Image Guided IMRT, Radiochemotherapy and MRI-based IGABT in Locally Advanced Cervical Cancer
Image Guided IMRT, Radiochemotherapy and MRI-based IGABT in Locally Advanced Cervical Cancer
The research group on adaptive image-guided radiotherapy for locally advanced cervical
 carcinoma completed the protocol for the EMBRACE II study in October 2018. This study will be
 carried out in the next few years at the University Clinic for Radiotherapy at the Medical
 University of Vienna and other international partner institutes. EMBRACE II builds on the
 findings of the current EMBRACE study. These are already implemented in everyday clinical
 practice in order to further improve the accuracy of the entire therapy of cervical
 carcinomas, using state-of-the-art techniques of tele- and brachytherapy. The aim of the
 EMBRACE II study is to maintain and enhance the excellent local tumor control as well as the
 nodal and systemic control for all tumor stages while minimizing the adverse reaction rates
 for all affected organs (rectum, sigmoid, urinary bladder, and vagina) to increase the
 quality of life of patients with cervical carcinomas.
The standard treatment of locally advanced cervical cancer is radio-chemotherapy including
 external beam radiotherapy (EBRT), brachytherapy (BT) and concomitant chemotherapy with
 weekly Cisplatin. Image Guided Adaptive Brachytherapy (IGABT), with repetitive MRI regarded
 as gold standard, is increasingly recognized as the new paradigm replacing 2D BT and
 spreading throughout the world. This spread is at present predominantly in Europe, North
 America and in many places in Asia. The Gyn GEC ESTRO Recommendations I-IV have been used as
 the conceptual frame for these developments during the last decade and are now embedded into
 the new ICRU/GEC ESTRO report 88 (International Commission on Radiation and Units) which is
 being published in 2015.

 Beside increasing mono-institutional clinical experience - also reported in literature -
 there is increasing clinical evidence and analyses from multi-institutional studies, in
 particular RetroEMBRACE (n=731) and EMBRACE (n>1350) about dose volume effects and outcome.
 The mature RetroEMBRACE clinical outcome data and dose volume effect analysis for disease
 outcome show an improved excellent local and pelvic control and survival and significant dose
 volume effects for IGABT. Overall treatment time was found to have significant impact on
 local control, and in addition, volume effects of EBRT were found (IMRT vs. 3D CRT) with
 impact on morbidity and quality of life. Furthermore, dose effects of chemotherapy (≥5
 cycles) were found to have impact on survival in advanced disease. Comprehensive analyses
 from both large patient cohorts reveal further relevant treatment parameters with major
 impact on disease outcome, morbidity and quality of life. In the international community the
 results from the EMBRACE studies are regarded as benchmark for future clinical research in
 this field. Based on the large success of the RetroEMBRACE and EMBRACE studies, the EMBRACE
 study and research group decided to continue the clinical research work and to initiate a
 consecutive EMBRACE II study with interventions derived from the evidence collected within
 the EMBRACE studies.

 INTERVENTIONS, AIMS AND HYPOTHESES

 The EMBRACE II interventions address local, nodal and systemic treatment as well as exposure
 of organs at risk:

 -  Increased use of IC/IS (intracavitary/interstitial) technique in BT

 -  Reduction of vaginal source loading

 -  Systematic utilisation of IMRT

 -  Utilisation of daily IGRT (set-up according to bony structures)

 -  EBRT target concept related to the primary tumour; concepts for organ at risk (OAR)
 contouring

 -  EBRT dose prescription and reporting

 -  Adaptation of EBRT nodal elective CTV according to risk of nodal and systemic recurrence

 -  Systematic application of simultaneous chemotherapy

 -  Reduction of overall treatment time

 The general aims of the EMBRACE II study are:

 -  To systematically apply IMRT with daily IGRT as well as advanced image guided adaptive
 BT in a prospective multi-centre setting

 -  To systematically implement a dose prescription protocol for IGABT

 -  To implement systematic contouring, prescription and reporting for EBRT CTV and OARs.

 -  To administer EBRT in different targets which are adapted to the risk of nodal and
 systemic failure: to improve para-aortic and

 -  systemic control in high risk patients and not to decrease lymph node control in low
 risk and intermediate risk patients

 -  To systematically administer simultaneous chemotherapy to EBRT to reach prescribed dose
 in as many patients as possible, in particular in high risk patients

 -  To benchmark an outstanding high level of local, nodal and systemic control as well as
 survival with application of advanced EBRT, BT and chemotherapy within limited overall
 treatment time

 -  To benchmark a low incidence of intermediate and major morbidity as well as a high level
 of quality of life with application of advanced EBRT, BT and chemotherapy

 Beside these general aims, there is a significant number of specific aims which refer to the
 prospective validation of dose volume parameters from the EMBRACE analyses (e.g. dose
 escalation for large tumors with increased application of IC/IS techniques), to explore and
 evaluate dose volume parameters for EBRT and to identify prognostic parameters.

