Image Guided IMRT, Radiochemotherapy and MRI-based IGABT in Locally Advanced Cervical Cancer

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.