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Purpose. Patient-tailored intracavitary/interstitial (IC/IS) brachytherapy (BT) applicators may increase dose conformity in cervical cancer patients. Current configuration planning methods in these custom applicators rely on manual specification or a small set of (straight) needles. This work introduces and validates a two-stage approach for establishing channel configurations in the 3D printed patient-tailored ARCHITECT applicator. Methods. For each patient, the patient-tailored applicator shape was based on the first BT application with a commercial applicator and integrated connectors to a commercial (Geneva) intrauterine tube and two lunar ring channels. First, a large candidate set was generated of channels that steer the needle to desired poses in the target region and are contained in the applicator. The channels' centrelines were represented by Bézier curves. Channels running between straight target segments and entry points were optimised and refined to ensure (dynamic) feasibility. Second, channel configurations were selected using geometric coverage optimisation. This workflow was applied to establish patient-tailored geometries for twenty-two patients previously treated using the Venezia applicator. Treatment plans were automatically generated using the in-house developed algorithm BiCycle. Plans for the clinically used configuration,TPclin, and patient-tailored configuration,TParch, were compared. Results. Channel configurations could be generated in clinically feasible time (median: 2651 s, range 1826-3812 s). AllTParchandTPclinplans were acceptable, but planning aims were more frequently attained with patient-tailored configurations (115/132 versus 100/132 instances). Median CTV IR D98and bladderD2cm3doses significantly improved (p<0.001 andp<0.01 respectively) inTParchplans in comparison withTPclinplans, and in approximately half of the patients dosimetric indices improved. Conclusion. Automated patient-tailored BT channel configuration planning for 3D printed applicators is clinically feasible. A treatment planning study showed that all plans met planning limits for the patient-tailored configurations, and in selected cases improved the plan quality in comparison with commercial applicator configurations., (Creative Commons Attribution license.)

Of the four molecular subtypes of endometrial cancer (EC), p53-abnormal (p53abn) EC is associated with abundant copy number alterations (CNAs) 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 protein (RB) expression using immunohistochemistry (IHC) has 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 MST 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 EC 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 EC were diagnosed at earlier stages than RB-retained p53abn EC (p=0.014). Interestingly, RB-lost p53abn EC showed prolonged time to overall recurrence (p=0.038), even within stage I alone (p=0.040). These findings highlight distinct morphomolecular features in RB-lost p53abn EC and confirm the utility of RB IHC as a surrogate for molecular RB1 alterations. This is the first study to show the potential use of RB in prognostic refinement of p53abn EC, although validation is warranted., (Copyright © 2024. Published by Elsevier Inc.)

Background: Electromagnetic Tracking (EMT) technology has been integrated in a prototype high-dose-rate brachytherapy (HDR-BT) afterloading device. Its potential for dwell position (DP) monitoring has earlier been demonstrated in prostate phantoms. However, its performance for prostate BT in the clinical setting remains to be assessed., Aim: Assess the reliability and value of EMT measurements in transrectal ultrasound-based (TRUS-based) and computed tomography-based (CT-based) prostate HDR-BT., Methods: EMT measurements were conducted on 20 patients undergoing dual-fraction prostate HDR-BT monotherapy. In each treatment fraction an individual TRUS-based or CT-based treatment plan was generated. The measurements were compared to DPs of manually reconstructed needles in those TRUS-based or CT-based treatment plans. An internal reference sensor was also placed in one needle to assess internal movement levels and its potential for movement correction., Results: For TRUS-based treatments, median Euclidean distances (ED) of 1.00 mm were observed between EMT measurements and manual DP determination. Reference sensor movement was minimal at a median of 0.18 mm. For DPs measured in the CT-room and treatment room, median EDs of 1.60 mm and 2.24 mm compared to CT-based DP determination respectively were observed, indicating the system's ability to detect changes in implant geometry over time and after patient repositioning. Median reference sensor movement of 0.97 mm was observed. Implementing reference sensor-based movement correction led to a significant but small decrease in ED for CT-based treatments., Conclusion: EMT is suitable for TRUS-based prostate HDR-BT quality assurance and error detection. While EMT can identify changes in implant geometry in CT-based prostate HDR-BT treatments, it showed lower accuracy in this setting., 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 © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Extensive glioblastoma infiltration justifies a 15-mm margin around the gross tumor volume (GTV) to define the radiotherapy clinical target volume (CTV). Amide proton transfer (APT)-weighted imaging could enable visualization of tumor infiltration, allowing more accurate GTV delineation. We quantified the impact of integrating APT-weighted imaging into GTV delineation of glioblastoma and compared two APT-weighted quantification methods-magnetization transfer ratio asymmetry (MTR asym ) and Lorentzian difference (LD) analysis-for target delineation., Methods: Nine glioblastoma patients underwent an extended imaging protocol prior to radiotherapy, yielding APT-weighted MTR asym and LD maps. From both maps, biological tumor volumes were generated (BTV MTRasym and BTV LD ) and added to the conventional GTV to generate biological GTVs (GTV bio,MTRasym and GTV bio,LD ). Wilcoxon signed-rank tests were performed for comparisons., Results: The GTV bio,MTRasym and GTV bio,LD were significantly larger than the conventional GTV (p ≤ 0.022), with a median volume increase of 9.3% and 2.1%, respectively. The GTV bio,MTRasym and GTV bio,LD were significantly smaller than the CTV (p = 0.004), with a median volume reduction of 72.1% and 70.9%, respectively. There was no significant volume difference between the BTV MTRasym and BTV LD (p = 0.074). In three patients, BTV MTRasym delineation was affected by elevated signals at the brain periphery due to residual motion artifacts; this elevation was absent on the APT-weighted LD maps., Conclusion: Larger biological GTVs compared to the conventional GTV highlight the potential of APT-weighted imaging for radiotherapy target delineation of glioblastoma. APT-weighted LD mapping may be advantageous for target delineation as it may be more robust against motion artifacts., Relevance Statement: The introduction of APT-weighted imaging may, ultimately, enhance visualization of tumor infiltration and eliminate the need for the substantial 15-mm safety margin for target delineation of glioblastoma. This could reduce the risk of radiation toxicity while still effectively irradiating the tumor., Trial Registration: NCT05970757 (ClinicalTrials.gov)., Key Points: Integration of APT-weighted imaging into target delineation for radiotherapy is feasible. The integration of APT-weighted imaging yields larger GTVs in glioblastoma. APT-weighted LD mapping may be more robust against motion artifacts than APT-weighted MTR asym ., (© 2024. The Author(s).)

Background and Purpose: To review available data on toxicity during and/or after treatment of abdominal-pelvic lymph node oligometastases (A-P LN) with stereotactic body radiation therapy (SBRT) and to provide an overview of adverse events and its relation to dose or fractionation., Material and Methods: For this systematic review, we searched MEDLINE, Embase, Web of Science Core Collection, and CINAH for studies published between the database inception and October 3rd, 2023. Inclusion criteria were (1) patients with 1-5 A-P LN oligometastases, (2) treatment with SBRT to a median prescribed dose of ≥55 Gy BED10, and (3) description of acute and/or late toxicity. There were no language or date restrictions., Results: A total of 35 studies, including 1,512 patients, were selected. Late grade 3 and 4 adverse events occurred in 0.6% and 0.1% of the patients treated for A-P LN oligometastases. All late adverse events grade ≥ 3 occurred after treatment of the tumor with a minimum BED10 of 72 Gy. Of the 11 patients with severe late toxicity, five patients were re-irradiated. Late grade 2 and 1 toxicity was reported in 3.4% and 8.3% of the patients. Acute toxicity grades 4, 3, 2, and 1 occurred in 0.1%, 0.2%, 4.4%, and 19.8% of the patients, respectively., Interpretation: SBRT for A-P LN oligometastases show low toxicity rates. Nearly 50% of late adverse events ≥ grade 3 were associated with re-irradiation.

