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      The EMBRACE II study: The outcome and prospect of two decades of evolution within the GEC-ESTRO GYN working group and the EMBRACE studies

      review-article

      a , 1 , b , 1 , * , a , c , a , d , e , f , g , h , i , j , k , l , m , a , a , a , b , b , a , b , a , c , a , o , g , n , a , b , c , the EMBRACE Collaborative Group 2

      Clinical and Translational Radiation Oncology

      Elsevier

      Cervix cancer, Brachytherapy, Adaptive radiotherapy, MRI guided radiotherapy, Local control, Morbidity

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          Graphical abstract

          Highlights

          • Image guided adaptive brachytherapy (IGABT) is changing clinical practice.

          • The EMBRACE studies benchmark IGABT in cervix cancer.

          • A multi-parametric dose prescription protocol is being validated in EMBRACE II.

          • EMBRACE II is hypothesised to improve outcome: disease, morbidity, quality of life.

          Abstract

          The publication of the GEC-ESTRO recommendations one decade ago was a significant step forward for reaching international consensus on adaptive target definition and dose reporting in image guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer. Since then, IGABT has been spreading, particularly in Europe, North America and Asia, and the guidelines have proved their broad acceptance and applicability in clinical practice. However, a unified approach to volume contouring and reporting does not imply a unified administration of treatment, and currently both external beam radiotherapy (EBRT) and IGABT are delivered using a large variety of techniques and prescription/fractionation schedules.

          With IGABT, local control is excellent in limited and well-responding tumours. The major challenges are currently loco-regional control in advanced tumours, treatment-related morbidity, and distant metastatic disease. Emerging evidence from the RetroEMBRACE and EMBRACE I studies has demonstrated that clinical outcome is related to dose prescription and technique. The next logical step is to demonstrate excellent clinical outcome with the most advanced EBRT and brachytherapy techniques based on an evidence-based prospective dose and volume prescription protocol.

          The EMBRACE II study is an interventional and observational multicentre study which aims to benchmark a high level of local, nodal and systemic control while limiting morbidity, using state of the art treatment including an advanced target volume selection and contouring protocol for EBRT and brachytherapy, a multi-parametric brachytherapy dose prescription protocol (clinical validation of dose constraints), and use of advanced EBRT (IMRT and IGRT) and brachytherapy (IC/IS) techniques (clinical validation). The study also incorporates translational research including imaging and tissue biomarkers.

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          Most cited references70

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          Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer

          Background To analyse the overall clinical outcome and benefits by applying protocol based image guided adaptive brachytherapy combined with 3D conformal external beam radiotherapy (EBRT) ± chemotherapy (ChT). Methods Treatment schedule was EBRT with 45–50.4 Gy ± concomitant cisplatin chemotherapy plus 4 × 7 Gy High Dose Rate (HDR) brachytherapy. Patients were treated in the “protocol period” (2001–2008) with the prospective application of the High Risk CTV concept (D90) and dose volume constraints for organs at risk including biological modelling. Dose volume adaptation was performed with the aim of dose escalation in large tumours (prescribed D90 > 85 Gy), often with inserting additional interstitial needles. Dose volume constraints (D2cc) were 70–75 Gy for rectum and sigmoid and 90 Gy for bladder. Late morbidity was prospectively scored, using LENT/SOMA Score. Disease outcome and treatment related late morbidity were evaluated and compared using actuarial analysis. Findings One hundred and fifty-six consecutive patients (median age 58 years) with cervix cancer FIGO stages IB–IVA were treated with definitive radiotherapy in curative intent. Histology was squamous cell cancer in 134 patients (86%), tumour size was >5 cm in 103 patients (66%), lymph node involvement in 75 patients (48%). Median follow-up was 42 months for all patients. Interstitial techniques were used in addition to intracavitary brachytherapy in 69/156 (44%) patients. Total prescribed mean dose (D90) was 93 ± 13 Gy, D2cc 86 ± 17 Gy for bladder, 65 ± 9 Gy for rectum and 64 ± 9 Gy for sigmoid. Complete remission was achieved in 151/156 patients (97%). Overall local control at 3 years was 95%; 98% for tumours 2–5 cm, and 92% for tumours >5 cm (p = 0.04), 100% for IB, 96% for IIB, 86% for IIIB. Cancer specific survival at 3 years was overall 74%, 83% for tumours 2–5 cm, 70% for tumours >5 cm, 83% for IB, 84% for IIB, 52% for IIIB. Overall survival at 3 years was in total 68%, 72% for tumours 2–5 cm, 65% for tumours >5 cm, 74% for IB, 78% for IIB, 45% for IIIB. In regard to late morbidity in total 188 grade 1 + 2 and 11 grade 3 + 4 late events were observed in 143 patients. G1 + 2/G3 + 4 events for bladder were n = 32/3, for rectum n = 14/5, for bowel (including sigmoid) n = 3/0, for vagina n = 128/2, respectively. Interpretation 3D conformal radiotherapy ± chemotherapy plus image (MRI) guided adaptive intracavitary brachytherapy including needle insertion in advanced disease results in local control rates of 95–100% at 3 years in limited/favourable (IB/IIB) and 85–90% in large/poor response (IIB/III/IV) cervix cancer patients associated with a moderate rate of treatment related morbidity. Compared to the historical Vienna series there is relative reduction in pelvic recurrence by 65–70% and reduction in major morbidity. The local control improvement seems to have impact on CSS and OS. Prospective clinical multi-centre studies are mandatory to evaluate these challenging mono-institutional findings.
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            Selection of patients for radiotherapy with protons aiming at reduction of side effects: the model-based approach.

