EviGUIDE - a tool for evidence-based decision making in image-guided adaptive brachytherapy for cervical cancer.

PURPOSE: To develop a novel decision-support system for radiation oncology that incorporates clinical, treatment and outcome data, as well as outcome models from a large clinical trial on magnetic resonance image-guided adaptive brachytherapy (MR-IGABT) for locally advanced cervical cancer (LACC). METHODS: A system, called EviGUIDE, was developed that combines dosimetric information from the treatment planning system, patient and treatment characteristics, and established tumor control probability (TCP), and normal tissue complication probability (NTCP) models, to predict clinical outcome of radiotherapy treatment of LACC. Six Cox Proportional Hazards models based on data from 1341 patients of the EMBRACE-I study have been integrated. One TCP model for local tumor control, and five NTCP models for OAR morbidities. RESULTS: EviGUIDE incorporates TCP-NTCP graphs to help users visualize the clinical impact of different treatment plans and provides feedback on achievable doses based on a large reference population. It enables holistic assessment of the interplay between multiple clinical endpoints and tumour and treatment variables. Retrospective analysis of 45 patients treated with MR-IGABT showed that there exists a sub-cohort of patients (20%) with increased risk factors, that could greatly benefit from the quantitative and visual feedback. CONCLUSION: A novel digital concept was developed that can enhance clinical decision- making and facilitate personalized treatment. It serves as a proof of concept for a new generation of decision support systems in radiation oncology, which incorporate outcome models and high-quality reference data, and aids the dissemination of evidence-based knowledge about optimal treatment and serve as a blueprint for other sites in radiation oncology.

Tools for large-scale data analytics of an international multi-center study in radiation oncology for cervical cancer.

PURPOSE: To develop and implement a software that enables centers, treating patients with state-of-the-art radiation oncology, to compare their patient, treatment, and outcome data to a reference cohort, and to assess the quality of their treatment approach. MATERIALS AND METHODS: A comprehensive data dashboard was designed, which al- lowed holistic assessment of institutional treatment approaches. The software was tested in the ongoing EMBRACE-II study for locally advanced cervical cancer. The tool created individualized dashboards and automatic analysis scripts, verified pro- tocol compliance and checked data for inconsistencies. Identified quality assurance (QA) events were analysed. A survey among users was conducted to assess usability. RESULTS: The survey indicated favourable feedback to the prototype and highlighted its value for internal monitoring. Overall, 2302 QA events were identified (0.4% of all collected data). 54% were due to missing or incomplete data, and 46% originated from other causes. At least one QA event was found in 519/1001 (52%) of patients. QA events related to primary study endpoints were found in 16% of patients. Sta- tistical methods demonstrated good performance in detecting anomalies, with precisions ranging from 71% to 100%. Most frequent QA event categories were Treatment Technique (27%), Patient Characteristics (22%), Dose Reporting (17%), Outcome 156 (15%), Outliers (12%), and RT Structures (8%). CONCLUSION: A software tool was developed and tested within a clinical trial in radia- tion oncology. It enabled the quantitative and qualitative comparison of institutional patient and treatment parameters with a large multi-center reference cohort. We demonstrated the value of using statistical methods to automatically detect implau- sible data points and highlighted common pitfalls and uncertainties in radiotherapy for cervical cancer.

Implementation of online workshops on image-guided adaptive brachytherapy (interventional radiotherapy) in locally advanced cervical cancer: Experience of BrachyAcademy.

