Radiotherapy in localized prostate cancer: a multicenter analysis evaluating tumor control and late toxicity after brachytherapy and external beam radiotherapy in 1293 patients.

BACKGROUND AND PURPOSE: Comparing oncological outcomes and toxicity after primary treatment of localized prostate cancer using HDR- or LDR-mono-brachytherapy (BT), or conventionally (CF) or moderately hypofractionated (HF) external beam radiotherapy. MATERIALS AND METHODS: Retrospectively, patients with low- (LR) or favorable intermediate-risk (IR) prostate cancer treated between 03/2000 and 09/2022 in two centers were included. Treatment was performed using either CF with total doses between 74 and 78 Gy, HF with 2.4-2.6 Gy per fraction in 30 fractions, or LDR- or HDR-BT. Biochemical control (BC) according to the Phoenix criteria, and late gastrointestinal (GI), and genitourinary (GU) toxicity according to RTOG/EORTC criteria were assessed. RESULTS: We identified 1293 patients, 697 with LR and 596 with IR prostate cancer. Of these, 470, 182, 480, and 161 were treated with CF, HF, LDR-BT, and HDR-BT, respectively. For BC, we did not find a significant difference between treatments in LR and IR (p = 0.31 and 0.72). The 5­year BC for LR was between 93 and 95% for all treatment types. For IR, BC was between 88% in the CF and 94% in the HF group. For CF and HF, maximum GI and GU toxicity grade ≥ 2 was between 22 and 27%. For LDR-BT, we observed 67% grade ≥ 2 GU toxicity. Maximum GI grade ≥ 2 toxicity was 9%. For HDR-BT, we observed 1% GI grade ≥ 2 toxicity and 19% GU grade ≥ 2 toxicity. CONCLUSION: All types of therapy were effective and well received. HDR-BT caused the least late toxicities, especially GI.

Biochemical control in intermediate- and high-risk prostate cancer after EBRT with and without brachytherapy boost.

PURPOSE: External beam radiotherapy (EBRT) with or without brachytherapy boost (BTB) has not been compared in prospective studies using guideline-recommended radiation dose and recommended androgen-deprivation therapy (ADT). In this multicenter retrospective analysis, we compared modern-day EBRT with BTB in terms of biochemical control (BC) for intermediate-risk (IR) and high-risk (HR) prostate cancer. METHODS: Patients were treated for primary IR or HR prostate cancer during 1999-2019 at three high-volume centers. Inclusion criteria were prescribed ≥ 76 Gy EQD2 (α/ß = 1.5 Gy) for IR and ≥ 78 Gy EQD2 (α/ß = 1.5 Gy) for HR as EBRT alone or with BTB. All HR patients received ADT and pelvic irradiation, which were optional in IR cases. BC between therapies was compared in survival analyses. RESULTS: Of 2769 initial patients, 1176 met inclusion criteria: 468 HR (260 EBRT, 208 BTB) and 708 IR (539 EBRT, 169 BTB). Median follow-up was 49 and 51 months for HR and IR, respectively. BTB patients with ≥ 113 Gy EQD2Gy experienced a stable, good BC outcome compared with BTB at lower doses. Patients treated with ≥ 113 Gy EQD2Gy also experienced significantly improved BC compared with EBRT (10-year BC failure rates after ≥ 113 Gy BTB and EBRT: respectively 20.4 and 41.8% for HR and 7.5 and 20.8% for IR). CONCLUSIONS: In patients with IR and HR prostate cancer, BTB with ≥ 113 Gy EQD2Gy offered a BC advantage compared with dose-escalated EBRT and lower BTB doses.

Are we making progress in curing advanced cervical cancer-again?

