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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT03005743
Other study ID # TMH-1587
Secondary ID
Status Recruiting
Phase N/A
First received December 21, 2016
Last updated January 18, 2018
Start date December 2016
Est. completion date December 2023

Study information

Verified date January 2018
Source Tata Memorial Hospital
Contact Umesh Mahantshetty, MD, DNB
Phone +91 2224177000
Email mahantshettyum@tmc.gov.in
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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 (
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.


Recruitment information / eligibility

Status Recruiting
Enrollment 1050
Est. completion date December 2023
Est. primary completion date December 2021
Accepts healthy volunteers No
Gender Female
Age group N/A and older
Eligibility 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

Study Design


Related Conditions & MeSH terms


Intervention

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]
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

Locations

Country Name City State
India Tata Memorial Hospital Mumbai Maharashtra

Sponsors (1)

Lead Sponsor Collaborator
Tata Memorial Hospital

Country where clinical trial is conducted

India, 

References & Publications (21)

Beriwal S, Kannan N, Kim H, Houser C, Mogus R, Sukumvanich P, Olawaiye A, Richard S, Kelley JL, Edwards RP, Krivak TC. Three-dimensional high dose rate intracavitary image-guided brachytherapy for the treatment of cervical cancer using a hybrid magnetic resonance imaging/computed tomography approach: feasibility and early results. Clin Oncol (R Coll Radiol). 2011 Dec;23(10):685-90. doi: 10.1016/j.clon.2011.08.007. Epub 2011 Sep 9. — View Citation

Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration (CCCMAC). Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: individual patient data meta-analysis. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD008285. doi: 10.1002/14651858.CD008285. Review. — View Citation

Dolezel M, Odrazka K, Vanasek J, Kohlova T, Kroulik T, Kudelka K, Spitzer D, Mrklovsky M, Tichy M, Zizka J, Jalcova L. MRI-based pre-planning in patients with cervical cancer treated with three-dimensional brachytherapy. Br J Radiol. 2011 Sep;84(1005):850-6. doi: 10.1259/bjr/75446993. — View Citation

Fidarova EF, Berger D, Schüssler S, Dimopoulos J, Kirisits C, Georg P, Bachtiary B, Pötter R. Dose volume parameter D2cc does not correlate with vaginal side effects in individual patients with cervical cancer treated within a defined treatment protocol with very high brachytherapy doses. Radiother Oncol. 2010 Oct;97(1):76-9. doi: 10.1016/j.radonc.2010.05.005. Epub 2010 Jun 17. — View Citation

Green J, Kirwan J, Tierney J, Vale C, Symonds P, Fresco L, Williams C, Collingwood M. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD002225. Review. — View Citation

Haie-Meder C, Chargari C, Rey A, Dumas I, Morice P, Magné N. MRI-based low dose-rate brachytherapy experience in locally advanced cervical cancer patients initially treated by concomitant chemoradiotherapy. Radiother Oncol. 2010 Aug;96(2):161-5. doi: 10.1016/j.radonc.2010.04.015. — View Citation

Haie-Meder C, Pötter R, Van Limbergen E, Briot E, De Brabandere M, Dimopoulos J, Dumas I, Hellebust TP, Kirisits C, Lang S, Muschitz S, Nevinson J, Nulens A, Petrow P, Wachter-Gerstner N; Gynaecological (GYN) GEC-ESTRO Working Group. Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (I): concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV. Radiother Oncol. 2005 Mar;74(3):235-45. Review. — View Citation

Kirwan JM, Symonds P, Green JA, Tierney J, Collingwood M, Williams CJ. A systematic review of acute and late toxicity of concomitant chemoradiation for cervical cancer. Radiother Oncol. 2003 Sep;68(3):217-26. Review. — View Citation

Kotsuma T, Yoshida K, Yamazaki H, Takenaka T, Konishi K, Isohashi F, Koizumi M, Tanaka E, Yoshioka Y. Preliminary results of magnetic resonance imaging-aided high-dose-rate interstitial brachytherapy for recurrent uterine carcinoma after curative surgery. J Radiat Res. 2011;52(3):329-34. Epub 2011 Mar 31. — View Citation

Mahantshetty U, Swamidas J, Khanna N, Engineer R, Merchant NH, Deshpande DD, Shrivastava S. Reporting and validation of gynaecological Groupe Euopeen de Curietherapie European Society for Therapeutic Radiology and Oncology (ESTRO) brachytherapy recommendations for MR image-based dose volume parameters and clinical outcome with high dose-rate brachytherapy in cervical cancers: a single-institution initial experience. Int J Gynecol Cancer. 2011 Aug;21(6):1110-6. doi: 10.1097/IGC.0b013e31821caa55. — View Citation

Mahantshetty U, Swamidas J, Khanna N, Engineer R, Merchant NH, Shrivastava S. Magnetic resonance image-based dose volume parameters and clinical outcome with high dose rate brachytherapy in cervical cancers--a validation of GYN GEC-ESTRO brachytherapy recommendations. Clin Oncol (R Coll Radiol). 2011 Jun;23(5):376-7. doi: 10.1016/j.clon.2011.02.006. Epub 2011 Mar 5. — View Citation