PURPOSE: To provide educational support to brachytherapy users during the COVID-19 pandemic, online workshops were developed and implemented by BrachyAcademy, non-profit peer-to-peer educational initiative in Elekta. METHODS AND MATERIALS: In 2021-2022 two online workshops were organized. Participating teams had to send a clinical case of locally advanced cervical cancer (LACC) including brachytherapy Digital Imaging and Communications in Medicine (DICOM) files and questions to the faculty. During the workshop, feedback was given to each clinical case by five faculty members (two Radiation Oncologists, one Radiologist, two Medical Physicists). Participants competed a post-workshop questionnaire which included combination of qualitative and quantitative questions via yes/no responses, Likert scale, and 1 to 10 scale. RESULTS: Twenty-one teams from eight countries (Europe, Asia, Latin America) participated in two online workshops. The total number of participants was 49. The clinical cases represented LACC with The International Federation of Gynecology and Obstetrics (FIGO) stages from IB3 to IVA. During both, Workshop1 (W1) and Workshop 2 (W2) the following areas of improvement were identified: familiarity with the GEC ESTRO and The International Commission on Radiation Units & Measurements, Report 89 (ICRU 89) recommendations for contouring and planning based on clinical drawings and MRI sequencing choice; appropriate applicator selection; experience with interstitial needles; appropriate applicator reconstruction; dose optimization. The participants rated both workshops with overall scores 8,3 for W1, and 8,5 for W2. In 82% participants the training course fully met expectations for W1, and in 76% in W2. CONCLUSIONS: We successfully implemented the online workshops on image-guided adaptive brachytherapy (IGABT) in LACC. Main performance issues and areas for improvement were identified based on multidisciplinary discussion of participant's clinical cases through all steps of the brachytherapy procedure. We encourage teams to consider online workshops in addition to hands-on training.

Risk Factors for Local Failure Following Chemoradiation and Magnetic Resonance Image-Guided Brachytherapy in Locally Advanced Cervical Cancer: Results From the EMBRACE-I Study.

PURPOSE: To report clinical and treatment characteristics, remission and failure patterns, and risk factors for local failure (LF) from the EMBRACE-I study. MATERIALS AND METHODS: EMBRACE-I was a prospective, observational, multicenter cohort study on magnetic resonance imaging-based image-guided adaptive brachytherapy (MR-IGABT) in locally advanced cervical cancer. Treatment consisted of external beam radiotherapy, concurrent chemotherapy, and MR-IGABT. LF was defined as progressive or recurrent disease in the cervix, uterus, parametria, pelvic wall, or vagina. Competing risk analysis was used to estimate local tumor control (LC) and Cox proportional regression models for multivariable analysis and dose-response analysis. RESULTS: One thousand three hundred eighteen patients with a median follow-up of 52 months were available for this analysis. Eighty-one patients had persistent disease 3 months after end of treatment. Of those, 60 patients achieved LC at 6-9 months without further treatment, whereas 21 patients had progressive disease. In addition, 77 patients developed a local recurrence after complete remission comprising a total number of 98 LFs. LFs were located inside the MR-IGABT target volumes in 90% of patients with LF. In multivariable analysis, histology, minimal dose to 90% of high-risk clinical target volume (CTVHR), maximum tumor dimension, CTVHR > 45 cm3, overall treatment time, tumor necrosis on magnetic resonance imaging at diagnosis, uterine corpus infiltration at diagnosis and at MR-IGABT, and mesorectal infiltration at MR-IGABT had significant impact on LF. Dose-response analysis showed that a minimal dose to 90% of 85 Gy to the CTVHR led to 95% (95% CI, 94 to 97) LC 3 years postintervention for squamous cell in comparison to 86% (95% CI, 81 to 90) for adeno/adenosquamous carcinoma histology. CONCLUSION: The present study demonstrates the safety and validity of the GYN GEC-ESTRO/ICRU-89 target concept and provides large-scale evidence for dose prescription and new risk factors for LF in MR-IGABT in locally advanced cervical cancer.

GEC-ESTRO (ACROP)-ABS-CBG Consensus Brachytherapy Target Definition Guidelines for Recurrent Endometrial and Cervical Tumors in the Vagina.

