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• Nodal disease, tumour width and local failure are risk factors for NF post-treatment for LACC. • Any CI nodes without PAO nodes' and 'any PAO nodes' are stronger risk factors than 'small pelvis' nodes. • Elective PAO-irradiation was associated with significantly less NF PAO. 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. 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). 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. 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. [ABSTRACT FROM AUTHOR]

Background and purpose Recently, a vaginal dose reporting method for combined EBRT and BT in cervical cancer patients was proposed. The current study was to evaluate vaginal doses with this method in a multicentre setting, wherein different applicators, dose rates and protocols were used. Material and methods In a subset of patients from the EMBRACE study, vaginal doses were evaluated. Doses at the applicator surface left/right and anterior/posterior and at 5 mm depth were measured. In addition, the dose at the Posterior–Inferior Border of Symphysis (PIBS) vaginal dose point and PIBS±2 cm, corresponding to the mid and lower vagina, was measured. Results 153 patients from seven institutions were included. Large dose variations expressed in EQD2 with α/β = 3 Gy were seen between patients, in particular at the top left and right vaginal wall (median 195 (range 61–947) Gy/178 (61–980) Gy, respectively). At 5 mm depth, doses were 98 (55–212) Gy/91 (54–227) Gy left/right, and 71 (51–145) Gy/67 (49–189) Gy anterior/posterior, respectively. The dose at PIBS and PIBS±2 cm was 41 (3–81) Gy, 54 (32–109) Gy and 5 (1–51) Gy, respectively. At PIBS+2 cm (mid vagina) dose variation was coming from BT. The variation at PIBS−2 cm (lower vagina) was mainly dependent on EBRT field border location. Conclusions This novel method for reporting vaginal doses coming from EBRT and BT through well-defined dose points gives a robust representation of the dose along the vaginal axis. In addition, it allows comparison of vaginal dose between patients from different centres. The doses at the PIBS points represent the doses at the mid and lower parts of the vagina. Large variations in dose throughout the vagina were observed between patients and centres. [ABSTRACT FROM AUTHOR]

Dosimetric intra-fraction uncertainties in MRI-guided brachytherapy were analysed for HR-CTV and OARs. While dose differences were generally small, individual outliers occurred. In contrast to HDR, patients treated with PDR show increased mean rectal dose over time. Re-imaging prior to dose delivery helps to detect unfavorable anatomical changes, and allows for intervention. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: To compare MRI-guided treatment planning approaches between four centres that use tandem-ovoid applicators. Material and methods: Four centres generated three treatment plans for four patients: standard, optimised intracavitary, and optimised intracavitary/interstitial. Prescribed D90 High-Risk CTV (HR-CTV) was 85Gy EQD2 (external-beam radiotherapy and brachytherapy), while the D2cc OAR limit was 90Gy EQD2 for bladder and 75Gy EQD2 for rectum, sigmoid, and bowel, respectively. DVH-parameters, source loading patterns and spatial dose distributions of the three treatment plans were compared. Results: The standard plans of the different centres were comparable with respect to the D90 HR-CTV, but differed in OAR doses. MRI-guided intracavitary optimisation resulted in organ sparing and smaller variation in DVH parameters between the centres. Adding interstitial needles led to target dose escalation while respecting the OAR constraints. However, substantial differences in relative weights of the applicator parts resulted in an increased variation in DVH parameters and locations of high dose regions. Conclusions: MRI-guided brachytherapy treatment planning optimisation provides the possibility to increase the dose to the HR-CTV and spare the OARs. Depending on the degree of conformity the centres make different choices in relative weighting of applicator parts, leading to different dose distributions. [Copyright &y& Elsevier]