Major improvements in radiotherapy over the past two decades in the definitive treatment of locally advanced cervical cancer have significantly improved loco-regional control and survival, whereas little progress has been made with chemotherapy since the implementation of concomitant cisplatin 25 years ago. However, the randomized study INTERLACE (A phase III multicenter trial of weekly induction chemotherapy followed by standard chemoradiation versus standard chemoradiation alone in patients with locally advanced cervical cancer) of neoadjuvant chemotherapy presented recently, has shown significant improvement in survival with the use of six cycles of weekly carboplatin and paclitaxel. Although INTERLACE is yet to be published, neoadjuvant chemotherapy is already being advocated as the new standard, and studies are being designed with neoadjuvant chemotherapy followed by chemoradiation and brachytherapy as the standard arm. It is noteworthy that INTERLACE was initiated before the improvements in radiotherapy mentioned above were broadly implemented. The survival rate in the standard arm of INTERLACE was therefore inferior to the results obtained with the latest state-of-the-art external beam radiotherapy and image guided adaptive brachytherapy (EMBRACE, Magnetic Resonance Imaging (MRI)-Guided Brachytherapy in Locally Advanced Cervical Cancer). Moreover, patient selection impedes the comparison of INTERLACE with other studies as the patients included in INTERLACE were younger, had better performance status, and had less advanced disease than in other studies. Notably patients with involved para-aortic nodes were excluded. In this review, we discuss neoadjuvant chemotherapy in the frame of the EMBRACE studies and show how the impact of modern radiotherapy and patient selection affects the interpretation of the results of INTERLACE. This has led us to conclude that neoadjuvant chemotherapy is not needed for the majority of patients with cervical cancer treated with definitive modern radiotherapy, and may cause harm. However, it is possible that short course neoadjuvant chemotherapy may benefit a minor subgroup of patients who need to be identified. Comprehensive understanding, including cost utility analyses, are needed to draw conclusions regarding the potential benefit of neoadjuvant chemotherapy in low and middle income countries with limited access to modern radiotherapy.

MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.

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.

Comparison of EBRT and I-125 seed brachytherapy concerning outcome in intermediate-risk prostate cancer.

PURPOSE: This study's objective was the comparison of external beam radiotherapy (EBRT) and I­125 seed brachytherapy regarding clinical outcome and development of side effects. PATIENTS AND METHODS: In all, 462 localized intermediate-risk prostate cancer patients treated between 2000 and 2019 at our department using either I­125 seed brachytherapy or EBRT with a dose of 74 or 78 Gy were included: 297 patients were treated with EBRT and 165 with seeds. Biochemical no evidence of disease (bNED) rates according to Phoenix definition as well as late gastrointestinal and urogenital side effects (EORTC/RTOG) were assessed. RESULTS: Patients were followed up yearly with a median follow-up of 54 (3-192) months. Observed bNED rates for 74 Gy, 78 Gy and seeds were 87, 92, and 88% after 5 years and 71, 85, and 76% after 9 years, respectively. No significant differences were found comparing seeds with 74 Gy (p = 0.81) and 78 Gy (p = 0.19), as well as between 74 and 78 Gy (p = 0.32). Concerning gastrointestinal side effects, EBRT showed significantly higher rates of RTOG grade ≥ 2 toxicity compared to seeds, but at no point of the follow-up more than 10% of all patients. However, genitourinary side effects were significantly more prevalent in patients treated with seeds, with 33% RTOG grade ≥ 2 toxicity 12 months after treatment. Nevertheless, both types of side effects decreased over time. CONCLUSION: Favorable intermediate-risk prostate cancer patients can be treated either by external beam radiotherapy (74/78 Gy) or permanent interstitial seed brachytherapy.

Hybrid TRUS/CT with optical tracking for target delineation in image-guided adaptive brachytherapy for cervical cancer.