PURPOSE: Representatives from the Gynecologic Groupe European de Curietherapie-European Society for Radiation Therapy and Oncology (GYN GEC-ESTRO), the American Brachytherapy Society (ABS), and the Canadian Brachytherapy Group (CBG) met to develop international consensus recommendations for target definitions for image-guided adaptive brachytherapy for vaginal recurrences of endometrial or cervical cancer. METHODS AND MATERIALS: Seventeen radiation oncologists and 2 medical physicists participated. Before an in-person meeting each participant anonymously contoured 3 recurrent endometrial/cervical cancer cases. Participants contoured the residual gross primary tumor volume (GTV-Tres), a high-risk clinical target volume (CTV-THR), and an intermediate-risk clinical target volume (CTV-TIR), on T2-weighted magnetic resonance images (MRIs). All contours were drawn using Falcon EduCase. Contours were reviewed at an in-person meeting during which a consensus document was created defining agreed-upon target definitions (Trial 1). After establishing these definitions, the group was sent one of the cases again (recurrent cervical cancer vaginal recurrence) and asked to contour the targets again (Trial 2). The Computerized Environment for Radiation Research (CERR) software (The Mathworks, Natwick, MA) was used to analyze the contours. Kappa statistics were generated to assess level of agreement between contours. A conformity index (CI), defined as the ratio between the intersection and union volume of a given pair of contours, was calculated. A simultaneous truth and performance level estimation (STAPLE) contour was created for the CTV-THR and CTV-TIR for the postmeeting case. RESULTS: Consensus definitions for GTV-Tres, CTV-THR, and CTV-TIR were established. Kappa statistics (Trial 1/Trial 2) for GTV-Tres, CTV-THR, and CTV-TIR were 0.536/0.583, 0.575/0.743 and 0.522/0.707. Kappa statistics for Trial 2 for the CTV-THR and CTV-TIR showed "substantial" agreement while the GTV-Tres remained at moderate agreement. CONCLUSIONS: This consensus provides recommendations to facilitate future collaborations for MRI-guided adaptive brachytherapy target definitions in endometrial/cervical vaginal recurrences.

Neural network-assisted automated image registration for MRI-guided adaptive brachytherapy in cervical cancer.

PURPOSE: In image-guided adaptive brachytherapy (IGABT) a quantitative evaluation of the dosimetric changes between fractions due to anatomical variations, can be implemented via rigid registration of images from subsequent fractions based on the applicator as a reference structure. With available treatment planning systems (TPS), this is a manual and time-consuming process. The aim of this retrospective study was to automate this process. A neural network (NN) was trained to predict the applicator structure from MR images. The resulting segmentation was used to automatically register MR-volumes. MATERIAL AND METHODS: DICOM images and plans of 56 patients treated for cervical cancer with high dose-rate (HDR) brachytherapy were used in the study. A 2D and a 3D NN were trained to segment applicator structures on clinical T2-weighted MRI datasets. Different rigid registration algorithms were investigated and compared. To evaluate a fully automatic registration workflow, the NN-predicted applicator segmentations (AS) were used for rigid image registration with the best performing algorithm. The DICE coefficient and mean distance error between dwell positions (MDE) were used to evaluate segmentation and registration performance. RESULTS: The mean DICE coefficient for the predicted AS was 0.70 ±â€¯0.07 and 0.58 ±â€¯0.04 for the 3D NN and 2D NN, respectively. Registration algorithms achieved MDE errors from 8.1 ±â€¯3.7 mm (worst) to 0.7 ±â€¯0.5 mm (best), using ground-truth AS. Using the predicted AS from the 3D NN together with the best registration algorithm, an MDE of 2.7 ±â€¯1.4 mm was achieved. CONCLUSION: Using a combination of deep learning models and state of the art image registration techniques has been demonstrated to be a promising solution for automatic image registration in IGABT. In combination with auto-contouring of organs at risk, the auto-registration workflow from this study could become part of an online-dosimetric interfraction evaluation workflow in the future.

Dosimetric impact of target definition in brachytherapy for cervical cancer - Computed tomography and trans rectal ultrasound versus magnetic resonance imaging.

Background and Purpose: Magnetic Resonance Imaging (MRI) based target definition in cervix brachytherapy is limited by its availability, logistics and financial implications, therefore, use of computed tomography (CT) and Trans Rectal UltraSonography (TRUS) has been explored. The current study evaluated the dosimetric impact of CT + TRUS based target volumes as compared to gold standard MRI. Methods and Materials: Images of patients (n = 21) who underwent TRUS followed by MRI and CT, were delineated with High-Risk Clinical Target Volume in CT (CTVHR-CT) and in MRI (CTVHR-MR). CTVHR-CT was drawn on CT images with TRUS assistance. For each patient, two treatment plans were made, on MRI and CT, followed by fusion and transfer of CTVHR-MR to the CT images, referred as CTVHR-MRonCT. The agreement between CTVHR-MRonCT and CTVHR-CT was evaluated for dosimetric parameters (D90, D98 and D50; Dose received by 90%, 98% and 50% of the volumes) using Bland-Altman plots, linear regression, and Pearson correlation. Results: No statistically significant systematic difference was found between MRI and CT. Mean difference (±1.96 SD) of D90, D98 and D50 between CTVHR-MRonCT and CTVHR-CT was 2.0, 1.2 and 5.6 Gy respectively. The number of patients who have met the dose constraints of D90 > 85 Gy were 90% and 80% in MR and in CT respectively, others were in the borderline, with a minimum dose of 80 Gy. The mean ± SD dose-difference between MR and CT plans for bladder was significant (5 ± 13 Gy; p = 0.12) for D0.1cm3, while others were statistically insignificant. Conclusion: CT + TRUS based delineation of CTVHR appear promising, provide useful information to optimally utilize for brachytherapy planning, however, MRI remains the gold standard.

