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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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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 EQD2 3 , 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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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 (NF PAO ) 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 NF PAO 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 NF PAO (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 NF PAO (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 NF PAO , particularly in patients with nodal disease in the 'small pelvis' and/or CI region at time of diagnosis., (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)

Background and Aim: External beam radiotherapy (EBRT) combined with brachytherapy has an essential role in the curative treatment of primary vaginal cancer. EBRT is associated with significant tumour shrinkage, making primary vaginal cancer suitable for image guided adaptive brachytherapy (IGABT). The aim of these recommendations is to introduce an adaptive target volume concept for IGABT of primary vaginal cancer., Methods: In December 2013, a task group was initiated within GYN GEC-ESTRO with the purpose to introduce an IGABT target concept for primary vaginal cancer. All participants have broad experience in IGABT and vaginal cancer brachytherapy. The target concept was elaborated as consensus agreement based on an iterative process including target delineation and dose planning comparison, retrospective analysis of clinical data and expert opinions., Results: Gynaecological examination and MR imaging are the modalities of choice for local tumour assessment. A specific template for standardised documentation with clinical drawings for vaginal cancer was developed. The adaptive target volume concept comprises different response-related target volumes. For EBRT these are related to the primary tumour and the lymph nodes, while for IGABT these are related to the primary tumour and are consisting of the residual gross tumour volume (GTV-T res ) and the high-, and intermediate risk clinical target volumes (CTV-T HR , CTV-T IR )., Conclusion: This target concept for IGABT of primary vaginal cancer defines adaptive target volumes for volumetric dose prescription and should improve comparability of different radiotherapy schedules of this rare disease. A prospective evaluation of the target volume concept within a multicentre study is planned., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Recent evidence from EMBRACE shows that around 16% patients with locally advanced cervical cancer (LACC) have residual tumor in distal parametrium (DP) and pelvic wall disease (LPW) after concurrent radio-chemotherapy (CCRT). Adequate target coverage with standard brachytherapy approaches represents a challenge. Therefore, we modified the Vienna I applicator with an add-on cap allowing for additional oblique needles into the DP/LPW (Vienna II). We report here the feasibility and clinical outcomes using Vienna II applicator in LACC patients treated in 2 institutions., Methods and Materials: 69 patients with residual disease in DP/LPW after CCRT were accrued. FIGO (2009) stage was 26% IIB, 52% III, 15% IVA, 7% IVB (para-aortic nodes). At diagnosis 91% had disease involving DP/LPW. After CCRT, patients underwent image guided adaptive brachytherapy (IGABT) using Vienna II applicator. IGABT details, acute complications, dose volume parameters and clinical outcome variables were compiled and analyzed., Results: Residual DP/LPW disease at BT was found in 90% patients. Median total number of needles were 7 [3-15], oblique 4 [1-7]. Manageable intraoperative utero-vaginal complications occurred in 8 patients and manageable arterial bleeding in 6 patients during removal. Mean distance between tandem and outer contour of CTV HR was 38 mm and mean CTV HR (±SD) volume was 69 ± 32 cm 3 . The mean D 90 CTV HR was 86 ± 7 Gy (EQD2) and mean (±SD) D 2cm 3 (Gy, EQD2) 86 ± 12, 68 ± 7, 68 ± 9 for bladder, rectum and sigmoid respectively. Actuarial LC, PFS, OS at 3/5 years was 76/72%, 56/50%, 62/54% and G3-4 late toxicities (n = 23) were observed in 14 patients (20%)., Conclusions: IGABT using Vienna II applicator allows for appropriate target coverage in tumors extending into DP/LPW at the time of BT. Clinical use is feasible and results in good local control, DFS and OS with moderate rate of acute and late ≥G3 toxicity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: To investigate the isodose surface volumes (ISVs) for 85, 75 and 60 Gy EQD2 for locally advanced cervix cancer patients., Materials and Methods: 1201 patients accrued in the EMBRACE I study were analysed. External beam radiotherapy (EBRT) with concomitant chemotherapy was followed by MR based image-guided adaptive brachytherapy (MR-IGABT). ISVs were calculated using a predictive model