OBJECTIVE: To prospectively compare the interobserver variability of combined transrectal ultrasound (TRUS)/computed tomography (CT)- vs. CT only- vs. magnetic resonance imaging (MRI) only-based contouring of the high-risk clinical target volume (CTVHR) in image-guided adaptive brachytherapy (IGABT) for locally advanced cervical cancer (LACC). METHODS: Five patients with LACC (FIGO stages IIb-IVa) treated with radiochemotherapy and IGABT were included. CT, TRUS, and T2-weighted MRI images were performed after brachytherapy applicator insertion. 3D-TRUS image acquisition was performed with a customized ultrasound stepper device and software. Automatic applicator reconstruction using optical tracking was performed in the TRUS dataset and TRUS and CT images were fused with rigid image registration with the applicator as reference structure. The CTVHR (based on the GEC-ESTRO recommendations) was contoured by five investigators on the three modalities (CTVHR_CT, CTVHR_TRUS-CT, and CTVHR_MRI). A consensus reference CTVHR_MRI (MRIref) was defined for each patient. Descriptive statistics and overlap measures were calculated using RTslicer (SlicerRT Community and Percutaneous Surgery Laboratory, Queen's University, Canada), comparing contours of every observer with one another and with the MRIref. RESULTS: The interobserver coefficient of variation was 0.18 ± 0.05 for CT, 0.10 ± 0.04 for TRUS-CT, and 0.07 ± 0.03 for MRI. Interobserver concordance in relation to the MRIref expressed by the generalized conformity index was 0.75 ± 0.04 for MRI, 0.51 ± 0.10 for TRUS-CT, and 0.48 ± 0.06 for CT. The mean CTVHR_CT volume of all observers was 71% larger than the MRIref volume, whereas the mean CTVHR_TRUS-CT volume was 15% larger. CONCLUSION: Hybrid TRUS-CT as an imaging modality for contouring the CTVHR in IGABT for LACC is feasible and reproducible among multiple observers. TRUS-CT substantially reduces overestimation of the CTVHR volume of CT alone while maintaining similar interobserver variability.

Impact of uncertainties related to noise indicator determination on observed exposure-effect relationship.

CONTEXT: Noise indicators are the basis to describe noise exposure-effect relationships. The assessment of these noise indicators in field studies includes various uncertainties, so that the true values differ from the determined values used for establishing curve fits. If the relationship between a noise indicator and its effect is nonlinear, uncertainties of the noise indicator modify the observed exposure-effect relationships. MATERIALS AND METHODS: The determination of an exposure-relationship curve fit within a field study was simulated based on the assumption of a given true exposure-relationship without uncertainties and normal distributed uncertainties for the observed noise indicator used for the statistics. RESULTS: In case of an upward curvature of the exposure-effect relationship, the uncertainty for the noise indicator value leads to an asymmetric effect for the curve fit. Uncertainties of the same amount of over- or underestimation will not result in an identical over- or underestimation of the observed effect. A simulation of this effect shows an increased curvature of the observed curve fit, with overestimated exposure-effect relationships. CONCLUSION: Although linear exposure-effect curves are not observed with a systematic shift, quadratic, cubic, and exponential curve forms include a systematic uncertainty in the presented exposure-response curve. If such curves are used to define threshold levels to limit harmful effects of noise, no further uncertainty margins are needed for those situations where the calculated noise indicator uncertainties are equal or lower than those present in the underlying field study.

Increased genitourinary fistula rate after bevacizumab in recurrent cervical cancer patients initially treated with definitive radiochemotherapy and image-guided adaptive brachytherapy.

BACKGROUND AND PURPOSE: Patients with recurrent cervical cancer (RecCC) who received definitive radiochemotherapy including image-guided adaptive brachytherapy (IGABT) as primary treatment are currently treated in our institution with palliative intent by chemotherapy (CHT) combined with bevacizumab (BEV). We aim to evaluate the risk of gastrointestinal (GI)/genitourinary (GU) fistula formation in these patients. MATERIALS AND METHODS: Data of 35 consecutive patients with RecCC treated initially with radiochemotherapy and IGABT were collected. Known and presumed risk factors associated with fistula formation were evaluated. Fistula rate was compared between patients receiving CHT or CHT+BEV. RESULTS: Of the 35 patients, 25 received CHT and 10 patients received CHT+BEV. Clinical characteristics were comparable. Fistulae were reported in 6 patients: two fistulae (8%) in the CHT group, four (40%) in the CHT+BEV group. GU fistula occurred in the CHT+BEV group only (3/4). Of these 6 patients with fistulae, 5 (83%) had undergone previous invasive procedures after the diagnosis of RecCC and 1 patient had undergone pelvic re-irradiation; 3/6 patients had developed a local recurrence. No other risk factors for fistula formation were identified. CONCLUSION: In patients with RecCC after definitive radiochemotherapy including IGABT, the addition of BEV to CHT may increase the risk for GU fistula formation, particularly after invasive pelvic procedures. Future clinical studies are required to identify predictors for fistula formation to subsequently improve patient selection for the addition of BEV in the RecCC setting.

A comparison of organs at risk doses in GYN intracavitary brachytherapy for different tandem lengths and bladder volumes.