Abstract: Purpose: To evaluate dosimetric parameters and clinical outcome for cervical cancer patients treated with chemo-radiation and MR-image guided adaptive brachytherapy (MR-IGABT) using tandem-ovoid applicators for intracavitary or combined intracavitary/interstitial approaches. Method: This retrospective analysis includes 46 patients treated between 2006 and 2008. Dose–volume parameters D90 HR-CTV (high-risk clinical target volume) and D2cc OARs (organs at risk) were determined and converted into biologically equivalent doses in 2Gy fractions (EQD2). Clinical outcome parameters (local control (LC), progression free survival (PFS) and overall survival (OS)) were analysed actuarially and late morbidity crude rates were scored using CTCAEv3.0. Results: Mean D90 HR-CTV was 84 (SD9) Gy EQD2 for HR-CTV volumes of mean 57 (SD37) cm3 at time of first brachytherapy (BT). Median follow-up was 41 (range, 4–67)months. Three year LC, PFS, and OS rates were 93, 71, and 65%, respectively. Node negative patients had significantly higher 3-year survival rates compared to node positive ones (PFS 85 versus 53% (p =0.013), OS 77 versus 50% (p =0.032), respectively) with an even larger difference for patients with FIGO stages IB-IIB (PFS 87 versus 42% (p =0.002), OS 83 versus 46% (p =0.007), respectively). Late grade 3–4 mainly gastrointestinal or vaginal morbidity was observed in 4 patients (9.5%). No correlations were seen between morbidity and D2cc OAR values. Conclusion: (Chemo-) radiation and MR-IGABT with tandem-ovoid applicators result in high LC and promising survival rates with reasonable morbidity. [Copyright &y& Elsevier]

Abstract: Purpose: To evaluate the effect of different α/β and half-time of repair T ½ on the assessment of clinical treatment plans for patients with cervical cancer. Materials and methods: We used EBRT and BT treatment plans of five patients, planned with MRI guided BT. We computed 3D EQD2 dose distributions of combined EBRT and BT treatments and calculated D90 of high-risk clinical target volume (HR-CTV) and D2cc for bladder and rectum, and the ratio D2cc(bladder)/D90(HR-CTV). BT was modelled as PDR (two applications of 32×60cGy) and HDR (two applications of 2×7Gy). We assumed a low, standard and high value for the biological parameters: HR-CTV α/β =5/10/15Gy and T ½ =0.5/1.5/2.5h; OAR α/β =2/3/4Gy; T ½ =0.5/1.5/4.5h. Results: The chosen variation in modelling parameters had a much larger effect on PDR treatments than on HDR treatments, especially for OAR, thus creating larger uncertainties. The relative mean range of the ratio D2cc(bladder)/D90(HR-CTV) is 72% for PDR and 25% for HDR. Out of the 125 modelled combinations 48 PDR plans and 23 HDR plans comply with clinical objectives. Conclusion: For HDR brachytherapy, only α/β has a significant impact on reported EQD2 values, whereas for PDR both α/β and T 1/2 are important. Generally, the ratio D2cc(bladder)/D90(HR-CTV) is more favourable for PDR, even considering the larger uncertainties in EQD2. [Copyright &y& Elsevier]

Abstract: Purpose: To compare two methods of DVH parameter determination for combined external beam and brachytherapy treatment of cervical cancer. Materials and methods: Clinical treatment plans from five patients were used in this study. We simulated two applications given with PDR (32×60cGy per application, given hourly) or HDR (4×7Gy in two applications; each application of two fractions of 7Gy, given within 17h) standard and optimised treatment plans, all combined with IMRT (25×1.8Gy). Additionally, we simulated an external beam (EBRT) boost to pathological lymph nodes or the parametrium (7×2Gy). We determined D90 of the high-risk CTV (HR-CTV) and D 2cc of bladder and rectum in EQD2 in two ways. (1) ‘Parameter adding’: assuming a uniform contribution of the EBRT dose distribution and adding the values of DVH parameters for the two brachytherapy insertions, and (2) ‘distributions adding’: summing 3D biological dose distributions of IMRT and brachytherapy plans and subsequently determining the values of the DVH parameters. We took α/β=10Gy for HR-CTV, α/β=3Gy otherwise and half-time of repair 1.5h. Results: Without EBRT boost, ‘parameter adding’ yielded a good approximation. With an EBRT boost to lymph nodes, the total D90 HR-CTV was underestimated by 2.6 (SD 1.3)% for PDR and 2.8 (SD 1.4)% for HDR. This was even worse with a parametrium boost: 9.1 (SD 6.2)% for PDR and 9.9 (SD 6.2)% for HDR. Conclusion: Without an EBRT boost ‘parameter adding’, as proposed by the GEC-ESTRO, yielded accurate results for the values for DVH parameters. If an EBRT boost is given ‘distributions adding’ should be considered. [Copyright &y& Elsevier]