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.)

The Gynecologic Cancer InterGroup (GCIG) Endometrial Cancer Consensus Conference on Clinical Research (ECCC) was held in Incheon, South Korea, Nov 2-3, 2023. The aims were to develop consensus statements for future trials in endometrial cancer to achieve harmonisation on design elements, select important questions, and identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and finalisation of 18 statements within four topic groups, addressing adjuvant treatment in high-risk disease; treatment for metastatic and recurrent disease; trial designs for rare endometrial cancer subgroups and special circumstances; and specific methodology and adaptation for trials in low-resource settings. In addition, eight areas of unmet need were identified. This was the first GCIG Consensus Conference to include patient advocates and an expert on inclusion, diversity, equity, and access to take part in all aspects of the process and output. Four early-career investigators were also selected for participation, ensuring that they represented different GCIG member groups and regions. Unanimous consensus was obtained for 16 of the 18 statements, with 97% concordance for the remaining two. Using the described methodology from previous Ovarian Cancer Consensus Conferences, this conference did not require even one minority statement. The high acceptance rate following active involvement in the preparation, discussion, and refinement of the statements by all representatives confirmed the consensus progress within a global academic setting, and the expectation that the ECCC will lead to greater harmonisation, actualisation, inclusion, and resolution of unmet needs in clinical research for individuals living with and beyond endometrial cancer worldwide., Competing Interests: Declaration of interests All authors report that the KGOG paid for their 2-night hotel stay and basic meals during the 2 days of the ECCC on Clinical Research meeting. CLC reports a research grant paid to her institution from Varian; payment to her institution for participation on a data safety monitoring board from Merck; and unpaid roles as chair of GCIG Endometrial Committee and member of Guidelines Committees for Endometrial cancer of the European Society of Gynaecologic Oncology (ESGO) and the European Society of Radiotherapy and Oncology. GE reports personal consulting fees from MSD, personal fees from Eisai, and support for attending a meeting or travel from MSD. LE reports personal consulting fees AstraZeneca, GSK, and MSD; personal fees from AstraZeneca and GSK, and support for attending a meeting or travel from AstraZeneca and GSK. RAN reports research grants paid to his institution from Elekta, Varian, and Accuray; and payment to his institution for presentations from Elekta and MSD. DL reports research grants both personal and paid to her institution from AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, MSD, Novartis, Pharmamar, and Seagen; personal grants from Corcept, Oncoinvest, and Sutro; and grants to her institution from Incyte and Roche; consulting fees from AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, Immunogen, MSD, Novartis, Oncoinvest, Pharmamar, Seagen, and Sutro; payment for presentations from Clovis Oncology, Corcept, Genmab, GSK, Immunogen, MSD, Novartis, Oncoinvest, Pharmamar, Seagen, and Sutro; support for attending a meeting or travel from AstraZeneca, Clovis Oncology, MSD and GSK; and payments for participation on a data safety monitoring board from AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, Immunogen, MSD, Novartis, Oncoinvest, Pharmamar, Seagen, and Sutro. AO reports research grants paid to his institution from AstraZeneca; consulting fees from Bristol Myers Squibb, uncompensated participation on data and safety monitoring boards of studies funded by AstraZeneca and GlaxoSmithKline; and unpaid roles as principal investigator on investigator-initiated trials and on steering committees of trials funded by AstraZeneca and GlaxoSmithKline. BP reports research grants from Tesaro/GSK, Merck, AstraZeneca, Karyopharm Therapeutics, Sutro, Incyte, Clovis Oncology, Roche/Genentech, Mersana, Celsion/Immunon, Imab, Takeda, Toray, VBL Therapeutics, InxMed, Agenus, Seagen, NRG Oncology, Duality Bio, Xencor, Onconova, Celgene, Sutro Biopharma, Novocure, Immunogen, Eisai, Acrivon, and Alkermes; consulting fees from Tesaro/GSK, AstraZeneca, Merck, Immunogen, Gynecologic Oncology Group (GOG) Foundation, SeaGen, Lily, Eisai, Signatera, Celsion, Butro Biopharma, Imvax, Incyte, InxMed, Onconova Therapeutics, R Pharm, Regeneron, and Duality Bio; payment for presentations from Bioascend, PERS, Vanium, Curio, OncLive, Yale University and PeerView; support for attending a meeting or travel from GOG Partners, payment for participation on a data safety monitoring board or advisory board from Sutro, AstraZeneca, GOG Foundation, Celsion/Immunon, Toray, InxMed, Imvax, Imab, Tesaro/GSK, Merck, Mersana, Nuvation, and BioNtech; and unpaid leadership roles in boards, societies and committees: Society of Gynecologic Oncology (SGO) Clinical Practice Committee Chair, SGO Board of Directors, SGO COVID-19 Taskforce co-chair, GOG Partners, and New York Obstetrical Society Second VP. BH reports textbook royalties from Elsevier; consulting fees from Tempus; honoraria for lectures from Leica and Projects in Knowledge; and unpaid leadership roles on the International Society of Gynecological Pathologists Board of Directors (as member at large) and on the Endometrial Cancer MSI Committee of the College of American Pathologists. IR-C reports research grants from AstraZeneca, Clovis, GSK, Mersana, BMS, and MSD; payment for presentations from AstraZeneca, Clovis, GSK, Mersana, BMS, MSD, Roche, Pharmamar, Seagen, Eisai, and Novartis; support for attending a meeting or travel from Roche, GSK, AstraZeneca, Pharmamar, and MSD; and payment for participation on a data safety monitoring board or advisory board from Clovis, Deciphera, Adaptimmue, Sutro, and Immunogen. DG reports support for attending meetings or travel from IGCS Board of Directors; payment for participation on a data and safety monitoring board from Merck, and a leadership role in NRG Oncology. AM reports payment for participation as independent statistician on data safety monitoring boards from ONY Biotech, Regeneron, and Genentech/Roche. NC reports payments or honoraria for presentations from GSK, Seagen, Akesobio, AstraZeneca, eTheRNA immunotherapies NV, Kartos, MSD, Mersana, ImmunoGen, Eisai, Seattle Genetics, TouchIME, and Medscape Oncology; support for attending a meeting or travel from Roche, Genmab, and Amgen; payment for participation on a data safety monitoring board or advisory board from GSK, Mersana, Seagen, ImmunoGen, Akesobio, Eisai, AstraZeneca, Mersana, Seattle Genetics, eTheRNA immunotherapies NV, and Kartos; and leadership roles as President of ESGO and Chair of European Network for Gynaecological Oncological Trial groups Early Drug Development Network. MAP reports grants paid to his institution from GSK; payment for participation on a data and safety monitoring board from GSK, AstraZeneca, Eisai, Merck, Immunogen, Clovis Oncology, Jazz Pharma, and SeaGen; and payment to his institution for a leadership role on a board or committee from NRG Oncology. MAB reports payment to his institution for participation on a data and safety monitoring board from Immunogen; and employment as physician at The Permanente Medical Group. J-WK, EA, SIK, J-YP, LM, PBO, AB, DM, VG, TB, CG, TM, HW, XM-G, WS, and GS declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: The multicentre randomised SPARC trial evaluated the efficacy of a nurse-led sexual rehabilitation intervention on sexual functioning, distress, dilator use, and vaginal symptoms after radiotherapy for gynaecological cancers., Methods: Eligible women were randomised to the rehabilitation intervention or care-as-usual. Four intervention sessions were scheduled over 12 months, with concurrent validated questionnaires and clinical assessments. Primary outcome was the Female Sexual Function Index (FSFI). A generalised-mixed-effects model compared groups over time., Results: In total, 229 women were included (n = 112 intervention; n = 117 care-as-usual). No differences in FSFI total scores were found between groups at any timepoint (P = 0.37), with 12-month scores of 22.57 (intervention) versus 21.76 (care-as-usual). The intervention did not significantly improve dilator use, reduce sexual distress or vaginal symptoms compared to care-as-usual. At 12 months, both groups had minimal physician-reported vaginal stenosis; 70% of women were sexually active and reported no or mild vaginal symptoms. After radiotherapy and brachytherapy, 85% (intervention) versus 75% (care-as-usual) of participants reported dilation twice weekly., Discussion: Sexual rehabilitation for women treated with combined (chemo)radiotherapy and brachytherapy improved before and during the SPARC trial, which likely contributed to comparable study groups. Best practice involves a sexual rehabilitation appointment 1 month post-radiotherapy, including patient information, with dilator guidance, preferably by a trained nurse, and follow-up during the first year after treatment., Clinical Trial Registration: NCT03611517., (© 2024. The Author(s).)

