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Purpose: The purpose of this study was to provide risk estimations for vaginal morbidity with regard to vaginal dilation (summarizing the use of dilators and/or sexual activity) in patients with locally advanced cervical cancer treated with definitive radiochemotherapy and image guided adaptive brachytherapy within the prospective, multi-institutional EMBRACE-I study., Methods and Materials: Physician-assessed vaginal morbidity (National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0), use of vaginal dilators, and patient-reported sexual activity (EORTC-CX24) were prospectively assessed at baseline and during regular follow-ups. Frequency analysis for vaginal dilation was performed in a subcohort of patients with ≥3 follow-ups. Regular dilation was defined if reported in ≥50% of follow-ups, and no/infrequent dilation if reported in <50%. Actuarial estimates were calculated with Kaplan-Meier method; comparisons were evaluated with the log-rank test. Univariate and multivariable Cox proportional hazard regressions were used to evaluate risk factors for vaginal stenosis G≥2., Results: The EMBRACE-I study included a total of 1416 patients (2008-2015); 882 were evaluated in the present report with a median follow-up of 60 months. Of those, 565 (64%) reported regular dilation. This was associated with a significantly lower 5-year risk of vaginal stenosis G≥2 compared with no/infrequent dilation (23% vs 37%, P ≤ .001). This univariate finding was confirmed by multivariable analysis, after adjusting for other risk factors (hazard ratio, 0.630; P = .001). Regular vaginal dilation was also associated with a significantly higher risk for vaginal dryness G≥1 (72% vs 67%, P = .028) and bleeding G≥1 (61% vs 34%, P ≤ .001)., Conclusions: Vaginal stenosis represents irreversible fibrotic changes that can cause pain during gynecologic examination and dyspareunia in locally advanced cervical cancer patients survivors. Regular vaginal dilation (defined as the use of dilators and/or sexual activity) is associated with a significantly lower risk for G≥2 vaginal stenosis, suggesting a potential improvement of vaginal patency. It is also associated with a significantly higher risk for mild G≥1 dryness and bleeding (no higher risk for G≥2), which can be clinically managed., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Purpose: BIOEMBRACE was designed to study the impact of biomarkers in addition to clinicopathological factors on disease outcomes in patients treated with chemoradiation and magnetic resonance imaging (MRI)-guided brachytherapy (BT) for locally advanced cervical cancer in the EMBRACE study., Methods and Materials: Between 2018 and 2021, 8 EMBRACE-I sites contributed tumor tissue for the immunohistochemistry of p16, PD-L1, and L1CAM. These biomarkers and clinicopathological factors (International Federation of Gynecology and Obstetrics 2009 stage, nodal status, histology, and necrosis on MRI) were analyzed to predict poor response at BT (high-risk clinical target volume [HR-CTV] ≥ 40 cc) at BT) and 5-year local control, pelvic control, and disease-free survival. Interaction between p16, PD-L1, radiation therapy dose (HR-CTV D90), and disease outcomes was investigated. Univariable and multivariable analyses were performed., Results: Two hundred sixty-four patients were included. The median HR-CTV D90 was 89 Gy (86-95). P-16 positive status, PD-L1 > 1%, and L1CAM ≥ 10% was noted in 86.6%, 20.1%, and 17.8% of patients, respectively. P16 negative status (odds ratio, 2.0; 95% CI, 1.0-5.7; P = .04) and necrosis on MRI (odds ratio, 2.1; 95% CI, 1.1-4.3; P < .02) independently predicted for HR-CTV ≥ 40 cc, as did the International Federation of Gynecology and Obstetrics stage and tumor width >5 cm. PD-L1 > 1% was associated with reduced local (82% vs 94%; P = .02) and pelvic control (79% vs 89%; P = .02). HR-CTV D90 < 85 Gy was associated with inferior 5-year local control in p16-positive patients, especially if PD-L1 was coexpressed. On multivariable analysis, PD-L1 > 1% was the only independent factor for 5-year local control (hazard ratio, 3.3; P = .04) and L1CAM ≥ 50% for pelvic control (hazard ratio, 5.5; 95% CI, 1.3-23.3; P = .02)., Conclusions: P16 negative status and tumor necrosis on MRI are independently associated with poor response to chemoradiation, whereas PD-L1 > 1% and L1CAM ≥ 50% have an independent impact on local and pelvic control, suggesting an impact of biomarker expression on outcomes. Further validation is needed., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: End of life communication (EOLC) is generally regarded as a challenging aspect of the medical profession, with high influences of culture, the physician's experience and awareness. The aim of the current study was to assess the awareness of Austrian oncologists towards EOLC practices in their daily clinical routine and to identify limiting and supporting factors of these conversations., Methods: Overall, 45 oncologists participated in the assessment in this cross-sectional, mixed-method design using semi-structured interviews and questionnaire., Results: Themes that occurred during the interviews included the initiation of EOLC, EOLC in practice, strategies for EOLC, limiting and supporting factors and consequences of EOLC. There were several variations in the EOLC approach, that is, the use of time frames, timing, initiation and the amount of details given to the patient., Conclusion: Oncologists agreed that EOLC is important in their daily clinical routine and for their patients. Nevertheless, there seems to be an underlying variation in approaches chosen by Austrian oncologists. This variation might be reduced by asking patients about their information preferences in advance and by routine implementation of communication guidelines, nomograms and prognostic calculators to reduce uncertainty., (© 2022 John Wiley & Sons Ltd.)

Purpose: Analyse outcomes of stage-I inoperable endometrial cancer (EC) patients from seven European centres treated with 3D-image-guided brachytherapy (IGBT) alone., Materials and Methods: From 2004 to 2018, 62 patients (41 stage-IA and 21 IB) were retrospectively studied, analysing anaesthetic procedure, applicator type, BT-planning imaging, clinical target volume (CTV), BT schedule, overall daily-dose equivalent to 2 Gy (EQD2 (α/β=4.5 or 3) ) to the CTV (α/β=4.5) and D2 cm 3 (α/β=3) for organs at risk. Complications were evaluated using CTCAEv4 scores. The 2 and 5 year survival was calculated [cancer-specific survival (CSS), disease-free survival (DFS), local relapse-free survival (LRFS), loco-regional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS)]. Descriptive analysis and the Kaplan-Meier method were used for survival analysis., Results: Mean follow-up: 32.8 months (SD 33.7). Spinal anaesthesia (38/62) followed by none (16/62) were the most common. Y-shaped Rotte applicators were used in 74% of patients. High-dose rate brachytherapy was administered in 89%. Median D90 to the CTV was 58.9 Gy (8.66-144 Gy). Eight patients presented relapse: four uterine, four nodal and four distant. The 2 and 5 year CSS was 93.3 and 80.5%, DFS 84.8 and 80.5%, LRFS was 93.1 and 88.7%, LRRFS was 91 and 91% and DMFS was 90.2 and 90.2%, respectively, CSS was better in stage-IA vs. IB (p = 0.043). Late vaginal and bladder G3-complication rates were 2.1%, respectively., Conclusion: Inoperable EC patients can be safely treated by BT with 2 and 5 year CSS of 93 and 80.5%, respectively, with even better results for IA cases. Prospective studies on 3D-IGBT are necessary to better analyse EC patient outcomes based on dose and treated volumes., (© 2021. Federación de Sociedades Españolas de Oncología (FESEO).)

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., 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 © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)