The purpose of this study was to investigate the concurrent effects of tandem length and bladder volume on dose to pelvic organs at risk (OARs) in HDR intracavitary brachytherapy treatment of cervical cancer. Twenty patients with locally advanced cervical cancer were selected for brachytherapy using Rotterdam applicators. The patients were CT scanned twice with empty and full bladder. Two treatment plans were prepared on each of the image sets. Patients were categorized into two groups; those treated with a tandem length of 4 cm or smaller (T ≤ 4 cm) and those with tandem length larger than 4 cm (T > 4 cm). Only one tandem tip angle of 30° was studied. Dose-volume histograms (DVHs) of OARs were calculated and compared. Bladder dose was significantly affected by both bladder volume and tandem physical length for T ≤ 4 cm. This was reflected on the values obtained for D2cm³, D1cm³, and D0.1cm³ for both empty and full bladder cases. When T > 4 cm, no correlation could be established between variations in bladder dose and blad-der volume. Rectum dose was generally lower when the bladder was empty and T > 4 cm. Dose to sigmoid was increased when T > 4 cm; this increase was larger when the bladder was full. Our results suggest that, for tandems longer than 4 cm, keeping the bladder empty may reduce the dose to rectum and sigmoid. This is contrary to cases where a shorter than 4 cm tandem is used in which a full bladder (about 50-120 cm³) tends to result in a lower dose to rectum and sigmoid. Attention should be given to doses to sigmoid with long tandem lengths, as a larger tandem generally results in a larger dose to sigmoid.

Evaluation of planning aims and dose prescription in image-guided adaptive brachytherapy and radiochemotherapy for cervical cancer: Vienna clinical experience in 225 patients from 1998 to 2008.

BACKGROUND: To assess planning aims (PAs) and dose prescription in image-guided adaptive brachytherapy (IGABT) of cervical cancer and investigate potential impact on clinical outcome. MATERIAL AND METHODS: Our study population consists of 225 consecutive cervical cancer patients (FIGO stages IB-IVA) treated between 1998 and 2008 at the Medical University of Vienna by external beam radiotherapy (EBRT) ± chemotherapy and IGABT. For this retrospective study, patients were stratified into two treatment groups: PA+ group, all dose constraints fulfilled for prescription; PA-, one or more dose constraints not fulfilled for prescription. The following dose constraints (EBRT+ IGABT) were applied: clinical target volume (CTV)HR D90 ≥ 85 Gy, D2cm3 Rectum < 70 Gy, D2cm3 Bladder < 90 Gy. Differences in patient, tumor and treatment characteristics and clinical outcome (event: local failure or grade 3 + 4 toxicity) were compared between Group 1 and 2. Further, the impact of learning period (1998-2000) and protocol period (2001-2008) on the fulfillment of PAs for dose prescription and clinical outcome was analyzed. RESULTS: In the PA+ group there were 77 (34%) and in the PA- group 148 (66%) patients. In the PA- group, CTVHR D90 < 85 Gy was prescribed in 82 patients, D2cm3 bladder > 90 Gy was prescribed in 80 patients and D2cm3 Rectum > 70 Gy in 60 patients. Fulfillment of the PA for dose prescription improved from 4% in the learning period to 48% in the protocol period. The five-year event-free interval was 64% in the learning period and 84% in the protocol period (p = 0.008). CONCLUSION: Fulfillment of all PAs for dose prescription is challenging - especially in patients with more advanced tumors. However, with growing experience fulfillment of PA for dose prescription can be significantly increased (learning and protocol period). Such increase in fulfilling PA for dose prescription is followed by a significant improvement in clinical outcome.

AAPM Task Group Report 267: A joint AAPM GEC-ESTRO report on biophysical models and tools for the planning and evaluation of brachytherapy.