Abstract: Purpose: To evaluate the methods of applicator reconstruction in 3D MR-based planning for brachytherapy of cervical cancer, and to investigate applicator shifts and changes in DVH parameters during PDR treatment. Methods: For each application MR scans with applicator in situ were made: three T2-weighted (4.5mm slices) Turbo Spin Echo (TSE) scans and a balanced Steady State Free Precession scan (1.5mm). Three observers tested two applicator reconstruction methods: (A) directly on the bSSFP scan and (B) on a resampled combination of the three T2-weighted scans. For 10 patients MR imaging was repeated on the second day of each PDR fraction to determine applicator shifts and changes in DVH parameters. Results: For both applicator reconstruction methods the interobserver variation for the DVH parameters was comparable (average <1.5% in dose). Differences between the two methods were larger (up to 6.4% for target) and were related to position differences during MR scanning. The average applicator shift relative to the pelvic structures was 5–6mm into the ventral direction and 3–4mm cranially. For a single PDR fraction, the average D90 (HR-CTV) on ‘day 2’ was 0.2 (SD 2.0)Gy lower than that for day 1. The average increase in D2cc (bladder) was 1.0 (SD 3.0)Gyαβ3 for a single PDR fraction. If the effect of both fractions was combined, for 1 patient a total decrease of D90 of 7Gyαβ10 was found, whereas for another patient the total increase in bladder dose was 12Gyαβ3. Conclusions: Applicator reconstruction on MR data is feasible. In the overall accuracy during PDR brachytherapy the reconstruction uncertainty is of minor importance. Applicator and/or organ movement during the course of the PDR fraction produce larger uncertainties. [Copyright &y& Elsevier]

• Overlap volume histograms can be used for prediction models of D 2cm3 values. • Prediction models are robust to interstitial needle use and applicator types. • Prediction models can be used in a multi-center setting. • Suboptimal plans can be detected when models are trained on high-quality data. Image-guided adaptive brachytherapy (IGABT) is a key component in the treatment of cervical cancer, but the nature of the clinical workflow makes it vulnerable to suboptimal plans, as the theoretical optimal plan depends heavily on organ configuration. Patient anatomy-based quality-assurance (QA) with overlap volume histograms (OVHs) is a promising tool to detect such suboptimal plans, and in this analysis its suitability as a multi-institutional clinical QA tool is investigated. A total of 223 plans of 145 patients treated in accordance with the current state-of-the-art IGABT protocols from UMC Utrecht (UMCU) and Erasmus MC (EMC) were included. Machine-learning models were trained to predict dose D 2cm3 to bladder, rectum, sigmoid and small bowel with the help of OVHs. For this strategy, points are sampled on the organs-at-risk (OARs), and the distances of the sampled points to the target are computed and combined in a histogram. Machine-learning models can then be trained to predict dose-volume histograms (DVHs) for unseen data. Single-center model robustness to needle use and applicator type and multi-center model translatability were investigated. Performance of models was assessed by the difference between planned (clinical) and predicted D 2cm3 values. Intra-validation of UMCU data demonstrated OVH model robustness to needle use and applicator type. The model trained on UMCU data was found to be robust within the same protocol on EMC data, for all investigated OARs. Mean squared error between planned and predicted D 2cm3 values of OARs ranged between 0.13 and 0.40 Gy within the same protocol, indicating model translatability. For the former protocol cohort of Erasmus MC large deviations were found between the planned and predicted D 2cm3 values, indicating plan deviation from protocol. Mean squared error for this cohort ranged from 0.84 to 4.71 Gy. OVH-based models can provide a solid basis for multi-institutional QA when trained on a sufficiently strict protocol. Further research will quantify the model's impact as a QA tool. [ABSTRACT FROM AUTHOR]

