WCB 2021 - Online

Session Item

May 06
09:00 - 10:15
Image guided BT and Outcome for Cervical Cancer: Update from different regions
09:00 - 09:18
EMBRACE experience
Ina Jürgenliemk-Schulz, The Netherlands


EMBRACE experience
Authors: Ina Schulz(University Medical Center Utrecht, Department of Radiation Oncology, Utrecht, The Netherlands), Richard Pötter(Medizinische Universität Wien,, Department Of Radiation Oncology, Vienna, Austria), Kari Tanderup, Christian Kirisits, Max Schmid, Kathrin Kirchheiner, Remi Nout, Sterfan Ecker, Astrid de Leeuw, Umesh Mahantshetty, Li Tee Tan, Jacob Lindegaard, ON BEHALF OF THE EMBRACE STUDY AND RESEARCH GROUP, Alina Sturdz, Lars Fokdal
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Abstract Text

To provide an overview on the multi-centre IntErnational studies on MRI-guided BRAchytherapy in locally advanced CErvical Cancer (EMBRACE): the retrospective RetroEMBRACE (RE), the prospective observational EMBRACE I (EI) and the interventional/observational EMBRACE II (EII).

RE, EI and EII provide comprehensive data from 731, 1416 and 284 pts (620 12/2019), respectively, with locally advanced cervical cancer (LACC) stage IB-IVA and IVB (in paraaortic nodes (PAN)). Pts were treated before start of EMBRACE in 12 centres (RE), from 2008-2015 in 23 centres (EI) and from 2016-12/2018 in 14 centres.  Treatment was definitive EBRT (3DCRT or IMRT/IGRT) and concurrent cisplatin followed by MR image guided adaptive brachytherapy (IGABT) with MRI available for at least one fraction. IGABT targets, OAR and dose volume parameters were reported following GEC-ESTRO recommendations (2005). In RE and EI dose prescription followed institutional guidelines. EBRT dose was 45-50Gy (1.5-2.0Gy/fraction). In EII a multiparametric dose prescription protocol is mandatory differentiating between soft and hard constraints for targets (GTV, CTV
HR, CTVIR) and for OARs (D2cm3 for bladder, rectum, sigmoid, bowel and rectovaginal point, bladder point (new vagina PIBS concept)). A new tumor and risk adapted LN target  concept was introduced for IMRT in EII: CTV-T, CTV-E, ITV, PTV (45 Gy) and CTV-N, SIB (~60Gy); PA IMRT was prescribed for high risk N+ pts. A comprehensive QA programme was applied in EI and EII. Patient, tumor, treatment and outcome characteristics (crude rates, actuarial estimates) are reported. Toxicity was prospectively assessed in EI, EII (CTCAEv3.0).

Median age was 53, 56, 51 years and FIGO
2009 stage distribution was for RE, EI, EII: IB in 17,18,15%, IIB 50, 52, 57%, IIIB 20,14,18%, IVA 3,3,3%, IVB 6,7%; 40,52,58% were node-positive (N+); 85,82,81% had squamous Ca, 9, 14, 16% adeno, 6, 4, 3% adenosquamous.
Mean EBRT dose was 46±2.5, 46±2, 45±1 Gy in RE, EI, EII. 3D CRT and IMRT was in 91 and 9% in RE, 59 and 41% in EI and IMRT/IGRT in 100% in EII. Para-aortic RT was in 15, 17, 30% in RE, EI, EII. V43Gy was mean 2390/1418 cm3 in EI/EII for pelvis and 2895/1765 cm3 in EI/EII for pelvis+PAN (Berger). 77, 95, 95% received chemoth. IGABT technique was intracavitary alone (IC) in 77, 57, 27 % and IC/interstitial (IS) in 23, 43, 73% in RE, EI, EII. Mean CTV
HR volume was 37±24, 33±19, 30±16 cm3 in RE, EI, EII: mean CTVHR D90% was overall 87±15, 89±9, 93±4 Gy10: for stage IB 93±17, 90±8, 93±3 Gy10; for stage IIB 88±14, 91±9, 93±4 Gy10; for stage IIIB 83±13, 87±8, 93±4 Gy10; for stage IVA 78±13, 83±10, 92±6 Gy10. Isodose surface volumes were adapted to volume of CTVHR: V85 Gy10 decreased overall by 23% compared to Pt A Standards.
In RE, EI, EII, mean D
2cm³ for bladder was 81±22, 76±10, 75±9 Gy3, rectum 64±9, 63±7, 59±6 Gy3, sigmoid 66±10, 64±7, 62±7 Gy3, bowel 64±9, 63±10, 59±9 Gy3, rectovaginal point 66±9, 62±7 Gy3.
Median follow up was 43, 51 mths for 731, 1318 pats, resp. for RE, EI. Overall 30, 25% pts had recurrence (multiple events possible) in RE, EI: crude failure rates were local 9.4, 7.4%; overall pelvic 13.1, 12.5%, nodal pelvic 5.6, 6.7%; PAN 8.6, 8%. 21, 14% had recurrence beyond PAN. At the time of analysis, 35, 27% pts had died, 27, 21% from disease progression. In RE and EI at 5 years, actuarial LC was 89, 92%, PC 84, 87%, DC 70, 74%, OS 65, 74%, CSS 73, 79% (table 1). 5-year OS was 71,81% for N- pts and 57, 67% for N+ pts.
In RE and EI crude G3-5 morbidity at 5 years was genito-urinary 5, 6.5%, gastro-intestinal 7, 7.6%, vagina 5, 6.1%.  

Age, local FIGO
2009 stage and histology are comparable within the EMBRACE studies. More nodal disease is diagnosed in EI and EII. EBRT technique changed from predominant 3DCRT in RE to 100% IMRT/IGRT in EII with markedly reduced volumes (V43 Gy) and increasing frequency of risk adapted PA RT. Concomitant chemotherapy is increased in EI and EII. IC/IS techniques have increased significantly during E1 and even more in EII which enables appropriate target coverage and OAR sparing. CTVHR D90% is overall increasing, in particular for large volumes. OAR D2cm3 are being reduced in EII. Dose homogeneity is much increasing for targets and OARs across patients.
From RE to EI overall local and pelvic control is excellent and even improving, based on systematic use of advanced MRI based IGABT including interstitial needles. Significant improvement is seen in stage IIIB and IVA. Para-aortic recurrence remains similar. Overall survival and Cancer specific survival are clearly improved.
Overall advanced MRI-based IGABT in combination with chemo-RT results in excellent and stable long-term local, pelvic and overall disease control and survival across all stages with limited severe morbidity. This EMBRACE experience should be used as benchmark for routine clinical practice as well as for design of any future clinical trials