based on Total Reference Air Kerma and compared to Point A-standard loading systems. Influence of fractionation schemes and dose rates was evaluated through comparison of ISVs for α/β 10 Gy and 3 Gy., Results: Median V85 Gy , V75 Gy and V60 Gy EQD2 10 were 72 cm 3 , 100 cm 3 and 233 cm 3 , respectively. Median V85 Gy EQD2 10 was 23% smaller than in standard 85 Gy prescription to Point A. For small (<25 cm 3 ), intermediate (25-35 cm 3 ) and large (>35 cm 3 ) CTV HR volumes, the V85 Gy was 57 cm 3 , 70 cm 3 and 89 cm 3 , respectively. In 38% of EMBRACE patients the V85 Gy was similar to standard plans with 75-85 Gy to Point A. 41% of patients had V85 Gy smaller than standard plans receiving 75 Gy at Point A, while 21% of patients had V85 Gy larger than standard plans receiving 85 Gy at Point A., Conclusions: MR-IGABT and individualized dose prescription during EMBRACE I resulted in improved target dose coverage and decreased ISVs compared to standard plans used with classical Point A based brachytherapy. The ISVs depended strongly on CTV HR volume which demonstrates that dose adaptation was performed per individual tumour size and response during EBRT., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Purpose: To evaluate the retina dose as a risk factor associated with loss of visual acuity (VA) in 106 Ru plaque brachytherapy., Material/methods: 45 patients receiving 106 Ru plaques brachytherapy (median follow-up 29.5 months) were included in this study. An in-house developed treatment planning system with Monte Carlo based dose calculation was used to perform treatment planning and dose calculation. Risk factors associated with loss of VA were evaluated using the Cox proportional hazards models, Kaplan-Meier estimates and Pearson correlation coefficients., Results: A significant correlation was found between VA loss and mean (r = 0.49, p = 0.001) and near maximum (r = 0.47, p = 0.001) retina dose D 2% and tumor basal diameter (r = 0.50, p < 0.001). The Kaplan-Meier and Cox proportional hazards model yielded a significantly higher risk for VA loss (>0.3Snellen) for patients receiving a maximum dose of >500 Gy (p = 0.002). A Cox multivariate analysis including the macula dose (p = 0.237) and basal diameter (p = 0.791) showed that a high maximum retinal dose is the best risk factor (p = 0.013) for VA loss., Conclusion: The study showed that retina dose (D 2% and D mean ) is a suitable predictor for VA loss., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: To analyze treatment plan robustness and plan optimization strategies of 106 Ru eye plaque brachytherapy using a novel software tool., Materials and Methods: A treatment planning software was developed that allows to calculate dose-volume metrics. Plaque misplacements were simulated and evaluated with respect to the effect on tumor coverage and dose changes in critical structures. Two treatment plan optimization approaches were analyzed: (a) reducing plaque size and (b) shifting the plaque away from organs-at-risk (OAR)., Results: Maximum tumor sizes were identified which can be covered by the prescribed dose for different robustness levels (0-2mm). For an apex height of 5mm a 1mm uncertainty yielded changes in D 2% to the lens of up to ±13Gy in anterior and ±20Gy to the optic nerve in posterior tumors. By reducing the plaque size D mean and D 2% to lens, optic nerve and macula were decreased by >60% for most simulated cases. Similarly, by shifting the plaque away from the lens dose reductions of 15%/mm in anterior and even 30%/mm in central tumors were achieved., Conclusion: Critical structures in the treatment of uveal melanomas with 106 Ru plaques can benefit from the proposed, computational treatment plan optimization., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aim: The aim of this study was to quantify the impact of different types and magnitudes of dosimetric uncertainties in cervix cancer brachytherapy (BT) on tumour control probability (TCP) and normal tissue complication probability (NTCP) curves., Materials and Methods: A dose-response simulation study was based on systematic and random dose uncertainties and TCP/NTCP models for CTV and rectum. Large patient cohorts were simulated assuming different levels of dosimetric uncertainties. TCP and NTCP were computed, based on the planned doses, the simulated dose uncertainty, and an underlying TCP/NTCP model. Systematic uncertainties of 3-20% and random uncertainties with a 5-30% standard deviation per BT fraction were analysed., Results: Systematic dose uncertainties of 5% lead to a 1% decrease/increase of TCP/NTCP, while random uncertainties of 10% had negligible impact on the dose-response curve at clinically relevant dose levels for target and OAR. Random OAR dose uncertainties of 30% resulted in an NTCP increase of 3-4% for planned doses of 70-80Gy EQD2., Conclusion: TCP is robust to dosimetric uncertainties when dose prescription is in the more flat region of the dose-response curve