Perez CA, Grigsby PW, Chao KS, Mutch DG, Lockett MA. Tumor size, irradiation dose, and long-term outcome of carcinoma of uterine cervix. Int J Radiat Oncol Biol Phys. 1998 May 1;41(2):307-17. Erratum in: Int J Radiat Oncol Biol Phys 1999 Nov 1;45(4):1093. — View Citation

Pötter R, Georg P, Dimopoulos JC, Grimm M, Berger D, Nesvacil N, Georg D, Schmid MP, Reinthaller A, Sturdza A, Kirisits C. Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer. Radiother Oncol. 2011 Jul;100(1):116-23. doi: 10.1016/j.radonc.2011.07.012. Epub 2011 Aug 5. — View Citation

Pötter R, Haie-Meder C, Van Limbergen E, Barillot I, De Brabandere M, Dimopoulos J, Dumas I, Erickson B, Lang S, Nulens A, Petrow P, Rownd J, Kirisits C; GEC ESTRO Working Group. Recommendations from gynaecological (GYN) GEC ESTRO working group (II): concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol. 2006 Jan;78(1):67-77. Epub 2006 Jan 5. — View Citation

Prescribing, Recording, and Reporting Brachytherapy for Cancer of the Cervix. J ICRU. 2013 Apr;13(1-2):NP. doi: 10.1093/jicru/ndw027. — View Citation

Schmid MP, Kirisits C, Nesvacil N, Dimopoulos JC, Berger D, Pötter R. Local recurrences in cervical cancer patients in the setting of image-guided brachytherapy: a comparison of spatial dose distribution within a matched-pair analysis. Radiother Oncol. 2011 Sep;100(3):468-72. doi: 10.1016/j.radonc.2011.08.014. Epub 2011 Sep 14. — View Citation

Sturdza A, Pötter R, Fokdal LU, Haie-Meder C, Tan LT, Mazeron R, Petric P, Šegedin B, Jurgenliemk-Schulz IM, Nomden C, Gillham C, McArdle O, Van Limbergen E, Janssen H, Hoskin P, Lowe G, Tharavichitkul E, Villafranca E, Mahantshetty U, Georg P, Kirchheiner K, Kirisits C, Tanderup K, Lindegaard JC. Image guided brachytherapy in locally advanced cervical cancer: Improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study. Radiother Oncol. 2016 Sep;120(3):428-433. doi: 10.1016/j.radonc.2016.03.011. Epub 2016 Apr 29. — View Citation

Takenaka T, Yoshida K, Tachiiri S, Yamazaki H, Aramoto K, Furuya S, Yoshida M, Ban C, Tanaka E, Honda K. Comparison of dose-volume analysis between standard Manchester plan and magnetic resonance image-based plan of intracavitary brachytherapy for uterine cervical cancer. J Radiat Res. 2012 Sep;53(5):791-7. doi: 10.1093/jrr/rrs033. Epub 2012 Jul 10. — View Citation

Vale C, Tierney J, Stewart L. Concomitant chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data. Gynecol Oncol. 2006 Feb;100(2):442-3. Epub 2005 Oct 17. — View Citation

Viswanathan AN, Beriwal S, De Los Santos JF, Demanes DJ, Gaffney D, Hansen J, Jones E, Kirisits C, Thomadsen B, Erickson B; American Brachytherapy Society. American Brachytherapy Society consensus guidelines for locally advanced carcinoma of the cervix. Part II: high-dose-rate brachytherapy. Brachytherapy. 2012 Jan-Feb;11(1):47-52. doi: 10.1016/j.brachy.2011.07.002. — View Citation

Yoshida K, Yamazaki H, Takenaka T, Kotsuma T, Yoshida M, Furuya S, Tanaka E, Uegaki T, Kuriyama K, Matsumoto H, Yamada S, Ban C. A dose-volume analysis of magnetic resonance imaging-aided high-dose-rate image-based interstitial brachytherapy for uterine cervical cancer. Int J Radiat Oncol Biol Phys. 2010 Jul 1;77(3):765-72. doi: 10.1016/j.ijrobp.2009.05.027. Epub 2009 Oct 14. — View Citation

* Note: There are 21 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary Local control Absolute benefit in local control rates by 10% for stages FIGO IIB and IIIB 2 years
Secondary Late toxicities Reduction in grade 3 and grade 4 (CTCAE) late toxicities from 10% to 5% (by 50%) 2 years
Secondary Pelvic control rates 2 years
Secondary Distant failure rates 2 years
Secondary Progression free & cause specific survival 2 years
Secondary Overall survival 2 years
Secondary Quality of life questionnaire EORTC QLQ C30 2 years
Secondary Quality life questionnaire EORTC QLQ CX24 2 years
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