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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]

The purpose of the study was to develop a methodology for vaginal dose-surface maps (DSMs) in patients with cervix cancer and to investigate dose-surface histogram metrics as predictors for vaginal stenosis (St) and mucositis (Muc). Thirty-one patients with locally advanced cervix cancer with no vaginal St/Muc (CTCAE-v3) G ≥ 2 at baseline were analyzed. Patients were divided in four morbidity groups: 15 with St/Muc G0/1, 6 with St G ≥ 2, 4 with St/Muc G ≥ 2, and 6 with Muc G ≥ 2. Patients received external beam radiotherapy and 4-fraction intracavitary/interstitial high-dose-rate brachytherapy using tandem and ovoids. DSMs were generated from inner/outer vaginal surfaces. DSMs of external beam radiotherapy and brachytherapy (Gy EQD2 3) were added based on a system of homologous points, to generate cumulative DSMs. Dose-surface histogram/dose-volume histogram parameters, location of high/intermediate-dose regions, rectovaginal reference point, vaginal lateral 5 mm point doses, and vagina/implant dimensions were investigated for St and Muc prediction. Average/difference DSMs and one-way analysis of variance were used to compare between groups. Best predictors of stenosis were D 15–25cm2 and upper-vagina S 65–120Gy (%). Cutoffs of ∼90 Gy EQD2 3 for D 20cm2 and ∼80% for S 65Gy to top 3 cm inner vaginal surface suitably discriminated for stenosis. Spatial dose location on average/difference DSMs showed significantly higher doses (by > 20 Gy, p < 0.001) over longer parts of the dorsolateral vagina and higher rectovaginal reference point doses for any G ≥ 2 morbidity, over the whole circumference of the upper vagina for G ≥ 2 stenosis. Dose-volume histogram parameters were dependent on vaginal wall thickness. An increase of wall thickness from 2 to 4 mm resulted in an increase of D 2cm3 (D 4cm3) of 16% (32%). A novel method was developed to generate vaginal DSMs and spatial-dose metrics. DSMs were found to correlate with vaginal stenosis. The findings of this study are promising and should be further validated on a larger patient cohort, treated with different applicators. [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]

Purpose: The goal of this study was to determine the dose contributions from image guided adaptive brachytherapy (IGABT) to individual suspicious pelvic lymph nodes (pLNN) in cervical cancer patients. Data were collected in two cancer centers, University of Pittsburgh Cancer Institute (UPCI) and University Medical Center Utrecht (UMCU). Material and methods: 27 and 15 patients with node positive cervical cancer treated with HDR (high dose rate) or PDR (pulsed dose rate)-IGABT were analyzed. HDR-IGABT (UPCI) was delivered with CT/MRI compatible tandem-ring applicators with 5.0-6.0 Gy x five fractions. PDR-IGABT (UMCU) dose was delivered with Utrecht tandem-ovoid applicators with 32 x 0.6 Gy x two fractions. Pelvic lymph nodes with short axis diameter of ≥ 5 mm on pre-treatment MRI or PET-CT were contoured for all BT-plans. Dose contributions to individual pLNN expressed as D90 (dose to 90% of the volume) were calculated from dose-volume histograms as absolute and relative physical dose (% of the reference dose) for each fraction. For each node, the total dose from all fractions was calculated, expressed in EQD2 (equivalent total dose in 2 Gy fractions). Results: Fifty-seven (UPCI) and 40 (UMCU) individual pLNN were contoured. The mean D90 pLNN was 10.8% (range 5.7-25.1%) and 20.5% (range 6.8-93.3%), respectively, and therefore different in the two centers. These values translate into 2.7 Gy (1.3-6.6 Gy) EQD2 and 7.1 Gy (2.2-36.7 Gy) EQD2, respectively. Differences are caused by the location of the individual nodes in relation to the spatial dose distribution of IGABT, differences in total dose administered and radiobiology (HDR versus PDR). Conclusions: The IGABT dose contribution to individual pelvic nodes depends on patient and treatment related factors, and varies considerably. [ABSTRACT FROM AUTHOR]

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]

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. [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]

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. [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]

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. [ABSTRACT FROM AUTHOR]

In 2008, the GEC ESTRO Gyn network launched the first multiinstitutional, observational, and prospective international study on MRI-guided brachytherapy in locally advanced cervical cancer patients (EMBRACE-I). EMBRACE-I was followed by EMBRACE-II from 2016 and ongoing. Among the aims of the EMBRACE studies are to benchmark morbidity outcomes and develop dose-volume effects and predictive models for morbidity. The EMBRACE studies collect both physician (CTCAE v.3) and patient (EORTC QLQ-C30/CX24) reported outcomes, including baseline information, in a regular follow-up schedule. The EMBRACE studies feature high numbers of patients (EMBRACE-I N = 1416, EMBRACE-II N = 1500 expected) enrolled from many institutions worldwide (EMBRACE-I n = 23, EMBRACE-II n = 45). This large-scale multiinstitutional approach offers a unique opportunity to investigate and develop new strategies for improving the quality of assessment and reporting of morbidity. This report presents an overview of the challenges and pitfalls regarding the assessment and reporting of morbidity encountered during more than a decade of development and research activities within the EMBRACE consortium. This includes the recognition and evaluation of inconsistencies in the morbidity assessment, and consequently, the provision of assistance and training in the scoring procedure to reduce systematic assessment bias. In parallel, a variety of methodological approaches were tested to comprehensively summarize morbidity outcomes, and a novel approach was developed to refine dose-effect models and risk factor analyses. The purpose of this report is to present an overview of these findings, describe the learning process, and the strategies that have consequently been implemented regarding educational activities, training, and dissemination. [ABSTRACT FROM AUTHOR]

