(Abstracted from Lancet Oncol 2025;26(10):1370-1381) Fifteen percent to 20% of endometrial cancer patients have a high-risk form of the disease; this classification indicates a higher risk of cancer recurrence and cancer-related death. The standard therapy for high-risk endometrial cancer is pelvic radiotherapy.

Of the 4 molecular subtypes of endometrial cancer (EC), p53-abnormal (p53abn) EC is associated with abundant copy number alterations and the worst clinical outcome. Patients with p53abn EC have the highest risk of disease recurrence and death, independent of tumor grade and histologic subtype. Currently, all invasive p53abn ECs are considered high risk, and no prognostic biomarkers have yet been found that can aid in clinical management. Here, we aimed to test whether loss of retinoblastoma (RB) protein expression using immunohistochemistry has the potential for prognostic refinement of p53abn EC. A large cohort of 227 p53abn ECs collected from the PORTEC-1/2/3 clinical trials and the Medisch Spectrum Twente cohort study was investigated, and RB loss was identified in 7.0% (n = 16/227). RB-lost p53abn ECs were predominantly high-grade endometrioid ECs (n = 6, 37.5%) and carcinosarcomas with endometrioid-type epithelial component (n = 5, 31.3%). Histologically, RB-lost p53abn ECs were typified by high-grade nuclear atypia (n = 16, 100%), predominantly solid growth pattern (n = 15/16, 93.8%), and polypoid growth (n = 9/16, 56.3%). Copy number loss involving the RB1 locus was identified in the majority of RB-lost p53abn EC (n = 13/14, 92.9%), explaining the loss of RB expression. Comparative analysis also showed that RB-lost p53abn ECs were diagnosed at earlier stages than RB-retained p53abn EC (P = .014). Interestingly, RB-lost p53abn EC showed prolonged time to overall recurrence (P = .038), even within stage I alone (P = .040). These findings highlight distinct morphomolecular features in RB-lost p53abn ECs and confirm the utility of RB immunohistochemistry as a surrogate for underlying molecular RB1 alterations. To our knowledge, this is the first study to show the potential use of RB in prognostic refinement of p53abn EC, although validation is warranted. (c) 2024 THE AUTHORS. Published by Elsevier Inc. on behalf of the United States & Canadian Academy of Pathology. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).

Background and purpose: Standard treatment for locally advanced cervical cancer (LACC) is chemoradiotherapy followed by a brachytherapy (BT) boost. However, BT is not always feasible and magnetic resonance (MR)-guided adaptive radiotherapy on the MR-Linac (MRL) might be an alternative. To investigate the dosimetric feasibility of MRL, BT and MRL treatment plans were compared intra-patient in terms of dosimetric differences, next to anatomical and conformity variations. Materials and methods: Two groups of ten patients with LACC treated with BT boost were selected: group 1 included patients for which at least one clinically established (EMBRACE II) treatment planning constraint was not achieved during BT, in group 2 all planning constraints were achieved.BT treatment plans were compared with MRL treatment plans (based on MRI scans without applicator in place) intra-patient, in terms of dose-volume histogram (DVH) parameters, target-to-OAR (organ at risk) surface distances and conformity ratios. Results: Group 1 resulted in similar prescribed target dose levels for MRL compared to BT, for group 2 all prescribed target dose levels were significantly higher for BT. Rectum D2cm3 was higher for all MRL treatment plans. Volumes of higher dose levels were larger for BT, volumes of lower dose levels were larger for MRL and the CTVHR to OAR (rectum, sigmoid, bowel) surface distance was greater for BT. Conclusion: This retrospective study demonstrates that with an MRL boost plan, in some situations it is possible to achieve established planning constraints. However, as rectum doses are higher and dose distributions are fundamentally different, BT remains the modality of choice. Clinical trials are necessary to investigate the influence of the MRL dose distribution on oncological outcomes.

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 fi nding 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 fi brotic 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. (c) 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

INTRODUCTION:Adjuvant chemotherapy in the treatment of endometrial cancer can be difficult to tolerate for older women. This study examined age-related differences in patient preferences for chemotherapy in women with high-risk endometrial cancer. METHODS:We re-analyzed data from the cross-sectional patient preference study PRETEC-2 to determine the difference between three age groups in minimally desired survival benefit of chemotherapy. For this, patients with high-risk endometrial cancer treated with adjuvant pelvic radiotherapy with or without chemotherapy completed a treatment trade-off questionnaire. Patients also rated the importance they attributed to treatment duration and acute and late side-effects for their decision on chemotherapy, which we analyzed by age group. RESULTS:A total of 171 patients (23% <60 years, 40% 60-69 years and 37% ≥70 years) were included in the analysis. Older patients had a significantly higher median minimally desired survival benefit for preferring chemoradiotherapy (5% for <60 years, 8% for 60-69 years and 15% for patients ≥70 years; (p<0.001)), and had the largest variability in minimally desired survival benefit. For a real-life five-year survival benefit of 5%, fewer older patients preferred the addition of chemotherapy to their treatment regimen (61.5% for <60 years, 45.6% for 60-69 years and 21.9% for ≥70 years; p<0.001). Furthermore, older patients rated both treatment duration (p=0.001) and long-term tingling or numbness (p=0.005) as significantly more important than their younger counterparts. CONCLUSION:There is more heterogeneity in the desired benefit of chemotherapy among patients aged 70 years or more compared to younger patients. This underlines the importance of recognizing individual differences and the need for shared decision-making.

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.