ESTRO 2025 Congress report I Donal Hollywood Award
The overall results of EMBRACE II were presented for the first time on 5 May at ESTRO 2025 by Professor Richard Pötter. The EMBRACE Collaborative Group received the Donal Hollywood Award for the performance and presentation of the EMBRACE II study.
Authors:
Richard Pötter, Kari Tanderup, Maximilian Schmid, Stefan Ecker, Jacob Lindegaard, Hendrike Westerveld, Alina Sturdza, Nicole Eder-Nesvacil, Kathrin Kirchheiner, Sofia Spampinato, Ina Jürgenliemk-Schulz, Christian Kirisits on behalf of the EMBRACE Collaborative Group
Background
The introduction of MR image-guided adaptive brachytherapy (IGABT) as a combined intracavitary and interstitial technique has been a major breakthrough in the management of locally advanced cervical cancer (LACC) during the last two decades. Several mono-institutional retrospective studies (2008-ongoing), a large retrospective multi-centre study (RetroEMBRACE (Sturdza, 2016)) and a prospective observational multi-centre cohort study (EMBRACE I (Pötter, 2021) have shown excellent local control (~90%); however, there was limited but still considerable severe organ morbidity (gastrointestinal (GI), urinary, vagina, fistula: crude ~15% (total)). Results for overall survival (OS) and progression-free survival were substantial at rates of 74% and 68% after five years (EMBRACE I). These studies systematically used concepts and terminology recommended by the Gyn GEC ESTRO working group (I-IV, 2005-2012) and the comprehensive International Commission on Radiation Units and Measurements/ESTRO Report 89 (2013).
EMBRACE II study
Based on these clinical results as available in 2015, and multiple dose/volume and dose/point effect analyses that were performed at that time (published 2016 and thereafter), a multi-centre prospective interventional cohort study was designed with multiple hypotheses on interventions and clinical outcomes. This became EMBRACE II.
The EMBRACE II study accrued 1449 patients between 2016 and December 2021 from 49 centres in Europe, Asia, North America and Australia.
Overall study design (interventions)
The following interventions were defined.
* Advanced tumour, node, distant metastasis (TNM2013) staging based on clinical and imaging findings (MRI, CT, PET-CT).
* New targets for external beam radiotherapy (EBRT) (5mm planning target volume (PTV) margins):
- tumour target: initial gross tumour volume for the primary tumour (GTV-T), initial high-risk clinical target volume for the same (CTV-THR ) and low-risk CTV-TLR
- elective lymph node (LN) targets (CTV-E): small pelvis incl. common iliac bifurcation LNs; large pelvis (LP) incl. aortic bifurcation LNs; and para-aortic (PAO) up to renal vessels only
- elective LN target selection: LP+PAO, if >2 LN involved or common iliac LN+
- involved LN boost target (CTV-N): GTV-N + 0-3mm; (simultaneous integrated boost (SIB)).
* Prescribed EBRT dose: 45Gy for all targets, 55-57Gy for LN SIB.
* MRI-based adaptive target definitions for brachytherapy (as practised in EMBRACE I).
* Highly conformal multi-parametric treatment planning applying multiple dose/volume and dose/point constraints for EBRT (conformity index <1.10) and for brachytherapy.
* Image-guided EBRT delivery (IGRT-IMRT).
* Concomitant weekly cis-platin (40mg/m2) with a minimum of five cycles.
* MR IGABT that enforces combined intracavitary/interstitial (IC/IS) techniques and achieves ≥90Gy equivalent dose in 2Gy fractions with an alpha/beta ratio of 10 (EQD210) in the adaptive CTV-THR and respects multiple constraints for the EQD2 with an alpha/beta ratio of 3 (EQD23) in defined organ-at-risk (OAR) volumes and points.
*Overall treatment time ≤50 days.
Performance and outcome of EMBRACE II interventions
To test the performance of the interventions, multiple hypotheses were formulated: on dose-volume and dose-point constraints for targets and OARs (brachytherapy), on elective PTV volume reduction (EBRT), on the number of chemotherapy cycles, and on overall treatment time.
The quality of these interventions was controlled through use of an upfront comprehensive accreditation procedure and regular online monitoring throughout the study.
