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Brachytherapy (BT) target dose and coverage are critical to the cure of locally advanced cervical cancer (CC). Advances in imaging, volumetric definitions, and BT planning aims/constraints have collectively been associated with improved tumor control outcomes over traditional practices. But some historic conventions remain in BT, such as applying uniform radiobiological parameters (RbP). Having previously generated a/b and T 1/2 from CC cell lines, we explored the potential impact of differing RbP against population-based outcomes in an era of MR-BT boost. All CC patients seen 1/2013 - 12/2015 in the Canadian province of Alberta (AB), and treated with radical (chemo)radiotherapy (external beam (EBRT) + BT), were identified. From health records, demographic, clinicopathologic, treatment and outcomes data were abstracted. Descriptive and Kaplan-Meier methods were supplemented by Cox-regression multivariable analysis (MVA), factoring in experimentally derived (exp) RbP for BT tumor doses (in addition to treated doses using conventional a/b and T 1/2 (10 Gy, 1.5 h)). 127 women (median age 50.5 y [23-82]) received curative (chemo)EBRT+BT in AB's 2 tertiary cancer centers (2:1), after exclusions (such as n=12 oligometastatic). Over half (73/125) were smokers. Squamous (SCC) predominated (76.4%) over adenocarcinoma-containing (ADC, 16.5%) or higher-risk (3.1%) histologies, with 3.9% incompletely characterized carcinoma. Primaries were mainly FIGO(2009) clinical stage IIB (37.8%, with the remainder IB 29.9%, IIA 10.2%, IIIA 2.4%, IIIB 15.0%, and IVA 3.9%); 61.4% were node(LN)-positive (pelvic and/or para-aortic (PA)) on imaging. Most (n=102) had weekly cisplatin (median 5 cycles [1-6]) with usual pelvic±PA EBRT (45-50.8 Gy EQD2 in 25-28 fx) and image-based intracavitary BT (67.7% PDR 1-2 fx, vs HDR 1-3 fx; 96.9% MRI; 15% hybrid interstitial). N=12 had initial hemostatic 1-2 fx (5-7.2 Gy); EBRT boost was sequential (3.6-21 Gy in 1.8-4 Gy/fx, to LN/parametria/pelvis) in n=26, simultaneous integrated in n=2. Median overall treatment time (OTT) was 48 days [38-112]. 9 of 127 had no chemotherapy. At BT, median HR-CTV volume was 29.8 cm3 [9.6-212.1], with median treated D90, 88.3 Gy EQD2 [53.4-122.1] (Point A 79.6 [56.3-146.2]). Applying a/b 5.6 Gy and T 1/2 3.4 h for SCC (4.3 Gy and 1.0 h for ADC), exp HR-CTV D90 and Point A medians were 102.0 [54.6-177.9] and 86.9 [57.7-225.8] Gy EQD2. Median follow-up was 83 months [4-115], with 5y-OS of 69.3% and pelvic LC, 79.9%. Clinical stage group (p=0.001) and OTT (p=0.008) were associated with OS (LN or chemotherapy status did not reach statistical significance). Exp target dose (Point A, p=0.029; D90, p=0.028) but not treated HR-CTV D90 or volume (trend only) also showed association. For ADC (not SCC), 5y-OS varied by exp, not treated, dose (Point A 79.5% vs 61.2%, p=0.013; D90 54.7% vs 80.3%, p=0.006). On MVA, OTT and exp Point A dose were significant predictors of OS after adjusting for age, chemo, stage, HR-CTV volume and smoking status. Pelvic LC differed, on univariate analysis, by stage (p=0.025), LN status (p=0.021), and exp D90 (p=0.022), with trends observed for OTT and HR-CTV volume but not histology, chemotherapy, BT imaging or center. 5y-LC of ADC also differed by exp Point A (93.2% vs 72.4%, p=0.062) and exp D90 (68.5% vs. 92.3%, p=0.019) doses, but not on MVA. Real-world late outcomes for a province-wide CC cohort are reflective of treatment factors, more so than disease burden. Further understanding of RbP is needed for optimum application in CC and outcomes-informed EBRT+BT dosing. [ABSTRACT FROM AUTHOR]

