Search

Purpose: To report clinical and treatment characteristics, remission and failure patterns, and risk factors for local failure (LF) from the EMBRACE-I study., Materials and Methods: EMBRACE-I was a prospective, observational, multicenter cohort study on magnetic resonance imaging-based image-guided adaptive brachytherapy (MR-IGABT) in locally advanced cervical cancer. Treatment consisted of external beam radiotherapy, concurrent chemotherapy, and MR-IGABT. LF was defined as progressive or recurrent disease in the cervix, uterus, parametria, pelvic wall, or vagina. Competing risk analysis was used to estimate local tumor control (LC) and Cox proportional regression models for multivariable analysis and dose-response analysis., Results: One thousand three hundred eighteen patients with a median follow-up of 52 months were available for this analysis. Eighty-one patients had persistent disease 3 months after end of treatment. Of those, 60 patients achieved LC at 6-9 months without further treatment, whereas 21 patients had progressive disease. In addition, 77 patients developed a local recurrence after complete remission comprising a total number of 98 LFs. LFs were located inside the MR-IGABT target volumes in 90% of patients with LF. In multivariable analysis, histology, minimal dose to 90% of high-risk clinical target volume (CTV HR ), maximum tumor dimension, CTV HR > 45 cm 3 , overall treatment time, tumor necrosis on magnetic resonance imaging at diagnosis, uterine corpus infiltration at diagnosis and at MR-IGABT, and mesorectal infiltration at MR-IGABT had significant impact on LF. Dose-response analysis showed that a minimal dose to 90% of 85 Gy to the CTV HR led to 95% (95% CI, 94 to 97) LC 3 years postintervention for squamous cell in comparison to 86% (95% CI, 81 to 90) for adeno/adenosquamous carcinoma histology., Conclusion: The present study demonstrates the safety and validity of the GYN GEC-ESTRO/ICRU-89 target concept and provides large-scale evidence for dose prescription and new risk factors for LF in MR-IGABT in locally advanced cervical cancer., Competing Interests: Maximilian P. SchmidHonoraria: ElektaResearch Funding: Elekta (Inst), Varian Medical Systems (Inst)Patents, Royalties, Other Intellectual Property: Patent: US20170120072 Umesh MahantshettyConsulting or Advisory Role: AstraZenecaResearch Funding: Varian Medical Systems (Inst) Kari TanderupResearch Funding: Varian Medical Systems (Inst), Elekta (Inst) Peter HoskinResearch Funding: Varian Medical Systems (Inst), Astellas Pharma (Inst), Bayer (Inst), Roche (Inst), Pfizer (Inst), Elekta (Inst), Bristol Meyers (Inst) Bradley R. PietersConsulting or Advisory Role: BD Bard (Inst)Research Funding: ElektaTravel, Accommodations, Expenses: BD BardOther Relationship: Elekta (Inst) Remi NoutConsulting or Advisory Role: Merck KGaA (Inst)Research Funding: Varian Medical Systems (Inst), Elekta (Inst), Accuray (Inst) Nicole NesvacilHonoraria: ElektaConsulting or Advisory Role: ElektaTravel, Accommodations, Expenses: Elekta Richard PötterResearch Funding: Elekta (Inst), Varian Medical Systems (Inst) Christian KirisitsHonoraria: ElektaResearch Funding: Elekta (Inst), Varian Medical (Inst)Patents, Royalties, Other Intellectual Property: Patent WO2015181632A1 on Methods and Systems for Brachytherapy Planning Based on Imaging DataNo other potential conflicts of interest were reported.

