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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03617133


Additional trial details provided through ANZCTR are available at the end of this record.


Registration number
NCT03617133
Ethics application status
Date submitted
13/07/2018
Date registered
6/08/2018

Titles & IDs
Public title
Image Guided IMRT, Radiochemotherapy and MRI-based IGABT in Locally Advanced Cervical Cancer
Scientific title
Image Guided Intensity Modulated External Beam Radiochemotherapy and MRI Based Adaptive BRAchytherapy in Locally Advanced CErvical Cancer
Secondary ID [1] 0 0
EMBRACE 2
Universal Trial Number (UTN)
Trial acronym
EMBRACEII
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Uterine Cervical Neoplasms 0 0
Condition category
Condition code
Cancer 0 0 0 0
Womb (Uterine or endometrial cancer)
Cancer 0 0 0 0
Cervical (cervix)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Other - Increased use of IC/IS technique in BT
Treatment: Other - Reduction of vaginal source loading
Treatment: Other - Systematic utilisation of IMRT
Treatment: Other - Utilisation of daily IGRT (set-up according to bony structures)
Treatment: Other - EBRT target concept related to the primary tumor (CTV-T) and internal motion; concepts for OAR contouring
Treatment: Other - EBRT dose prescription and reporting
Treatment: Other - Adaptation of EBRT nodal elective CTV according to risk of nodal and systemic recurrence
Treatment: Drugs - Systemic application of simultaneous chemotherapy
Other interventions - Reduction of overall treatment time

Other: Standard arm - General and specific aims of EMBRACEII as well as the multiple quantitative hypotheses are based on technical data, dose volume parameters and clinical results of the prospective observational study EMBRACEI (NCT00920920, 3 year data 2015) and the retrospective RetroEMBRACE (3/5 year data 2015). The performance of EMBRACE II interventions and clinical outcome in terms of disease- (local, nodal, systemic control, OS, CSS) and morbidity-outcome (various organs and endpoints) is thus based on recent clinical evidence with radiochemotherapy and image guided adaptive brachytherapy. The expected effect of EMBRACE II interventions on clinical outcome is estimated from comparative analyses of interventions in subgroups of Retro-/EMBRACE (partly published). Based on the Retro-/EMBRACE benchmark, the estimated outcome including a confidence interval is quantified for each clinical endpoint in the overall cohort as well as different subgroups for an overall expected patient number of 1000.


Treatment: Other: Increased use of IC/IS technique in BT
In EMBRACE II, the improved therapeutic window (through increased application of IC/IS) will be exploited for tumour dose-(de-)escalation and/or OAR dose de-escalation. In tumours with large residual CTVHR volumes at time of brachytherapy, dose-escalation has the potential to improve local control significantly. In limited size CTVHR volumes dose-de-escalation will be performed since dose de-escalation has minor impact on local control while it has potential to reduce morbidity. The strategy of EMBRACEII is to aim for an application of the IC/IS technique in at least 20% of the patients in each institution. The threshold of 20% is relevant for a classical stage distribution of \~20% IB, \~50% IIB, \~20% IIIB and \~10% others. If a given patient population includes significantly higher proportions of limited or extensive disease, the threshold of 20% IC/IS applications must be adapted.

Treatment: Other: Reduction of vaginal source loading
A multicenter investigation in 50 EMBRACE patients from 3 institutions (Mohamed SM. et al, in submission 2015) shows that reduced loading in ring/ovoids and increased loading in tandem (and needles when available) can be applied without compromising CTVHR and GTVres dose. Decrease of relative vaginal loading from a mean of 50% to 33% had potential to reduce ICRU recto-vaginal dose by a mean of 4±4Gy, and furthermore, bladder and rectum doses could be reduced by 2-3Gy with the same re-arrangement of loading. Similar evidence is available from a study on simulation of different intracavitary standard loading patterns in EMBRACE patients, where it was shown that limited size tumours could often be covered by tandem loading alone (Nkiwane KS. et al. 2013).