Highlights • Nodal failure rate after chemo-radiation and MRI guided BT is 11%. • Nodal failure rates for the N− and N+ group were 7 and 16% • Complete remission after treatment was seen in 95% of N+ patients. • Nodes at diagnosis were mainly located in the pelvis, nodal failures more often in PAO. • Forty-one percent of nodal failure patients had failure outside the treated volume. Abstract Purpose/Objective(s) To investigate the patterns of nodal failure in patients enrolled in the international multicentre EMBRACE study. Materials/Methods Nodal disease at diagnosis (N−, N+) and nodal failure were analysed per region (NF) (pelvic (parametrial, common iliac, internal/external iliac), inguinal and para-aortic (PAO)) in 1338 patients. Treatment consisted of chemo-radiation and MRI guided brachytherapy. PAO radiotherapy and/or nodal boost was left to the treating centre. At time of diagnosis 52% of patients had pathologic nodes. Frequency analyses were performed in relation to patient, primary tumour and nodal disease characteristics, and treatment related factors. Results Median follow up was 34 months and 83% of NF occurred within 24 months. At diagnosis 99% of the N+ patients had pathologic nodes in the pelvis and 14% in the PAO. NF pelvic and NF PAO were reported in 55% and 68% of patients with NF, respectively. Overall NF was reported in 152 patients (11%); 7 and 16% for N- and N+ patients. Of the patients with NF, 41% were located outside the elective target (39% PAO), 40% inside and 35% inside the nodal boost target. Twelve percent of N+ patients that received a nodal boost had a NF inside the nodal boost target. Conclusion Within the EMBRACE study cohort the overall number of patients developing nodal failure is low, significantly lower for N− compared to N+ patients. Pathological nodes at diagnosis are mainly located in the pelvis, whereas nodal failures are more often reported in the PAO region. About 40% of all nodal failures were reported outside the treatment targets. [ABSTRACT FROM AUTHOR]

• Overlap volume histograms can be used for prediction models of D 2cm3 values. • Prediction models can be used in a multi-center setting to detect suboptimal plans. • Plan quality improvement is possible for suboptimal plans detected by the prediction model. Image-guided adaptive brachytherapy (IGABT) is an important modality in the cervical cancer treatment, and plan quality is sensitive to time pressure in the workflow. Patient anatomy-based quality-assurance (QA) with overlap volume histograms (OVHs) has been demonstrated to detect suboptimal plans (outliers). This analysis quantifies the possible improvement of plans detected as outliers, and investigates its suitability as a clinical QA tool in a multi-center setting. In previous work OVH-based models were investigated for the use of QA. In this work a total of 160 plans of 68 patients treated in accordance with the current state-of-the-art IGABT protocol from Erasmus MC (EMC) were analyzed, with a model based on 120 plans (60 patients) from UMC Utrecht (UMCU). Machine-learning models were trained to define QA thresholds, and to predict dose D 2cm3 to bladder, rectum, sigmoid and small bowel with the help of OVHs of the EMC cohort. Plans out of set thresholds (outliers) were investigated and retrospectively replanned based on predicted D 2cm3 values. Analysis of replanned plans demonstrated a median improvement of 0.62 Gy for all Organs At Risk (OARs) combined and an improvement for 96 % of all replanned plans. Outlier status was resolved for 36 % of the replanned plans. The majority of the plans that could not be replanned were reported having implantation complications or insufficient coverage due to tumor geometry. OVH-based QA models can detect suboptimal plans, including both unproblematic BT applications and suboptimal planning circumstances in general. OVH-based QA models demonstrate potential for clinical use in terms of performance and user-friendliness, and could be used for knowledge transfer between institutes. Further research is necessary to differentiate between (sub)optimal planning circumstances. [ABSTRACT FROM AUTHOR]

Purpose Vaginal stenosis is a major problem following radiotherapy in cervical cancer. We investigated a new dose planning strategy for vaginal dose de-escalation (VDD). Materials and methods Fifty consecutive locally advanced cervical cancer patients without lower or middle vaginal involvement at diagnosis from 3 institutions were analysed. External beam radiotherapy was combined with MRI-guided brachytherapy. VDD was obtained by decreasing dwell times in ovoid/ring and increasing dwell times in tandem/needles. The aim was to maintain the target dose (D90 of HR-CTV ⩾ 85 Gy EQD2) while reducing the dose to the surface of the vagina to <140% of the physical fractional brachytherapy dose corresponding to a total EQD2 of 85 Gy. Results The mean vaginal loading (ovoid/ring) was reduced from 51% to 33% of the total loading with VDD, which significantly reduced the dose to the vaginal dose points ( p < 0.001) without compromising the target dose. The dose to the ICRU recto-vaginal point was reduced by a mean of 4 ± 4 Gy EQD2 ( p < 0.001), while doses to bladder and rectum (D 2cm 3 ) were reduced by 2 ± 2 Gy and 3 ± 2 Gy, respectively ( p < 0.001). Conclusions VDD significantly reduces dose to the upper vagina which is expected to result in reduction of vaginal stenosis. [ABSTRACT FROM AUTHOR]