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.)

Predicting distant recurrence of endometrial cancer (EC) is crucial for personalized adjuvant treatment. The current gold standard of combined pathological and molecular profiling is costly, hampering implementation. Here we developed HECTOR (histopathology-based endometrial cancer tailored outcome risk), a multimodal deep learning prognostic model using hematoxylin and eosin-stained, whole-slide images and tumor stage as input, on 2,072 patients from eight EC cohorts including the PORTEC-1/-2/-3 randomized trials. HECTOR demonstrated C-indices in internal (n = 353) and two external (n = 160 and n = 151) test sets of 0.789, 0.828 and 0.815, respectively, outperforming the current gold standard, and identified patients with markedly different outcomes (10-year distant recurrence-free probabilities of 97.0%, 77.7% and 58.1% for HECTOR low-, intermediate- and high-risk groups, respectively, by Kaplan-Meier analysis). HECTOR also predicted adjuvant chemotherapy benefit better than current methods. Morphological and genomic feature extraction identified correlates of HECTOR risk groups, some with therapeutic potential. HECTOR improves on the current gold standard and may help delivery of personalized treatment in EC., (© 2024. The Author(s).)

Objective: To investigate differences in standard clinico-radiological evaluation versus Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for reporting survival outcomes in patients with locally advanced cervical cancer treated with chemoradiation and brachytherapy., Methods: Between November 2017 and March 2020, patients recruited in cervical cancer trials were identified. MRI at diagnosis and at least one follow-up imaging was mandatory. Disease-free survival and progression-free survival were determined using standard evaluation (clinical examination and symptom-directed imaging) and RECIST 1.1. Agreement between criteria was estimated using κ value. Sensitivity analysis was done to test the sensitivity, specificity, and accuracy of RECIST 1.1 in detecting response to treatment., Results: Sixty-nine eligible patients had at least one target lesion. Thirty-three patients (47.8%) had pathological lymph nodes. Of these 33 patients, RECIST 1.1 classified only 18% (6/33) as 'target nodal lesions' and the remaining nodes as 'non-target'. There were 6 (8.7%) and 8 (11.6%) patients with disease events using RECIST 1.1 and standard evaluation, respectively. The disease-free survival at 12, 18, and 24 months using RECIST 1.1 was 94.2%, 91.2%, 91.2%, and with standard evaluation was 94.2%, 89.7%, and 88.2%, respectively (p=0.58). Whereas, progression-free survival at 12, 18, and 24 months using RECIST 1.1 and standard evaluation were same (94.2%, 91.2%, and 91.2%, respectively). The κ value was 0.84, showing strong agreement in assessing disease-free survival, although an absolute difference of 3% between endpoint assessment methodologies. RECIST 1.1 had a sensitivity of 75% (95% CI 34.91% to 96.81%), specificity of 100% (95% CI 94.13% to 100%), and accuracy of 97.1% (95% CI 89.92% to 99.65%)., Conclusions: The study showed 1.5% and 3% difference in disease-free survival at 18 and 24 months and no difference in progression-free survival between RECIST 1.1 and standard evaluation in a patient cohort with low event rate., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: To investigate the trade-off between bone marrow sparing (BMS) and dose to organs at risk (OARs) for intensity modulated proton therapy (IMPT) for women with locally advanced cervical cancer (LACC)., Materials and Methods: Twenty LACC patients were retrospectively included. IMPT plans were created for each patient using automated treatment planning. These plans progressively reduced bone marrow mean doses by steps of 1 GyRBE, while constraining target coverage and conformality. The relation between bone marrow dose and bladder, small bowel, rectum, and sigmoid doses was evaluated., Results: A total of 140 IMPT plans were created. Plans without BMS had an average [range] bone marrow mean dose of 17.3 [14.7-21.6] Gy RBE  , which reduced to 12.0 [10.0-14.0] Gy RBE  with maximum BMS. The mean OAR dose [range] increased modestly for 1 Gy RBE  BMS: 0.2 [0.0 - 0.6] Gy RBE  for bladder, 0.3 [-0.2 - 0.7] Gy RBE  for rectum, 0.4 [0.1 - 0.8] Gy RBE  for small bowel, and 0.2 [-0.2 - 0.4] Gy RBE  for sigmoid. Moreover, for maximum BMS, mean OAR doses [range] escalated by 3.3 [0.1 - 6.7] Gy RBE  for bladder, 5.8 [1.8 - 12.4] Gy RBE  for rectum, 3.9 [1.6 - 5.9] Gy RBE  for small bowel, and 2.7 [0.6 - 5.9] Gy RBE  for sigmoid., Conclusion: Achieving 1 Gy RBE  BMS for IMPT is feasible for LACC patients with limited dosimetric impact on other OARs. While further bone marrow dose reduction is possible for some patients, it may increase OAR doses substantially for others. Hence, we recommend a personalized approach when introducing BMS into clinical IMPT treatment planning to carefully assess individual patient benefits and risks., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Numerous studies have shown that older women with endometrial cancer have a higher risk of recurrence and cancer-related death. However, it remains unclear whether older age is a causal prognostic factor, or whether other risk factors become increasingly common with age. We aimed to address this question with a unique multimethod study design using state-of-the-art statistical and causal inference techniques on datasets of three large, randomised trials., Methods: In this multimethod analysis, data from 1801 women participating in the randomised PORTEC-1, PORTEC-2, and PORTEC-3 trials were used for statistical analyses and causal inference. The cohort included 714 patients with intermediate-risk endometrial cancer, 427 patients with high-intermediate risk endometrial cancer, and 660 patients with high-risk endometrial cancer. Associations of age with clinicopathological and molecular features were analysed using non-parametric tests. Multivariable competing risk analyses were performed to determine the independent prognostic value of age. To analyse age as a causal prognostic variable, a deep learning causal inference model called AutoCI was used., Findings: Median follow-up as estimated using the reversed Kaplan-Meier method was 12·3 years (95% CI 11·9-12·6) for PORTEC-1, 10·5 years (10·2-10·7) for PORTEC-2, and 6·1 years (5·9-6·3) for PORTEC-3. Both overall recurrence and endometrial cancer-specific death significantly increased with age. Moreover, older women had a higher frequency of deep myometrial invasion, serous tumour histology, and p53-abnormal tumours. Age was an independent risk factor for both overall recurrence (hazard ratio [HR] 1·02 per year, 95% CI 1·01-1·04; p=0·0012) and endometrial cancer-specific death (HR 1·03 per year, 1·01-1·05; p=0·0012) and was identified as a significant causal variable., Interpretation: This study showed that advanced age was associated with more aggressive tumour features in women with endometrial cancer, and was independently and causally related to worse oncological outcomes. Therefore, our findings suggest that older women with endometrial cancer should not be excluded from diagnostic assessments, molecular testing, and adjuvant therapy based on their age alone., Funding: None., Competing Interests: Declaration of interests JW is supported by core funding of the University of Zurich to the Computational and Translational Pathology Lab led by VHK at the Department of Pathology and Molecular Pathology, University Hospital and University of Zurich. RAN has received grants (to institution) from the Dutch Cancer Society, Dutch Research Council, Elekta, Varian, and Accuray; payment or honoraria (to institution) for lectures and presentations from Elekta; and is chair of the Dutch Gynecological Oncology Group. AL-C declares having received payment or honoraria for multiple lectures and presentations. AL has received a PhD student grant from AstraZeneca; honoraria (to institution) for presentations from GSK, AstraZeneca, and MSD; support for attending meetings from OSEimmuno, AstraZeneca, and MSD; and honoraria (to institution) for participation on Data Safety Monitoring Board or Advisory Board from Genmab, AstraZeneca, MSD, and GSK. NS declares having received personal payment for participation in Advisory Boards of Astra-Zeneca–MSD and Glaxo-SmithKline. HWN has received grants or contracts (to institution) from Merck and the Dutch Cancer Society. VHK receives funding by the University of Zurich; has acted as an invited speaker for Sharing Progress in Cancer Care (SPCC) and holds sponsored research agreements with Roche and IAG unrelated to the content of this study; has served as an invited speaker on behalf of Indica Labs unrelated to the content of this study; is on an advisory board of Takeda (unrelated to the content of this study); and is a member of the European Key Opinion Leader Network in Digital Pathology supported by Roche. CLC has received clinical trial grants for the PORTEC-1, PORTEC-2, and PORTEC-3 trials (to institution) from the Dutch Cancer Society. NH has received unrestricted research grants (to institution) from the Dutch Cancer Society; personal payment for an educational lecture for specialist nurses in oncology (V&VN), unrelated to the current work; has a patent on a deep learning algorithm on endometrial cancer, unrelated to the current work; and is a member of a Data Safety Monitoring Board of the Apollo study (EudraCT number: 2022-002500-21). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: The steep radiation dose gradients in cervical cancer brachytherapy (BT) necessitate a thorough understanding of the behavior of afterloader source cables or needles in the curved channels of (patient-tailored) applicators., Purpose: The purpose of this study is to develop and validate computer models to simulate: (1) BT source positions, and (2) insertion forces of needles in curved applicator channels. The methodology presented can be used to improve the knowledge of instrument behavior in current applicators and aid the development of novel (3D-printed) BT applicators., Methods: For the computer models, BT instruments were discretized in finite elements. Simulations were performed in SPACAR by formulating nodal contact force and motion input models and specifying the instruments' kinematic and dynamic properties. To evaluate the source cable model, simulated source paths in ring applicators were compared with manufacturer-measured source paths. The impact of discrepancies on the dosimetry was estimated for standard plans. To validate needle models, simulated needle insertion forces in curved channels with varying curvature, torsion, and clearance, were compared with force measurements in dedicated 3D-printed templates., Results: Comparison of simulated with manufacturer-measured source positions showed 0.5-1.2 mm median and <2.0 mm maximum differences, in all but one applicator geometry. The resulting maximum relative dose differences at the lateral surface and at 5 mm depth were 5.5% and 4.7%, respectively. Simulated insertion forces for BT needles in curved channels accurately resembled the forces experimentally obtained by including experimental uncertainties in the simulation., Conclusion: The models developed can accurately predict source positions and insertion forces in BT applicators. Insights from these models can aid novel applicator design with improved motion and force transmission of BT instruments, and contribute to the estimation of overall treatment precision. The methodology presented can be extended to study other applicator geometries, flexible instruments, and afterloading systems., (© 2024 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background and Purpose: Although MRI-based image guided adaptive brachytherapy (IGABT) for locally advanced cervical cancer (LACC) has resulted in favorable outcomes, it can be logistically complex and time consuming compared to 2D image-based brachytherapy, and both physically and emotionally intensive for patients. This prospective study aims to perform time-action and patient experience analyses during IGABT to guide further improvements., Materials and Methods: LACC patients treated with IGABT were included for the time-action (56 patients) and patient experience (29 patients) analyses. Times per treatment step were reported on a standardized form. For the patient experience analysis, a baseline health status was established with the EQ-5D-5L questionnaire and the perceived pain, anxiety and duration for each treatment step were assessed with the NRS-11., Results: The median total procedure time from arrival until discharge was 530 (IQR: 480-565) minutes. Treatment planning (delineation, reconstruction, optimization) required the most time and took 175 (IQR: 145-195) minutes. Highest perceived pain was reported during applicator removal and treatment planning, anxiety during applicator removal, and duration during image acquisition and treatment planning. Perceived pain, anxiety and duration were correlated. Higher pre-treatment pain and anxiety scores were associated with higher perceived pain, anxiety and duration., Conclusion: This study highlights the complexity, duration and impact on patient experience of the current IGABT workflow. Patient reported pre-treatment pain and anxiety can help identify patients that may benefit from additional support. Research and implementation of measures aiming at shortening the overall procedure duration, which may include logistical, staffing and technological aspects, should be prioritized., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Women with locally advanced cervical cancer (LACC) undergoing primary platinum-based chemoradiotherapy and brachytherapy often experience toxicities. Normal-tissue complication probability (NTCP) models quantify toxicity risk and aid in optimizing radiation therapy to minimize side effects. However, it is unclear which predictors to include in an NTCP model. The aim of this systematic review was to provide an overview of the identified predictors contributing to gastrointestinal (GI), genitourinary (GU), and vaginal toxicities and insufficiency fractures for LACC., Methods and Materials: A systematic search was performed and articles evaluating the relationship between predictors and toxicities in women with LACC treated with primary chemoradiation were included. The Quality In Prognosis Studies tool was used to assess risk of bias, with high-risk studies being excluded from further analysis. Relationships between dose-volume parameters, patient and treatment characteristics, and toxicity endpoints were analyzed., Results: Seventy-three studies were identified. Twenty-six had a low or moderate risk of bias and were therefore included. Brachytherapy-related dose-volume parameters of the GI tract, including rectum and bowel equivalent dose in 2 Gy fractions (EQD2) D2 cm 3 , were frequently related to toxicities, unlike GU dose-volume parameters. Furthermore, (recto)vaginal point doses predicted toxicities. Few studies evaluated external beam radiation therapy dose-volume parameters and identified rectum EQD2 V30 Gy, V40 Gy, and V55 Gy, bowel and bladder EQD2 V40 Gy as toxicity predictors. Also, total reference air kerma and vaginal reference length were associated with toxicities. Relationships between patient characteristics and GI toxicity were inconsistent. The extent of vaginal involvement at diagnosis, baseline symptoms, and obesity predicted GU or vaginal toxicities. Only 1 study evaluated insufficiency fractures and demonstrated lower pretreatment bone densities to be associated., Conclusions: This review detected multiple candidate predictors of toxicity. Larger studies should consider insufficiency fractures, assess dose levels from external beam radiation therapy, and quantify the relationship between the predictors and treatment-related toxicities in women with LACC to further facilitate NTCP model development for clinical use., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Universal tumor screening in endometrial carcinoma (EC) is increasingly adopted to identify individuals at risk of Lynch syndrome (LS). These cases involve mismatch repair-deficient (MMRd) EC without MLH1 promoter hypermethylation (PHM). LS is confirmed through the identification of germline MMR pathogenic variants (PV). In cases where these are not detected, emerging evidence highlights the significance of double-somatic MMR gene alterations as a sporadic cause of MMRd, alongside POLE/POLD1 exonuclease domain (EDM) PV leading to secondary MMR PV. Our understanding of the incidence of different MMRd EC origins not related to MLH1-PHM, their associations with clinicopathologic characteristics, and the prognostic implications remains limited. In a combined analysis of the PORTEC-1, -2, and -3 trials (n = 1254), 84 MMRd EC not related to MLH1-PHM were identified that successfully underwent paired tumor-normal tissue next-generation sequencing of the MMR and POLE/POLD1 genes. Among these, 37% were LS associated (LS-MMRd EC), 38% were due to double-somatic hits (DS-MMRd EC), and 25% remained unexplained. LS-MMRd EC exhibited higher rates of MSH6 (52% vs 19%) or PMS2 loss (29% vs 3%) than DS-MMRd EC, and exclusively showed MMR-deficient gland foci. DS-MMRd EC had higher rates of combined MSH2/MSH6 loss (47% vs 16%), loss of >2 MMR proteins (16% vs 3%), and somatic POLE-EDM PV (25% vs 3%) than LS-MMRd EC. Clinicopathologic characteristics, including age at tumor onset and prognosis, did not differ among the various groups. Our study validates the use of paired tumor-normal next-generation sequencing to identify definitive sporadic causes in MMRd EC unrelated to MLH1-PHM. MMR immunohistochemistry and POLE-EDM mutation status can aid in the differentiation between LS-MMRd EC and DS-MMRd EC. These findings emphasize the need for integrating tumor sequencing into LS diagnostics, along with clear interpretation guidelines, to improve clinical management. Although not impacting prognosis, confirmation of DS-MMRd EC may release patients and relatives from burdensome LS surveillance., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To investigate and compare overall survival (OS), disease-free survival (DFS) and toxicity of women who underwent either chemoradiotherapy with or without prior lymph node debulking or upfront chemotherapy followed by radiotherapy and hyperthermia (triple therapy) for locally advanced cervical cancer (LACC) to identify a potential role for triple therapy., Methods: Women with histologically proven LACC and with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB2 and IIA2 to IVA were included. Cox regression analyses were used for calculating hazard ratios and to adjust for confounding variables. A multivariable logistic regression analysis was used to examine the influence of covariates on toxicity., Results: A total of 370 patients were included of whom 58% ( n = 213) received chemoradiotherapy (CRT), 18% ( n = 66) received node-debulking followed by chemoradiotherapy (LND-CRT) and 25% ( n = 91) received triple therapy (TT). Five-year OS was comparable between the three treatment groups, with 53% (95% confidence interval 46-59%) in the CRT group, 45% (33-56%) in the LND-CRT group and 53% (40-64%) in the TT group ( p = 0.472). In the adjusted analysis, 5-year OS and DFS were comparable between the three treatment groups. No chemotherapy-related differences in toxicity were observed., Conclusion: This study suggests that the toxicity and survival of TT is similar to CRT or LND-CRT.