Treatment: Other: Systematic utilisation of IMRT
Many institutions deliver 3D conformal radiotherapy (3D CRT) based on a four-field box technique although IMRT has been available for a number of years. The practice in EMBRACEI has been utilisation of IMRT and 3D CRT in 27% and 73% of the patients, respectively. However, EMBRACE morbidity data as well as data published by Mundt et al (Mundt AJ. et al. 2003) indicate that IMRT significantly reduces the incidence of bowel morbidity, and therefore IMRT is considered as instrumental for reducing the incidence of bowel morbidity and with a potential also to be beneficial for urinary morbidity.

Treatment: Other: Utilisation of daily IGRT (set-up according to bony structures)
PTV margins of 10 mm to the elective lymph node target are currently applied in many institutions. This margin is related to set-up uncertainties with patient positioning performed based on skin marks. However, currently, most institutions have in-room imaging available which makes it possible to perform daily imaging and couch correction according to fusion on bony anatomy. With daily imaging, bony image fusion, and couch correction, a margin reduction from 10mm to 5mm can be performed without compromising target coverage (Laursen LV. et al. 2012). The 5mm margin reduction has potential to decrease the volume irradiated to 43Gy by approximately 500cm, which is expected to decrease bowel morbidity by \~50%.

Treatment: Other: EBRT target concept related to the primary tumor (CTV-T) and internal motion; concepts for OAR contouring
New target concepts are introduced for EBRT related to primary tumor: initial CTV-T, initial CTV-HR, initial CTV-LR and ITV-LR. Use of this novel contouring approach in conjunction with available MRI allows to target safely the visible tumor (CTV-T) and the high risk region (CTV-HRintitial) while consenting for dose to a low risk region (CTV-LRinitial). Anatomical changes due to organ filling variation and cervix/uterus position are considered. ITV-LR is outlined using planning scan and MR images in patients with MRI in treating position while a fixed margin is added to the CTV-LR initial in patients with only diagnostic MRI. New concepts are introduced for OAR contouring. Bowel loops are outlined in one volume restricted to the outer contour, including the mesenterium, for better approximation of the bowel volume and dose constraints. Rectum/sigmoid structures are contoured distinctly. Vaginal lower border is 2,5cm from the caudal extend of the tumor (2cm ITV-LR initial + 0,5cm PTV).

Treatment: Other: EBRT dose prescription and reporting
There is currently a significant variation with regard to EBRT dose and fractionation in the EMBRACE study with doses ranging from 45Gy to 50Gy and being delivered in 25-30 fractions. Furthermore, there is a wide variety of lymph node boosting strategies. In EMBRACEII, the EBRT dose and fractionation to the elective lymph node CTV and initial CTV-T is fixed at 45Gy in 25 fractions, and lymph node boosting must be performed as a simultaneous integrated boost. The dose de-escalation from 50Gy to 45Gy has potential to reduce morbidity. A system of reporting dose to targets and OARs is introduced in terms of dose volume parameters and a system of point dose reporting for the vagina.

Treatment: Other: Adaptation of EBRT nodal elective CTV according to risk of nodal and systemic recurrence
EMBRACEII applies a risk adapted target concept for nodal CTV. This target concept is based on pattern of nodal recurrence analysis which shows 50% of recurrences beyond the classical L5/S1 cranial pelvic field border. A target volume "Large Pelvis" is defined for intermediate risk patients and includes internal, external, common iliac, obturator and presacral nodes. For high risk patients, defined as common iliac or \>2 nodes involved, the para-aortic region is included. For low risk patients, defined as stage IA/IB1/IIA1, N0, small cell carcinoma (SCC), no uterine invasion, "Small Pelvis" is defined which is "Large Pelvis" without common iliac nodes. Intermediate risk is defined as not high and not low risk.

Treatment: Drugs: Systemic application of simultaneous chemotherapy
According to international standard and evidence, simultaneous chemotherapy (CHT) (min. 5x40 mg/m2 cis Platinum) was prescribed in the EMBRACE protocol for all patients, who qualify for its administration. Certain rules were given for adaption according to international guidelines. 90-95% of EMBRACE patients received simultaneous CHT. Most of the EMBRACE cohort is consecutive patients representing the cervix cancer patient population in the respective centers. About 70% of patients received =5 cycles, while 30% received 0-4 cycles. CHT has impact on systemic control, which is pronounced in high risk patients (node positive and/or stage III/IV) with a 20% difference in systemic recurrence. A center effect has been found in the ability to administer chemotherapy with 15-85% of the patients receiving =5 cycles of CHT. To reach optimal outcome, particularly in the high risk group, the EMBRACEII protocol also focusses on appropriate administration of CHT following international guidelines.