Purpose: Brachytherapy is most often applied in the curative or salvage setting, but many forms of brachytherapy can be helpful for symptom palliation. Declining utilization is seen, for multiple reasons, such as lack of awareness, insufficient expertise, or poor access to equipment. High level evidence for many types of palliative brachytherapy has been lacking. The objective of the current study was to review the evidence for utilization and efficacy of brachytherapy to palliate symptoms from cancer., Materials and Methods: We performed a systematic search in EMBASE and MEDLINE for English-language articles published from January 1980 to May 2022 that described brachytherapy used for a palliative indication in adults with a diagnosis of cancer (any subtype) and at least one symptom related outcome. Individual case reports and conference abstracts were excluded. All publications were independently screened by two investigators for eligibility., Results: The initial search identified 3637 abstracts of which 129 were selected for in-depth review. The number of studies (total number of patients) included in the final analysis varied widely by tumor site with the majority (68.2%) involving either lung or esophageal cancer. Despite a limited number of prospective trials that assessed the efficacy of brachytherapy for symptom management, there was a positive effect on palliation of symptoms across all tumor types. There was no clear trend in the number of publications over time. The most commonly cited symptom indications for palliation by brachytherapy were dysphagia, dyspnea, pain and bleeding., Conclusions: Brachytherapy can provide palliation for patients with advanced cancer, across different tumor sites and clinical scenarios. However, high level evidence in the literature to support palliative applications of brachytherapy is lacking or limited for many tumor sites. There appears to be a strong publication bias towards positive studies in favor of brachytherapy. Beyond anecdotal reports and individual practices, outcomes research can further our understanding of the role of brachytherapy in palliating advanced cancers of all types, and should be encouraged., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

This novel deep-learning (DL) algorithm addresses the challenging task of predicting uterine shape and location when deformed from its natural anatomy by the presence of an intrauterine (tandem)/intravaginal (ring) applicator during brachytherapy (BT) treatment for locally advanced cervical cancer. Paired pelvic MRI datasets from 92 subjects, acquired without (pre-BT) and with (at-BT) applicators, were used. We propose a novel automated algorithm to segment the uterus in pre-BT MR images using a deep convolutional neural network (CNN) incorporated with autoencoders. The proposed neural net is based on a pre-trained CNN Inception V4 architecture. It predicts a compressed vector by applying a multi-layer autoencoder, which is then back-projected into the segmentation contour of the uterus. Following this, another transfer learning approach using a modified U-net model is employed to predict the at-BT uterus shape from pre-BT MRI. The complex and large deformations of the uterus are quantified using free form deformation method. The proposed algorithm yielded an average Dice Coefficient (DC) of 94.1±3.3 and an average Hausdorff Distance (HD) of 4.0±3.1 mm compared to the manually defined ground truth by expert clinicians. Further, the modified U-net prediction of the at-BT uterus resulted in a DC accuracy of 88.1±3.8 and HD of 5.8±3.6 mm. The mean uterine surface point-to-point displacement was 25.0 [10.0-62.5] mm from the pre-BT position. Our unique DL method can thus successfully predict tandem-deformed uterine shape and position from MR images taken before the BT implant procedure i.e. without the applicator in place. Clinical relevance-The proposed DL-based framework can be incorporated as an automatic prediction tool of uterine deformation due to applicator insertion for personalized BT treatments. It holds promise for more streamlined clinical/technical decision-making before BT applicator insertion resulting in improved dosimetric outcomes.

