What we do
About our project
Background
Primary vaginal cancer is rare, accounting for about 3% of gynecologic cancers. Treatment is often based on protocols for locally advanced cervical cancer, including radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT). Managing vaginal recurrences from other gynecologic cancers (endometrial, cervical) with IGABT represents also a promising approach. Specific target concepts for primary and recurrent vaginal cancer were developed by GYN GEC-ESTRO, ABS and CBG. The IntErnational observational study on primary chemoradiotherapy and iMage-based adaptive BRAchytherapy for Vaginal cancEr (EMBRAVE) study aims to validate these concepts in a multicenter setting, improving evidence-based treatments and outcomes for primary vaginal cancer and vaginal recurrences.
Objective and hypothesis
The aim of the EMBRAVE study is to improve clinical outcomes for vaginal cancer patients treated with radio(chemo)therapy and IGABT. Specific goals include developing evidence-based IGABT recommendations for treatment and identifying prognostic factors for outcomes, morbidity, and quality of life. Parallel cohorts will provide prospective data on rare histological subtypes and IGABT-only treatments. The EMBRAVE study is an observational, prospective cohort study. Defined endpoints include oncological outcomes (disease control; disease-free, disease-specific and overall survival), morbidity events (genitourinary, gastrointestinal, bone and general toxicity), and feasibility of systemic therapy, all assessed at 2 and 5 years.
Study population and sample size
Adult patients with primary vaginal cancer (stage I-IVA) or non-metastasized vaginal recurrences treated with curative radio(chemo)therapy and MRI-based IGABT using the new target concepts are eligible for this study. Rare histological subtypes, carcinoma in situ (VAIN) and IGABT-only treatments, are also eligible for a parallel cohort.
This observational registry study has no patient limit. With 100 patients, oncological and morbidity outcomes, dose analysis, and target concepts validation can be estimated. At 300 patients, multivariable analyses can assess the effect of multiple predictors for disease and clinical outcome, with greater accuracy as more patients are included.
Treatment
Vaginal cancer patients are treated with external-beam radiotherapy (EBRT), a boost with MRI-based IGABT, and concurrent chemotherapy (Cisplatin) if applicable. EBRT is delivered with 45Gy/25fractions using intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT) and image-guidance (recommended cone-beam CT). IGABT is delivered with high-dose or pulsed-dose rate and intracavitary or intracavitary/interstitial technique. Dose prescription for IGABT is according institutional practice, but contouring follows the target concept recommendations for primary vaginal cancer or vaginal recurrences, with at least the first fraction using MRI as mandatory requirement.
Our research focus
Reference for state-of-the-art treatment
Estimate the incidence of treatment failure
Oncological outcomes will be evaluated at 2 and 5 years after treatment:
• Local control
• Regional control
• Distant control
• Disease-free survival
• Disease-specific survival
• Overall survival
Estimate the incidence of acute and late morbidity
Acute and Late (<3/≥3 months after treatment) morbidity will be evaluated (CTCAEv5.0):
• Genitourinary
• Gastro-intestinal
• Skin
• Lymph oedema
• Bone -
• General (e.g. fatigue)
Estimate the impact of treatment on patient-reported symptoms and quality of life (QoL)
Patient-reported outcome will be reported using selected items from the EORTC questionnaire modules:
• C30
• CX24
• EN24
• VU34
Prognostic parameters for clinical outcomes
Identifying patient-, disease- and treatment-related prognostic parameters is crucial for understanding disease and morbidity behavior and guiding treatment decisions.
Clinical outcomes include local, regional, and distant control, overall survival, and grade 3-5 morbidity at 2 and 5 years, EORTC symptoms and QoL and persistent morbidity according to the LAPERS method.
Predictors include radiotherapy dose, use of systemic treatment, tumor size and stage, and response to EBRT.
Evidence-based recommendations for radiotherapy
The dose planning recommendations will be determined through consensus by the EMBRAVE research group. Optimized dose aims and constraints for both targets and organs at risk will be established. These doses will be selected to balance the likelihood of achieving effective tumor control with minimizing the risk of treatment-induced morbidity. Careful consideration will be given to maximizing therapeutic efficacy while minimizing adverse events and impact on QoL, ensuring that the treatment is both effective and safe. This approach will guide personalized treatment planning, tailored to each patient’s specific characteristics, to improve clinical outcomes and reduce potential complications.