at doses >75Gy. For OARs, improved clinical outcome is expected by reduction of uncertainties via sophisticated dose delivery and treatment verification., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To compare the maximum high risk clinical target volume (CTV HR ) dimensions and image quality between magnetic resonance imaging (MRI), transrectal ultrasound (TRUS) and computed tomography (CT) in image guided adaptive brachytherapy (IGABT) of locally advanced cervical cancer., Material and Methods: All patients with locally advanced cervical cancer treated with radiochemotherapy and IGABT between 09/2012-05/2013 were included in this study. T2-weighted MRI (1.5 tesla), TRUS and CT were performed before (MRI preBT , TRUS preBT ) and/or after (MRI BT , TRUS BT and CT BT ) insertion of the applicator. 3D TRUS image acquisition was done with a customized US stepper device and software. The HR CTV was defined on 3D image sequences acquired with different imaging modalities by one blinded observer, in accordance to the GEC-ESTRO recommendations for MRI-based target volume delineation, as the complete cervical mass including the tumour, any suspicious areas of parametrial involvement and the normal cervical stroma. Maximum HR CTV width and thickness were measured on transversal planes. Image quality was classified using the following scoring system: Grade 0: not depicted, Grade 1: inability to discriminate, margin not recognizable, Grade 2: fair discrimination, margin indistinct, Grade 3: excellent discrimination, margin distinct. Descriptive statistics, mean differences between the groups, with MRI BT as reference, and a paired t-test were calculated., Results: Images from 19 patients (FIGO IB: 3, IIB: 9, IIIB: 5, IVB: 2) were available for analysis. The mean difference in maximum HR CTV width of TRUS BT, TRUS preBT, MRI preBT, CT BT to MRI BT was 0.0mm±4.7 (n.s.), -1.1mm±5.6 (n.s.), 0.7mm±6.4 (n.s.) and 13.8mm±6.7 (p<0.001). The mean difference in maximum HR CTV thickness of TRUS BT, TRUS preBT, MRI preBT, CT BT to MRI BT was -3.4mm±5.9 (p=0.037), -3.4mm±4.2 (p<0.001), 2.0mm±6.1 (n.s.) and 13.9mm±6.3 (p<0.001). Mean scores of image quality of the target volume was 2.9 for TRUS preBT , 2.3 for TRUS BT , 2.9 for MRI preBT , 2.7 for MRI BT and 2.1 for CT BT ., Conclusion: For the assessment of the HR CTV in IGABT of cervical cancer, TRUS is within the intraobserver variability of MRI. TRUS is superior to CT as it yields systematically smaller deviations from MRI, with good to excellent image quality. Small differences of TRUS HR CTV thickness are likely related to differences in image slice orientation and compression of the cervix by the TRUS probe before insertion of the brachytherapy applicator., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: To compare the dosimetric impact of organ and target variations relative to the applicator for intracavitary brachytherapy by a multicentre analysis with different application techniques and fractionation schemes., Material and Methods: DVH data from 363 image/contour sets (120 patients, 6 institutions) were included for 1-6 fractions per patient, with imaging intervals ranging from several hours to ∼20 days. Variations between images acquired within one (intra-application) or between consecutive applicator insertions (inter-application) were evaluated. Dose plans based on a reference MR or CT image series were superimposed onto subsequent image sets and D(2cm(3)) for the bladder, rectum and sigmoid and D(90) for HR CTV were recorded., Results: For the whole sample, the systematic dosimetric variations for all organs at risk, i.e. mean variations of D(2cm(3)), were found to be minor (<5%), while random variations, i.e. standard deviations were found to be high due to large variations in individual cases. The D(2cm(3)) variations (mean±1SD) were 0.6±19.5%, 4.1±21.7% and 1.6±26.8%, for the bladder, rectum and sigmoid. For HR CTV, the variations of D90 were found to be -1.1±13.1% for the whole sample. Grouping of the results by intra- and inter-application variations showed that random uncertainties for bladder and sigmoid were 3-7% larger when re-implanting the applicator for individual fractions. No statistically significant differences between the two groups were detected in dosimetric variations for the HR CTV. Using 20% uncertainty of physical dose for OAR and 10% for HR CTV, the effects on total treatment dose for a 4 fraction HDR schedule at clinically relevant dose levels were found to be 4-8 Gy EQD2 for OAR and 3 Gy EQD2 for HR CTV., Conclusions: Substantial variations occur in fractionated cervix cancer BT with higher impact close to clinical threshold levels. The treatment approach has to balance uncertainties for individual cases against the use of repetitive imaging, adaptive planning and dose delivery., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To investigate dosimetric uncertainties of MRI-based cervix cancer brachytherapy, when applying