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 (TS D ) and at BT (TS BT ) by the sum of points obtained from the 8 locations at the 2 occasions., Results: Median TS D and TS BT 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 (CTV HR ), CTV HR D90 (minimal dose to 90% of the target volume), D2cm 3 bladder (minimal dose to the most exposed 2 cm 3 of the bladder), and D2cm 3 rectum. TS regression (TS BT ≤5) was associated with improved local control and survival and with less morbidity compared with patients with TS BT 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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective . Brachytherapy (BT) dose prescriptions for locally advanced cervical cancer are made with account for the radiobiological parameters, α/β ratio and halftime of repair ( T 1/2 experimental technique using clinical high-dose-rate (HDR) and pulsed-dose-rate (PDR) Ir-192 brachytherapy afterloaders to quantify these parameters in vitro experimental technique using clinical high-dose-rate (HDR) and pulsed-dose-rate (PDR) Ir-192 brachytherapy afterloaders to quantify these parameters in vitro and to contextualize findings within contemporary practice. Approach . To efficiently quantify α/β and T 1/2 , in vitro experiments more reflective of clinical BT practice than traditional clonogenic survival assays were developed and applied to four squamous cell carcinoma cell lines (CaSki, C-33A, SiHa, and SW756). Radiation was delivered using single acute and fractionated dose treatments with a conventional irradiator and clinical HDR and PDR BT afterloaders. For the latter, a novel b rachytherapy a fterloader i n vitro r adiation d elivery a pparatus (BAIRDA) was developed. Main Results . The α/β and T 1/2 values determined using BAIRDA and the conventional irradiator showed close agreement, validating the novel apparatus and technique. For CaSki, C-33A, SiHa, and SW756, the BAIRDA-measured α/β ratios (5.2 [4.6-5.8], 5.6 [4.5-6.6], 6.3 [4.9-7.7], and 5.3 [4.7-6.0] Gy, respectively) were consistently smaller, while the T 1/2 (3.3 [2.7-3.9], 2.7 [2.0-3.3], 2.8 (2.4-3.1], and 4.8 [4.1-5.4] hours) larger, than the widely accepted values in clinical practice ( α/β = 10 Gy; T 1/2  = 1.5 h). Significance . In vitro experiments using BAIRDA provided evidence for differences between the conventionally selected and experimentally determined α/β ratio and T 1/2 . Treatment regimens using HDR-BT and PDR-BT, designed to deliver equivalent radiobiological doses based on conventional values, were shown to differ by up to 27 Gy EQD2 - an effect that could impact treatment outcomes in cervical cancer. Furthermore, with BAIRDA, we have developed a novel method for radiobiological research in BT., (© 2022 Institute of Physics and Engineering in Medicine.)

Objective: To assess risk factors for nodal failure (NF) after definitive (chemo)radiotherapy and image-guided brachytherapy for locally advanced cervical cancer (LACC) for patients treated in the EMBRACE I study., Materials and Methods: Data for pelvic NF and para-aortic (PAO) NF (NF PAO ) were analysed. After multiple imputation, univariable and multivariable Cox-regression was performed for clinical and treatment-related variables. For patients with affected pelvic nodes but no PAO nodes at diagnosis, additional analyses were performed for two subgroups: 1. 'small pelvis' nodes in internal and external iliac, obturator, parametrial, presacral and/or common iliac (CI) region and 2. any CI nodes (subgroup of 1)., Results: 1338 patients with 152 NF and 104 NF PAO events were analysed with a median follow-up of 34.2 months (IQR 16.4-52.7). For the entire group, larger tumour width, nodal risk groups (in particular any CI nodes without PAO nodes), local failure, and lower Hb-nadir increased the risk of NF. Elective PAO-irradiation was independently associated with a decreased risk of NF PAO (HR 0.53, 95%-CI 0.28-1.00, p = 0.05). For subgroup 1, having 'any CI nodes without PAO nodes' and local failure significantly increased NF risk. Additionally, elective PAO-irradiation was associated with less risk of NF PAO (HR 0.38, 95%-CI 0.17-0.86, p = 0.02). For subgroup 2 only local failure was associated with higher risk of NF., Conclusion: In this patient cohort, nodal disease and tumour width at diagnosis, as well as local failure, are risk factors for NF after definitive treatment. Having either 'any PAO nodes' (with or without pelvic nodes) or 'any CI nodes' (without PAO nodes) are stronger risk factors than involvement of nodes in the small pelvis alone. Elective PAO-irradiation was associated with significantly less NF PAO , particularly in patients with nodal disease in the 'small pelvis' and/or CI region at time of diagnosis., (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)