Purpose: The clinical significance of the p53-abnormal (p53abn) molecular subtype in stage I low-grade endometrioid endometrial carcinoma (EEC) is debated. We aimed to review pathologic and molecular characteristics, and outcomes of stage I low-grade p53abn EEC in a large international cohort., Experimental Design: Previously diagnosed stage I p53abn EC (POLE-wild-type, mismatch repair-proficient) low-grade EEC from Canadian retrospective cohorts and PORTEC-1&2 trials were included. Pathology review was performed by six expert gynecologic pathologists blinded to p53 status. IHC profiling, next-generation sequencing, and shallow whole-genome sequencing was performed. Kaplan-Meier method was used for survival analysis., Results: We identified 55 stage I p53abn low-grade EEC among 3,387 cases (2.5%). On pathology review, 17 cases (31%) were not diagnosed as low-grade EEC by any pathologists, whereas 26 cases (47%) were diagnosed as low-grade EEC by at least three pathologists. The IHC and molecular profile of the latter cases were consistent with low-grade EEC morphology (ER/PR positivity, patchy p16 expression, PIK3CA and PTEN mutations) but they also showed features of p53abn EC (TP53 mutations, many copy-number alterations). These cases had a clinically relevant risk of disease recurrence (5-year recurrence-free survival 77%), with pelvic and/or distant recurrences observed in 12% of the patients., Conclusions: A subset of p53abn EC is morphologically low-grade EEC and exhibit genomic instability. Even for stage I disease, p53abn low-grade EEC are at substantial risk of disease recurrence. These findings highlight the clinical relevance of universal p53-testing, even in low-grade EEC, to identify women at increased risk of recurrence., (©2023 The Authors; Published by the American Association for Cancer Research.)

Purpose: The molecular classification of endometrial cancer (EC) has proven to have prognostic value and is predictive of response to adjuvant chemotherapy. Here, we investigate its predictive value for response to external beam radiotherapy (EBRT) and vaginal brachytherapy (VBT) in early-stage endometrioid EC (EEC)., Methods: Data of the randomized PORTEC-1 trial (n = 714) comparing pelvic EBRT with no adjuvant therapy in early-stage intermediate-risk EC and the PORTEC-2 trial (n = 427) comparing VBT with EBRT in early-stage high-intermediate-risk EC were used. Locoregional (including vaginal and pelvic) recurrence-free survival was compared between treatment groups across the four molecular classes using Kaplan-Meier's methodology and log-rank tests., Results: A total of 880 molecularly classified ECs, 484 from PORTEC-1 and 396 from PORTEC-2, were included. The majority were FIGO-2009 stage I EEC (97.2%). The median follow-up was 11.3 years. No locoregional recurrences were observed in EC with a pathogenic mutation of DNA polymerase-ε ( POLE mut EC). In mismatch repair-deficient (MMRd) EC, locoregional recurrence-free survival was similar after EBRT (94.2%), VBT (94.2%), and no adjuvant therapy (90.3%; P = .74). In EC with a p53 abnormality (p53abn EC), EBRT (96.9%) had a substantial benefit over VBT (64.3%) and no adjuvant therapy (72.2%; P = .048). In EC with no specific molecular profile (NSMP EC), both EBRT (98.3%) and VBT (96.2%) yielded better locoregional control than no adjuvant therapy (87.7%; P < .0001)., Conclusion: The molecular classification of EC predicts response to radiotherapy in stage I EEC and may guide adjuvant treatment decisions. Omitting radiotherapy seems to be safe in POLE mut EC. The benefit of radiotherapy seems to be limited in MMRd EC. EBRT yields a significantly better locoregional recurrence-free survival than VBT or no adjuvant therapy in p53abn EC. VBT is the treatment of choice for NSMP EC as it is as effective as EBRT and significantly better than no adjuvant therapy for locoregional tumor control.