Prognostic Implications of Uterine Cervical Cancer Regression During Chemoradiation Evaluated by the T-Score in the Multicenter EMBRACE I Study.

PURPOSE: A simple scoring system (T-score, TS) for integrating findings from clinical examination and magnetic resonance imaging (MRI) of the primary tumor at diagnosis has shown strong prognostic capability for predicting local control and survival in locally advanced cervical cancer treated with chemoradiation and MRI-guided brachytherapy (BT). The aim was to validate the performance of TS using the multicenter EMBRACE I study and to evaluate the prognostic implications of TS regression obtained during initial chemoradiation. METHODS AND MATERIALS: EMBRACE I recruited 1416 patients, of whom 1318 were available for TS. Patients were treated with chemoradiation followed by MRI-guided BT. A ranked ordinal scale of 0 to 3 points was used to assess 8 anatomic locations typical for local invasion of cervical cancer. TS was calculated separately at diagnosis (TSD) and at BT (TSBT) by the sum of points obtained from the 8 locations at the 2 occasions. RESULTS: Median TSD and TSBT was 5 and 4, respectively. TS regression was observed in 71% and was an explanatory variable for BT technique (intracavitary vs intracavitary/interstitial) and major dose-volume histogram parameters for BT, such as high-risk clinical target (CTVHR), CTVHR D90 (minimal dose to 90% of the target volume), D2cm3 bladder (minimal dose to the most exposed 2 cm3 of the bladder), and D2cm3 rectum. TS regression (TSBT≤5) was associated with improved local control and survival and with less morbidity compared with patients with TSBT remaining high (>5) despite initial chemoradiation. TS regression was significant in multivariate analysis for both local control and survival when analyzed in consort with already established prognostic parameters related to the patient, disease, and treatment. CONCLUSIONS: TS was validated in a multicenter setting and proven to be a strong multidisciplinary platform for integration of clinical findings and imaging with the ability to quantitate local tumor regression and its prognostic implications regarding BT technique, dose-volume histogram parameters, local control, survival, and morbidity.

Dose-effect relationship between vaginal dose points and vaginal stenosis in cervical cancer: An EMBRACE-I sub-study.

BACKGROUND AND PURPOSE: To evaluate dose-effect relationships between vaginal dose points and vaginal stenosis in patients treated for locally advanced cervical cancer with radio(chemo)therapy and image-guided adaptive brachytherapy. MATERIAL AND METHODS: Patients from six centres participating in the EMBRACE-I study were included. Information on doses to different vaginal dose points, including the Posterior-Inferior Border of Symphysis (PIBS) points and recto-vaginal reference (RV-RP) point, were retrieved from the treatment planning system. In addition, the vaginal reference length (VRL) was evaluated. Vaginal stenosis was prospectively assessed according to the CTCAEv3.0 system at baseline and follow-up. Primary endpoint was grade 2 or higher (G ≥ 2) vaginal stenosis. Impact of dose to the vaginal dose points, and impact of VRL, age, vaginal involvement and applicator on vaginal stenosis G ≥ 2 was evaluated with a Cox proportional-hazard regression model. RESULTS: 301 patients were included. Median follow-up was 49 months. During follow-up, the incidence of G0, G1, G2, and G3 vaginal stenosis was 25% (76), 52% (158), 20% (59) and 3% (8), respectively. Median total doses to PIBS+2 cm, PIBS, PIBS-2 cm and the RV-RP were 52.9 (IQR 49.3-64.7), 41.0 (IQR 15.4-49.0), 4.1 (IQR 2.9-7.0) and 64.6 (IQR 60.0-70.6) Gy EQD23, respectively. Higher doses to the PIBS, PIBS + 2 cm and RV-RP points were significantly associated with increased risk for vaginal stenosis G ≥ 2. Other risk factors for vaginal stenosis were: vaginal involvement at diagnosis, higher age, shorter VRL and use of a tandem-ovoid applicator. CONCLUSION: Higher doses to the PIBS+2 cm, PIBS and RV-RP dose points are associated with vaginal stenosis G ≥ 2.