Purpose: To identify patient- and treatment-related risk factors for fistula, bleeding, cystitis, pain and difficulty in voiding in locally advanced cervical cancer patients treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT)., Material and Methods: Morbidity within the EMBRACE-I study was prospectively reported for physician-assessed (CTCAE) fistula, bleeding and cystitis and patient-reported (EORTC) pain and difficulty in voiding. Analysis of risk factors was performed in patients without bladder infiltration. Risk factors were tested with Cox regression for grade (G) ≥ 3 cystitis, for G ≥ 2 fistula, bleeding and cystitis, and for EORTC "very much" and "quite a bit" or worse., Results: Of 1416 patients enrolled, 1153 and 884 patients without bladder infiltration were evaluable for the analysis of CTCAE and EORTC items, respectively. Median follow-up was 48[3-120] months. Crude incidence rates for G ≥ 2 fistula, bleeding and cystitis were 0.7%, 2.7% and 8.8%, respectively, and 16% and 14% for "quite a bit" or worse pain and difficulty in voiding, respectively. Baseline urinary morbidity and overweight/obesity were significant risk factors for most endpoints. Bladder D 2cm3 correlated with G ≥ 2 fistula, bleeding and cystitis, while ICRU bladder point dose correlated with EORTC pain "quite a bit" or worse. An increase from 75 Gy to 80 Gy in bladder D 2cm3 resulted in an increase from 8% to 13% for 4-year actuarial estimate of G ≥ 2 cystitis., Conclusion: Clinical and treatment-related risk factors for bladder fistula, bleeding and cystitis were identified within a prospective and multi-institutional setting. A dose-effect was established with bladder D 2cm3 , reinforcing the importance of continued optimization during individualized IGABT planning., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: To identify patient- and treatment-related risk factors and dose-effects for urinary frequency and incontinence in locally advanced cervical cancer (LACC) treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT)., Material and Methods: Physician-assessed (CTCAE) and patient-reported (EORTC) frequency and incontinence recorded in the EMBRACE-I study were analysed. Risk factors analysis was performed in patients without bladder infiltration and with baseline morbidity available. Cox regression was used for CTCAE grade (G) ≥ 3 and G ≥ 2 and for EORTC "very much" and "quite a bit" or worse. Logistic regression was used for late persistent morbidity defined when CTCAE G ≥ 1 or EORTC ≥ "quite a bit" were scored in at least half of follow-ups., Results: Longitudinal data on 1153 and 884 patients were available for CTCAE and EORTC analysis, respectively. Median follow-up was 48[3-120] months. Crude incidence rates of G≥2 were 13% and 11% for frequency and incontinence, respectively. Baseline morbidity and overweight-obesity were risk factors for both symptoms. Elderly patients were at higher risk for incontinence. Patients receiving conformal-radiotherapy were at higher risk for frequency. ICRU bladder point (ICRU-BP) dose was a stronger predictor for incontinence than bladder D 2cm3 . The 5-year actuarial estimate of G ≥ 2 incontinence increased from 11% to 20% with ICRU-BP doses > 75 Gy compared to ≤ 65 Gy. Frequency showed weaker associations with dose., Conclusion: ICRU-BP dose, in addition to clinical parameters, is a risk factor for urinary incontinence and shows a dose-effect after radio(chemo)therapy and IGABT. ICRU-BP dose should be monitored during treatment planning alongside volumetric parameters. Frequency seems associated with larger irradiated volumes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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/m 2 , 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 cm 3 (IQR 20-40) and median minimal dose to 90% of the clinical target volume (D 90% ) 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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: In the metastatic or recurrent cervical cancer, systemic chemotherapy constitutes the main treatment. Though there is an increasing use of high dose external radiation and brachytherapy in the metastatic setting, no consensus exists., Methods: A 17-item survey was designed with additional case-based questions to explore present management of oligo-metastatic and oligo-recurrent cervix cancer within EMBRACE research group participating sites. The questions were