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Image Based Brachytherapy in Locally Advanced Cervical Cancers - a Randomized Controlled Trial (COMBAT-Cx)

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ClinicalTrials.gov Identifier: NCT03005743
Recruitment Status : Recruiting
First Posted : December 29, 2016
Last Update Posted : January 23, 2018
Sponsor:
Information provided by (Responsible Party):
Dr Umesh Mahantshetty, Tata Memorial Hospital

Tracking Information
First Submitted Date  ICMJE December 21, 2016
First Posted Date  ICMJE December 29, 2016
Last Update Posted Date January 23, 2018
Study Start Date  ICMJE December 2016
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 25, 2016)
Local control [ Time Frame: 2 years ]
Absolute benefit in local control rates by 10% for stages FIGO IIB and IIIB
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03005743 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 25, 2016)
  • Late toxicities [ Time Frame: 2 years ]
    Reduction in grade 3 and grade 4 (CTCAE) late toxicities from 10% to 5% (by 50%)
  • Pelvic control rates [ Time Frame: 2 years ]
  • Distant failure rates [ Time Frame: 2 years ]
  • Progression free & cause specific survival [ Time Frame: 2 years ]
  • Overall survival [ Time Frame: 2 years ]
  • Quality of life questionnaire EORTC QLQ C30 [ Time Frame: 2 years ]
  • Quality life questionnaire EORTC QLQ CX24 [ Time Frame: 2 years ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Image Based Brachytherapy in Locally Advanced Cervical Cancers - a Randomized Controlled Trial
Official Title  ICMJE COnventional Radiography Based Intracavitary Brachytherapy (Standard Arm) Versus Magnetic Resonance Image Based BrAchyTherapy (Study Arm) in Locally Advanced Cervical Cancers: A Phase III Randomized Controlled Trial (COMBAT - Cervix Trial)
Brief Summary Purpose of the study is to determine whether Image based brachytherapy is superior in terms of local control to Conventional radiograph based brachytherapy in locally advanced cervical cancers in a Phase III randomized setting.
Detailed Description

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 which are conventional radiography based surrogates for tumour (Manchester point A prescription point) and normal tissues [International commission on Radiation Units and Measurements (ICRU) Bladder and Rectum point]. This conventional radiography based planning has been adopted universally for ease of delivering safe doses with reasonably good local control rates (stage IIB - 85%; Stage IIIB - 65%) and acceptable acute and late toxicities (</=10% grade III/IV). Thus, for several decades conventional radiography based prescription has been standard of care universally. But these conventional radiography based surrogates have been proved to be only rough estimates and do not always correlate in 3 dimensional (3D) anatomy for neither tumour nor normal tissues for actual doses delivered and outcomes in terms of control rates and toxicities respectively. Several studies have been published demonstrating limitations and criticizing this point based treatments. In 2006, a working group from Groupe Européen de Curiethérapie- European Society for Therapeutic Radiology and Oncology (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 Magnetic Resonance (MR) image based Intracavitary Brachytherapy (ICBT). The major advantage of this technique is the possibility to conform the dose given by BT with regard to volume (3D) for both tumour and critical normal tissues (bladder, rectum, sigmoid mainly). Thus, by repetitive imaging performed before each BT treatment it is possible to adapt dose given as per 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. Clinical Outcome data from Vienna, Paris and Mumbai have shown potential in improved local control rates with acceptable toxicities so far. Prospectively treated more than 100 patients with image based brachytherapy from Vienna Group have shown improved local control rates across all stages with decreased toxicity on comparisons with historical series of patients treated with Conventional Radiography based BT [13-19]. Also, a phase II multicentre intercontinental study using MR Image Based Brachytherapy (EMBRACE: European study on MRI-guided Brachytherapy in Locally Advanced Cervical Cancer) has been implemented and tested in various centres across the world including Tata Memorial Hospital, Mumbai. Over 600 patients have been recruited in the study so far. Based on the experience collected so far, the image based BT approach is expected to have a major impact on the clinical outcome for II B and III B (increase in local control rates by 10-20%) with concomitant decrease in the rates of late normal tissue toxicity (<5% Grade ¾), as compared to historical results for point based conventional treatment prescriptions [20].

