PORTEC-4a: Molecular Profile-based Versus Standard Adjuvant Radiotherapy in Endometrial Cancer (PORTEC-4a)

Randomised Phase III Trial of Molecular Profile-based Versus Standard Recommendations for Adjuvant Radiotherapy for Women With Early Stage Endometrial Cancer: PORTEC-4a Trial

This is prospective, multicenter, randomised phase III trial among women with endometrial cancer with high-intermediate risk features to investigate the role of an integrated clinicopathological and molecular risk profile to determine if participants should receive no adjuvant therapy, vaginal brachytherapy or external beam radiotherapy based on a favourable, intermediate or unfavourable profile as compared to standard adjuvant vaginal brachytherapy.

Study Overview

• Status: Active, not recruiting
• Conditions: Endometrial Cancer Stage I; Endometrial Cancer Stage II
• Intervention / Treatment: Radiation: Vaginal brachytherapy; Radiation: External beam radiotherapy; Other: Observation

Detailed Description

Adjuvant therapy for women with endometrial cancer has increasingly been tailored to prognostic factors to prevent overtreatment and select those women for adjuvant treatment who will have a clinically relevant reduction of the risk of relapse by the adjuvant treatment. Risk profiles have traditionally been based on clinicopathological factors such as age, stage, grade, LVSI and depth of invasion. Newer, both molecular-genetic (the cancer genome atlas subgroups) or immunohistochemistry-based (L1-CAM) risk factors have become available which are strongly related to outcomes and risk of cancer spread. In a comprehensive analysis of the PORTEC-1 and-2 biobank an integrated clinicopathological and molecular risk profile was determined which separated the current high-intermediate risk group of endometrial cancer in 3 separate groups (favourable, intermediate or unfavourable) with clearly separated outcomes, which is now prospectively tested in the clinic to determine adjuvant treatment. This is the first randomised trial using the molecular risk factors to assign adjuvant treatment for women with stage I-II high-intermediate risk endometrial cancer.

• Study Type: Interventional
• Enrollment (Estimated): 550
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria
    • Medical University, Vienna
• Belgium
  • Gent, Belgium
    • University Hospital Gent
• Czechia
  • Praha, Czechia
    • CEEGOG, General Faculty Hospital and First Faculty of Medicine, Charles University, Prague
• France
  • Paris, France
    • Hôpital Européen Georges-Pompidou
  • Paris, France
    • Hopital Tenon
  • Paris, France
    • GINECO group - Institut Goustave Roussy
• Germany
  • Berlin, Germany
    • Sankt Gertrauden Krankenhaus
  • Düsseldorf, Germany
    • Kaiserswerther Diakonie
  • Essen, Germany
    • Evang. Kliniken Essen-Mitte
  • Heidelberg, Germany
    • Universitätsklinikum Heidelberg
  • Lübeck, Germany
    • Universitätsklinikum Schleswig-Holstein, Campus Lübeck
  • Münich, Germany
    • Rotkreuzklinikum Munchen
  • Tübingen, Germany
    • University Hospital
• Ireland
  • Dublin, Ireland
    • CancerTrials Ireland - St James Hospital (SLRON SJH)
  • Dublin, Ireland
    • CancerTrials Ireland - St Luke's Hospital (SLRON SLH)
• Netherlands
  • Amsterdam, Netherlands
    • Academic Medical Center
  • Amsterdam, Netherlands
    • NKI / Antoni van Leeuwenhoekhuis
  • Arnhem, Netherlands
    • Radiation Therapy Group
  • Den Haag, Netherlands
    • Haaglanden Medical Center
  • Eindhoven, Netherlands
    • Catharina Hospital
  • Groningen, Netherlands
    • University Medical Center Groningen
  • Leeuwarden, Netherlands
    • Radiotherapy Institute Friesland
  • Leiden, Netherlands
    • Leiden University Medical Center
  • Maastricht, Netherlands
    • MAASTRO radiation oncology clinic
  • Nijmegen, Netherlands
    • Radboud University Medical Center
  • Rotterdam, Netherlands
    • ErasmusMC Cancer Center
  • Tilburg, Netherlands
    • Verbeeten Institute
  • Utrecht, Netherlands
    • University Medical Center Utrecht
  • Vlissingen, Netherlands
    • Zuidwest Radiotherapy Institute
  • Zwolle, Netherlands
    • Isala Clinics
• Switzerland
  • Lucerne, Switzerland
    • Kantonsspital Frauenklinik Lucerne

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically confirmed endometrioid type endometrial carcinoma, International Federation of Gynecology and Obstetrics (FIGO) 2009 stage I, with one of the following combinations of stage, grade, age, and lymph-vascular space invasion (LVSI):

  1. Stage IA, grade 3 (any age, with or without LVSI)
  2. Stage IB, grade 1 or 2 and age >60 years
  3. Stage IB, grade 1-2 with documented LVSI
  4. Stage IB, grade 3 without LVSI
  5. Stage II (microscopic), grade 1
• World Health Organization (WHO)-performance status 0-2
• Written informed consent

Exclusion Criteria:

• Any other stage and type of endometrial carcinoma
• Histological types serous carcinoma or clear cell carcinoma (at least 10% if mixed type), or undifferentiated or neuroendocrine carcinoma
• Uterine sarcoma (including carcinosarcoma)
• Previous malignancy (except for non-melanomatous skin cancer) < 5 yrs
• Previous pelvic radiotherapy
• Expected interval between the operation and start of radiotherapy exceeding 8 weeks