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. [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]

Purpose: To describe the evolution of external beam radiation therapy (EBRT) from EMBRACE-I (general guidelines for EBRT) to the initial phase of the EMBRACE-II study (detailed protocol for EBRT).Methods and Materials: EMBRACE-I enrolled 1416 locally advanced cervical cancer patients treated with chemoradiation including image-guided adaptive brachytherapy during 2008 to 2015. From March 2016 until March 2018, 153 patients were enrolled in the ongoing EMBRACE-II study, which involves a comprehensive detailed strategy and accreditation procedure for EBRT target contouring, treatment planning, and image guidance. EBRT planning target volumes (PTVs), treated volumes (V43 Gy), and conformity index (CI; V43 Gy/PTV) were evaluated in both studies and compared.Results: For EMBRACE-I, conformal radiation therapy (60% of patients) or intensity-modulated radiation therapy (IMRT) and volumetric arc therapy (VMAT; 40%) was applied with 45 to 50 Gy over 25 to 30 fractions to the elective clinical target volume (CTV). For pelvic CTVs (82%), median PTV and V43 Gy volumes were 1549 and 2390 mL, respectively, and CI was 1.54. For pelvic plus paraortic nodal (PAN) CTVs (15%), median PTV and V43 Gy volumes were 1921 and 2895 mL, and CI was 1.51. For pelvic CTVs treated with 45 to 46 Gy, the use of conformal radiation therapy was associated with a median V43 Gy volume that was 546 mL larger than with IMRT/VMAT. For pelvic CTVs treated with IMRT, the use of a dose prescription ≥48 Gy was associated with a median V43 Gy volumes that was 428 mL larger than with a dose prescription of 45 to 46 Gy. For EMBRACE-II, all patients were treated with: IMRT/VMAT, daily IGRT, 45 Gy over 25 fractions for the elective CTV, and simultaneously integrated boost for pathologic lymph nodes. For pelvic CTVs (61%), median PTV and V43 Gy volumes were 1388 and 1418 mL, and CI was 1.02. For pelvic plus PAN CTVs (32%), median PTV and V43 Gy volumes were 1720 and 1765 mL, and CI was 1.03. From EMBRACE-I to initial II, median V43 Gy was decreased by 972 mL (41%) and 1130 mL (39%), and median CI decreased from 1.54 to 1.02 and 1.51 to 1.03 for pelvic and pelvic plus PAN irradiation, respectively.Conclusions: Application of IMRT/VMAT, IGRT, and a 45-Gy dose provides the potential of higher conformality inducing significant reduction of treated volume. Adherence to a detailed protocol including comprehensive accreditation, as in EMBRACE-II, reduces considerably V43 Gy and V50 Gy and improves conformality and interinstitutional consistency. [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]

Purpose To demonstrate that V 60 Gy, V 75 Gy, and V 85 Gy isodose surface volumes can be accurately estimated from total reference air kerma (TRAK) in cervix cancer MRI-guided brachytherapy (BT). Methods and Materials 60 Gy, 75 Gy, and 85 Gy isodose surface volumes levels were obtained from treatment planning systems (V TPS ) for 239 EMBRACE study patients from five institutions treated with various dose rates, fractionation schedules and applicators. An equation for estimating V TPS from TRAK was derived. Furthermore, a surrogate Point A dose (Point A*) was proposed and tested for correlation with V 75 Gy. Results Predicted volumes V pred = 4965 (TRAK/dref) 3/2 + 170 (TRAK/dref) − 1.5 gave the best fit to V TPS . The difference between V TPS and predicted volumes was 0.0% ± 2.3%. All volumes were predicted within 10%. The prediction was valid for ( 1 ) high-dose rate and pulsed dose rate, ( 2 ) intracavitary vs. intracavitary/interstitial applicators, and ( 3 ) tandem-ring, tandem-ovoid, and mold. Point A* = 14 TRAK was converted to total EQD 2 and showed high correlation with V 75 Gy. Conclusions TRAK derived Isodose surface volumes may become a tool for assessment of treatment intensity. Furthermore, surrogate Point A ∗ doses can be applied for both intracavitary and intracavitary/interstitial BT and can be used to compare treatments across fractionation schedules. [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]

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]