designed to elicit prevailing practices in the management of de-novo oligo-metastasis and oligo-recurrent setting after completing the primary treatment of cervix cancer. The survey was sent electronically with two rounds of email reminders to respond over a 2-week survey period. The online survey was designed such that it was mandatory to complete all questions. The responses were recorded and results were summarized as proportions and summary statistics were generated., Results: Twenty-two centers responded to this survey. A majority (90%) of respondents reported a low incidence of de-novo oligo-metastatic cervical cancer in their practice (<5%), with a higher proportion of patients with oligo-recurrence after completing primary treatment (5-10%). All responding sites preferred to treat pelvic disease in the de-novo oligo-metastatic setting albeit with different fractionation regimens. While 68.2% of respondents recommended chemo-radiation and brachytherapy, 31.8% considered additional systemic therapy. Overall 77.3% centers recommended the use of stereotactic ablative radiation therapy to oligo-metastasis. For out-of-field nodal recurrences, 63.7% of respondents considered treating with curative intent, while 59% preferred treating in-field recurrence with palliative intent. A vast majority of the participating centers (90%) have stereotactic radiation therapy capacity and would consider a clinical trial addressing oligo-metastatic and oligo-recurrent cervical cancer., Conclusion: Although contemporary practice is variable, a substantial proportion of EMBRACE centers consider high dose radiation in de-novo metastatic and oligo-recurrence settings. However, there is clear need for a joint clinical protocol and prospective studies to address the role of high dose radiation within oligo-recurrent and oligo-metastatic scenarios., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: This report describes the persistence of late substantial treatment-related patient-reported symptoms (LAPERS) in the multi-institutional EMBRACE study on magnetic resonance image guided adaptive brachytherapy in locally advanced cervical cancer (LACC)., Methods and Materials: Patient-reported symptoms (European Organization for Research and Treatment of Cancer [EORTC]-C30/CX24) and physician-assessed morbidity (Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) were assessed at baseline and regular timepoints during follow-up. Patients with sufficient EORTC follow-up (baseline and ≥3 late follow-up visits) were analyzed. LAPERS events were defined as the presence of substantial EORTC symptoms (quite a bit/very much) for at least half of the assessments (persistence) and progression beyond baseline condition (treatment-related). For each EORTC symptom, the ratio between LAPERS rates and crude incidence rates of substantial symptoms was calculated to represent the proportion of symptomatic patients with persisting symptoms. For 9 symptoms with a corresponding EORTC/CTCAE assessment, the overlap of LAPERS and severe morbidity events (grades 3-5) was evaluated., Results: Of 1047 patients with EORTC available, 741 had sufficient follow-up for the LAPERS analyses. The median follow-up was 59 months (interquartile range, 42-70 months). Across all symptoms, the proportion of patients with LAPERS events (LAPERS rates) was in median 4.6% (range, 0.0% vaginal bleeding to 20.4% tiredness). Urinary frequency, neuropathy, fatigue, insomnia, and menopausal symptoms revealed LAPERS rates of >10%. Vomiting, blood in stool, urinary pain/burning, and abnormal vaginal bleeding displayed LAPERS rates of <1%. A median of 19% of symptomatic patients (interquartile range, 8.0%-28.5%) showed persistent long-term symptoms (LAPERS events). In symptoms with a corresponding EORTC/CTCAE assessment, 12% of LAPERS events were accompanied by a severe CTCAE event., Conclusions: Within this large cohort of survivors of LACC, a subgroup of patients with persistent symptoms (LAPERS events) was identified. For symptoms with a corresponding EORTC/CTCAE assessment, the vast majority of LAPERS events occurred in patients without corresponding severe physician-assessed morbidity. These findings emphasize the importance of distinguishing between transient and persisting symptoms in the aftercare of LACC survivors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Interstitial brachytherapy (ISBT) can be effective for vaginal tumors due to its ability to deliver conformal treatment with 3D planning. As there is no consensus for 3D vaginal brachytherapy (BT) contouring, the goals of this study are to evaluate the