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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03617133
Recruitment Status : Recruiting
First Posted : August 6, 2018
Last Update Posted : May 27, 2020
Information provided by (Responsible Party):
Richard Pötter, Medical University of Vienna

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Uterine Cervical Neoplasms Radiation: Increased use of IC/IS technique in BT Radiation: Reduction of vaginal source loading Radiation: Systematic utilisation of IMRT Radiation: Utilisation of daily IGRT (set-up according to bony structures) Radiation: EBRT target concept related to the primary tumor (CTV-T) and internal motion; concepts for OAR contouring Radiation: EBRT dose prescription and reporting Radiation: Adaptation of EBRT nodal elective CTV according to risk of nodal and systemic recurrence Drug: Systemic application of simultaneous chemotherapy Other: Reduction of overall treatment time Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1000 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Interventional, observational, validation study to EMBRACE I
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Image Guided Intensity Modulated External Beam Radiochemotherapy and MRI Based Adaptive BRAchytherapy in Locally Advanced CErvical Cancer
Actual Study Start Date : April 2016
Estimated Primary Completion Date : April 2021
Estimated Study Completion Date : April 2031

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cervical Cancer

Arm Intervention/treatment
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.
Radiation: 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.

Radiation: 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).

Radiation: 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.

Radiation: 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%.

Radiation: 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).

Radiation: 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.

Radiation: 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.

Drug: 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: 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.

Primary Outcome Measures :
  1. local control [ Time Frame: 5 years ]
  2. nodal control [ Time Frame: 5 years ]
  3. systemic control [ Time Frame: 5 years ]
  4. overall survival [ Time Frame: 5 years ]
  5. overall morbidity [ Time Frame: 5 years ]
  6. health-related quality of life: physical functioning [ Time Frame: 5 years ]
    European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire. Scores ranging from 0 to 100, higher scores indicating better functioning.

  7. health-related quality of life: role functioning [ Time Frame: 5 years ]
    European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire. Scores ranging from 0 to 100, higher scores indicating better functioning.

  8. health-related quality of life: social functioning [ Time Frame: 5 years ]
    European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire. Scores ranging from 0 to 100, higher scores indicating better functioning.

Secondary Outcome Measures :
  1. cancer specific survival [ Time Frame: 5 years ]
  2. disease specific survival [ Time Frame: 5 years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03617133

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Contact: Richard Pötter, MD 0043140400 ext 28760
Contact: Kari Tanderup, PhD

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Medical University of Vienna Recruiting
Vienna, Austria, 1090
Contact: Richard Pötter, MD    0043140400 ext 26920   
Sponsors and Collaborators
Medical University of Vienna
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Principal Investigator: Richard Pötter, MD Medical University of Vienna
Additional Information:
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Responsible Party: Richard Pötter, Principal investigator, Medical University of Vienna Identifier: NCT03617133    
Other Study ID Numbers: EMBRACE 2
First Posted: August 6, 2018    Key Record Dates
Last Update Posted: May 27, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Uterine Cervical Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Uterine Cervical Diseases
Uterine Diseases