two HDR fractions for each applicator insertion and their clinical relevance., Methods: 21 patients with 84 MRI-examinations and fractions were investigated. After insertion of the MRI compatible tandem-ring applicator, an MRI-set was recorded and the treatment plan optimised for the first fraction. Prior to the second fraction 16-20 h later a second MRI-set was recorded, and the dose distribution from the plan of the previous day superimposed and analysed. The same procedure was repeated for fractions 3 and 4. Dose from EBRT and brachytherapy was normalised to 2 Gy-fractionation (EQD2), added up to a total dose, and compared to a calculated total dose if only 1 MRI-examination per insertion is available., Results: The total D(90) for High risk (HR) CTV was 1.2±2.7 Gy(αβ10) (1±3%) (mean±1SD) lower by individual MRI-evaluation of each fraction compared to 1 MRI per insertion. The D(2cm(3)) increased by 0.7±4.7 Gy(αβ3) (1±6%) for bladder, 1.1±2.4 Gy(αβ3) (2±4%) for rectum and decreased by 0.8±3.4 Gy(αβ3) (1±5%) for sigmoid. For HR CTV the individual approach did not identify any case with a decrease of D(90) >5 Gy(αβ10). For the bladder 3 cases, for the rectum no case and for the sigmoid 1 case was identified with an increase of D(2cm(3)) >5 Gy(αβ3). For the bladder all dose variations of more than 5 Gy(αβ3) could have been avoided by ensuring a constant bladder filling. Individual MRI-evaluation did not determine any case where dose constraints were not fulfilled., Conclusions: For the treatment schedule as applied in this study, geometric differences between applicator, target and OAR result in overall dosimetric changes, which seem to be of minor relevance in regard to clinical dose volume constraints applied at present., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To investigate and test the feasibility of adaptive 3D image based BT planning for cervix cancer patients in settings with limited access to MRI, using a combination of MRI for the first BT fraction and planning of subsequent fractions on CT., Material and Methods: For 20 patients treated with EBRT and HDR BT with tandem/ring applicators two sets of treatment plans were compared. Scenario one is based on the "gold standard" with individual MRI-based treatment plans (applicator reconstruction, target contouring and dose optimization) for two BT applications with two fractions each. Scenario two is based on one initial MRI acquisition with an applicator in place for the planning of the two fractions of the first BT application and reuse of the target contour delineated on MRI for subsequent planning of the second application on CT. Transfer of the target from MRI of the first application to the CT of the second one was accomplished by use of an automatic applicator-based image registration procedure. Individual dose optimization of the second BT application was based on the transferred MRI target volume and OAR structures delineated on CT. DVH parameters were calculated for transferred target structures (virtual dose from MRI/CT plan) and CT-based OAR. The quality of the MRI/CT combination method was investigated by evaluating the CT-based dose distributions on MRI-based target and OAR contours of the same application (real dose from MRI/CT plan)., Results: The mean difference between the MRI based target volumes (HR CTVMRI2) and the structures transferred from MRI to CT (HR CTVCT2) was -1.7±6.6 cm(3) (-2.9±20.4%) with a median of -0.7 cm(3). The mean difference between the virtual and the real total D90, based on the MRI/CT combination technique was -1.5±4.3 Gy EQD2. This indicates a small systematic underestimation of the real D90., Conclusions: A combination of MRI for first fraction and subsequent CT based planning is feasible and easy when automatic applicator-based image registration and target transfer are technically available. The results show striking similarity to fully MRI-based planning in cases of small tumours and intracavitary applications, both in terms of HR CTV coverage and respecting of OAR dose limits. For larger tumours and complex applications, as well as situations with unfavourable OAR topography, especially for the sigmoid, MRI based adaptive BT planning remains the superior method., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Purpose: It has been shown that a cumulative dose of ≥87 Gy (EQD2) of external beam radiotherapy (EBRT) and image guided adaptive brachytherapy (IGABT) to the high risk clinical target volume (HR CTV) confer a local control rate >95% in locally advanced cervical cancer. This study examines the dose distribution within the HR CTV and intermediate (IR) CTV in patients with cervical cancer treated with definitive EBRT +/- concomitant chemotherapy and MRI-based IGABT between patients with local recurrence (LR) and patients in continuous complete local remission (CCLR)., Material and Methods: From 1998 to 2010, 265 patients were treated with definitive EBRT +/- concomitant chemotherapy and