Primary vaginal malignancies are rare, comprising only 2% of all female genital tract malignancies in adults and 4.5% in children. As part of its mission to improve the quality of care for women with gynecological cancers across Europe, the European Society of Gynaecological Oncology (ESGO) jointly with the European Society for Radiotherapy & Oncology (ESTRO) and the European Society of Pediatric Oncology (SIOPe) developed evidence-based guidelines in order to improve the management of patients with vaginal cancer within a multidisciplinary setting.ESTRO/ESGO/SIOPe nominated practicing clinicians who are involved in the management of vaginal cancer patients and have demonstrated leadership through their expertise in clinical care and research, their national and international engagement and profile as well as dedication to the topics addressed to serve on the expert panel (13 experts across Europe comprising the international development group). To ensure that the statements were evidence based, the current literature was reviewed and critically appraised.In the case of absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the international development group. Prior to publication, the guidelines were reviewed by 112 independent international practitionners in cancer care delivery and patient representatives and their comments and input were incorporated and addressed accordingly.These guidelines cover comprehensively the diagnostic pathways as well as the surgical, radiotherapeutical and systemic management and follow-up of adult patients (including those with rare histological subtypes) and pediatric patients (vaginal rhabdomyosarcoma and germ cell tumours) with vaginal tumours., Competing Interests: Competing interests: CC has reported advisory boards for GSK and MSD; SL has reported advisory boards for GSK, MSD, Novartis and AstraZeneca;MPS has reported grants and personal fees for workshops from Elekta AB; CF has reported advisory board for Roche, Tesaro, GSK, MDS/AZ, Clovis., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

In 2018, the European Society of Gynecological Oncology (ESGO) jointly with the European Society for Radiotherapy and Oncology (ESTRO) and the European Society of Pathology (ESP) published evidence-based guidelines for the management of patients with cervical cancer. Given the large body of new evidence addressing the management of cervical cancer, the three sister societies jointly decided to update these evidence-based guidelines. The update includes new topics to provide comprehensive guidelines on all relevant issues of diagnosis and treatment in cervical cancer. To serve on the expert panel (27 experts across Europe) ESGO/ESTRO/ESP nominated practicing clinicians who are involved in managing patients with cervical cancer and have demonstrated leadership through their expertise in clinical care and research, national and international engagement, profile, and dedication to the topics addressed. To ensure the statements were evidence based, new data identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the international development group. Before publication, the guidelines were reviewed by 155 independent international practitioners in cancer care delivery and patient representatives. These updated guidelines are comprehensive and cover staging, management, follow-up, long-term survivorship, quality of life and palliative care. Management includes fertility sparing treatment, early and locally advanced cervical cancer, invasive cervical cancer diagnosed on a simple hysterectomy specimen, cervical cancer in pregnancy, rare tumors, recurrent and metastatic diseases. The management algorithms and the principles of radiotherapy and pathological evaluation are also defined., Competing Interests: Declaration of competing interests CCh has reported advisory boards for GSK, MSD and EISAI; SFL has reported advisory boards for MSD, GSK, AstraZeneca and Novartis; DL has reported consultant honoria from AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Amgen, Seagen and PharmaMar, advisory boards for AstraZeneca, Merck Serono, Seagen, Immunogen, Genmab, Oncoinvest, Corcept and Sutro, research institutional funding from Clovis Oncology, GSK, MSD and PharmaMar, research sponsored by AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, Incyte, MSD, Roche, Seagen and Novartis, and speakers’ bureau activities for AstraZeneca, Clovis Oncology, GSK, MSD and PharmaMar; UM has reported advisory boards for AstraZeneca (Steering committee member for CALLA Study); RN has reported research grants from Elekta, Varian, Accuray, Dutch Research Council, and Dutch Cancer Society; AO has reported personal fees for advisory board membersip from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, EMD Serono, F. Hoffmann-La Roche, Genmab/Seagen, GSK, ImmunoGen, Itheos, Merck Sharp & Dohme de Espana, SA, Mersana Thereapeutics, Novocure, PharmaMar, piIME Oncology, Roche, Sattucklabs, Sutro Biopharma and Tesaro, and personal fees for travel/accomodation from AstraZeneca, PharmaMar and Roche; DQ has reported advisory boards for Mimark inc; MPS has reported research grants and personal fees for workshops from Elekta AB; DC, MRR, FP, CC, AF, DF, DJK, FJ, CK, PM, RN, FPec, JP, SR, AS, VS, KT, IZ and JCL have reported no conflicts of interest., (Copyright © 2023 ESGO, ESTRO, ESP. Published by Elsevier B.V. All rights reserved.)

Background: Radiotherapy (RT) is the standard of care for most advanced head and neck squamous cell carcinoma (HNSCC) and results in an unfavorable 5-year overall survival of 40%. Despite strong biological rationale, combining RT with immune checkpoint inhibitors does not result in a survival benefit. Our hypothesis is that the combination of these individually effective treatments fails because of radiation-induced immunosuppression and lymphodepletion. By integrating modern radiobiology and innovative radiotherapy concepts, the patient's immune system could be maximally retained by (1) increasing the dose per fraction so that the total dose and number of fractions can be reduced (HYpofractionation), (2) redistributing the radiation dose towards a higher peak dose within the tumor center and a lowered elective lymphatic field dose (Dose-redistribution), and (3) using RAdiotherapy with protons instead of photons (HYDRA)., Methods: The primary aim of this multicenter study is to determine the safety of HYDRA proton- and photon radiotherapy by conducting two parallel phase I trials. Both HYDRA arms are randomized with the standard of care for longitudinal immune profiling. There will be a specific focus on actionable immune targets and their temporal patterns that can be tested in future hypofractionated immunoradiotherapy trials. The HYDRA dose prescriptions (in 20 fractions) are 40 Gy elective dose and 55 Gy simultaneous integrated boost on the clinical target volume with a 59 Gy focal boost on the tumor center. A total of 100 patients (25 per treatment group) will be recruited, and the final analysis will be performed one year after the last patient has been included., Discussion: In the context of HNSCC, hypofractionation has historically only been reserved for small tumors out of fear for late normal tissue toxicity. To date, hypofractionated radiotherapy may also be safe for larger tumors, as both the radiation dose and volume can be reduced by the combination of advanced imaging for better target definition, novel accelerated repopulation models and high-precision radiation treatment planning and dose delivery. HYDRA's expected immune-sparing effect may lead to improved outcomes by allowing for future effective combination treatment with immunotherapy., Trial Registration: The trial is registered at ClinicalTrials.gov; NCT05364411 (registered on May 6th, 2022)., (© 2023. The Author(s).)