• Doses to the vaginal dose points predicts well the risk of vaginal morbidity. • Higher doses to the vaginal PIBS points are associated with vaginal stenosis. • A shorter vaginal reference length is associated with ≥grade 2 vaginal stenosis. 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. 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. 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. Higher doses to the PIBS+2 cm, PIBS and RV-RP dose points are associated with vaginal stenosis G ≥ 2. [ABSTRACT FROM AUTHOR]

• Online RTQA with minimal data transfer is feasible and reduces manpower burden • Expert evaluation with qualitative feedback improved contouring compliance. • The Jaccard Conformity Index was not a reliable alternative to expert assessment. • Common delineation errors were identified which form the basis for ongoing education. • Strategies to improve engagement with educational content are needed. EMBRACE-II is an international prospective study of IMRT and MRI-guided adaptive brachytherapy (IGABT) in locally advanced cervix cancer. An online radiotherapy quality assurance (RTQA) programme with minimal data transfer and supporting continuing medical education (CME) was implemented for IMRT contouring. Participant contours for six volumes-of-interest (VOIs) on one benchmark case were scored (2 = excellent, 1 = fair, 0 = revision required) against a consensus reference contour. For contours receiving a 0 or 1 score, additional qualitative comments were provided. The Jaccard conformity index (JCI) was retrospectively calculated. User interaction with CME content (pre-accreditation questionnaire, contouring atlas, practice cases, quizzes, internal target volume (ITV-T) guide) was analysed. 78 clinicians submitted contours for evaluation. 41% passed at the first attempt, 44% after one revision and 6% after two or more revisions. 9% did not re-submit after failing. The lowest mean scores were for the elective nodal CTV (CTV-E) (1.01/2) and ITV-T (1.06/2). 60 different errors across the six VOIs were identified; five potentially had high impact on loco-regional control. A JCI cut-off of 0.7 would have identified 87% contours that failed expert assessment, but also excluded 54% of passing contours. 39 clinicians responded to the pre-accreditation questionnaire – 36% anticipated difficulties with the ITV-T and 13% with the CTV-E. 35% clinicians contoured on the practice cases, 17% answered a quiz, 96% used the atlas and 38% the ITV-T guide. Expert evaluation with qualitative feedback improved contouring compliance. The JCI is not a reliable alternative to expert assessment. Moderate uptake of optional CME content limited evaluation. [ABSTRACT FROM AUTHOR]

Highlights • Establish EBRT treatment planning compliance through a dummy-run (EMBRACE II). • Plan quality development after introducing novel EBRT planning concepts. • Individual feedback improves EBRT plan quality and inter-center consistency. Abstract Background and purpose The EMBRACE II study combines state-of-the-art Image-Guided Adaptive Brachytherapy in cervix cancer with an advanced protocol for external beam radiotherapy (EBRT) which specifies target volume selection, contouring and treatment planning. In EMBRACE II, well-defined EBRT is an integral part of the overall treatment strategy with the primary aim of improving nodal control and reducing morbidity. The EMBRACE II EBRT planning concept is based on improved conformality through relaxed coverage criteria for all target volumes. For boosting of lymph nodes, a simultaneous integrated boost and coverage probability planning is applied. Before entering EMBRACE II, institutes had to go through accreditation. Material and methods As part of accreditation, a treatment planning dummy-run included educational blocks and submission of an examination case provided by the study coordinators. Seventy-one centers submitted 123 EBRT dose distributions. Replanning was required if hard constraints were violated or planning concepts were not fully accomplished. Dosimetric parameters of original and revised plans were compared. Results Only 11 plans violated hard constraints. Twenty-seven centers passed after first submission. 27 needed one and 13 centers needed more revisions. The most common reasons for revisions were low conformality, relatively high OAR doses or insufficient lymph node coverage reduction. Individual feedback on planning concepts improved plan quality considerably, resulting in a median body V43Gy reduction of 158 cm3 from first plan submission to approved plan. Conclusion A dummy-run as applied in EMBRACE II, consisting of training and examination cases enabled us to test institutes' treatment planning capabilities, and improve plan quality. [ABSTRACT FROM AUTHOR]