EMBRACE is a study on MRI guided brachytherapy (BT) in locally advanced cervical cancer. Today point-based two-dimensional BT is most often used for definitive radiotherapy in cervical cancer. However, MRI guided Image Based brachytherapy is increasingly being used in several centres, and the results reported so far are very promising. 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 to adapt the dose given by BT to the anatomy of each individual patient taking into account not only the position of organs at risk but also the tumour regression which often is obtained by preceding external beam radiotherapy and chemotherapy. Based on the experience collected so far, the image based BT approach significantly improves the dose-volume histogram (DVH) parameters and the improved dose delivered seems to have a major impact on the clinical outcome with a concomitant decrease in the rates of both local failure and morbidity. Preliminary results of ongoing studies including RETRO EMBRACE (600 patients - retrospective multicentric analysis) and EMBRACE (1000 patients recruited so far prospectively multicentric) also suggest excellent local control rates & minimal clinical significant toxicities.

Hypothesis: The clinical outcome of radical radiation therapy including Conventional radiography based brachytherapy for International Federation of Gynecology and Obstetrics (FIGO) Stage IIB and IIIB reported in historical series is 75% and 55% local control rates and grade ¾ rectal / bladder toxicities of 10-15%. With the addition of concomitant cisplatin chemotherapy there is an additional local control benefit of 5-10% and potentially increase in late toxicities (no substantial evidence for toxicities reported so far). With the MR Image Based Brachytherapy approach, mono-institutional series and phase II multicentric international study, the results reported so far show an improvement in local control rates to 96% and 86% for IIB and IIIB respectively and late toxicities <5% reported so far. We propose this randomized control study to test the following hypothesis: With the use of MR Image Based Brachytherapy (Study Arm) in locally advanced cervical cancers (Stratified for Stage IIB and IIIB), there will be an absolute increase in local control rates by 10% and reduction in late rectal and bladder toxicities by 5% - 10% as compared to the Conventional radiography based ICBT. Thus, for demonstrating absolute local control benefit of 10% in Stages IIB (85% to 95%) and Stage IIIB (65% to 75%) a total of 1050 patients (350 patients with Stage IIB and 650 patients with stage IIB respectively) will be accrued.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cervical Cancer
Intervention  ICMJE
  • Radiation: Magnetic Resonance Image based Brachytherapy
    MRI based BT prescription will be in accordance to the GEC-ESTRO guidelines [Intention will be to treat the whole cervix and the remaining residual tumour tissue at the primary site at the time of BT (high risk-clinical target volume) to a dose level analogue to the dose level previously prescribed for point-A]
  • Radiation: Conventional Radiograph based Brachytherapy
    The standard conventional radiography based prescription will be according to Manchester system Point A and bladder & rectum ICRU point dose constraints
Study Arms  ICMJE
  • Experimental: MR based BT
    Magnetic Resonance Image based Brachytherapy
    Intervention: Radiation: Magnetic Resonance Image based Brachytherapy
  • Conventional BT
    Conventional Radiograph based Brachytherapy
    Intervention: Radiation: Conventional Radiograph based Brachytherapy
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 25, 2016)
1050
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2023
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Cancer of the uterine cervix considered suitable for curative treatment with definitive radio-(chemo) therapy including MRI guided Brachytherapy.
  • Positive biopsy showing squamous-cell carcinoma, adenocarcinoma or adeno-squamous cell carcinoma of the uterine cervix.
  • Stage IIB/IIIB according to FIGO and tumor node metastasis (TNM) guidelines
  • Suitable for Brachytherapy boost
  • MRI of pelvis at diagnosis is performed
  • MRI, Computed Tomography (CT) or Positron Emission Tomography (PET) -CT of the retroperitoneal space and abdomen at diagnosis is performed to rule out Para-aortic lymph node metastasis.
  • Patient informed consent
  • Pre-treatment Haemoglobin level >10 g/dL

Exclusion Criteria:

  • Other primary malignancies except carcinoma in situ of the cervix and basal cell carcinoma of the skin.
  • Metastatic disease
  • Patients with para-aortic metastatic nodes (stage IVB) to the level of L2 vertebra or further dissemination
  • 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 neoadjuvant chemotherapy
  • Contraindications to MRI
  • Contraindications to BT
  • Active infection or severe medical condition endangering treatment delivery.
  • Pregnant, lactating or childbearing potential without adequate contraception
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Umesh Mahantshetty, MD, DNB +91 2224177000 ext 7168 mahantshettyum@tmc.gov.in
Listed Location Countries  ICMJE India
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03005743
Other Study ID Numbers  ICMJE TMH-1587
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Dr Umesh Mahantshetty, Tata Memorial Hospital
Study Sponsor  ICMJE Tata Memorial Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Umesh Mahantshetty, MD, DNB Professor, Department of Radiation Oncology, Tata memorial Hospital, Mumbai 400012
PRS Account Tata Memorial Hospital
Verification Date January 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP