Monday 5 May | 11:40-11:55 | Plenary Hall
Interview with Richard Pötter on behalf of the EMBRACE collaborative group
The EMBRACE Collaborative Group unites 49 institutions—including Vienna Medical University, Aarhus University Hospital, and Utrecht University Hospital—across Europe, Asia, and North America in advancing cancer research and care.
What have been the essentials for the development of the EMBRACE Collaborative Group?
The first steps: building the Gyn GEC ESTRO working group and the Gyn GEC ESTRO network
The essentials of this collaborative group can only be understood from the background of developments within ESTRO and GEC ESTRO starting around 2000 with the initiation of the GEC ESTRO Gyn working group: the collaborative efforts of this group have been focusing on establishing an improvement of clinical practice integrating advanced imaging, radiation hard- and software developments into the management of locally advanced cervical cancer creating a common new concept and language and replacing the long tradition of point A based treatment practice. These activities were impacted through GEC ESTRO meeting workshops in 1997 (3D imaging) and 1998 (Revision of ICRU 38) on Cervix cancer brachytherapy and linked to the early phase of designing the new ICRU report (89) on cervix cancer brachytherapy.
These efforts comprised the development of concepts for MRI guided adaptive brachytherapy in limited size task groups (Gyn GEC ESTRO Rec I, II, 2005, 2006), change of applicator design (intracavitary/interstitial IJROBP 2005, 2006), MRI assisted DVH and point based treatment planning with point and dose volume constraints, biological modelling (linear-quadratic model), and applicator reconstruction. This was achieved through continuous intra- and inter-institutional group communication on growing clinical experience and upcoming challenges with intensive cooperation between clinicians and medical physicists, through dissemination of new knowledge and through continuous education and training efforts, e.g. through ESTRO annual Gynae Teaching Courses (since 2004), hands-on workshops (start 2005), seminars, fellowships, institutional visits etc.
Key was the focus on change of clinical practice using the new concepts and a new common language which aimed at improving clinical outcome of LACC both for disease and morbidity.
In order to broaden the collaboration platform, the Gyn GEC-ESTRO Working Group then initiated in 2005 at the GEC ESTRO meeting in Budapest an open network to promote collaboration between the increasing number of persons and institutions with research and development interests and activities as shown through initiating IGABT.
The focus was on joint further research and development, improvement of clinical practice, as well as on education and dissemination; through continuous multi-disciplinary communication and collaboration on major issues of interest. This focus was facilitated through (bi)-annual in person meetings (workshop type) with four major task groups (applicator development and reconstruction, imaging and target volume contouring, treatment planning, clinical studies). These regular topic orientated meetings became the driving backbone of major developments in this new field, resulting in several further benchmark publications, eg Gyn GEC ESTRO recom III, IV on applicator reconstruction in 2010, on imaging in 2011.
How did these various Gyn GEC ESTRO developments impact on the initiation of clinical trials such as EMBRACE I and RetroEMBRACE.
In order to validate the new target concepts and the suggestions for dose volume reporting for IGABT in a large clinical multi-centre prospective setting, the task group on clinical studies of the Gyn GEC ESTRO network launched in 2008 the ‘‘IntErnational study on MRI-based BRAachytherapy in CErvical cancer”(EMBRACE I). This was a prospective observational multi-center cohort study focussing on local control and morbidity as primary endpoints, formulating multiple general and specific aims for investigation, such as dose-volume-effect relations for targets and OARs. EMBRACE was an academic trial, sponsored by the Medical University of Vienna, with some administrative support for the study center in Vienna and also for Aarhus through Elekta and Varian. The driving force was the continuous intensive cooperation between clinicians/clinical researchers and medical physicists/physicist researchers.
This EMBRACE I study became the birthplace of the multi-disciplinary EMBRACE Collaborative Group.
During the first years of EMBRACE I, the major focus was on creating and establishing appropriate structures to achieve a high quality in study performance in the 24 participating institutions (eg through a dummy run on target contouring and treatment planning (published 2015)); in parallel a complex multi-centre electronic data collection was set up comprising detailed patient, tumor, treatment and outcome characteristics, including morbidity and quality of life within a five year follow-up period. Regular bilateral communication and annual physical meetings of the whole study group in Vienna with participants from all centres were established; these took place regularly from 2008-2020. The Vienna Study Office (weekly meetings) and also Aarhus University (several visits in Vienna/year) became the major driving forces shaping these challenging developments, also now with support of IT specialists. With growing experience investing continuous intensive personnel input into this complex multi-centre study performance and with the rapid increase of broad information from the complex data collection, the need for intensive clinical research efforts became more and more evident.
In addition, in order to receive multi-centre clinical evidence as soon as possible from the period preceding the EMBRACE study, a retrospective study was launched, in which 12 pioneer centres participated (RetroEMBRACE, 731 patients) using comparable methodology, endpoints and data structure as EMBRACE.
In Vienna, several international fellows and postdoc researchers started working on important EMBRACE related research questions as well as some postdoc researchers in Aarhus, Utrecht and Paris, using material as collected within the RetroEMBRACE and the EMBRACE I studies; this work was facilitated through workshops on specific questions and on methodological issues (eg dose effect analyses). These efforts then became the continuously growing research wing of the EMBRACE Collaborative Group, which was later extended through a PhD based research model addressing specific questions within a PhD project (eg overall GI and GU morbidity, G3-5 morbidity); a growing amount of publications followed from 2016 onwards. These increasing research efforts comprised also a growing number of more disciplines involved, from physics and technology, methodology, clinical medicine, psycho-oncology, biology, computer science.
Two major efforts to receive large scale research money for this field on the European Commission level failed (GynART 2011, MERIT 2013 (FP7)), not for scientific reasons (highest scores), but as international reviewers questioned the clinical relevance of LACC related research using advanced radiation technologies.
Parallel to the running EMBRACE studies, the GEC ESTRO Gyn network continued to work on specific IGABT related issues through several communication channels, such as bilateral and limited size group meetings, visits and regular in person workshops. These efforts resulted in several studies on uncertainties (special issue RadiothOncol 2013), the finalisation of the RetroEMBRACE study (2016) and a special green journal issue on gynaecological radiotherapy in 2016, with particular focus on cervix IGABT and clinical outcome.
The GEC-ESTRO Gyn network has then been working on further recommendations using specific task groups addressing (1) CT contouring for brachytherapy in cervix cancer (2021), (2) Treatment planning in cervix brachytherapy (work in progress), (3) Image registration for brachytherapy, (4) Target definition for brachytherapy in vaginal cancer (2019). An observational study on IGABT in vaginal cancer (EMBRAVE) started in 2024.
The published Gyn GEC-ESTRO Recommendations I-IV were in use as the conceptual framework for the implementation of IGABT worldwide. They became embedded and further developed into the new ICRU/ESTRO report 89 on cervix cancer brachytherapy, published 2016, setting the conceptual frame for cervix cancer brachytherapy worldwide. From the European side, this report was mainly driven by members of the GEC ESTRO Gyn Group, at the same time coordinators of EMBRACE I.
There was continuous communication and interaction between these network related R&D activities, the education and dissemination activities (eg workshops and ESTRO Gyn Teaching courses (overview published 2020)) and the EMBRACE study activities.
Based on the growing technical and clinical evidence - mainly from the EMBRACE studies - IGABT and IGRT/IMRT became the major pillars of the multidisciplinary ESGO-ESTRO-ESP recommendations for the radiotherapy management of cervical cancer in Europe (2018,2023).
How was the further evolution towards providing prospective clinical evidence for the effects of IGABT and IGRT/IMRT through EMBRACE II?
In order to investigate prospectively the efficacy of defined (new) interventions such as IGABT and IGRT/IMRT on clinical outcome, the EMBRACE Collaborative Group assigned 2013 a protocol writing committee to design EMBRACE II, based on the physics and clinical evidence as collected so far then from EMBRACE I (n=1200) and RetroEMBRACE (n=731). Mutiple hypotheses on EBRT, BT and Chemotherapy interventions were formulated and on various disease and morbidity outcome endpoints. In order to facilitate regular communication for this considerable task, weekly international multi-disciplinary on-line meetings were launched. A final comprehensive protocol for the interventional EMBRACE II study could so be finished through these continuous joint efforts by October 2015. EMBRACE II then started in spring 2016. These weekly Monday meetings became the backbone of the international communication of the growing EMBRACE Collaborative Group in regard to clinical trial performance as well as to EMBRACE related research and have been active since then through 2025.
In EMBRACE II, for achieving optimal radiotherapy in 49 participating centers, both for EBRT and BT, a detailed accreditation and dummy run procedure was set up for EMBRACE II (Duke 2020, Seppenwoolde 2019). In addition, a specific on-line QA programme was established which enabled the continuous control of major patient, tumor, intervention and outcome parameters on a „per patient“ and „per center“ basis (Ecker 2023, Monitor). Appropriate measures were taken on a regular basis in order to reach the aims as formulated in the EMBRACE II protocol throughout the study accrual period from 2016-2021. Thereafter (2022-2023), a joint QA check „per center“ and „per patient“ on the major parameters was performed using the electronic database through an enlarged QA group; appropriate measures were taken for optimization as necessary, mainly through center contact. A specific central QA procedure was performed „per patient“ for disease, death and morbidity (G3-5) events during 2024 and 2025; again appropriate measures were taken for clarification through center contact and following optimization of data quality as appropriate.
In parallel to running the EMBRACE II study, major clinical research efforts were continued by the EMBRACE Collaborative Group to systematically evaluate results from EMBRACE I and also RetroEMBRACE, using descriptive and analytical methods (eg MVAs), both on disease, morbidity and QoL outcome and on radiation technique, dose-volume and dose-point related clinical effects. Several major publications resulted from these efforts during the recent years providing high level evidence and made the EMBRACE Collaborative Group the world leading group in the modern clinical radio-oncological management of locally advanced cervical cancer.