Highlights • MR-IGABT in cervix cancer improved target coverage and reduced irradiated volumes. • ISVs correlated with CTV HR volumes showing dose adaptation with tumour size. • From the perspective of normal tissue complications PDR was more sparing than HDR. • Larger EBRT doses of 50 Gy increased the irradiated volumes at doses of 60 Gy. Abstract 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 cm3, 100 cm3 and 233 cm3, respectively. Median V85 Gy EQD2 10 was 23% smaller than in standard 85 Gy prescription to Point A. For small (<25 cm3), intermediate (25–35 cm3) and large (>35 cm3) CTV HR volumes, the V85 Gy was 57 cm3, 70 cm3 and 89 cm3, 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. [ABSTRACT FROM AUTHOR]

• Novel concept for decision-support in radiation oncology. • Software with integration of data from large multi-national study for MR-IGABT. • Individualized output based on tumour and treatment characteristics. • Assessment of clinical impact of treatment plan based on TCP and NTCP models. • Feedback on achievable dose distributions based on large reference cohort. 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). 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. 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. 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. [ABSTRACT FROM AUTHOR]

• Development of a comprehensive data dashboard for radiation oncology. • Tested within an international multi-center study. • Centers can compare their treatment approach with reference population. • Automatically detect implausibilities in patient, treatment, and outcome data. • Overview of the most common pitfalls and uncertainties in current radiotherapy for cervical cancer. 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. 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. 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%). 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. [ABSTRACT FROM AUTHOR]

Background and purpose Regarding latest developments, the need of a radiotherapy ‘Patterns of Care’ survey was expressed by the Dutch National Platform Radiotherapy for Gynaecological Cancer (LPRGT). Therefore, this study investigated current practice for cervical cancer in all 16 radiation oncology centres in the Netherlands specialised in gynaecological oncology. Material and methods A structured ‘patterns of care’ questionnaire was completed and followed by an in-depth interview with radiation oncologists from all radiotherapy centres specialised in gynaecological oncology. Specific topics addressed were: definition of target volumes, treatment preparation, imaging for treatment planning, treatment planning, and image-guided adaptive radiotherapy for external beam radiotherapy and brachytherapy. Results Current radiotherapy practice in the Netherlands for cervical cancer appears to be in accordance with international standards. However, at the time of the survey some differences were revealed that might have relevant clinical impact. For instance: 1) Half of the centres acquired positron emission tomography combined with CT (PET-CT) for staging and target delineation for every patient, 2) The definition of upper border of the para-aortal lymph node area and dose prescription for external beam radiotherapy varied between the centres, and 3) 12 centres used a single treatment plan for delivering EBRT, and four used a plan-of-the-day strategy with a library of 3–4 treatment plans. Conclusions Most differences were found at the cutting edge of clinical evidence. However, the majority of these uncertainties are topics being addressed in current and planned (inter)national studies. [ABSTRACT FROM AUTHOR]

Purpose For patients with cervical cancer the delivery of chemotherapy with radiotherapy improves survival compared with radiotherapy alone. However, high rates of acute hematologic toxicity occur when combining both therapies due to the damage of the red bone marrow (RBM). This study aimed to reduce the radiation damage to the RBM. A tool has been developed for semi-automatic delineation of the red bone marrow based on MR-only. This delineation can be included into the treatment planning process to reduce the volume of RBM irradiated in patients receiving pelvic radiation therapy. Methods 13 patients with cervical cancer were enrolled. All the patients underwent MR, CT and FDG-PET imaging. A tool for RBM determination from water and fat MR images was developed. Our MR-based RBM tool was optimized and validated with the FDG-PET scans of the patients. Results Our tool identified RBM regions in the pelvic area. The mean total volume of these regions was 34% of the pelvic bone marrow. The corresponding SUV values based on the FDG-PET scans were above the reported threshold of active/red bone marrow. Conclusion This study shows that delineations of the RBM for the radiotherapy with RBM sparing can be generated semi-automatically using MR scans only. [ABSTRACT FROM AUTHOR]

