TransPORTEC and AIR-MEC.

Paul Bessette

Professeur, Faculté de médecine et des sciences de la santé FMSS Département d'obstétrique-gynécologie Sujet de recherche Cancer de l'appareil reproducteur, Cancer héréditaire, Gènes de susceptibilité, Signalisation cellulaire et cancer, Chimiothérapie, Prévention en santé Disciplines de recherche Obstétrique et gynécologie, Oncologie Intérêts de recherche Au plan clinique, Dr Paul Bessette étudie les antiangiogènes et les modificateurs de la réponse dans le traitement des cancers gynécologiques. Des essais cliniques basés sur la médecine personnalisée, tenant compte des particularités de chaque patiente, mais aussi des caractéristiques (profil moléculaire) de la tumeur, sont aussi à l’étude. Au plan fondamental, en plus de participer à la banque de tissus ovariens du CHUS, une étroite collaboration du Dr Paul Bessette avec les chercheurs fondamentaux de l'établissement vise à une meilleure compréhension de la biologie, de l’auto-immunité et de la chimiorésistance associée au cancer. Une meilleure compréhension de ces aspects mènera à un changement de la vision du traitement empirique des cancers gynécologiques vers des traitements individualisés. Expérience académique Professeur Titulaire Plein Temps Universitaire (PTU). (2009-). Université de Sherbrooke. Canada. Professeur Agrégé Plein Temps Universitaire (PTU). (2000-2009). Université de Sherbrooke. Canada. Professeur Adjoint Plein Temps Universitaire (PTU). (1997-2000). Université de Sherbrooke. Canada. Professeur d'Enseignement Clinique (PEC). (1995-1997). Université de Sherbrooke. Canada. Prix et distinctions Carl Nimrod award - Université Sherbrooke. Association of Academic Professionals in Obstetrics and Gynaecology (APOG). (Distinction). Certificat de mérite - Université de Sherbrooke. Association Canadienne pour l'Éducation Médicale (ACÉM). (Prix). Contribution exemplaire. Regroupement des Gynécologues Oncologues du Québec (RGOQ). (Honneur). Excellence in teaching award. Association of Professors of Gynecology and Obstetrics (APGO). (Prix). Excellence pédagogique. Département d'obstétrique et de gynécologie du CHUS et de l'Université de Sherbrooke. (Prix). Mention spéciale de l'innovation pédagogique en développement professionnel continu. Faculté de Médecine et des Sciences de la Santé de l'Université de Sherbrooke. (Prix). National faculty award for excellence in resident education. Council on Resident Education in Obstetrics and Gynecology (CREOG). (Prix). Prix collectif du mérite - INHERIT BRCAs. Conseil Québécois de Lutte contre le Cancer (CQLC). (Prix). Prix collectif de la Fédération des Associations des Étudiantes et étudiants en Médecine du Québec (FAÉMQ). Fédération médicale étudiante du Québec (FMEQ). (Prix).

Tessa A Rutten