Background: The European Society of Gynaecological Oncology (ESGO) has previously defined and established a list of quality indicators for the surgical treatment of cervical cancer. As a continuation of this effort to improve overall quality of care for cervical cancer patients across all aspects, ESGO and the European SocieTy for Radiotherapy and Oncology (ESTRO) initiated the development of quality indicators for radiation therapy of cervical cancer., Objective: To develop a list of quality indicators for radiation therapy of cervical cancer that can be used to audit and improve clinical practice by giving to practitioners and administrators a quantitative basis to improve care and organizational processes, notably for recognition of the increased complexity of modern external radiotherapy and brachytherapy techniques., Methods: Quality indicators were based on scientific evidence and/or expert consensus. The development process included a systematic literature search for identification of potential quality indicators and documentation of scientific evidence, consensus meetings of a group of international experts, an internal validation process, and external review by a large international panel of clinicians (n=99)., Results: Using a structured format, each quality indicator has a description specifying what the indicator is measuring. Measurability specifications are detailed to define how the quality indicators will be measured in practice. Targets were also defined for specifying the level which each unit or center should be aiming to achieve. Nineteen structural, process, and outcome indicators were defined. Quality indicators 1-6 are general requirements related to pretreatment workup, time to treatment, upfront radiation therapy, and overall management, including active participation in clinical research and the decision making process within a structured multidisciplinary team. Quality indicators 7-17 are related to treatment indicators. Quality indicators 18 and 19 are related to patient outcomes., Discussion: This set of quality indicators is a major instrument to standardize the quality of radiation therapy in cervical cancer. A scoring system combining surgical and radiotherapeutic quality indicators will be developed within an envisaged future ESGO accreditation process for the overall management of cervical cancer, in an effort to support institutional and governmental quality assurance programs., Competing Interests: Competing interests: CC has reported personal fees and non-financial support from GSK, MSD, and AstraZeneca, and service as an investigator for clinical trials sponsored by TherAgulX and Roche. AS has reported grants for travelling and teaching from Elekta AB. RAN has reported conducting research sponsored by Elekta, Varian, and Accuray. CF has reported being on the advisory board for Roche, Tesaro, GSK, MDS/AZ, and Clovis., (© IGCS and ESGO 2023. Re-use permitted under CC BY. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Aims: External beam radiotherapy (EBRT) for prostate cancer (PCa) has rapidly advanced over the years. Advanced techniques with altered dose distributions may have an impact on second haematological cancer (SHC) risks. We assessed SHC risk after EBRT for PCa and explored whether this risk has changed over the years., Materials and Methods: Patients diagnosed with a T1-T3 PCa between 1990 and 2015 were selected from the Netherlands Cancer Registry. Patients treated with EBRT were assigned to EBRT eras based on the date of diagnosis. These eras represented two-dimensional radiotherapy (2D-RT; 1991-1996), three-dimensional conformal radiotherapy (3D-CRT; 1998-2005) or advanced EBRT (2008-2015). Standardised incidence ratios (SIR) and absolute excess risks (AER) were calculated overall and by EBRT era. Sub-hazard ratios (sHRs) were calculated for the comparison of EBRT versus radical prostatectomy and active surveillance., Results: PCa patients with EBRT as the primary treatment (n = 37 762) had an increased risk of developing a SHC (SIR = 1.20; 95% confidence interval 1.13-1.28) compared with the Dutch male general population. Estimated risks were highest for the 2D-RT era (SIR = 1.32; 95% confidence interval 1.14-1.67) compared with the 3D-CRT era (SIR = 1.16; 95% confidence interval 1.05-1.27) and the advanced EBRT era (SIR = 1.21; 95% confidence interval 1.07-1.36). AER were limited, with about five to six extra cases per 10 000 person-years. Relative risk analysis (EBRT versus radical prostatectomy/active surveillance) showed significant elevation with EBRT versus active surveillance (sHR = 1.17; 95% confidence interval 1.03-1.33; P = 0.017), but not for EBRT versus radical prostatectomy (sHR = 1.08; 95% confidence interval 0.94-1.23; P = 0.281)., Conclusion: Increased SHC risks after EBRT for PCa cancer were observed for all EBRT eras compared with the general Dutch male population. Excess risks for EBRT versus other PCa treatment groups were found for only EBRT versus active surveillance., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Risk-assessment of endometrial cancer (EC) is based on clinicopathological factors and molecular subgroup. It is unclear whether adding hormone receptor expression, L1CAM expression or CTNNB1 status yields prognostic refinement., Methods: Paraffin-embedded tumour samples of women with high-risk EC (HR-EC) from the PORTEC-3 trial (n = 424), and a Dutch prospective clinical cohort called MST (n = 256), were used. All cases were molecularly classified. Expression of L1CAM, ER and PR were analysed by whole-slide immunohistochemistry and CTNNB1 mutations were assessed with a next-generation sequencing. Kaplan-Meier method, log-rank tests and Cox's proportional hazard models were used for survival analysis., Results: In total, 648 HR-EC were included. No independent prognostic value of ER, PR, L1CAM, and CTNNB1 was found, while age, stage, and adjuvant chemotherapy had an independent impact on risk of recurrence. Subgroup-analysis showed that only in NSMP HR-EC, ER-positivity was independently associated with a reduced risk of recurrence (HR 0.33, 95%CI 0.15-0.75)., Conclusions: We confirmed the prognostic impact of the molecular classification, age, stage, and adjuvant CTRT in a large cohort of high-risk EC. ER-positivity is a strong favourable prognostic factor in NSMP HR-EC and identifies a homogeneous subgroup of NSMP tumours. Assessment of ER status in high-risk NSMP EC is feasible in clinical practice and could improve risk stratification and treatment., (© 2023. The Author(s).)