Even before the pandemic, clinical training opportunity for brachytherapy (BT) procedures has been decreasing. In locally advanced cervix cancer (CC), this has been linked to declining BT utilization and poorer clinical outcomes. This work describes the culmination of our early exploration into how to augment resident training in CCBT, distilling and integrating educational keys for a first-in-kind immersive, hands-on, and interaction-enabled virtual reality (VR) simulator for CCBT applicator insertion procedures. Informal needs assessment in consultation with frontline experts and novice stakeholders identified the basic competencies thought to be required to successfully execute a CCBT applicator insertion procedure according to local standards. There was early recognition that, even before a curricular intervention could be designed, a versatile training tool would be needed. After reviewing international guidelines relating to CCBT and BT training, procedure-based learning outcomes were articulated, then selected and simplified for programming a basic goal-oriented simulation (sim) in VR. A clinical vignette of a typical CC case was crafted, with specific narrative stops amenable to building knowledge, skills, and behaviors. Emphasis on the "why" and the "how" of certain BT steps was built in. Procedural milestones were generalizable to trainees with varying degrees of clinical BT experience, with some steps or 'interactions' made evaluable (go, no go) in this linear design. Gamification expanded options for cross-linking and reinforcing learning concepts. To the extent feasible, realism was incorporated into the physical representation of sim objects, such as CT-scanned surgical instruments and an intracavitary/interstitial BT applicator (Elekta, Netherlands; with permission), extracted as user-configurable additions to the 3D immersive operating room (OR) environment coded on Unreal engine v. 2.46 (Epic Games, US). A working prototype was generated for a single-player VR sim, broadly mimicking the procedural steps for actual CCBT applicator insertion. Despite an estimated runtime of 20 minutes, depending on user proficiency with CCBT and with VR technology (headset, hand controllers), the sim can start/stop at user discretion, and be shown on-screen to non-playing observers in a classroom setting. The game can also be run iteratively offline, enabling self-paced study of CCBT procedural steps in sequence, repeated execution for kinesthetic learning, and easy focus on recurring problem areas. The user starts the sim in OR, with a computer-generated patient draped and BT instrument tray at the ready. The case vignette and step-by-step instructions trigger the user to complete specific procedural tasks in the correct order; sim will not advance otherwise. Hints are given when needed. Pop-up multiple choice questions, in between BT sim interactions, are formative, drawing on basic recall, understanding, and application, to strengthen learning of core concepts in CCBT. Further contextual information is given at end of sim, to better situate procedural learnings with post-procedure processes (e.g. applicator verification and BT planning). A novel VRsim tool, inspired by educational design principles, was created as proof-of-concept for guided performance-oriented learning of CCBT procedural aspects. Broader range and complexity of simulated procedures is planned, with higher level of user interaction and realism. Prospective evaluation of face (realism) and content (usefulness) validity will inform on its potential, as part of comprehensive CCBT instructional programming. [ABSTRACT FROM AUTHOR]

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 ( D 90 ) 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 D 90 to the prescribed dose quite similarly for TGT plans. Using the MAX approach, the HR-CTV D 90 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 D 90 . Consequently, dose escalation for MRI-guided cervix BT appears feasible in this manner should clinical circumstances warrant. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [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]

• 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]

• Urinary morbidity after treatment of locally advanced cervical cancer is prevalent. • Bladder dose constraints based on a high level clinical evidence are not available. • EMBRACE I provides prospective morbidity data for analysis in a large cohort. • Individual physician and patient reported urinary endpoints were analysed in EMBRACE I. • Bladder fistula, bleeding and cystitis showed dose–effect with bladder D 2cm3. 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). 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. 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. 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. [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]

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. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [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]