Toward 3D-TRUS image-guided interstitial brachytherapy for cervical cancer.

PURPOSE: To qualitatively and quantitatively analyze needle visibility in combined intracavitary and interstitial cervical cancer brachytherapy on 3D transrectal ultrasound (TRUS) in comparison to gold standard MRI. METHODS AND MATERIALS: Image acquisition was done with a customized TRUS stepper unit and software (Medcom, Germany; Elekta, Sweden; ACMIT, Austria) followed by an MRI on the same day with the applicator in place. Qualitative assessment was done with following scoring system: 0 = no visibility 1 (= poor), 2 (= fair), 3 (= excellent) discrimination, quantitative assessment was done by measuring the distance between each needle and the tandem two centimeters (cm) above the ring and comparing to the respective measurement on MRI. RESULTS: Twenty-nine implants and a total of 188 needles (132 straight, 35 oblique, 21 free-hand) were available. Overall, 79% were visible (87% straight, 51% oblique, 76% free-hand). Mean visibility score was 1.4 ± 0.5 for all visible needles. Distance of the visible needles to tandem was mean ± standard deviation (SD) 21.3 millimeters (mm) ± 6.5 mm on MRI and 21.0 mm ± 6.4 mm on TRUS, respectively. Difference between MRI and TRUS was max 14 mm, mean ± SD -0.3 mm ± 2.6 mm. 11% differed more than 3 mm. CONCLUSIONS: Straight needles were better detectable than oblique needles (87% vs. 51%). Detectability was impaired by insufficient rotation of the TRUS probe, poor image quality or anatomic variation. As needles show a rather indistinct signal on TRUS, online detection with a standardized imaging protocol in combination with tracking should be investigated, aiming at the development of real time image guidance and online treatment planning.

Risk factors for nodal failure after radiochemotherapy and image guided brachytherapy in locally advanced cervical cancer: An EMBRACE analysis.

OBJECTIVE: To assess risk factors for nodal failure (NF) after definitive (chemo)radiotherapy and image-guided brachytherapy for locally advanced cervical cancer (LACC) for patients treated in the EMBRACE I study. MATERIALS AND METHODS: Data for pelvic NF and para-aortic (PAO) NF (NFPAO) were analysed. After multiple imputation, univariable and multivariable Cox-regression was performed for clinical and treatment-related variables. For patients with affected pelvic nodes but no PAO nodes at diagnosis, additional analyses were performed for two subgroups: 1. 'small pelvis' nodes in internal and external iliac, obturator, parametrial, presacral and/or common iliac (CI) region and 2. any CI nodes (subgroup of 1). RESULTS: 1338 patients with 152 NF and 104 NFPAO events were analysed with a median follow-up of 34.2 months (IQR 16.4-52.7). For the entire group, larger tumour width, nodal risk groups (in particular any CI nodes without PAO nodes), local failure, and lower Hb-nadir increased the risk of NF. Elective PAO-irradiation was independently associated with a decreased risk of NFPAO (HR 0.53, 95%-CI 0.28-1.00, p = 0.05). For subgroup 1, having 'any CI nodes without PAO nodes' and local failure significantly increased NF risk. Additionally, elective PAO-irradiation was associated with less risk of NFPAO (HR 0.38, 95%-CI 0.17-0.86, p = 0.02). For subgroup 2 only local failure was associated with higher risk of NF. CONCLUSION: In this patient cohort, nodal disease and tumour width at diagnosis, as well as local failure, are risk factors for NF after definitive treatment. Having either 'any PAO nodes' (with or without pelvic nodes) or 'any CI nodes' (without PAO nodes) are stronger risk factors than involvement of nodes in the small pelvis alone. Elective PAO-irradiation was associated with significantly less NFPAO, particularly in patients with nodal disease in the 'small pelvis' and/or CI region at time of diagnosis.

Image-Guided Adaptive Brachytherapy (IGABT) for Primary Vaginal Cancer: Results of the International Multicenter RetroEMBRAVE Cohort Study.