During recent years, also advanced statistical methods have been applied in various dedicated sophisticated research projects in order to better understand certain (complex) effects of treatment (eg using Bayesian networks, trajectory analyses) or to arrive at new parameters for assessing morbidity outcome (eg Lapers, Cumulative Toxicity Score). This has resulted in some diversification of EMBRACE related multi-disciplinary research which so far had mainly dealt with clinical issues and parameters which had been well prospectively defined in the EMBRACE protocols and needs to be prospectively tested in clinical trials.
To summarize, it is noteworthy that most achievements of the EMBRACE Collaborative Group in the various fields were reached with a minimum of formalized procedures. The achievements were mainly driven through intensive topic orientated efforts, which were initiated, directed and organized through several collaborative personalities acting through various channels of open communication and multi-disciplinary cooperation within an overall spirit of understanding and confidence. One of the key elements for success has been continuous constructive discussion between people, coming from different backgrounds with different opinions. The joint mission was to create sustainable value for making treatment for our patients better and better….
What are the next steps after completion of EMBRACE II?
The presentation of overall results at ESTRO 2025 in Vienna and at more international and national meetings are the next steps. In parallel, the publication of the overall results of EMBRACE II is projected for Lancet Oncology. Several research projects are on their way related to EMBRACE II, such as image based target definition, dose volume parameters for BT and EBRT, lymph node characteristics, and acute morbidity. Some of these projects have already been presented and some important are shown at ESTRO 2025 and are in the process of publication.
A further comprehensive research plan needs to be set up soon. This plan will allow for opening major clinical research avenues for the management of LACC and to investigate comprehensive and detailed clinical scenarios for relevant clinical questions: these investigations will address various patient, tumor and treatment characteristics and specific issues for overall outcome, but also for local, nodal and systemic outcome and survival. Furthermore, the wealth of data on morbidity will allow deeper insights into adverse side effects related to pre-existing conditions and to different forms of treatment (IGABT, 3DCRT, IGRT/IMRT) and also in relation to tumor burden. Attractive will be the use of the large combined EMBRACE databases (>3.500 patients) for many of these issues and to investigate the evolution of technology and the related effects on disease and morbidity outcome.
Overall, it will be essential for the further evolution of the EMBRACE Collaborative Group to maintain the innovative and dynamic spirit of the past with widespread and open communication patterns within various limited and large size multi-disciplinary group settings. The major issue will be to further advance gynaecologic cancer related radiation technology and also systemic treatment according to individual risk. This is even more important, as major new interest has come up – in paricular in the gynaecological and medical oncological community through level III - evidence on immunotherapy and neo-adjuvant chemotherapy. The place of such new systemic treatment needs to be well understood in the frame of the outstanding EMBRACE evidence, which has become and will remain international standard of care. It will be essential – as successfully practiced in the past two decades – to continue with a constructive interplay between the various platforms and networks for discussion and dissemination as having been available in ESTRO and GEC ESTRO and the various activities, persons and platforms of the EMBRACE Collaborative Group. Major joint widespread positive energies are needed to meet the upcoming future challenges in the field of gynaecological radiation oncology.
What are the key questions and the future steps for launching a next generation of EMBRACE studies?
Based on the EMBRACE experience, new studies are being launched in 2025 (EMBRACE III) addressing various relevant questions such as:
- real world outcome of Image Guided simultaneous Radiochemotherapy including MR IGABT in LACC (EMBRACE II-protocol) using evidence based decision making in order to tailor treatment according to individual risk („eviguide“). Questions on the additional value of immunotherapy and neo-adjuvant chemotherapy will be addressed. (PROMISE)
- outcome of CT IGABT and simultaneous Radiochemotherapy (IMPACT) for centers which have limited access to MRI
- retrospective comparison of EMBRACE II with real world outcome in various EMBRACE II centers (REWIND)
- Randomized study on the reduction of EBRT dose (45 vs 40 Gy) in low risk LACC patients, applying the EMBRACE II protocol (RAPID)
- Drug study (immunotherapy) in addition to advanced chemoradiotherapy and IGABT for patients with high risk LACC
What does the award mean for the EMBRACE Collaborative Group?
The EMBRACE Collaborative Group is proud for receiving this award!
The Group is grateful to ESTRO that this Donal Hollywood award is given to the whole group, i.e. to all members. This fact underlines that ESTRO understands and awards that the extensive EMBRACE work was only possible through huge multi-disciplinary collaborative efforts undertaken by many people continuously and intensively throughout almost two decades.
This award is dedicated to patients with Locally Advanced Cervical Cancer who participate in clinical studies and so contribute to further improvement of management of LACC.
EMBRACE Collaborative Group