BACKGROUND: Vaginal brachytherapy is currently recommended as adjuvant treatment in patients with high-intermediate risk endometrial cancer to maximize local control and has only mild side effects and no or limited impact on quality of life. However, there is still considerable overtreatment and also some undertreatment, which may be reduced by tailoring adjuvant treatment to the patients' risk of recurrence based on molecular tumor characteristics. PRIMARY OBJECTIVES: To compare the rates of vaginal recurrence in women with high-intermediate risk endometrial cancer, treated after surgery with molecular-integrated risk profile-based recommendations for either observation, vaginal brachytherapy or external pelvic beam radiotherapy or with standard adjuvant vaginal brachytherapy STUDY HYPOTHESIS: Adjuvant treatment based on a molecular-integrated risk profile provides similar local control and recurrence-free survival as current standard adjuvant brachytherapy in patients with high-intermediate risk endometrial cancer, while sparing many patients the morbidity of adjuvant treatment and reducing healthcare costs. TRIAL DESIGN: A multicenter, international phase III randomized trial (2:1) of molecular-integrated risk profile-based adjuvant treatment (experimental arm) or adjuvant vaginal brachytherapy (standard arm). MAJOR INCLUSION/EXCLUSION CRITERIA: Women aged 18 years and over with a histological diagnosis of high-intermediate risk endometrioid endometrial cancer after total abdominal or laparoscopic hysterectomy and bilateral salpingo-oophorectomy. High-intermediate risk factors are defined as: (i) International Federation of Gynecology and Obstetrics stage IA (with invasion) and grade 3; (ii) stage IB grade 1 or 2 with age ≥60 and/or lymph-vascular space invasion; (iii) stage IB, grade 3 without lymph-vascular space invasion; or (iv) stage II (microscopic and grade 1). ENDPOINTS: The primary endpoint is vaginal recurrence. Secondary endpoints are recurrence-free and overall survival; pelvic and distant recurrence; 5-year vaginal control (including treatment for relapse); adverse events and patient-reported symptoms and quality of life; and endometrial cancer-related healthcare costs. SAMPLE SIZE: 500 eligible and evaluable patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Estimated date for completing accrual will be late 2021. Estimated date for presentation of (first) results is expected in 2023. TRIAL REGISTRATION: The trial is registered at clinicaltrials.gov (NCT03469674) and ISRCTN (11659025).

Biomedical Data Sciences Leiden University Medical Center Leiden Zuid Holland The Netherlands

Comprehensive Cancer Centre Utrecht Utrecht The Netherlands

Gynecologic Oncology Centre Department of Obstetrics and Gynaecology 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Medical Statistics Leiden University Medical Center Leiden Zuid Holland The Netherlands

Obstetrics and Gynecology University Medical Centre Groningen University of Groningen Groningen Groningen The Netherlands

Pathology Leiden University Medical Center Leiden Zuid Holland The Netherlands

Radation Oncology Radiotherapy Group Arnhem Gelderland The Netherlands

Radiation Oncology Amsterdam University Medical Centers University of Amsterdam Amsterdam Noord Holland The Netherlands

Radiation Oncology Catharina Hospital Eindhoven Noord Brabant The Netherlands

Radiation Oncology Erasmus Medical Center Cancer Institute Rotterdam Zuid Holland The Netherlands

Radiation Oncology Haaglanden Medical Center Den Haag Zuid Holland The Netherlands

Radiation Oncology Institut Gustave Roussy Villejuif Île de France France

Radiation Oncology Institute Verbeeten Tilburg Noord Brabant The Netherlands

Radiation Oncology Isala Klinieken Zwolle Overijssel The Netherlands

Radiation Oncology Leiden University Medical Center Leiden Zuid Holland The Netherlands

Radiation Oncology Maastricht University Medical Centre Maastricht Limburg The Netherlands

Radiation Oncology Netherlands Cancer Institute Amsterdam Noord Holland The Netherlands