PURPOSE: This study assessed outcomes following the nowadays standing treatment for primary vaginal cancer with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT) in a multicenter patient cohort. METHODS: Patients treated with computer tomography (CT)-MRI-assisted-based IGABT were included. Retrospective data collection included patient, tumor and treatment characteristics. Late morbidity was assessed by using the CTCAE 3.0 scale. RESULTS: Five European centers included 148 consecutive patients, with a median age of 63 years. At a median follow-up of 29 months (IQR 25-57), two- and five-year local control were 86% and 83%; disease-free survival (DFS) was 73% and 66%, and overall survival (OS) was 79% and 68%, respectively. Crude incidences of ≥ grade-three urogenital, gastro-intestinal and vaginal morbidity was 8%, 3% and 8%, respectively. Lymph node metastasis was an independent prognostic factor for disease-free survival (DFS). Univariate analysis showed improved local control in patients with T2-T4 tumors if >80 Gy EQD2α/ß10 was delivered to the clinical target volume (CTV) at the time of brachytherapy. CONCLUSIONS: In this large retrospective multicenter study, IGABT for primary vaginal cancer resulted in a high local control with acceptable morbidity. These results compared favorably with two-dimensional (2D) radiograph-based brachytherapy and illustrate that IGABT plays an important role in the treatment of vaginal cancer.

MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.

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.

An MR-only acquisition and artificial intelligence based image-processing protocol for photon and proton therapy using a low field MR.

OBJECTIVE: Recent developments on synthetically generated CTs (sCT), hybrid MRI linacs and MR-only simulations underlined the clinical feasibility and acceptance of MR guided radiation therapy. However, considering clinical application of open and low field MR with a limited field of view can result in truncation of the patient's anatomy which further affects the MR to sCT conversion. In this study an acquisition protocol and subsequent MR image stitching is proposed to overcome the limited field of view restriction of open MR scanners, for MR-only photon and proton therapy. MATERIAL AND METHODS: 12 prostate cancer patients scanned with an open 0.35T scanner were included. To obtain the full body contour an enhanced imaging protocol including two repeated scans after bilateral table movement was introduced. All required structures (patient contour, target and organ at risk) were delineated on a post-processed combined transversal image set (stitched MRI). The postprocessed MR was converted into a sCT by a pretrained neural network generator. Inversely planned photon and proton plans (VMAT and SFUD) were designed using the sCT and recalculated for rigidly and deformably registered CT images and compared based on D2%, D50%, V70Gy for organs at risk and based on D2%, D50%, D98% for the CTV and PTV. The stitched MRI and the untruncated MRI were compared to the CT, and the maximum surface distance was calculated. The sCT was evaluated with respect to delineation accuracy by comparing on stitched MRI and sCT using the DICE coefficient for femoral bones and the whole body. RESULTS: Maximum surface distance analysis revealed uncertainties in lateral direction of 1-3mm on average. DICE coefficient analysis confirms good performance of the sCT conversion, i.e. 92%, 93%, and 100% were obtained for femoral bone left and right and whole body. Dose comparison resulted in uncertainties below 1% between deformed CT and sCT and below 2% between rigidly registered CT and sCT in the CTV for photon and proton treatment plans. DISCUSSION: A newly developed acquisition protocol for open MR scanners and subsequent Sct generation revealed good acceptance for photon and proton therapy. Moreover, this protocol tackles the restriction of the limited FOVs and expands the capacities towards MR guided proton therapy with horizontal beam lines.

Evidence-Based Dose Planning Aims and Dose Prescription in Image-Guided Brachytherapy Combined With Radiochemotherapy in Locally Advanced Cervical Cancer.

The last 2 decades have witnessed the development and broad adoption of image-guided adaptive brachytherapy (IGABT) combined with radiochemotherapy in patients with locally advanced cervical cancer. A variety of brachytherapy techniques and dose/fractionation schedules have been applied, and until recently, there was no strong evidence available for preferring one approach to another. However, large volumes of data have now provided high level clinical evidence for dose-effect relations for both disease and morbidity endpoints. It is therefore now possible to apply evidence based dose planning aims and dose prescription protocols in IGABT for locally advanced cervical cancer. This review gives an overview of targets/organs-at-risk and disease/morbidity endpoints which are relevant in the context of treatment planning and dose prescription in IGABT. The dosimetric and clinical evidence is summarized to support the implementation of dose prescription protocols which include hard and soft constraints for targets and organs at risk.