            Most new radiation techniques, have been introduced primarily to reduce the dose to normal tissues in order to prevent radiation-induced side effects. Radiotherapy with protons is such a radiation technique that due to its superior beam properties compared to photons enables better sparing of normal tissues. This paper describes a stepwise methodology to select patients for proton therapy when the primary aim is to reduce side effects. This method has been accepted by the Dutch health authorities to select patients for proton therapy. In addition, an alternative method is described in case randomised controlled trials are considered not appropriate. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
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              Effect of tumor dose, volume and overall treatment time on local control after radiochemotherapy including MRI guided brachytherapy of locally advanced cervical cancer.

              Currently, there is no consensus on dose prescription in image guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer. The purpose of this study was to provide evidence based recommendations for tumor dose prescription based on results from a multi-center patient series (retroEMBRACE).
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                Author and article information

                Contributors
                Journal
                Clin Transl Radiat Oncol
                Clin Transl Radiat Oncol
                Clinical and Translational Radiation Oncology
                Elsevier
                2405-6308
                11 January 2018
                February 2018
                11 January 2018
                : 9
                : 48-60
                Affiliations
                [a ]Department of Radiation Oncology, Comprehensive Cancer Center, Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Austria
                [b ]Department of Oncology, Aarhus University Hospital, Denmark
                [c ]Department of Radiation Oncology, University Medical Centre Utrecht, The Netherlands
                [d ]Department of Radiation Oncology, Leiden University Medical Center, The Netherlands
                [e ]Departments of Oncology, Radiology and Gynae-oncology, Addenbrooke’s Hospital, Cambridge University Hospitals National Health Service Trust, United Kingdom
                [f ]Radiation Oncology Department, Gustave Roussy Cancer Campus Grand Paris, France
                [g ]Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, India
                [h ]Department of Radiation Oncology, Institute of Oncology, Ljubljana, Slovenia
                [i ]Cancer Centre, Mount Vernon Cancer Centre, United Kingdom
                [j ]Department of Oncology, Oslo University Hospital, Oslo, Norway
                [k ]Department of Radiotherapy and Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
                [l ]Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
                [m ]Department of Radiation Oncology, University Hospital Gasthuisberg, Leuven, Belgium
                [n ]Department of Radiation Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands
                [o ]Department of Radiation Oncology, Centre Hospitalier de l’Université de Montréal, Montreal University, Montreal, Canada
                Author notes
                [* ]Corresponding author at: Department of Oncology, Aarhus University Hospital, 8000 Aarhus C, Denmark.Department of OncologyAarhus University Hospital8000 Aarhus CDenmark karitand@ 123456rm.dk
                [1]

                Equal contribution and shared first authorship.

                [2]

                See Appendix C.

                Article
                S2405-6308(17)30075-7
                10.1016/j.ctro.2018.01.001
                5862686
                533342d9-4283-4849-9a3c-0a026c0ed9db
                © 2018 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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