variability in practices and contouring, and to develop consensus concepts on target definitions., Methods: A survey/contouring study was conducted with 16 radiation oncologists from 10 Canadian academic centers. The study included three vaginal ISBT cases. Participants were provided staging, prebrachytherapy (pre-BT), and BT MRIs. Participants responded to a questionnaire and contoured on the provided images. Agreement between contours was analyzed. A meeting was held to develop consensus definitions of targets., Results: Median ISBT experience was 3.5 years. All 16 participants regularly contour with MRI, whereas three also plan on MRI. For the three cases, there was variation into how CTV HR and CTV IR was defined. Kappa statistics showed higher agreement with bulky tumors (mean 0.59) as compared with small residual tumors (mean 0.29). For all cases, kappa was highest in pre-BT GTV res as compared with BT GTV res (mean 0.58, 0.46). Consensus concepts to define targets were developed., Conclusions: Variations exist in how ISBT targets are defined for vaginal tumors. Highest contouring variability was seen with small residual at BT. Contouring is more consistent on pre-BT MRI as compared with BT MRI suggesting a needle distortion effect. Consensus CTV HR and CTV IR definitions have been developed and further work is warranted to establish international standards., (Copyright © 2019 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the pattern of manifestation of fatigue, insomnia and hot flashes within the prospective, observational, multi-center EMBRACE study., Methods: Morbidity was prospectively assessed according to CTCAE v.3 and patient-reported outcome with EORTC QLQ-C30/CX24 at baseline and regular follow-up. Analyses of crude incidence, prevalence rates and actuarial estimates were performed., Results: A total of 1176 patients were analyzed with a median follow-up of 27 months. At baseline, CTCAE G1/G2 prevalence rates for fatigue were 29%/6.2%, for insomnia 18%/3.1% and for hot flashes 7.9%/1.6% with respective 3-year prevalence rates of 29%/6.8%, 17%/4.4% and 19%/5.9%. Similar patterns of manifestation were seen in patient-reported EORTC outcomes. The 3-year actuarial estimates for G ≥ 3 CTCAE fatigue, insomnia and hot flashes were 5.5%, 4.7% and 1.9%. Younger age was associated with significantly higher risk for fatigue, insomnia and hot flashes., Conclusion: Fatigue, insomnia and hot flashes occurred mainly in the mild to moderate range. Fatigue and insomnia were already present before treatment and showed minor fluctuations or recovery during follow-up, whereas hot flashes showed a considerable increase after treatment. More research is needed to evaluate contributing risk factors in order to define intervention strategies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: To explore maximum high-risk clinical target volume (HR-CTV) doses that can be practically achieved when organs at risk (OARs; bladder, rectum, and sigmoid) doses are allowed to equal current recommended thresholds in MRI-based intracavitary brachytherapy (BT) planning for cervical cancer., Methods and Materials: Planning MRI sets were retrieved for 21 patients who received pulsed-dose-rate BT boost. Plans were generated using manual optimization (MO) by adjusting dwell positions and times to obtain the prescribed HR-CTV isodose that includes 90% of target (D90) coverage of 35 Gy while limiting OAR doses to below recommended tolerances (prescribed dose target [TGT] plans). Additional planning was performed with automatic volume optimization (VO) to evaluate target coverage relative to the MO plans. The MO and VO approaches were then applied with the objective of obtaining the highest possible HR-CTV coverage when OAR doses were allowed to equal threshold tolerance values (maximized [MAX] plans). A two-tailed paired t test was performed to determine the statistical significance of the results; significance level set at p < 0.013., Results: MO and VO planning techniques could conform HR-CTV D90 to the prescribed dose quite similarly for TGT plans. Using the MAX approach, the HR-CTV D90 could be increased by 30% and 37% for MO and VO, respectively, without exceeding OAR thresholds. Sigmoid and often rectum were the dose-limiting structures during MAX planning., Conclusions: Simple differences in the approach to volumetric MRI-based cervix BT treatment planning can impact HR-CTV D90. Consequently, dose escalation for MRI-guided cervix BT appears feasible in this manner should clinical circumstances warrant., (Copyright © 2014 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)