Other interventions: Reduction of overall treatment time
Several studies indicate that maintaining an overall treatment time (OTT) of \<=50 days is important for local control. RetroEMBRACE data confirms that OTT remains of importance in the realm of IGABT. As there is significant variation of OTT across patients and institutions in retroEMBRACE, the EMBRACEII study aims to reduce the OTT so that the majority of patients (\>80%) will adhere to the \<=50 day threshold. The measures to reduce OTT in EMBRACE is to systematically apply 25 fractions of EBRT including lymph node boost, and furthermore to carefully plan the BT schedule, so that brachytherapy is delivered towards the end of EBRT and/or directly after EBRT.
Intervention code [1] 0 0
Treatment: Other
Intervention code [2] 0 0
Treatment: Drugs
Intervention code [3] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
local control
Timepoint [1] 0 0
5 years
Primary outcome [2] 0 0
nodal control
Timepoint [2] 0 0
5 years
Primary outcome [3] 0 0
systemic control
Timepoint [3] 0 0
5 years
Primary outcome [4] 0 0
overall survival
Timepoint [4] 0 0
5 years
Primary outcome [5] 0 0
overall morbidity
Timepoint [5] 0 0
5 years
Primary outcome [6] 0 0
health-related quality of life: physical functioning
Timepoint [6] 0 0
5 years
Primary outcome [7] 0 0
health-related quality of life: role functioning
Timepoint [7] 0 0
5 years
Primary outcome [8] 0 0
health-related quality of life: social functioning
Timepoint [8] 0 0
5 years
Secondary outcome [1] 0 0
cancer specific survival
Timepoint [1] 0 0
5 years
Secondary outcome [2] 0 0
disease specific survival
Timepoint [2] 0 0
5 years

Eligibility
Key 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
Minimum age
18 Years
Maximum age
99 Years
Sex
Females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Not applicable
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/04/2016
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/04/2031
Actual
Sample size
Target
1000
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
Austria
State/province [1] 0 0
Vienna