Use of systemic therapy
The use of systemic treatment in will be evaluated based on:
• Feasibility of completing systemic therapy
• Prevalence of systemic therapy-related morbidities that limit its completion
• Estimated benefit of adding systemic therapy compared to radiotherapy alone
These factors will help determine the effectiveness and tolerability of systemic therapy in combination with radiotherapy, assessing whether the potential benefits outweigh the risks of additional morbidity. Estimating the added value of systemic therapy versus radiotherapy alone may be biased by confounding, but adjustments will be made, as a randomized trial is unlikely due to the rarity of vaginal cancer.
Collaborations
- Aarhus University Hospital, Aarhus, Denmark
- Amsterdam University Medical Centre, Amsterdam, the Netherlands
- Gustave Roussy Cancer Campus, Villejuif, France
- Leiden University Medical Centre. Leiden, the Netherlands
- Medical University of Vienna, Vienna, Austria
Publications
Kamrava M et al. GEC-ESTRO (ACROP)-ABS-CBG Consensus Brachytherapy Target Definition Guidelines for Recurrent Endometrial and Cervical Tumors in the Vagina. Int J Radiat Oncol Biol Phys. 2023 Mar 1;115(3):654-663. doi: 10.1016/j.ijrobp.2022.09.072.
Kirchheiner K et al. Late, Persistent, Substantial, Treatment-Related Symptoms After Radiation Therapy (LAPERS): A New Method for Longitudinal Analysis of Late Morbidity-Applied in the EMBRACE Study. Int J Radiat Oncol Biol Phys. 2020 Feb 1;106(2):300-309. doi: 10.1016/j.ijrobp.2019.10.027.
Pötter R et al. MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study. Lancet Oncol. 2021 Apr;22(4):538-547. doi: 10.1016/S1470-2045(20)30753-1.
Pötter R et al. The EMBRACE II study: The outcome and prospect of two decades of evolution within the GEC-ESTRO GYN working group and the EMBRACE studies. Clin Transl Radiat Oncol. 2018 Jan 11;9:48-60. doi: 10.1016/j.ctro.2018.01.001.
Schmid MP et al. GEC-ESTRO GYN Working Group. Recommendations from gynaecological (GYN) GEC-ESTRO working group - ACROP: Target concept for image guided adaptive brachytherapy in primary vaginal cancer. Radiother Oncol. 2020 Apr;145:36-44. doi: 10.1016/j.radonc.2019.11.005.
Vittrup AS et al. Persistence of Late Substantial Patient-Reported Symptoms (LAPERS) After Radiochemotherapy Including Image Guided Adaptive Brachytherapy for Locally Advanced Cervical Cancer: A Report From the EMBRACE Study. Int J Radiat Oncol Biol Phys. 2021 Jan 1;109(1):161-173. doi: 10.1016/j.ijrobp.2020.08.044.
Westerveld H et al. Definitive radiotherapy with image-guided adaptive brachytherapy for primary vaginal cancer. Lancet Oncol. 2020 Mar;21(3):e157-e167. doi: 10.1016/S1470-2045(19)30855-1.
Our team
Erasmus Medical Center (sponsor), Rotterdam, the Netherlands
Remi Nout (Principal Investigator)
Jérémy Godart
Sofia Spampinato
René Vernhout
Henrike Westerveld
Email: EMBRAVE.studyoffice@erasmusmc.nl
Aarhus University Hospital, Aarhus, Denmark
Simon Buus
Steffen Hokland
Amsterdam University Medical Center, Amsterdam, the Netherlands
Danique Barten
Colette van den Broek
Bradley Pieters
Jan Wiersma
Gustave Roussy Cancer Campus, Villejuif, France
Sophie Espenel
Isabelle Dumas
Hôpital Pitié-Salpêtrière, Paris, France
Cyrus Chargari
Leiden University Medical Center, Leiden, the Netherlands
Ellen Kerkhof
Laura Velema
Medical University of Vienna, Vienna, Austria
Nicole Eder-Nesvacil
Maximilian Schmid
