EMBRACE I

In 2008 the GEC-ESTRO Gyn network initiated the EMBRACE study which has successfully finalised accrual in December 2015 with a total of 1416 patients. The EMBRACE study is internationally recognised as the most ambitious study worldwide to evaluate and benchmark image guided brachytherapy in a prospective multicentre study. The EMBRACE research group is responsible for the clinical research structure, and currently >20 research studies are published (see under references) or are in progress addressing questions such as local, nodal and systemic recurrences; bladder, bowel, and vaginal morbidity; QoL; prognostic and predictive parameters; physics parameters, 3D QA etc. A vaginal substudy is evaluating in more detail vaginal side effects, vaginal dose and patient reported outcome measures.

EMBRACE I coordinators:

• Richard Pötter (PI) (MUW)
• Jacob Lindegaard (AUH)
• Christian Kirisits (MUW)
• Kari Tanderup (AUH)

Background

The standard treatment of locally advanced cervical cancer is radio-chemotherapy including external beam radiotherapy (EBRT), brachytherapy (BT) and concomitant chemotherapy with weekly Cisplatin. While image based conformal EBRT is routinely used, prescription and reporting of BT is still based on specific dose points defined in 2D. Thus, for several decades the BT dose has most often been prescribed and reported to the Manchester point A defined according to different traditions.

Recently, a working group from GEC-ESTRO has published recommendations on contouring of tumour target and organs at risk (OAR) as well as on dose volume parameters to be reported for image guided BT in definitive radiotherapy for locally advanced cervical cancer. These recommendations are mainly derived from retrospective single institution experience with MRI based intracavitary BT. The major advantage of this technique is the possibility to conform the dose given by BT with regard to both volume (3D) and time (4D). Thus, by repetitive imaging performed before each BT implant it is possible adapt the dose given by BT to the anatomy of each individual patient taking into account not only the position of OAR but also the tumour regression which often is obtained by preceding EBRT and chemotherapy. Based on the experience collected so far, the image based BT approach is expected to have a major impact on the clinical outcome with a concomitant decrease in the rates of both local failure and morbidity.

Aims

• To introduce MRI based 3D-4D BT in locally advanced cervical cancer in a multicenter setting within the frame of a prospective observational study.
• To establish a bench-mark for clinical outcome with image based BT in a large patient population with respect to local control, survival, morbidity and QoL
• To establish a reference material with regard to image based DVH parameters according to the guidelines from the GEC ESTRO working group.
• To correlate image based DVH parameters for CTV and for OAR with outcome
• To develop prognostic and predictive statistical models for clinical outcome including volumetric, dosimetric, clinical and biological risk factors
• To establish radiobiological parameter estimates that will allow a precise risk estimation in individual patients and aid in the development of new treatment protocols

Type of design

The study is a multicenter prospective observational study. Reporting on the key clinical treatment and outcome parameters are mandatory while study of QoL and other companion studies are optional for the individual department. 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, FIGO stage IB, IIA, IIB, IIIA, IIIB and IVA in whom definitive radiotherapy with curative intent is planned are qualified for the study. Patients with para-aortic metastatic nodes (stage IVB) to the level of L2 are also eligible but patients with further dissemination are not.

Staging should as a minimal include gynaecological examination, MRI of the pelvis, abdominal CT or MRI and chest radiography. Further investigations are applied if necessary (e.g. cystoscopy, rectoscopy) or normally done according to institutional practice (e.g. PET-CT).

Treatment of patients in the trial

All patients will receive both EBRT 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 a/b = 10 Gy for tumour effects and a/b=3 Gy for late normal tissue damage. The repair half time is assumed to be 1.5 hrs.

EBRT should be delivered in accordance with specific defined rules for target definition, treatment planning, dose, fractionation and overall treatment time. Target definition for EBRT will be based on 3D imaging by CT or PET-CT. The elective target for nodal disease (low-risk clinical target volume LR-CTV) will be treated with 45-50 Gy by use of EBRT only. Macroscopic disease out of range from significant dose contribution from intracavitary BT (massive pelvic side wall disease or metastatic pelvic and para-aortic nodes) should be dealt with by additional measures such as combined interstitial-intracavitary BT or by a simultaneous integrated EBRT boost to a dose level of 55-65 Gy. Intensity modulatedradiotherapy (IMRT) and/or Image guided radiotherapy (IGRT) may be used. Dose per fraction of EBRT should be 1.5-2.0 Gy in the elective volume whereas fraction sizes of 2.0-2.4 Gy should be used in targets encompassing macroscopic tumour not treated with BT. Maximal treatment time including both EBRT and BT is 50 days.

For BT the choice of applicator and implant procedures should follow the usual standard of the individual department. However, BT treatment planning will be based on MRI imaging with the applicator in situ according to the GEC-ESTRO guidelines and additional criteria for MRI sequencing, contouring, applicator reconstruction, and dose optimization. The intention is to treat the whole cervix and the remaining residual tumour tissue at the primary site at time of BT (high risk-clinical target volume, HR-CTV) to a dose level analogue to the dose level previously prescribed for point-A. An alternative (complementary) approach is to treat the volume according to the tumour extension at diagnosis (intermediate risk-clinical target volume, IR-CTV) to a dose level equivalent to the dose level previously prescribed for the ICRU reference volume. The dose level chosen for HR-CTV or IR CTV in this protocol and the DVH constraints is to follow the individual departmental practice, i.e. there is no general dose prescription and DVH constraints in the EMBRACE protocol.

With regard to chemotherapy, weekly concomitant Cisplatin (40 mg/m2) for 5-6 courses is standard unless chemotherapy is precluded by patient age, co-morbidity and toxicity.

Quality assurance

Only approved departments and investigators can contribute to patients to the protocol. It is the responsibility of the study coordinators to evaluate and approve participation. Approval requires a successful dummy run and an individual assessment of the performance of each participating 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.

Outcome measures

Local control within the specific BT targets (HR-CTV and IR-CTV) and morbidity related to OAR in the pelvis are the primary outcome measures. Secondary endpoints include regional control, disease free survival and overall survival. 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). QoL will also be systematically recorded in patients treated at departments participating in the QoL part of the protocol (to follow as an optional protocol amendment).

Evaluation of outcome measures

Remission status (complete, partial, stable & progressive disease) will be evaluated 3 months after treatment by pelvic 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 MRI will be repeated at 12 after treatment or in case of suspected recurrence. Morbidity will be scored systematically at base line and at each time point during follow-up. Quality of life questionnaires are distributed at regular intervals both at diagnosis (base line) and during follow up.

Sample size and data maturity

The study aims at recruiting more than 600 patients in 3 years and to follow them for at least another 3 years to allow for a meaningful assessment of the endpoints by univariate and multivariate analysis.”

Study protocol

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