Radiation Oncology Radboudumc Nijmegen Gelderland The Netherlands

Radiation Oncology Radiotherapy Institute Friesland Leeuwarden Friesland The Netherlands

Radiation Oncology St Luke's Hospital Dublin Dublin Ireland

Radiation Oncology University Hospital Ghent Gent Oost Vlaanderen Belgium

Radiation Oncology University Medical Centre Groningen University of Groningen Groningen Groningen The Netherlands

Radiation Oncology University Medical Centre Utrecht Utrecht The Netherlands

Radiation Oncology Zuidwest Radiotherapeutic Institute Vlissingen Zeeland The Netherlands

Women's Health Rotkreuzklinikum Munchen Munchen Bayern Germany

Women's Health Universitätsklinikum Tübingen Tübingen Baden Württemberg Germany

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Colombo N, Creutzberg C, Amant F, et al. . ESMO-ESGO-ESTRO consensus conference on endometrial cancer: diagnosis, treatment and follow-up. Int J Gynecol Cancer 2016;26:2–30. 10.1097/IGC.0000000000000609 PubMed DOI PMC

ASTEC/EN.5 Study Group, Blake P, Swart AM, et al. . Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis. Lancet 2009;373:137–46. 10.1016/S0140-6736(08)61767-5 PubMed DOI PMC

Creutzberg CL, van Putten WLJ, Koper PCM, et al. . Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. Lancet 2000;355:1404–11. 10.1016/S0140-6736(00)02139-5 PubMed DOI

Keys HM, Roberts JA, Brunetto VL, et al. . A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2004;92:744–51. 10.1016/j.ygyno.2003.11.048 PubMed DOI

Nout RA, Smit VTHBM, Putter H, et al. . Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial. Lancet 2010;375:816–23. 10.1016/S0140-6736(09)62163-2 PubMed DOI

Creutzberg CL, Nout RA, Lybeert MLM, et al. . Fifteen-year radiotherapy outcomes of the randomized PORTEC-1 trial for endometrial carcinoma. Int J Radiat Oncol Biol Phys 2011;81:e631–8. 10.1016/j.ijrobp.2011.04.013 PubMed DOI

Bosse T, Peters EEM, Creutzberg CL, et al. . 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. Eur J Cancer 2015;51:1742–50. 10.1016/j.ejca.2015.05.015 PubMed DOI

Wortman BG, Creutzberg CL, Putter H, et al. . Ten-year results of the PORTEC-2 trial for high-intermediate risk endometrial carcinoma: improving patient selection for adjuvant therapy. Br J Cancer 2018;119:1067–74. 10.1038/s41416-018-0310-8 PubMed DOI PMC

Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al. . Integrated genomic characterization of endometrial carcinoma. Nature 2013;497:67–73. 10.1038/nature12113 PubMed DOI PMC

Talhouk A, McConechy MK, Leung S, et al. . A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer 2015;113:299–310. 10.1038/bjc.2015.190 PubMed DOI PMC

Stelloo E, Nout RA, Osse EM, et al. . Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC cohorts. Clin Cancer Res 2016;22:4215–24. 10.1158/1078-0432.CCR-15-2878 PubMed DOI

Kommoss FK, Karnezis AN, Kommoss F, et al. . L1Cam further stratifies endometrial carcinoma patients with no specific molecular risk profile. Br J Cancer 2018;119:480–6. 10.1038/s41416-018-0187-6 PubMed DOI PMC

Wortman BG, Bosse T, Nout RA, et al. . Molecular-integrated risk profile to determine adjuvant radiotherapy in endometrial cancer: evaluation of the pilot phase of the PORTEC-4a trial. Gynecol Oncol 2018;151:69–75. 10.1016/j.ygyno.2018.07.020 PubMed DOI

León-Castillo A, Gilvazquez E, Nout R, et al. . Clinicopathological and molecular characterisation of 'multiple-classifier' endometrial carcinomas. J Pathol 2020;250:312–22. 10.1002/path.5373 PubMed DOI PMC

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ClinicalTrials.gov
NCT03469674

ISRCTN
ISRCTN11659025