• Impact of morbidity on quality of life (QOL) of cancer survivors depends on severity and persistence. • Prospective data from EMBRACE-I allowed to assess the association for cervical cancer survivors. • All persistent symptoms were significantly associated with QOL aspects, but with different magnitude. • Role functioning and global health/general QOL were the most impaired aspects reported by patients. • Persistent pain and fatigue were more detrimental compared to other organ-related symptoms. To quantify the association of persistent morbidity with different aspects of quality of life (QOL) in locally advanced cervical cancer (LACC) survivors. Longitudinal outcome from the EMBRACE-I study was evaluated. Patient-reported symptoms and QOL were prospectively scored (EORTC-C30/CX24) at baseline and regular follow-ups. Physician-assessed symptoms were also reported (CTCAEv.3). Persistent symptoms were defined if present in at least half of the follow-ups. QOL items were linearly transformed into a continuous scale. Linear mixed-effects models (LMM) were applied to evaluate and quantify the association of persistent symptoms with QOL. Overall QOL deterioration was evaluated by calculating the integral difference in QOL over time obtained with LMM for patients without and with persistent symptoms. Out of 1416 patients enrolled, 741 with baseline and ≥ 3 late follow-ups were analyzed (median 59 months). Proportions of persistent EORTC symptoms ranged from 21.8 % to 64.9 % (bowel control and tiredness). For CTCAE the range was 11.3–28.6 % (limb edema and fatigue). Presence of any persistent symptom was associated with QOL, although with varying magnitude. Role functioning and Global health/QOL were the most impaired aspects. Fatigue and pain showed large differences, with reductions of around 20 % for most of the QOL aspects. Among organ-related symptoms, abdominal cramps showed the largest effect. Persistent symptoms are associated with QOL reductions in LACC survivors. Organ-related symptoms showed smaller differences than general symptoms such as fatigue and pain. In addition to optimizing treatment to minimize organ-related morbidity, effort should be directed towards a more comprehensive and targeted morbidity management. [ABSTRACT FROM AUTHOR]

Purpose Upfront quality assurance (QA) is considered essential when starting a multicenter clinical trial in radiotherapy. Despite the long experience gained for external beam radiotherapy (EBRT) trials, there are only limited audit QA methods for brachytherapy (BT) and none include the specific aspects of image guided adaptive brachytherapy (IGABT). Methods and materials EMBRACE is a prospective multicenter trial aiming to assess the impact of (MRI)-based IGABT in locally advanced cervical cancer. An EMBRACE dummy run was designed to identify sources and magnitude of uncertainties and errors considered important for the evaluation of clinical, and dosimetric parameters and their relation to outcome. Contouring, treatment planning and dose reporting was evaluated and scored with a categorical scale of 1–10. Active feedback to centers was provided to improve protocol compliance and reporting. A second dummy run was required in case of major deviations (score <7) for any item. Results Overall 27/30 centers passed the dummy run. 16 centers had to repeat the dummy run in order to clarify major inconsistencies to the protocol. The most pronounced variations were related to contouring for both EBRT and BT. Centers with experience in IGABT (>30 cases) had better performance as compared to centers with limited experience. Conclusion The comprehensive dummy run designed for the EMBRACE trial has been a feasible tool for QA in IGABT of cervix cancer. It should be considered for future IGABT trials and could serve as the basis for continuous quality checks for brachytherapy centers. [ABSTRACT FROM AUTHOR]

Background and purpose To evaluate volume changes and position shifts and their contribution to treatment margins of pelvic and para-aortic lymph nodes during Intensity Modulated Radiation Therapy (IMRT) for advanced cervical cancer. Materials and methods Seventeen patients with visible nodes on MR images underwent T2-weighted MR scans before and weekly during the course of IMRT. Thirty-nine pelvic and para-aortic nodes were delineated on all scans. Margins accommodating for volume and position changes were taken from the boundaries of the nodal volumes in the six main directions. Results Nodal volume regression from the pre-treatment situation to week 4 was 58% on average (range: 11.7% increase to 100% decrease). Nodal volumes partly increased between the pre-treatment scans and the scans in weeks 1-3, but in week 4 all nodes except one had regressed. Around the nodal volumes manually derived ITV margins accounting for volume changes and position shifts of 7.0, 4.0, 7.0, 8.0, 7.0 and 9.0 mm to the medial, lateral, anterior, posterior, superior and inferior directions were needed to cover 95% of all nodes. Conclusions We used weekly MR scans to derive inhomogeneous margins that accommodate for nodal volume and position changes during treatment. These margins should be taken into consideration when planning external beam radiotherapy (EBRT) boosts, especially for highly conformal boosting techniques. [ABSTRACT FROM AUTHOR]

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 ∼20days. 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 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 , 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 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 4–8Gy EQD2 for OAR and 3Gy 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. [ABSTRACT FROM AUTHOR]