Brachytherapy utilizes a multitude of radioactive sources and treatment techniques that often exhibit widely different spatial and temporal dose delivery patterns. Biophysical models, capable of modeling the key interacting effects of dose delivery patterns with the underlying cellular processes of the irradiated tissues, can be a potentially useful tool for elucidating the radiobiological effects of complex brachytherapy dose delivery patterns and for comparing their relative clinical effectiveness. While the biophysical models have been used largely in research settings by experts, it has also been used increasingly by clinical medical physicists over the last two decades. A good understanding of the potentials and limitations of the biophysical models and their intended use is critically important in the widespread use of these models. To facilitate meaningful and consistent use of biophysical models in brachytherapy, Task Group 267 (TG-267) was formed jointly with the American Association of Physics in Medicine (AAPM) and The Groupe Européen de Curiethérapie and the European Society for Radiotherapy & Oncology (GEC-ESTRO) to review the existing biophysical models, model parameters, and their use in selected brachytherapy modalities and to develop practice guidelines for clinical medical physicists regarding the selection, use, and interpretation of biophysical models. The report provides an overview of the clinical background and the rationale for the development of biophysical models in radiation oncology and, particularly, in brachytherapy; a summary of the results of literature review of the existing biophysical models that have been used in brachytherapy; a focused discussion of the applications of relevant biophysical models for five selected brachytherapy modalities; and the task group recommendations on the use, reporting, and implementation of biophysical models for brachytherapy treatment planning and evaluation. The report concludes with discussions on the challenges and opportunities in using biophysical models for brachytherapy and with an outlook for future developments.

High-risk clinical target volume delineation in CT-guided cervical cancer brachytherapy: impact of information from FIGO stage with or without systematic inclusion of 3D documentation of clinical gynecological examination.

PURPOSE: The aim of the study was to improve computed tomography (CT)-based high-risk clinical target volume (HR CTV) delineation protocols for cervix cancer patients, in settings without any access to magnetic resonance imaging (MRI) at the time of brachytherapy. Therefore the value of a systematic integration of comprehensive three-dimensional (3D) documentation of repetitive gynecological examination for CT-based HR CTV delineation protocols, in addition to information from FIGO staging, was investigated. In addition to a comparison between reference MRI contours and two different CT-based contouring methods (using complementary information from FIGO staging with or without additional 3D clinical drawings), the use of standardized uterine heights was also investigated. MATERIAL AND METHODS: Thirty-five cervix cancer patients with CT- and MR-images and 3D clinical drawings at time of diagnosis and brachytherapy were included. HR CTV(stage) was based on CT information and FIGO stage. HR CTV(stage + 3Dclin) was contoured on CT using FIGO stage and 3D clinical drawing. Standardized HR CTV heights were: 1/1, 2/3 and 1/2 of uterine height. MRI-based HR CTV was delineated independently. Resulting widths, thicknesses, heights, and volumes of HR CTV(stage), HR CTV(stage + 3Dclin) and MRI-based HR CTV contours were compared. RESULTS: The overall normalized volume ratios (mean ± SD of CT/MRI(ref) volume) of HR CTV(stage) and HR stage + 3Dclin were 2.6 (± 0.6) and 2.1 (± 0.4) for 1/1 and 2.3 (± 0.5) and 1.8 (± 0.4), for 2/3, and 1.9 (± 0.5) and 1.5 (± 0.3), for 1/2 of uterine height. The mean normalized widths were 1.5 ± 0.2 and 1.2 ± 0.2 for HR CTV(stage) and HR CTV(stage + 3Dclin), respectively (p < 0.05). The mean normalized heights for HR CTV(stage) and HR CTV(stage + 3Dclin) were both 1.7 ± 0.4 for 1/1 (p < 0.05.), 1.3 ± 0.3 for 2/3 (p < 0.05) and 1.1 ± 0.3 for 1/2 of uterine height. CONCLUSION: CT-based HR CTV contouring based on FIGO stage alone leads to large overestimation of width and volume. Target delineation accuracy can systematically improve through incorporation of additional information from comprehensive 3D documentation of repetitive gynecological examination in the contouring protocol, and thus help to improve the accuracy of dose optimization in settings with limited access to imaging facilities at the time of brachytherapy. If CT information is only available, minimum 2/3 of uterine height may be a good surrogate for the height of HR CTV.

Magnetic resonance imaging for assessment of parametrial tumour spread and regression patterns in adaptive cervix cancer radiotherapy.

