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

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.

Keywords: Adaptive radiotherapy; Brachytherapy; Cervix cancer; Local control; MRI guided radiotherapy; Morbidity.

Graphical abstract

Fig. 1

The figure demonstrates the principles for dose de-escalation and dose escalation in EMBRACE II. The current distribution of CTV_HR dose and volume in the EMBRACE study is shown (each point represents one patient). A number of 6 dose and volume groups are defined according to cut-points of 85 Gy and 95 Gy for the adaptive CTV_HR D90 and of 30 cm³ for the CTV_HR volume. For each dose-volume group the expected actuarial local control at 3 years is indicated, according to dose-effect data from the retroEMBRACE study .

Fig. 2

Schematic diagram for EBRT and brachytherapy targets in cervical cancer, stage IIB bulky disease and good response after chemo-radiotherapy: coronal, transversal and sagittal view. For further details see figure 3.3 and 9.6 in the EMBRACE II protocol adapted from figure 5.10 from ICRU report 89 . Panel A: EBRT targets: large GTV-T_init, initial CTV-T_HR, and initial CTV-T_LR. Panel B: Brachytherapy targets: limited GTV-T_res (residual GTV), adaptive CTV-T_HR, and CTV-T_IR (GTV-T_init plus margins around the CTV-T_HR). Maximum width, thickness and height of the adaptive CTV-T_HR are indicated.

Fig. 3

Schematic Diagram for lymph node elective CTVs based on risk of lymphatic spread, “Small Pelvis”, “Large Pelvis”, “Large Pelvis + para-aortic”. The risk groups are defined in .