IGABT. Twenty-four LRs were documented. For the statistical analysis all patients with LR were matched to patients in CCLR from our database according to the following criteria: FIGO stage, histology, lymph node status, tumour size and chemotherapy. DVH parameters (D50, D90, D98, D100) were reported for HR CTV and IR CTV. In order to report the minimum dose in the region where the recurrence occurred, the HR CTV/IR CTV were divided into four quadrants on transversal planes. The minimum dose at the HR CTV/IR CTV contour was measured (within the corresponding quadrant closest to the LR) in the treatment planning system. A mean minimum point dose (MPD) was calculated by averaging these measurements on four consecutive slices at the level of the recurrence for each of the 4 brachytherapy fractions. EQD2 doses were calculated by summation of all BT and external beam therapy fractions. For each matched patient in the control group the measurements were performed on the same quadrant and at the same level., Results: Sufficient image data were available for 21 LRs. Eight central failures and 13 non-central failures were observed. The mean D90 and D100 for HR CTV were 77 Gy and 61 Gy for patients with LR and 95 Gy and 71 Gy for patients in CCLR, respectively (p<0.01). The MPD for HR CTV was 72 Gy for patients in the LR arm and 99 Gy for patients in the CCLR arm (p<0.01). In the LR arm seven patients had a D90 for HR CTV ≥87 Gy, however, in only three patients the MPD was ≥87 Gy., Conclusion: This study demonstrated significant differences in local outcome according to the delivered dose. In 85% of the LRs systematic low dose regions with less than 87 Gy were found at HR CTV contour. Systematic low dose regions leading to local recurrence could be detected even if a D90 HR CTV ≥87 Gy was applied. In addition to DVH parameters, inspection of the spatial dose distribution remains a key point in dose prescription., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: To analyse the overall clinical outcome and benefits by applying protocol based image guided adaptive brachytherapy combined with 3D conformal external beam radiotherapy (EBRT)±chemotherapy (ChT)., Methods: Treatment schedule was EBRT with 45-50.4Gy±concomitant cisplatin chemotherapy plus 4×7Gy High Dose Rate (HDR) brachytherapy. Patients were treated in the "protocol period" (2001-2008) with the prospective application of the High Risk CTV concept (D90) and dose volume constraints for organs at risk including biological modelling. Dose volume adaptation was performed with the aim of dose escalation in large tumours (prescribed D90>85Gy), often with inserting additional interstitial needles. Dose volume constraints (D(2cc)) were 70-75Gy for rectum and sigmoid and 90Gy for bladder. Late morbidity was prospectively scored, using LENT/SOMA Score. Disease outcome and treatment related late morbidity were evaluated and compared using actuarial analysis., Findings: One hundred and fifty-six consecutive patients (median age 58years) with cervix cancer FIGO stages IB-IVA were treated with definitive radiotherapy in curative intent. Histology was squamous cell cancer in 134 patients (86%), tumour size was >5cm in 103 patients (66%), lymph node involvement in 75 patients (48%). Median follow-up was 42months for all patients. Interstitial techniques were used in addition to intracavitary brachytherapy in 69/156 (44%) patients. Total prescribed mean dose (D90) was 93±13Gy, D(2cc) 86±17Gy for bladder, 65±9Gy for rectum and 64±9Gy for sigmoid. Complete remission was achieved in 151/156 patients (97%). Overall local control at 3years was 95%; 98% for tumours 2-5cm, and 92% for tumours >5cm (p=0.04), 100% for IB, 96% for IIB, 86% for IIIB. Cancer specific survival at 3years was overall 74%, 83% for tumours 2-5cm, 70% for tumours >5cm, 83% for IB, 84% for IIB, 52% for IIIB. Overall survival at 3years was in total 68%, 72% for tumours 2-5cm, 65% for tumours >5cm, 74% for IB, 78% for IIB, 45% for IIIB. In regard to late morbidity in total 188 grade 1+2 and 11 grade 3+4 late events were observed in 143 patients. G1+2/G3+4 events for bladder were n=32/3, for rectum n=14/5, for bowel (including sigmoid) n=3/0, for vagina n=128/2, respectively., Interpretation: 3D conformal radiotherapy±chemotherapy plus image (MRI) guided adaptive intracavitary brachytherapy including needle insertion in advanced disease results in local control rates of 95-100% at 3years in limited/favourable (IB/IIB) and 85-90% in large/poor response (IIB/III/IV) cervix cancer patients associated with a moderate rate of treatment related morbidity. Compared to the historical Vienna series there is relative reduction in pelvic recurrence by 65-70% and reduction in major morbidity. The local control improvement seems to have impact on CSS and OS. Prospective clinical multi-centre studies are mandatory to evaluate these challenging mono-institutional findings., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)