TY - JOUR
T1 - MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study
AU - Pötter, Richard
AU - Tanderup, Kari
AU - Schmid, Maximilian Paul
AU - Jürgenliemk-Schulz, Ina
AU - Haie-Meder, Christine
AU - Fokdal, Lars Ulrik
AU - Sturdza, Alina Emiliana
AU - Hoskin, Peter
AU - Mahantshetty, Umesh
AU - Segedin, Barbara
AU - Bruheim, Kjersti
AU - Huang, Fleur
AU - Rai, Bhavana
AU - Cooper, Rachel
AU - van der Steen-Banasik, Elzbieta
AU - van Limbergen, Erik
AU - Pieters, Bradley Rumwell
AU - Tan, Li-Tee
AU - Nout, Remi Abubakar
AU - de Leeuw, Astrid Agatha Catharina
AU - Ristl, Robin
AU - Petric, Primoz
AU - Nesvacil, Nicole
AU - Kirchheiner, Kathrin
AU - Kirisits, Christian
AU - Lindegaard, Jacob Christian
AU - EMBRACE Collaborative Group
AU - Chargari, Cyrus
AU - Dumas, Isabelle
AU - Lowe, Gerry
AU - Swamidas, Jamema
AU - Hudej, Robert
AU - Paulsen Hellebust, Taran
AU - Menon, Geetha
AU - Oinam, Arun S.
AU - Bownes, Peter
AU - Christiaens, Melissa
AU - de Brabandere, Marisol
AU - Janssen, Hilde
AU - Oosterveld, Bernard
AU - Koedooder, Kees
AU - Langeland Marthinsen, Anne Beate
AU - Sundset, Marit
AU - Whitney, Diane
AU - Ketelaars, Martijn
AU - Lutgens, Ludy C. H. W.
AU - Reinniers, Brigitte
AU - Mora, Itxa
AU - Villafranca, Elena
AU - Antal, Gergely
AU - Westerveld, Henrike
N1 - Funding Information: The EMBRACE-I study was essentially an academic study. Major in-kind contributions were provided through the Department of Radiation Oncology, Medical University Vienna, in form of academic personnel and infrastructure. Significant in-kind contributions were made by Aarhus University. Unrestricted research grants from Elekta AB and Varian Medical Systems provided financial support for personnel in the study office, IT support, and meetings. We thank the patients who participated in this trial. We thank the multidisciplinary clinical and research teams and the principal investigators and the study physicists at the 24 participating centres. We thank the Vienna study office at the Department of Radiation Oncology, Medical University Vienna, for their continuous support; at present Tamara Diendorfer (academic study secretary) and Dragan Misimovic (data manager); in the past Thomas Liederer, Ian Dilworth, and Elke D?rr. We thank Johannes Dimopoulos, Petra Georg, Elena Fidarova, and Mario Federico as study physicians and Petra Trnkova, Karen Nkiwane, and Joanna Gora as study physicists. We thank Stefan Ecker (Vienna), Stephanie Smet (Leuven), Dina Najjari Jamal (Barcelona), Katarina Majercakova (Barcelona), Laura Motisi (Z?rich), Israel Fortin (Montreal), Henrike Westerveld (Amsterdam), Susovan Banerjee (New Delhi), Noha Jastaniyah (Riad), Kenji Yoshida (Tottori), Pittaya Dankulchai (Bangkok), Jusheng An (Beijing), Neamat Hegazy (Alessandria), Joyce Siu Yu Wong (Hong kong), and Margit Valgma (Tallin) as research fellows in Vienna for their academic support. We thank the Aarhus EMBRACE research group (KT, JCL, LUF) and the Aarhus research fellows Nina Boje Kibsgaard Jensen, Sofia Spampinato, Anders Schwartz-Vittrup, Monica Serban, Thomas Berger, Marianne Sanggaard Assenholt for their academic support. We thank S?ren Bentzen for his support in designing the concept of EMBRACE-I. NN and CK were supported by Austrian Science Fund (FWF, project KLI-695 and project L562-B19). KT was supported by the Danish Cancer Society. Publisher Copyright: © 2021 Elsevier Ltd
PY - 2021/4/1
Y1 - 2021/4/1
N2 - Background: The concept of the use of MRI for image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer was introduced 20 years ago. Here, we report on EMBRACE-I, which aimed to evaluate local tumour control and morbidity after chemoradiotherapy and MRI-based IGABT. Methods: EMBRACE-I was a prospective, observational, multicentre cohort study. Data from patients from 24 centres in Europe, Asia, and North America were prospectively collected. The inclusion criteria were patients older than 18 years, with biopsy-proven squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, The International Federation of Gynecology and Obstetrics (FIGO) stage IB–IVA disease or FIGO stage IVB disease restricted to paraaortic lymph metastasis below the L1–L2 interspace, suitable for curative treatment. Treatment consisted of chemoradiotherapy (weekly intravenous cisplatin 40 mg/m2, 5–6 cycles, 1 day per cycle, plus 45–50 Gy external-beam radiotherapy delivered in 1·8–2 Gy fractions) followed by MRI-based IGABT. The MRI-based IGABT target volume definition and dose reporting was according to Groupe Européen de Curiethérapie European Society for Radiation Oncology recommendations. IGABT dose prescription was open according to institutional practice. Local control and late morbidity were selected as primary endpoints in all patients available for analysis. The study was registered with ClinicalTrials.gov, NCT00920920. Findings: Patient accrual began on July 30, 2008, and closed on Dec 29, 2015. A total of 1416 patients were registered in the database. After exclusion for not meeting patient selection criteria before treatment, being registered but not entered in the database, meeting the exclusion criteria, and being falsely excluded, data from 1341 patients were available for analysis of disease and data from 1251 patients were available for assessment of morbidity outcome. MRI-based IGABT including dose optimisation was done in 1317 (98·2%) of 1341 patients. Median high-risk clinical target volume was 28 cm3 (IQR 20–40) and median minimal dose to 90% of the clinical target volume (D90%) was 90 Gy (IQR 85–94) equi-effective dose in 2 Gy per fraction. At a median follow-up of 51 months (IQR 20–64), actuarial overall 5-year local control was 92% (95% CI 90–93). Actuarial cumulative 5-year incidence of grade 3–5 morbidity was 6·8% (95% CI 5·4–8·6) for genitourinary events, 8·5% (6·9–10·6) for gastrointestinal events, 5·7% (4·3–7·6) for vaginal events, and 3·2% (2·2–4·5) for fistulae. Interpretation: Chemoradiotherapy and MRI-based IGABT result in effective and stable long-term local control across all stages of locally advanced cervical cancer, with a limited severe morbidity per organ. These results represent a positive breakthrough in the treatment of locally advanced cervical cancer, which might be used as a benchmark for clinical practice and all future studies. Funding: Medical University of Vienna, Aarhus University Hospital, Elekta AB, and Varian Medical Systems.
AB - Background: The concept of the use of MRI for image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer was introduced 20 years ago. Here, we report on EMBRACE-I, which aimed to evaluate local tumour control and morbidity after chemoradiotherapy and MRI-based IGABT. Methods: EMBRACE-I was a prospective, observational, multicentre cohort study. Data from patients from 24 centres in Europe, Asia, and North America were prospectively collected. The inclusion criteria were patients older than 18 years, with biopsy-proven squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, The International Federation of Gynecology and Obstetrics (FIGO) stage IB–IVA disease or FIGO stage IVB disease restricted to paraaortic lymph metastasis below the L1–L2 interspace, suitable for curative treatment. Treatment consisted of chemoradiotherapy (weekly intravenous cisplatin 40 mg/m2, 5–6 cycles, 1 day per cycle, plus 45–50 Gy external-beam radiotherapy delivered in 1·8–2 Gy fractions) followed by MRI-based IGABT. The MRI-based IGABT target volume definition and dose reporting was according to Groupe Européen de Curiethérapie European Society for Radiation Oncology recommendations. IGABT dose prescription was open according to institutional practice. Local control and late morbidity were selected as primary endpoints in all patients available for analysis. The study was registered with ClinicalTrials.gov, NCT00920920. Findings: Patient accrual began on July 30, 2008, and closed on Dec 29, 2015. A total of 1416 patients were registered in the database. After exclusion for not meeting patient selection criteria before treatment, being registered but not entered in the database, meeting the exclusion criteria, and being falsely excluded, data from 1341 patients were available for analysis of disease and data from 1251 patients were available for assessment of morbidity outcome. MRI-based IGABT including dose optimisation was done in 1317 (98·2%) of 1341 patients. Median high-risk clinical target volume was 28 cm3 (IQR 20–40) and median minimal dose to 90% of the clinical target volume (D90%) was 90 Gy (IQR 85–94) equi-effective dose in 2 Gy per fraction. At a median follow-up of 51 months (IQR 20–64), actuarial overall 5-year local control was 92% (95% CI 90–93). Actuarial cumulative 5-year incidence of grade 3–5 morbidity was 6·8% (95% CI 5·4–8·6) for genitourinary events, 8·5% (6·9–10·6) for gastrointestinal events, 5·7% (4·3–7·6) for vaginal events, and 3·2% (2·2–4·5) for fistulae. Interpretation: Chemoradiotherapy and MRI-based IGABT result in effective and stable long-term local control across all stages of locally advanced cervical cancer, with a limited severe morbidity per organ. These results represent a positive breakthrough in the treatment of locally advanced cervical cancer, which might be used as a benchmark for clinical practice and all future studies. Funding: Medical University of Vienna, Aarhus University Hospital, Elekta AB, and Varian Medical Systems.
UR - http://www.scopus.com/inward/record.url?scp=85103374444&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/S1470-2045(20)30753-1
DO - https://doi.org/10.1016/S1470-2045(20)30753-1
M3 - Article
SN - 1470-2045
VL - 22
SP - 538
EP - 547
JO - lancet oncology
JF - lancet oncology
IS - 4
ER -