Funding & Sponsors
Primary sponsor type
Other
Name
Medical University of Vienna
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Universitaire Ziekenhuizen KU Leuven
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
Aarhus University Hospital
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
Rigshospitalet, Denmark
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
Odense University Hospital
Address [4] 0 0
Country [4] 0 0
Other collaborator category [5] 0 0
Other
Name [5] 0 0
North Estonia Medical Centre
Address [5] 0 0
Country [5] 0 0
Other collaborator category [6] 0 0
Other
Name [6] 0 0
Institut Bergonié
Address [6] 0 0
Country [6] 0 0
Other collaborator category [7] 0 0
Other
Name [7] 0 0
Gustave Roussy, Cancer Campus, Grand Paris
Address [7] 0 0
Country [7] 0 0
Other collaborator category [8] 0 0
Other
Name [8] 0 0
University Hospital Heidelberg
Address [8] 0 0
Country [8] 0 0
Other collaborator category [9] 0 0
Other
Name [9] 0 0
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Address [9] 0 0
Country [9] 0 0
Other collaborator category [10] 0 0
Other
Name [10] 0 0
Oslo University Hospital
Address [10] 0 0
Country [10] 0 0
Other collaborator category [11] 0 0
Other
Name [11] 0 0
Institute of Oncology Ljubljana
Address [11] 0 0
Country [11] 0 0
Other collaborator category [12] 0 0
Other
Name [12] 0 0
Complejo Hospitalario de Navarra
Address [12] 0 0
Country [12] 0 0
Other collaborator category [13] 0 0
Other
Name [13] 0 0
Hospital Clinic of Barcelona
Address [13] 0 0
Country [13] 0 0
Other collaborator category [14] 0 0
Other
Name [14] 0 0
Skane University Hospital
Address [14] 0 0
Country [14] 0 0
Other collaborator category [15] 0 0
Other
Name [15] 0 0
Region Örebro County
Address [15] 0 0
Country [15] 0 0
Other collaborator category [16] 0 0
Other
Name [16] 0 0
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Address [16] 0 0
Country [16] 0 0
Other collaborator category [17] 0 0
Other
Name [17] 0 0
Radiotherapiegroep
Address [17] 0 0
Country [17] 0 0
Other collaborator category [18] 0 0
Other
Name [18] 0 0
Leiden University Medical Center
Address [18] 0 0
Country [18] 0 0
Other collaborator category [19] 0 0
Other
Name [19] 0 0
Maastro Clinic, The Netherlands
Address [19] 0 0
Country [19] 0 0
Other collaborator category [20] 0 0
Other
Name [20] 0 0
UMC Utrecht
Address [20] 0 0
Country [20] 0 0
Other collaborator category [21] 0 0
Other
Name [21] 0 0
The Netherlands Cancer Institute
Address [21] 0 0
Country [21] 0 0
Other collaborator category [22] 0 0
Other
Name [22] 0 0
Radboud University Medical Center
Address [22] 0 0
Country [22] 0 0
Other collaborator category [23] 0 0
Other
Name [23] 0 0
Catharina Ziekenhuis Eindhoven
Address [23] 0 0
Country [23] 0 0
Other collaborator category [24] 0 0
Other
Name [24] 0 0
Erasmus Medical Center
Address [24] 0 0
Country [24] 0 0
Other collaborator category [25] 0 0
Other
Name [25] 0 0
Cambridge University Hospitals NHS Foundation Trust
Address [25] 0 0
Country [25] 0 0
Other collaborator category [26] 0 0
Other
Name [26] 0 0
The Leeds Teaching Hospitals NHS Trust
Address [26] 0 0
Country [26] 0 0
Other collaborator category [27] 0 0
Other
Name [27] 0 0
The Christie NHS Foundation Trust
Address [27] 0 0
Country [27] 0 0
Other collaborator category [28] 0 0
Other
Name [28] 0 0
University Hospitals Coventry and Warwickshire NHS Trust
Address [28] 0 0
Country [28] 0 0
Other collaborator category [29] 0 0
Other
Name [29] 0 0
University Hospitals Bristol and Weston NHS Foundation Trust
Address [29] 0 0
Country [29] 0 0
Other collaborator category [30] 0 0
Other
Name [30] 0 0
Royal Marsden NHS Foundation Trust
Address [30] 0 0
Country [30] 0 0
Other collaborator category [31] 0 0
Other
Name [31] 0 0
Cross Cancer Institute
Address [31] 0 0
Country [31] 0 0
Other collaborator category [32] 0 0
Other
Name [32] 0 0
McGill University
Address [32] 0 0
Country [32] 0 0
Other collaborator category [33] 0 0
Other
Name [33] 0 0
Princess Margaret Hospital, Canada
Address [33] 0 0
Country [33] 0 0
Other collaborator category [34] 0 0
Other
Name [34] 0 0
Tom Baker Cancer Centre
Address [34] 0 0
Country [34] 0 0
Other collaborator category [35] 0 0
Other
Name [35] 0 0
Loyola University Chicago
Address [35] 0 0
Country [35] 0 0
Other collaborator category [36] 0 0
Other
Name [36] 0 0
M.D. Anderson Cancer Center
Address [36] 0 0
Country [36] 0 0
Other collaborator category [37] 0 0
Other
Name [37] 0 0
University of Pittsburgh
Address [37] 0 0
Country [37] 0 0
Other collaborator category [38] 0 0
Other
Name [38] 0 0
Pamela Youde Nethersole Eastern Hospital
Address [38] 0 0
Country [38] 0 0
Other collaborator category [39] 0 0
Government body
Name [39] 0 0
Tuen Mun Hospital
Address [39] 0 0
Country [39] 0 0
Other collaborator category [40] 0 0
Other
Name [40] 0 0
Post Graduate Institute of Medical Education and Research, Chandigarh
Address [40] 0 0
Country [40] 0 0
Other collaborator category [41] 0 0
Other
Name [41] 0 0
Tata Memorial Centre
Address [41] 0 0
Country [41] 0 0
Other collaborator category [42] 0 0
Other
Name [42] 0 0
Chulalongkorn University
Address [42] 0 0
Country [42] 0 0
Other collaborator category [43] 0 0
Other
Name [43] 0 0
Siriraj Hospital
Address [43] 0 0
Country [43] 0 0
Other collaborator category [44] 0 0
Other
Name [44] 0 0
Liverpool Hospital, Sydney
Address [44] 0 0
Country [44] 0 0
Other collaborator category [45] 0 0
Other
Name [45] 0 0
Maisonneuve-Rosemont Hospital
Address [45] 0 0
Country [45] 0 0
Other collaborator category [46] 0 0
Government body
Name [46] 0 0
National Cancer Institute, Slovakia
Address [46] 0 0
Country [46] 0 0
Other collaborator category [47] 0 0
Other
Name [47] 0 0
Institut Català d'Oncologia
Address [47] 0 0
Country [47] 0 0
Other collaborator category [48] 0 0
Other
Name [48] 0 0
Ludwig-Maximilians - University of Munich
Address [48] 0 0
Country [48] 0 0
Other collaborator category [49] 0 0
Other
Name [49] 0 0
Mount Vernon Cancer Centre
Address [49] 0 0
Country [49] 0 0
Other collaborator category [50] 0 0
Other
Name [50] 0 0
St Thomas' Hospital, London
Address [50] 0 0
Country [50] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Richard Pötter, MD
Address 0 0
Medical University of Vienna
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Richard Pötter, MD
Address 0 0
Country 0 0
Phone 0 0
0043140400
Fax 0 0
Email 0 0
richard.poetter@akhwien.at
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT03617133