PURPOSE: To investigate the impact of magnetic resonance imaging (MRI)-morphologic differences in parametrial infiltration on tumour response during primary radiochemotherapy in cervical cancer. MATERIAL AND METHODS: Eighty-five consecutive cervical cancer patients with FIGO stages IIB (n = 59) and IIIB (n = 26), treated by external beam radiotherapy (± chemotherapy) and image-guided adaptive brachytherapy, underwent T2-weighted MRI at the time of diagnosis and at the time of brachytherapy. MRI patterns of parametrial tumour infiltration at the time of diagnosis were assessed with regard to predominant morphology and maximum extent of parametrial tumour infiltration and were stratified into five tumour groups (TG): 1) expansive with spiculae; 2) expansive with spiculae and infiltrating parts; 3) infiltrative into the inner third of the parametrial space (PM); 4) infiltrative into the middle third of the PM; and 5) infiltrative into the outer third of the PM. MRI at the time of brachytherapy was used for identifying presence (residual vs. no residual disease) and signal intensity (high vs. intermediate) of residual disease within the PM. Left and right PM of each patient were evaluated separately at both time points. The impact of the TG on tumour remission status within the PM was analysed using χ(2)-test and logistic regression analysis. RESULTS: In total, 170 PM were analysed. The TG 1, 2, 3, 4, 5 were present in 12%, 11%, 35%, 25% and 12% of the cases, respectively. Five percent of the PM were tumour-free. Residual tumour in the PM was identified in 19%, 68%, 88%, 90% and 85% of the PM for the TG 1, 2, 3, 4, and 5, respectively. The TG 3-5 had significantly higher rates of residual tumour in the PM in comparison to TG 1 + 2 (88% vs. 43%, p < 0.01). CONCLUSION: MRI-morphologic features of PM infiltration appear to allow for prediction of tumour response during external beam radiotherapy and chemotherapy. A predominantly infiltrative tumour spread at the time of diagnosis resulted in a significantly higher rate of residual tumour in the PM at the time of brachytherapy in comparison to a predominantly expansive tumour spread.

Implementation of online workshops on image-guided adaptive brachytherapy (interventional radiotherapy) in locally advanced cervical cancer: Experience of BrachyAcademy.

PURPOSE: To provide educational support to brachytherapy users during the COVID-19 pandemic, online workshops were developed and implemented by BrachyAcademy, non-profit peer-to-peer educational initiative in Elekta. METHODS AND MATERIALS: In 2021-2022 two online workshops were organized. Participating teams had to send a clinical case of locally advanced cervical cancer (LACC) including brachytherapy Digital Imaging and Communications in Medicine (DICOM) files and questions to the faculty. During the workshop, feedback was given to each clinical case by five faculty members (two Radiation Oncologists, one Radiologist, two Medical Physicists). Participants competed a post-workshop questionnaire which included combination of qualitative and quantitative questions via yes/no responses, Likert scale, and 1 to 10 scale. RESULTS: Twenty-one teams from eight countries (Europe, Asia, Latin America) participated in two online workshops. The total number of participants was 49. The clinical cases represented LACC with The International Federation of Gynecology and Obstetrics (FIGO) stages from IB3 to IVA. During both, Workshop1 (W1) and Workshop 2 (W2) the following areas of improvement were identified: familiarity with the GEC ESTRO and The International Commission on Radiation Units & Measurements, Report 89 (ICRU 89) recommendations for contouring and planning based on clinical drawings and MRI sequencing choice; appropriate applicator selection; experience with interstitial needles; appropriate applicator reconstruction; dose optimization. The participants rated both workshops with overall scores 8,3 for W1, and 8,5 for W2. In 82% participants the training course fully met expectations for W1, and in 76% in W2. CONCLUSIONS: We successfully implemented the online workshops on image-guided adaptive brachytherapy (IGABT) in LACC. Main performance issues and areas for improvement were identified based on multidisciplinary discussion of participant's clinical cases through all steps of the brachytherapy procedure. We encourage teams to consider online workshops in addition to hands-on training.

Brachytherapy boost in anal canal cancer - A GEC ESTRO PDR task force meta-analysis.