Quality of treatment was also supported through the provision of continuous education and training activities for EMBRACE II participants during courses, workshops and on-site visits.
Overall, almost all hypotheses on the performance and results of the well-defined interventions could be confirmed.
A considerable reduction of the elective PTV volume was achieved from a median of 2.450cm3 in EMBRACE I to 1.477cm3 in EMBRACE II: absolute reduction ~1000cm3, relative reduction ~40%. This was due to reduced PTV margins and highly conformal treatment planning, which was indicated by a conformity index of 1.03 for LP and 1.05 for LP+PAO. Median PTV-N was low at 39cm3 per patient, as was the treated volume (56/58Gy) due to the application of coverage probability planning.
Dose-volume constraints for IGABT were achieved for large and limited-size adaptive CTV-THR at median dose 92Gy EQD210 (interquartile range: 91,95). For OARs (EQD23): rectum 2cm3 with median 58Gy (53,63) and recto-vaginal point with 60Gy (56,64). They were achieved partly for the bladder (2cm3 with 75Gy (69,80)). This was due to increased use of combined IC/IS techniques (74% vs. 43% in EMBRACE I) and multi-parametric treatment planning based on the EMBRACE II protocol with multiple soft- and hard-dose constraints.
Overall treatment time was a median of 43 days, clearly within the assumed limit of ≤50 days.
The intended number of ≥5 cycles of cis-platin in 80% of patients was not completely reached; this figure was 74%.
EMBRACE Clinical Outcome (Hypotheses and results)
Based on clinical results as available from RetroEMBRACE and EMBRACE I in 2014/2015, multiple hypotheses were formulated regarding clinical outcome at three years. All hypotheses assumed a priori (some) improvement of clinical outcome due to the systematic application of the multiple therapeutic interventions as defined in the EMBRACE II protocol (Pötter, 2018; Tanderup, 2020). This was widely achieved (see preceding paragraph).
The composition of the cohort in regard to age, performance status, stage and histology was comparable to EMBRACE I.
All hypotheses on clinical outcomes were confirmed or exceeded.
In the following, the clinical outcome results are specified (data from November 2024) with the assumed hypothetical numbers in parentheses.
Disease-related outcomes after three years (actuarial data): local control 93% (93%), nodal control 91% (90%), distant control 88% (86%), overall disease control 80%, OS 87% (81%), disease-specific survival (DSS) 88% (85%), disease-free survival (DFS) 78%. For high-risk patients (any N+, any T3, T4) (keynote A18 like EMBRACE II cohort), OS, DSS and DFS rates were 84% (71%), 86% (76%), and 73%. For patients without para-aortic LN metastases (INTERLACE like EMBRACE II cohort), OS, DSS and DFS rates were 89%, 91% and 80%.
Morbidity-related outcomes (crude data): G3-G5 morbidity 8.9%, urinary 2.8% (6%), GI 3.7% (6%), vagina 3.2% (3%). For the fistula, the rate was 1% compared with 3% in EMBRACE I. Crude ≥G3 morbidity (urinary, GI, vagina, fistula) in EMBRACE I was 15% (Visser, 2023). For G4 and G5 morbidity (GI, urinary, vagina, fistula) with 1%, there was a relative reduction of ~ 80% compared with EMBRACE I.
Summary and Conclusions
Overall, these excellent results for all disease-outcome parameters which proved the multiple hypotheses with small confidence intervals (1-2%), represent a comprehensive prospective multi-centre validation of the former results from retrospective and prospective studies, in particular, RetroEMBRACE and EMBRACE I.
EMBRACE II therefore provides a comprehensive, valid, reproducible and reliable protocol with very high predictive values for disease and morbidity outcomes for patient cohorts that are comparable with those included in the EMBRACE studies.
Disease- and morbidity-related clinical outcomes were improved for all parameters compared overall with EMBRACE I results (Lancet Oncol, 2021; Schmid, 2023; Visser, 2023).