 General and specific hypotheses were formulated for the various interventions (BT, EBRT,
 chemotherapy) and endpoints (disease, morbidity, quality of life).

 TYPE OF DESIGN The study is a multicenter prospective interventional study with some areas
 for observational research (e.g. dose-volume histogram (DVH) for IMRT). Reporting on the key
 patient, tumor, treatment and outcome parameters is mandatory including disease, morbidity
 and quality of life. Sub-studies as on adaptive IMRT and translational research are optional
 for cooperation between individual departments. Patient registration and reporting will be
 performed by the individual investigator via the internet to a central database.

 PATIENTS TO BE INCLUDED Patients with newly biopsy proven squamous carcinoma, adenocarcinoma
 or adeno-squamous carcinoma of the uterine cervix, International Federation of Gynecology and
 Obstetrics (FIGO) stage IB, IIA, IIB, IIIA, IIIB and IVA (and nodal status according to TNM)
 in whom definitive radio-chemotherapy with curative intent is planned are qualified for the
 study. Treatment has to include IGABT with MRI and IMRT with IGRT and ≥5 cycles of
 cis-Platin. Patients with para-aortic metastatic nodes (stage IVB) to the level of L2 are
 also eligible but patients with further dissemination are not (M0). Patient work up and
 staging includes as a minimum patient characteristics with performance status and blood tests
 (e.g. haemoglobin, lymphocytes), tumor status (biopsy), gynaecological examination, MRI of
 the pelvis, abdominal CT or MRI, whole body FDG PET-CT (preferably) or at least chest CT.
 Further investigations are applied if necessary (e.g. cystoscopy, rectoscopy) or done
 according to institutional practice (e.g. laparoscopic lymph node assessment). Baseline
 morbidity scoring and quality of life questionnaire are mandatory.

 TREATMENT OF PATIENTS IN THE TRIAL All patients will receive both EBRT and concomitant
 chemotherapy and BT. Summation of EBRT and BT doses will be performed by calculation of a
 biologically equivalent dose in 2 Gy per fraction (EQD2) using the linear-quadratic model
 with alpha/beta = 10 Gy for tumour effects and alpha/beta = 3 Gy for late normal tissue
 damage. The repair half time is assumed to be 1.5 hrs. EBRT has to be delivered as IMRT/VMAT
 (Volumetric Modulated Arc Therapy) with daily cone beam CT (IGRT) in 25 fractions with 1.8 Gy
 to a total dose of 45 Gy given in 5 weeks. Target definition is MRI based (initial GTV) for
 the CTV-T with an initial HR and LR CTV-T and an ITV-T (Internal Target Volume). CT or MRI
 based nodal Target (CTV-E) is according to risk of nodal spread "Small Pelvis", "Large
 Pelvis" or "Large Pelvis + Para-aortic Region". Overall CTV/ITV to PTV margin is 5 mm.
 Involved nodes are boosted preferably based on Positron Emission Tomography (PET) CT with
 10-15 Gy and treated as simultaneous integrated boost within 5 weeks (2.2-2.4 Gy per
 fraction). A range for DVH parameters for the various OARs - contoured according to specific
 protocols - is taken into account for treatment planning. The LR CTV-T and the CTV- E will be
 treated with 45 Gy by use of EBRT (PTV45). Maximal treatment time including both EBRT and BT
 is 50 days. Brachytherapy is prescribed with dose escalation for advanced disease with large
 adaptive CTV-THR including IC/IS techniques and dose de-escalation for limited size CTV-THR
 to spare organs at risk and in particular the upper vagina. The primary imaging method is MRI
 with the applicator in place which enables definition of the relevant volumes of interest
 directly on the images for treatment planning: GTVres, adaptive CTVHR, CTVIR and organ
 volumes. The applicator and the reference points are reconstructed in the same image series.
 All treatment plans have to be optimized to achieve defined planning aims for dose and volume
 parameters for tumor (D98 for GTVres) and target volumes (e.g. D90-95 Gy for adaptive
 CTV-THR) and for 2cm3 reference volumes for OARs (e.g. <80 Gy for bladder, <65 Gy for rectum)
 and for vaginal reference points (recto-vaginal point < 65 Gy, PIBS). If the planning aims
 cannot be achieved, limits for the finally prescribed dose levels are defined for GTVres,
 CTVHR, CTVIR, point A, bladder, rectum, sigmoid bowel and vagina. Planning aim doses and
 limits for the finally prescribed dose levels are based on the experience of the previous
 retroEMBRACE and EMBRACE trials. For chemotherapy weekly concomitant Cisplatin (40 mg/m2) for
 5-6 courses is standard unless chemotherapy is precluded by patient age, co-morbidity and
 toxicity. Aim is to apply minimum 5 cycles of cis-Platin, in particular in advanced disease.