Purpose: A meta-analysis is presented comparing clinical outcomes and toxicities between high dose rate (HDR) and pulsed dose rate (PDR) brachytherapy (BT) for anal cancer. Methods and material: Retrospective or prospective clinical trials were identified on electronical databases. Data were collected per Preferred Reporting Items for Systematic Reviews and meta-Analyses guidelines. Pooled effect size for HDR and PDR BT were compared using subgroup analyses. Results: Nine retrospective studies with a total of 481 patients treated were included of which 219 with HDR and 262 with PDR. Significant differences were observed between the two groups for baseline characteristics and treatment. The cumulative proportion of stage T3-T4 was lower in the HDR group, 0.15 [95 % confidence interval (CI) 0.07-0.29] vs 0.27 [95 %CI 0.09-0.57] in the LDR group, p < 0.001. Lower BT doses (in equivalent 2-Gy fraction dose) were given for patients in the HDR group, 11.9 Gy [95 %CI 8.2-15.5] vs 19.5 Gy [95 %CI 15.0-24.0] in the PDR group, p < 0.001. No significant differences were found for clinical outcomes or toxicities. The pooled effect size of the overall survival at 5 years for HDR and PDR was respectively 0.82 [95 %CI 0.70-0.94] and 0.82 [95 %CI 0.73-0.91], p > 0.99. The 5 years local control was 0.86 [95 % confidence interval (CI) 0.81-0.91] and 0.83 [95 %CI 0.77-0.89], p = 0.62. Cumulative toxicity-related colostomy proportion was 0.04 [95 %CI 0.02-0.09] and 0.03 [95 %CI 0.02-0.07], p = 0.85. Conclusion: Both modalities provided a good profile of tolerance and are effective organ conservative strategies for patients with anal canal cancer. In parallel with ongoing developments to better determine the optimal fractionation and dose for HDR-BT treatments, especially in large tumors, PDR BT still has a crucial role for dose escalation strategy in advanced cases.

EviGUIDE - a tool for evidence-based decision making in image-guided adaptive brachytherapy for cervical cancer.

PURPOSE: To develop a novel decision-support system for radiation oncology that incorporates clinical, treatment and outcome data, as well as outcome models from a large clinical trial on magnetic resonance image-guided adaptive brachytherapy (MR-IGABT) for locally advanced cervical cancer (LACC). METHODS: A system, called EviGUIDE, was developed that combines dosimetric information from the treatment planning system, patient and treatment characteristics, and established tumor control probability (TCP), and normal tissue complication probability (NTCP) models, to predict clinical outcome of radiotherapy treatment of LACC. Six Cox Proportional Hazards models based on data from 1341 patients of the EMBRACE-I study have been integrated. One TCP model for local tumor control, and five NTCP models for OAR morbidities. RESULTS: EviGUIDE incorporates TCP-NTCP graphs to help users visualize the clinical impact of different treatment plans and provides feedback on achievable doses based on a large reference population. It enables holistic assessment of the interplay between multiple clinical endpoints and tumour and treatment variables. Retrospective analysis of 45 patients treated with MR-IGABT showed that there exists a sub-cohort of patients (20%) with increased risk factors, that could greatly benefit from the quantitative and visual feedback. CONCLUSION: A novel digital concept was developed that can enhance clinical decision- making and facilitate personalized treatment. It serves as a proof of concept for a new generation of decision support systems in radiation oncology, which incorporate outcome models and high-quality reference data, and aids the dissemination of evidence-based knowledge about optimal treatment and serve as a blueprint for other sites in radiation oncology.

Tools for large-scale data analytics of an international multi-center study in radiation oncology for cervical cancer.

PURPOSE: To develop and implement a software that enables centers, treating patients with state-of-the-art radiation oncology, to compare their patient, treatment, and outcome data to a reference cohort, and to assess the quality of their treatment approach. MATERIALS AND METHODS: A comprehensive data dashboard was designed, which al- lowed holistic assessment of institutional treatment approaches. The software was tested in the ongoing EMBRACE-II study for locally advanced cervical cancer. The tool created individualized dashboards and automatic analysis scripts, verified pro- tocol compliance and checked data for inconsistencies. Identified quality assurance (QA) events were analysed. A survey among users was conducted to assess usability. RESULTS: The survey indicated favourable feedback to the prototype and highlighted its value for internal monitoring. Overall, 2302 QA events were identified (0.4% of all collected data). 54% were due to missing or incomplete data, and 46% originated from other causes. At least one QA event was found in 519/1001 (52%) of patients. QA events related to primary study endpoints were found in 16% of patients. Sta- tistical methods demonstrated good performance in detecting anomalies, with precisions ranging from 71% to 100%. Most frequent QA event categories were Treatment Technique (27%), Patient Characteristics (22%), Dose Reporting (17%), Outcome 156 (15%), Outliers (12%), and RT Structures (8%). CONCLUSION: A software tool was developed and tested within a clinical trial in radia- tion oncology. It enabled the quantitative and qualitative comparison of institutional patient and treatment parameters with a large multi-center reference cohort. We demonstrated the value of using statistical methods to automatically detect implau- sible data points and highlighted common pitfalls and uncertainties in radiotherapy for cervical cancer.