These findings must be appreciated in the frame of the following treatment parameters, which were improved when compared with EMBRACE I:
- New EBRT targets (tumour and lymph nodes) are feasible in a multi-centre setting,
- considerable reduction of PTV-E and PTV-N volumes,
- considerable reduction of 45Gy EBRT (40%) and 55-60Gy LN boost volumes,
- reduction of 85Gy brachytherapy volumes,
- decrease in elective EBRT target dose,
- increase in para-aortic elective irradiation and LN boosting,
- increased use of combined IC/IS techniques,
- increase of doses in brachytherapy targets,
- decrease of doses to most OARs,
- increased application of ≥5 cycles of cisplatin, and
- reduction of overall treatment time.
These EMBRACE II results compare favourably with what has been published so far, even when additional systemic treatment is included, such as neoadjuvant chemotherapy (Lindegaard, 2024; Petric, 2025) or immunotherapy (Schmid, 2024).
Therefore, the EMBRACE II protocol is to become the new standard-of-care for the management of LACC and should be introduced into clinical practice as broadly and comprehensively as possible, based on the updated European Society of Gynaecological Oncology/European Society of Pathology//ESTRO guidelines (Cibula, 2023). Furthermore, for the understanding and future performance of clinical trials in LACC, this EMBRACE II protocol, with the results as achieved, should serve as the benchmark and as the control arm in any future randomized trials.
Prof Richard Pötter, MD, PhD
Department of Radiation Oncology
Medical University of Vienna
Vienna, Austria
On behalf of the EMBRACE II study group
References of interest:
Proferred Paper Abstract 2638: EMBRACE II - a multicenter prospective interventional cohort study on IGRT-IMRT+cisplatin+MR-IGABT in locally advanced cervix cancer: overall results.
Radiotherapy and Oncology, 2025 May, Volume 206, S837-S840
Sturdza A, Pötter R, Fokdal LU, Haie-Meder C, Tan LT, Mazeron R, Petric P, Šegedin B, Jurgenliemk-Schulz IM, Nomden C, Gillham C, McCardell O, Van Limbergen E, Janssen H, Hoskin P, Lowe G, Tharavichitkul E, Villafranca E, Mahantshetty U, Georg P, Kirchheiner K, Kirisits C, Tanderup K, Lindegaard JC.
Image-guided brachytherapy in locally advanced cervical cancer: Improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study.
Radiother Oncol. 2016 Sep;120(3):428-433. doi: 10.1016/j.radonc.2016.03.011.
Pötter R, Tanderup K, Schmid MP, Jürgenliemk-Schulz I, Haie-Meder C, Fokdal LU, Sturdza AE, Hoskin P, Mahantshetty U, Segedin B, Bruheim K, Huang F, Rai B, Cooper R, van der Steen-Banasik E, Van Limbergen E, Pieters BR, Tan LT, Nout RA, De Leeuw AAC, Ristl R, Petric P, Nesvacil N, Kirchheiner K, Kirisits C, Lindegaard JC; EMBRACE Collaborative Group.
MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.
Lancet Oncol. 2021 Apr;22(4):538-547. doi: 10.1016/S1470-2045(20)30753-1. PMID: 33794207.
Pötter R, Tanderup K, Kirisits C, de Leeuw A, Kirchheiner K, Nout R, Tan LT, Haie-Meder C, Mahantshetty U, Segedin B, Hoskin P, Bruheim K, Rai B, Huang F, Van Limbergen E, Schmid M, Nesvacil N, Sturdza A, Fokdal L, Jensen NBK, Georg D, Assenholt M, Seppenwoolde Y, Nomden C, Fortin I, Chopra S, van der Heide U, Rumpold T, Lindegaard JC, Jürgenliemk-Schulz I; EMBRACE Collaborative Group.
The EMBRACE II study: The outcome and prospect of two decades of evolution within the GEC-ESTRO GYN working group and the EMBRACE studies.
Clin Transl Radiat Oncol. 2018 Jan 11;9:48-60. doi: 10.1016/j.ctro.2018.01.001. PMID: 29594251; PMCID: PMC5862686.
Evidence-Based Dose Planning Aims and Dose Prescription in Image-Guided Brachytherapy Combined With Radiochemotherapy in Locally Advanced Cervical Cancer.
Tanderup K, Nesvacil N, Kirchheiner K, Serban M, Spampinato S, Jensen NBK, Schmid M, Smet S, Westerveld H, Ecker S, Mahantshetty U, Swamidas J, Chopra S, Nout R, Tan LT, Fokdal L, Sturdza A, Jürgenliemk-Schulz I, de Leeuw A, Lindegaard JC, Kirisits C, Pötter R.