Abstract: Image-guided brachytherapy in cervical cancer is increasingly replacing X-ray based dose planning. In image-guided brachytherapy the geometry of the applicator is extracted from the patient 3D images and introduced into the treatment planning system; a process referred to as applicator reconstruction. Due to the steep brachytherapy dose gradients, reconstruction errors can lead to major dose deviations in target and organs at risk. Appropriate applicator commissioning and reconstruction methods must be implemented in order to minimise uncertainties and to avoid accidental errors. Applicator commissioning verifies the location of source positions in relation to the applicator by using auto-radiography and imaging. Sectional imaging can be utilised in the process, with CT imaging being the optimal modality. The results from the commissioning process can be stored as library applicators. The importance of proper commissioning is underlined by the fact that errors in library files result in systematic errors for clinical treatment plans. While the source channel is well visualised in CT images, applicator reconstruction is more challenging when using MR images. Availability of commercial dummy sources for MRI is limited, and image artifacts may occur with titanium applicators. The choice of MR sequence is essential for optimal visualisation of the applicator. Para-transverse imaging (oriented according to the applicator) with small slice thickness (⩽5mm) is recommended or alternatively 3D MR sequences with isotropic voxel sizes. Preferably, contouring and reconstruction should be performed in the same image series in order to avoid fusion uncertainties. Clear and correct strategies for the applicator reconstruction will ensure that reconstruction uncertainties have limited impact on the delivered dose. Under well-controlled circumstances the reconstruction uncertainties are in general smaller than other brachytherapy uncertainties such as contouring and organ movement. [Copyright &y& Elsevier]

Abstract: Purpose: To perform a qualitative and quantitative comparison of different treatment planning methods used in different centres for MRI-based brachytherapy (BT) of cervical cancer. Materials and methods: Two representative patients with advanced cervical cancer (1 “limited volume case”; 1 “extensive volume case”) were planned for brachytherapy (BT) with a tandem-ring applicator by six different centres. During a workshop all centres produced an institutional standard plan and an MRI-based adaptive treatment plan for each case. Optimisation was based on the fractionation schedule (HDR, PDR) and method according to the institutional protocol. Results: The loading pattern, dwell times, shape of the point A isodose varied considerably between institutional standard plans, as did dose–volume parameters for high risk CTV (HR-CTV) and also for the D2cc for OAR, violating the dose–volume constraints in many situations. During optimisation, the centres stayed as close as possible to the standard loading pattern and dwell times. The dose distributions and dose–volume parameters between the plans from the different centres became much more comparable after optimisation. The prescribed dose to the HR-CTV could be achieved in the limited volume case by all centres, in the extensive case only if additional needles were applied. Conclusion: Treatment planning for gynaecologic brachytherapy based on different traditions shows less variation in regard to target coverage and OAR dose, when 3D image-based optimisation is performed with a uniform prescription protocol. [Copyright &y& Elsevier]

Abstract: Purpose: To study the impact of MRI-guided treatment planning on dose/volume parameters in pulsed dose rate (PDR) brachytherapy (BT) for cervical cancer. Additionally, we investigated the potential benefit of an intracavitary/interstitial (IC/IS) modification of the classical tandem ovoid applicator. Material and methods: For 24 patients we compared Standard PDR BT plans, Scaled Standard plans and MRI-guided Optimised plans. The total EBRT/BT prescribed dose to Manchester point A or to 90% of the HR-CTV (D90 HR-CTV) expressed in EQD2 was 80Gyαβ10 in 17 patients (Period I) and 84Gyαβ10 in 7 patients (Period II). The constraints to 2 cm3 of the OAR were 90Gyαβ3 for bladder and 75Gyαβ3 for rectum, sigmoid and bowel. Most cases were treated with a traditional intracavitary tandem ovoid applicator. In 6 patients we used a newly designed combined IC/IS modification for the second PDR fraction and investigated the benefit of the interstitial part. Results: The average gain of MRI-guided optimisation expressed in D90 HR-CTV was 4±9Gyαβ10 (p <0.001) and 10±7Gyαβ10 (p =0.003) in the two periods. The dose to 2 cm3 of the OAR met the constraints. In the group that was treated with the combined IC/IS approach, we could increase the D90 HR-CTV for the second PDR fraction with 5.4±4.2Gyαβ10 (p =0.005) and the D100 with 4.8±3.1Gyαβ10 (p =0.07). Conclusions: Three-dimensional MRI-guided treatment planning and optimisation improves the DVH parameters compared to conventional planning strategies. Additional improvement can be achieved by using a combined IC/IS approach. [Copyright &y& Elsevier]