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Molecular profile based treatment; Determination of the integrated clinicopathological and molecular profile to determine adjuvant treatment: observation for favourable profile; vaginal brachytherapy for intermediate profile; external beam radiotherapy for unfavourable profile	Radiation: Vaginal brachytherapy; Internal radiation of the vaginal vault using a vaginal cylinder, 21 Gy in 3 out-patient sessions over 2 weeks; Radiation: External beam radiotherapy; External beam pelvic radiotherapy on a linear accelerator, 48.6 Gy in 27 out-patients sessions over 5.5 weeks; Other: Observation; No radiation therapy, but active follow-up and quality of life questionnaires as in the groups who have adjuvant treatment
Active Comparator: Vaginal brachytherapy; Adjuvant vaginal brachytherapy (standard treatment)	Radiation: Vaginal brachytherapy; Internal radiation of the vaginal vault using a vaginal cylinder, 21 Gy in 3 out-patient sessions over 2 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vaginal recurrence	Total vaginal recurrence and vaginal recurrence as first failure	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Treatment-related symptoms according to CTCAE v 4.0	5 years
Health-related cancer-specific quality of life	Cancer-specific quality of life (European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQC-30) - clinically relevant changes on QLQC30 functioning scales, general quality of life and general cancer symptoms	5 years
Endometrial cancer-related symptoms and quality of life	Endometrial cancer-related specific symptoms (EORTC EN24 module)- clinically relevant changes on these scales (quite a bit/very much vs no or mild symptoms)	5 years
Relapse-free survival	Relapse-free survival (survival without relapse)	5 years
Survival	Overall survival (all-cause death)	5 years
5-year vaginal control including treatment for relapse	Long-term local control including salvage treatment for local relapse	5 years
Pelvic recurrence (total)	Total pelvic recurrences	5 years
Pelvic recurrence as first failure	Pelvic recurrence as first failure	5 years
Distant recurrence (total)	Total distant recurrences	5 years
Distant recurrence as first failure	Distant recurrence as first failure	5 years
Endometrial cancer related health care costs	All hospital based health care costs used with primary treatment or during followup for treatment of adverse events and/or treatment for relapse	5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence (vaginal and total) per risk profile	Vaginal, pelvic and distant relapse split by risk profile and compared between the 2 arms	5 years

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: Comprehensive Cancer Centre The Netherlands; Dutch Cancer Society
• Investigators: Study Chair: Carien L. Creutzberg, MD, PhD, Leiden University Medical Center, Dept of Radiation Oncology; Principal Investigator: Remi A. Nout, MD, PhD, ErasmusMC Dept of Radiation Oncology; Principal Investigator: Anne-Sophie van den Heerik, MD, Leiden University Medical Center, Dept of Radiation Oncology

Publications and helpful links

General Publications

• van den Heerik ASVM, Horeweg N, Nout RA, Lutgens LCHW, van der Steen-Banasik EM, Westerveld GH, van den Berg HA, Slot A, Koppe FLA, Kommoss S, Mens JWM, Nowee ME, Bijmolt S, Cibula D, Stam TC, Jurgenliemk-Schulz IM, Snyers A, Hamann M, Zwanenburg AG, Coen VLMA, Vandecasteele K, Gillham C, Chargari C, Verhoeven-Adema KW, Putter H, van den Hout WB, Wortman BG, Nijman HW, Bosse T, Creutzberg CL. PORTEC-4a: international randomized trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer. Int J Gynecol Cancer. 2020 Dec;30(12):2002-2007. doi: 10.1136/ijgc-2020-001929. Epub 2020 Oct 12.
• Wortman BG, Bosse T, Nout RA, Lutgens LCHW, van der Steen-Banasik EM, Westerveld H, van den Berg H, Slot A, De Winter KAJ, Verhoeven-Adema KW, Smit VTHBM, Creutzberg CL; PORTEC Study Group. Molecular-integrated risk profile to determine adjuvant radiotherapy in endometrial cancer: Evaluation of the pilot phase of the PORTEC-4a trial. Gynecol Oncol. 2018 Oct;151(1):69-75. doi: 10.1016/j.ygyno.2018.07.020. Epub 2018 Aug 3.
• Nero C, Ciccarone F, Pietragalla A, Duranti S, Daniele G, Scambia G, Lorusso D. Adjuvant Treatment Recommendations in Early-Stage Endometrial Cancer: What Changes With the Introduction of The Integrated Molecular-Based Risk Assessment. Front Oncol. 2021 Sep 1;11:612450. doi: 10.3389/fonc.2021.612450. eCollection 2021.

Helpful Links

• Study website

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2016
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: March 8, 2018
• First Submitted That Met QC Criteria: March 16, 2018
• First Posted (Actual): March 19, 2018

Study Record Updates

• Last Update Posted (Actual): October 11, 2023
• Last Update Submitted That Met QC Criteria: October 10, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Radiotherapy; Vaginal brachytherapy; Molecular risk factors
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Endometrial Neoplasms
• Other Study ID Numbers: P16.054; UL2011-5336 (Other Grant/Funding Number: Dutch Cancer Society); ISRCTN11659025 (Registry Identifier: ISRCTN Registry); NTR5841 (Registry Identifier: Netherlands Trials Registry)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Specifics will be decided and made public on website at a later stage, most probably from 5 years after final publication onwards
• IPD Sharing Time Frame: From 5 years after final publication onwards
• IPD Sharing Access Criteria: Upon written application with a clear decription of aim, methods and analysis plan, publication plan, after approval from the study team
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No