Semin Radiat Oncol. 2020 Oct;30(4):311-327. doi: 10.1016/j.semradonc.2020.05.008. PMID: 32828387
Schmid MP, Lindegaard JC, Mahantshetty U, Tanderup K, Jürgenliemk-Schulz I, Haie-Meder C, Fokdal LU, Sturdza A, Hoskin P, Segedin B, Bruheim K, Huang F, Rai B, Cooper R, van der Steen-Banasik E, Van Limbergen E, Pieters BR, Petric P, Ramazanova D, Ristl R, Kannan S, Hawaldar R, Ecker S, Kirchheiner K, Tan LT, Nout R, Nesvacil N, de Leeuw A, Pötter R, Kirisits C; EMBRACE Collaborative Group.
Risk Factors for Local Failure Following Chemoradiation and Magnetic Resonance Image-Guided Brachytherapy in Locally Advanced Cervical Cancer: Results From the EMBRACE-I Study.
J Clin Oncol. 2023 Apr 1;41(10):1933-1942. doi: 10.1200/JCO.22.01096. Epub 2023 Jan 4. PMID: 36599120.
Vittrup AS, Kirchheiner K, Pötter R, Fokdal LU, Jensen NBK, Spampinato S, Haie-Meder C, Schmid MP, Sturdza AE, Mahantshetty U, Hoskin P, Segedin B, Bruheim K, Rai B, Wiebe E, van der Steen-Banasik E, Cooper R, Van Limbergen E, Sundset M, Pieters BR, Kirisits C, Lindegaard JC, Jürgenliemk-Schulz IM, Nout R, Tanderup K; EMBRACE Collaborative Group.
Overall Severe Morbidity After Chemo-Radiation Therapy and Magnetic Resonance Imaging-Guided Adaptive Brachytherapy in Locally Advanced Cervical Cancer: Results From the EMBRACE-I Study.
Int J Radiat Oncol Biol Phys. 2023 Jul 15;116(4):807-824. doi:10.1016/j.ijrobp.2023.01.002. Epub 2023 Jan 12. PMID: 36641039.
Lindegaard JC, Petric P, Tan LT, Hoskin P, Schmid MP, Jürgenliemk-Schulz I, Mahantshetty U, Kirisits C, Pötter R.
Are we making progress in curing advanced cervical cancer-again?
Int J Gynecol Cancer. 2024 Dec 2;34(12):1940-1945. doi:10.1136/ijgc-2024-005572. PMID: 38986568; PMCID: PMC11671937.
Schmid MP, Petric P, Mahantshetty U, Kirisits C, Tanderup K, Jürgenliemk-Schulz I, Lindegaard J, Pötter R.
Correspondence (Letter to the Editor):
In regard to Keynote A18: „We ensured high-quality radiotherapy delivery, which is
required to assess the true benefit of the combination strategy“
Lancet. 2024 Nov 23;404(10467):2050-2051. Table in appendix doi:10.1016/S0140-6736(24)02231-1. PMID: 39580199.
Petric P, Lindegaard JC, Schmid MP, Jürgenliemk-Schulz I, Mahantshetty U, Kirisits C, Pötter R.
Correspondence (Letter to the Editor):
Neoadjuvant chemotherapy according to the INTERLACE trial should NOT be the new standard for locally advanced cervical cancer treated with chemoradiation and brachytherapy
Lancet. 2025, in press
Cibula D, Rosaria Raspollini M, Planchamp F, Centeno C, Chargari C, Felix A, Fischerová D, Jahnn-Kuch D, Joly F, Kohler C, Lax S, Lorusso D, Mahantshetty U, Mathevet P, Raj Naik M, Nout RA, Oaknin A, Peccatori F, Persson J, Querleu D, Rubio Bernabé S, Schmid MP, Stepanyan A, Svintsitskyi V, Tamussino K, Zapardiel I, Lindegaard J.
ESGO/ESTRO/ESP Guidelines for the management of patients with cervical cancer - Update 2023.
Radiother Oncol. 2023 Jul;184:109682. doi:10.1016/j.radonc.2023.109682. Epub 2023 May 1. PMID: 37336614.