Overall Severe Morbidity After Chemo-Radiation Therapy and Magnetic Resonance Imaging-Guided Adaptive Brachytherapy in Locally Advanced Cervical Cancer: Results From the EMBRACE-I Study.

PURPOSE: To evaluate overall severe late morbidity (grade ≥3) in patients with locally advanced cervical cancer treated with chemo-radiation therapy and magnetic resonance image guided adaptive brachytherapy within the prospective EMBRACE-I study, and to compare the results with published literature after standard radiograph based brachytherapy (BT). METHODS AND MATERIALS: From 2008 to 2015 the EMBRACE-I study enrolled 1416 patients. Morbidity was assessed (Common Terminology Criteria for Adverse Events version 3.0) every 3 months the 1st year, every 6 months the second and third year, and yearly thereafter and 1251 patients had available follow-up on late morbidity. Morbidity events (grade 3-5) were summarized as the maximum grade during follow-up (crude incidence rates) and actuarial estimates at 3 and 5 years. To compare with the published literature on standard radiograph based BT, Common Terminology Criteria for Adverse Events scores from the EMBRACE-I study were retrospectively converted into a corresponding score in the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer system. RESULTS: In total, 534 severe events occurred in 270 patients; 429 events were grade 3 and 105 were grade 4 events. Actuarial estimates for grade ≥3 gastrointestinal (GI), genitourinary (GU), vaginal and fistula events at 5 years were 8.5% (95% confidence interval [CI], 6.9%-10.6%), 6.8% (95% CI, 5.4%-8.6%), 5.7% (95% CI, 4.3%-7.6%), and 3.2% (95% CI, 2.2%-4.5%), respectively. The 5-year actuarial estimate for organ-related events (GI, GU, vaginal, or fistula) was 18.4% (95% CI, 16.0%-21.2%). The 5-year actuarial estimate when aggregating all G≥3 endpoints (GI, GU, vaginal, fistulas, and non-GI/GU/vaginal) was 26.6% (95% CI, 23.8%-29.6%). Thirteen patients had a treatment-related death, 8 of which were associated with GI morbidity. CONCLUSIONS: This report assesses severe morbidity from the largest prospective study on chemo-radiation therapy and image guided adaptive brachytherapy for locally advanced cervical cancer to date. Severe late morbidity was limited per endpoint and organ category, but considerable when aggregated across organs and all endpoints. The late morbidity results in the EMBRACE-I study compare favorably with published literature on standard radiograph based BT for GI morbidity, vaginal morbidity, and fistulas.

Risk Factors for Local Failure Following Chemoradiation and Magnetic Resonance Image-Guided Brachytherapy in Locally Advanced Cervical Cancer: Results From the EMBRACE-I Study.

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 (CTVHR), maximum tumor dimension, CTVHR > 45 cm3, 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 CTVHR 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.

The Effect of Land-Use Categories on Traffic Noise Annoyance.

Land-use categories are often used to define the exposure limits of national environmental noise policies. Often different guideline values for noise are applied for purely residential areas versus residential areas with mixed-use. Mixed-use includes living plus limited activities through crafts, commerce, trade, agriculture, and forestry activities. This differentiation especially when rating noise from road, railway, and air traffic might be argued by different expectations and therefore noise annoyance in those two categories while scientific evidence is missing. It should be tested on empirically derived data. Surveys from two studies in the state of Tyrol in urban and rural areas were retrospectively matched with spatial data to analyze the potential different influences on noise effects. Using non-parametric tests, the correlation between land-use category on self-reported noise sensitivity and noise annoyance was investigated. Exposure-response for the two analyzed land-use categories showed no significant impact on noise sensitivity and exposure-response relationships for the three traffic noise sources. Including only noise annoyance, there is not sufficient evidence to define different noise policies for those two land-use categories.