Additional trial details provided through ANZCTR
Accrual to date
Recruiting in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 11
Liverpool Hospital
Recruitment hospital [2] 12
Campbelltown Hospital
Recruitment postcode(s) [1] 11
2170
Recruitment postcode(s) [2] 12
2560
Funding & Sponsors
Primary sponsor
Hospital
Primary sponsor name
South Western Sydney Local Health District
Primary sponsor address
South Western Sydney Local Health District (SWSLHD)
Locked Bag 7103 Liverpool BC NSW 1871
Primary sponsor country
Australia
Ethics approval
Ethics application status
Approved
Ethics committee name [1] 9
South Western Sydney Local Health District Human Research Ethics Committee
Address [1] 9
South Western Sydney Local Health District (SWSLHD) Locked Bag 7103 Liverpool BC NSW 1871
Country [1] 9
Australia
Date submitted for ethics approval [1] 9
27/05/2019
Approval date [1] 9
25/06/2019
Ethics approval number [1] 9
2019/ETH00443
 
Public notes

Contacts
Principal investigator
Title 89 0
Dr
Name 89 0
Karen Lim
Address 89 0
South Western Sydney Local Health District (SWSLHD) Locked Bag 7103 Liverpool BC NSW 1871
Country 89 0
Australia
Phone 89 0
+61 2 8738 9805
Fax 89 0
+61 2 8738 9819
Email 89 0
karen.lim@health.nsw.gov.au
Contact person for public queries
Title 90 0
Ms
Name 90 0
Tess Afinidad
Address 90 0
South Western Sydney Local Health District (SWSLHD) Locked Bag 7103 Liverpool BC NSW 1871
Country 90 0
Australia
Phone 90 0
+61 2 8738 9146
Fax 90 0
+61 2 8738 9205
Email 90 0
tess.afinidad@health.nsw.gov.au
Contact person for scientific queries
Title 91 0
Dr
Name 91 0
Karen Lim
Address 91 0
South Western Sydney Local Health District (SWSLHD) Locked Bag 7103 Liverpool BC NSW 1871
Country 91 0
Australia
Phone 91 0
+61 2 8738 9805
Fax 91 0
+61 2 8738 9819
Email 91 0
karen.lim@health.nsw.gov.au