 QUALITY ASSURANCE Only approved departments and investigators can enroll patients into the
 protocol. This approval is under the responsibility of the study coordinators. The approved
 departments are at present those that have contributed continuously to EMBRACE in a
 considerable number of patients. These departments have to go additionally through a QA
 procedure for IMRT/IGRT. New departments will have to go through a quality assurance (QA)
 procedure both for IGABT and IMRT/IGRT. Approval requires a compliance questionnaire,
 successful training, registration and submission of cases and positive evaluation by the
 study coordinators for each centre. There is no formal on site monitoring, but patient files
 and treatment plans must be kept at least until closure of the protocol and final analysis of
 the results is obtained. Continuous data monitoring is performed through the study offices in
 Vienna and Aarhus and through Utrecht for the centres in the Netherlands. Continuous
 education will be offered through ACT and annual workshops and EMBRACE meetings.

 OUTCOME MEASURES Local and nodal (pelvic) control within the specific EBRT and BT targets
 (HR-CTV-T, IR-CTV, LR CTV-T; CTV-E, CTV-N) and morbidity related to OAR in the pelvis and the
 para-artic region as well as overall survival, cancer specific survival and systemic control
 are the primary outcome measures. All endpoints will be evaluated by actuarial statistics.
 Morbidity will be scored by use of the Common Terminology Criteria for Adverse Events (CTCAE
 v3.0/4.0). QoL will also be systematically recorded in all patients.

 EVALUATION OF OUTCOME MEASURES Tumor and nodal remission status (complete, uncertain
 complete, partial, stable & progressive disease) will be evaluated 3 months after treatment
 by pelvic (para-aortic, CT) MRI and gynaecological examination. Regular follow-up including
 gynaecological examination will then be instituted with planned appointments 6, 9, 12, 18,
 24, 30, 36, 48 and 60 months after treatment. Pelvic (para-aortic, CT) MRI will be repeated
 at 12 months after treatment or in case of suspected recurrence. Morbidity and quality of
 life will be scored systematically at base line and at each time point during follow-up.

 SAMPLE SIZE AND DATA MATURITY The study aims at recruiting 1000 patients in 4 years and to
 follow them for at least 5 years to allow for a meaningful assessment of the endpoints by
 univariate and multivariate analysis.
Inclusion Criteria:

 -  Cancer of the uterine cervix considered suitable for curative treatment with
 definitive radio-(chemo)therapy including MRI guided BT

 -  Positive biopsy showing squamous-cell carcinoma, adenocarcinoma or adeno-squamous cell
 carcinoma of the uterine cervix.

 -  Staging according to FIGO and TNM guidelines

 -  MRI of pelvis at diagnosis is performed

 -  MRI, CT or PET-CT of the retroperitoneal space and abdomen at diagnosis is performed

 -  MRI with the applicator in place at the time of (first) BT will be performed

 -  Para-aortic metastatic nodes below L1-L2 are allowed

 -  Patient informed consent

 Exclusion Criteria:

 -  Other primary malignancies except carcinoma in situ of the cervix and basal cell
 carcinoma of the skin

 -  Small cell neuroendocrine cancer, melanoma and other rare cancers in the cervix

 -  Metastatic disease above and beyond the retroperitoneal para-aortic L1-L2 interspace

 -  Previous pelvic or abdominal radiotherapy

 -  Previous total or partial hysterectomy

 -  Combination of preoperative radiotherapy with surgery

 -  Patients receiving BT only

 -  Patients receiving EBRT only

 -  Patients receiving neo-adjuvant chemotherapy or other forms of antineoplastic
 treatment apart from weekly concomitant cisplatin (40 mg/2). However, adjuvant
 chemotherapy in the form of 4 courses of 3 weekly Carboplatin (AUC 5) and Paclitaxel
 (155 mg/m2) is allowed according to departmental policy.

 -  Contra indications to MRI

 -  Contra indications to BT