Education and training for image-guided adaptive brachytherapy for cervix cancer-The (GEC)-ESTRO/EMBRACE perspective.

Image-guided adaptive brachytherapy (IGABT) has been shown to improve local/regional control and survival for cervix cancer patients while reducing morbidity. However, the technique is complex involving several conceptual, methodological, and technical innovations compared to conventional brachytherapy. The delivery of high-quality IGABT which will translate into improved outcomes is therefore critically dependent on effective education and training of all health professionals involved in the brachytherapy treatment process. This paper reviews the (GEC)-ESTRO/EMBRACE initiatives for education and training to promote the dissemination and implementation of IGABT for cervix cancer worldwide. The new skills required in different health professionals for successful implementation of IGABT are described. The achievements and challenges of current educational strategies for disseminating IGABT are discussed. Innovations to improve the effectiveness of current and future educational strategies are explored.

Hybrid TRUS/CT with optical tracking for target delineation in image-guided adaptive brachytherapy for cervical cancer.

OBJECTIVE: To prospectively compare the interobserver variability of combined transrectal ultrasound (TRUS)/computed tomography (CT)- vs. CT only- vs. magnetic resonance imaging (MRI) only-based contouring of the high-risk clinical target volume (CTVHR) in image-guided adaptive brachytherapy (IGABT) for locally advanced cervical cancer (LACC). METHODS: Five patients with LACC (FIGO stages IIb-IVa) treated with radiochemotherapy and IGABT were included. CT, TRUS, and T2-weighted MRI images were performed after brachytherapy applicator insertion. 3D-TRUS image acquisition was performed with a customized ultrasound stepper device and software. Automatic applicator reconstruction using optical tracking was performed in the TRUS dataset and TRUS and CT images were fused with rigid image registration with the applicator as reference structure. The CTVHR (based on the GEC-ESTRO recommendations) was contoured by five investigators on the three modalities (CTVHR_CT, CTVHR_TRUS-CT, and CTVHR_MRI). A consensus reference CTVHR_MRI (MRIref) was defined for each patient. Descriptive statistics and overlap measures were calculated using RTslicer (SlicerRT Community and Percutaneous Surgery Laboratory, Queen's University, Canada), comparing contours of every observer with one another and with the MRIref. RESULTS: The interobserver coefficient of variation was 0.18 ± 0.05 for CT, 0.10 ± 0.04 for TRUS-CT, and 0.07 ± 0.03 for MRI. Interobserver concordance in relation to the MRIref expressed by the generalized conformity index was 0.75 ± 0.04 for MRI, 0.51 ± 0.10 for TRUS-CT, and 0.48 ± 0.06 for CT. The mean CTVHR_CT volume of all observers was 71% larger than the MRIref volume, whereas the mean CTVHR_TRUS-CT volume was 15% larger. CONCLUSION: Hybrid TRUS-CT as an imaging modality for contouring the CTVHR in IGABT for LACC is feasible and reproducible among multiple observers. TRUS-CT substantially reduces overestimation of the CTVHR volume of CT alone while maintaining similar interobserver variability.

Investigating conditional GAN performance with different generator architectures, an ensemble model, and different MR scanners for MR-sCT conversion.

Recent developments in magnetic resonance (MR) to synthetic computed tomography (sCT) conversion have shown that treatment planning is possible without an initial planning CT. Promising conversion results have been demonstrated recently using conditional generative adversarial networks (cGANs). However, the performance is generally only tested on images from one MR scanner, which neglects the potential of neural networks to find general high-level abstract features. In this study, we explored the generalizability of the generator models, trained on a single field strength scanner, to data acquired with higher field strengths. T2-weighted 0.35T MRIs and CTs from 51 patients treated for prostate (40) and cervical cancer (11) were included. 25 of them were used to train four different generators (SE-ResNet, DenseNet, U-Net, and Embedded Net). Further, an ensemble model was created from the four network outputs. The models were validated on 16 patients from a 0.35T MR scanner. Further, the trained models were tested on the Gold Atlas dataset, containing T2-weighted MR scans of different field strengths; 1.5T(7) and 3T(12), and 10 patients from the 0.35T scanner. The sCTs were dosimetrically compared using clinical VMAT plans for all test patients. For the same scanner (0.35T), the results from the different models were comparable on the test set, with only minor differences in the mean absolute error (MAE) (35-51HU body). Similar results were obtained for conversions of 3T GE Signa and the 3T GE Discovery images (40-62HU MAE) for three of the models. However, larger differences were observed for the 1.5T images (48-65HU MAE). The overall best model was found to be the ensemble model. All dose differences were below 1%. This study shows that it is possible to generalize models trained on images of one scanner to other scanners and different field strengths. The best metric results were achieved by the combination of all networks.

Definitive radiotherapy with image-guided adaptive brachytherapy for primary vaginal cancer.

Primary vaginal cancer is a rare cancer and clinical evidence to support recommendations on its optimal management is insufficient. Because primary vaginal cancer resembles cervical cancer in many aspects, treatment strategies are mainly adopted from evidence in locally advanced cervical cancer. To date, the organ-sparing treatment of choice is definitive radiotherapy, consisting of external beam radiotherapy and brachytherapy, combined with concurrent chemotherapy. Brachytherapy is an important component of the treatment and its steep dose gradient enables the delivery of high doses of radiation to the primary tumour, while simultaneously sparing the surrounding organs at risk. The introduction of volumetric CT or MRI image-guided adaptive brachytherapy in cervical cancer has led to better pelvic control and survival, with decreased morbidity, than brachytherapy based on x-ray radiographs. MRI-based image-guided adaptive brachytherapy with superior soft-tissue contrast has also been adopted sporadically for primary vaginal cancer. This therapy has had promising results and is considered to be the state-of-the-art treatment for primary vaginal cancer in standard practice.

Ring Versus Ovoids and Intracavitary Versus Intracavitary-Interstitial Applicators in Cervical Cancer Brachytherapy: Results From the EMBRACE I Study.

PURPOSE: The aim of this study was to investigate the influence of brachytherapy technique and applicator type on target dose, isodose surface volumes, and organ-at-risk (OAR) dose. METHODS AND MATERIALS: Nine hundred two patients treated with tandem/ovoids (T&O) (n = 299) and tandem/ring (T&R) (n = 603) applicators from 16 EMBRACE centers were analyzed. Patients received external beam radiation therapy and magnetic resonance imaging guided brachytherapy with dose prescription according to departmental practice. Centers were divided into 4 groups, according to applicator/technique: Ovoids and ring centers treating mainly with the intracavitary (IC) technique and ovoids and ring centers treating routinely with the intracavitary/interstitial (IC/IS) technique. V85Gy EQD210, CTVHR D90% (EQD210), and bladder, rectum, sigmoid, and vaginal 5-mm lateral-point doses (EQD23) were evaluated among center groups. Differences between T&O and T&R were tested with multivariable analysis. RESULTS: For similar point A doses, mean CTVHR D90% was 3.3 Gy higher and V85Gy was 23% lower for ring-IC compared with ovoids-IC centers (at median target volumes). Mean bladder/rectum doses (D2cm3 and ICRU-point) were 3.2 to 7.7 Gy smaller and vaginal 5-mm lateral-point was 19.6 Gy higher for ring-IC centers. Routine use of IC/IS technique resulted in increased target dose, whereas V85Gy was stable (T&R) or decreased (T&O); reduced bladder and rectum D2cm3 and bladder ICRU-point by 3.5 to 5.0 Gy for ovoids centers; and similar OAR doses for ring centers. CTVHR D90% was 2.8 Gy higher, bladder D2cm3 4.3 Gy lower, rectovaginal ICRU-point 4.8 Gy lower, and vagina 5-mm lateral-point 22.4 Gy higher for ring-IC/IS versus ovoids-IC/IS centers. The P values were <.002 for all comparisons. Equivalently, significant differences were derived from the multivariable analysis. CONCLUSIONS: T&R-IC applicators have better target dose and dose conformity than T&O-IC in this representative patient cohort. IC applicators fail to cover large target volumes, whereas routine application of IC/IS improves target and OAR dose considerably. Patients treated with T&R show a more favorable therapeutic ratio when evaluating target, bladder/rectum doses, and V85Gy. A comprehensive view on technique/applicators should furthermore include practical considerations and clinical outcome.