Objective: The EMBRACE-vaginal morbidity substudy prospectively evaluated physician-assessed vaginal changes and patient-reported-outcomes (PRO) on vaginal and sexual functioning problems and distress in the first 2-years after image-guided radio(chemo)therapy and brachytherapy for locally advanced cervical cancer., Methods: Eligible patients had stage IB1-IIIB cervical cancer with ≤5 mm vaginal involvement. Assessment of vaginal changes was graded using CTCAE. PRO were assessed using validated Quality-of-Life and sexual questionnaires. Statistical analysis included Generalized-Linear-Mixed-Models and Spearman's rho-correlation coefficients., Results: 113 eligible patients were included. Mostly mild (grade 1) vaginal changes were reported over time in about 20% (range 11-37%). At 2-years, 47% was not sexually active. Approximately 50% of the sexually active women reported any vaginal and sexual functioning problems and distress over time; more substantial vaginal and sexual problems and distress were reported by up to 14%, 20% and 8%, respectively. Physician-assessed vaginal changes and PRO sexual satisfaction differed significantly (p ≤ .05) between baseline and first follow-up, without further significant changes over time. No or only small associations between physician-assessed vaginal changes and PRO vaginal functioning problems and sexual distress were found., Conclusions: Mild vaginal changes were reported after image-guided radio(chemo)therapy and brachytherapy, potentially due to the combination of tumors with limited vaginal involvement, EMBRACE-specific treatment optimization and rehabilitation recommendations. Although vaginal and sexual functioning problems and sexual distress were frequently reported, the rate of substantial problems and distress was low. The lack of association between vaginal changes, vaginal functioning problems and sexual distress shows that sexual functioning is more complex than vaginal morbidity alone., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Endometrial cancer can be molecularly classified into POLE mut , mismatch repair deficient (MMRd), p53 abnormal (p53abn), and no specific molecular profile (NSMP) subgroups. We aimed to develop an interpretable deep learning pipeline for whole-slide-image-based prediction of the four molecular classes in endometrial cancer (im4MEC), to identify morpho-molecular correlates, and to refine prognostication., Methods: This combined analysis included diagnostic haematoxylin and eosin-stained slides and molecular and clinicopathological data from 2028 patients with intermediate-to-high-risk endometrial cancer from the PORTEC-1 (n=466), PORTEC-2 (n=375), and PORTEC-3 (n=393) randomised trials and the TransPORTEC pilot study (n=110), the Medisch Spectrum Twente cohort (n=242), a case series of patients with POLE mut endometrial cancer in the Leiden Endometrial Cancer Repository (n=47), and The Cancer Genome Atlas-Uterine Corpus Endometrial Carcinoma cohort (n=395). PORTEC-3 was held out as an independent test set and a four-fold cross validation was performed. Performance was measured with the macro and class-wise area under the receiver operating characteristic curve (AUROC). Whole-slide images were segmented into tiles of 360 μm resized to 224 × 224 pixels. im4MEC was trained to learn tile-level morphological features with self-supervised learning and to molecularly classify whole-slide images with an attention mechanism. The top 20 tiles with the highest attention scores were reviewed to identify morpho-molecular correlates. Predictions of a nuclear classification deep learning model serve to derive interpretable morphological features. We analysed 5-year recurrence-free survival and explored prognostic refinement by molecular class using the Kaplan-Meier method., Findings: im4MEC attained macro-average AUROCs of 0·874 (95% CI 0·856-0·893) on four-fold cross-validation and 0·876 on the independent test set. The class-wise AUROCs were 0·849 for POLE mut (n=51), 0·844 for MMRd (n=134), 0·883 for NSMP (n=120), and 0·928 for p53abn (n=88). POLE mut and MMRd tiles had a high density of lymphocytes, p53abn tiles had strong nuclear atypia, and the morphology of POLE mut and MMRd endometrial cancer overlapped. im4MEC highlighted a low tumour-to-stroma ratio as a potentially novel characteristic feature of the NSMP class. 5-year recurrence-free survival was significantly different between im4MEC predicted molecular classes in PORTEC-3 (log-rank p<0·0001). The ten patients with aggressive p53abn endometrial cancer that was predicted as MMRd showed inflammatory morphology and appeared to have a better prognosis than patients with correctly predicted p53abn endometrial cancer (p=0·30). The four patients with NSMP endometrial cancer that was predicted as p53abn showed higher nuclear atypia and appeared to have a worse prognosis than patients with correctly predicted NSMP (p=0·13). Patients with MMRd endometrial cancer predicted as POLE mut had an excellent prognosis, as do those with true POLE mut endometrial cancer., Interpretation: We present the first interpretable deep learning model, im4MEC, for haematoxylin and eosin-based prediction of molecular endometrial cancer classification. im4MEC robustly identified morpho-molecular correlates and could enable further prognostic refinement of patients with endometrial cancer., Funding: The Hanarth Foundation, the Promedica Foundation, and the Swiss Federal Institutes of Technology., Competing Interests: Declaration of interests HWN and JJJ declare grants from Merck, NH declares grants from Varian, and VHK declares research funding from Roche, unrelated to the subject of this manuscript. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: Osteoradionecrosis (ORN) is a severe late complication after radiotherapy but current knowledge on ORN risks in the setting of postoperative radiotherapy (PORT) is limited. We studied the incidence and risk factors of ORN in patients with oral cavity cancers (OCC, treated with PORT., Patients and Methods: A retrospective cohort study was conducted including OCC patients (mainly squamous cell) treated with postoperative intensity modulated radiotherapy between 2010 and 2018 with > 1 year disease-free survival. Cumulative incidences of ORN were computed using the Kaplan Meier method. Clinical and dosimetric risk factors for mandibular ORN were evaluated using Cox regression models., Results: Within our cohort (N = 227, median follow-up 49 months) we observed 46 cases of ORN, mainly in the mandible (n = 41). The cumulative incidence of mandibular ORN was 15.9 % (SE 2.5 %) at three years and 19.8 % (SE 3.0 %) at five years. At univariable analysis, smoking, mandibular mandibulotomy or segment resection, mean dose to the mandible, and mandible volume (%) ≥ 60 Gy (V60) were significantly associated with increased ORN risks. At multivariable analysis, smoking (HR 2.13, 95 %CI 1.12-4.06) and V60 (HR 1.02 per 1 % increase, 95 %CI 1.01-1.04) remained predictive factors. For active smokers with a high V60 ≥ 40 % we observed rapid ORN development with a 1-year incidence of 29 % vs 6 % for others (p < 0.01)., Conclusion: OCC Patients treated with PORT are at high risk for mandibular ORN. We identified the mandibular volume receiving ≥ 60 Gy as the dominant risk factor, especially in active smokers. Limiting high-dose volumes at treatment planning may decrease ORN risks., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Drug repurposing is an alternative development pathway that utilizes the properties of drugs approved for other diseases and builds on available safety and pharmacological data to develop the drug as a potential treatment for other diseases. A literature-based approach was performed to identify drug repurposing opportunities in cervical cancer to inform future research and trials., Methods: We queried PubMed for each drug included in two databases (ReDO&#95;DB and CDcervix&#95;DB, which include 300+ non-cancer drugs and 200+ cancer drugs not used in cervical cancer, respectively) and manually assessed all abstracts for relevance and activity in cervix cancer, and type of evidence. Subsequently, we also performed a search of clinical trial databases where we generated a list of registered trials in cervical cancer with all drugs from our databases., Results: Of the 534 drugs from both databases, 174 (33%) had at least one relevant abstract or registered trial in cervical cancer. 94 (18%) drugs had at least human data available, and 52 (10%) drugs were evaluated in registered trials. To prioritize drugs to consider for future trials, all 174 drugs were further assessed for strength of scientific rationale, feasibility for integration in cervical cancer standard of care, evidence of radiosensitization, and potential mechanism of action. Out of the 174 drugs, 38 (22%) potential drug candidates were selected., Conclusion: This study resulted in a list of candidate drugs for potential evaluation in cervical cancer. Many drugs might warrant additional (pre)clinical investigation, which could be done in a coordinated manner using platform trials., Competing Interests: Competing interests: RN receives research grants from Dutch Research Council, Dutch Cancer Society, Varian, Elekta, Accuray and is an advisory board MSD: Global Gynecologic Cancer MDT Forum 2021., (© IGCS and ESGO 2022. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Purpose: A simple scoring system (T-score, TS) for integrating findings from clinical examination and magnetic resonance imaging (MRI) of the primary tumor at diagnosis has shown strong prognostic capability for predicting local control and survival in locally advanced cervical cancer treated with chemoradiation and MRI-guided brachytherapy (BT). The aim was to validate the performance of TS using the multicenter EMBRACE I study and to evaluate the prognostic implications of TS regression obtained during initial chemoradiation., Methods and Materials: EMBRACE I recruited 1416 patients, of whom 1318 were available for TS. Patients were treated with chemoradiation followed by MRI-guided BT. A ranked ordinal scale of 0 to 3 points was used to assess 8 anatomic locations typical for local invasion of cervical cancer. TS was calculated separately at diagnosis (TS D ) and at BT (TS BT ) by the sum of points obtained from the 8 locations at the 2 occasions., Results: Median TS D and TS BT was 5 and 4, respectively. TS regression was observed in 71% and was an explanatory variable for BT technique (intracavitary vs intracavitary/interstitial) and major dose-volume histogram parameters for BT, such as high-risk clinical target (CTV HR ), CTV HR D90 (minimal dose to 90% of the target volume), D2cm 3 bladder (minimal dose to the most exposed 2 cm 3 of the bladder), and D2cm 3 rectum. TS regression (TS BT ≤5) was associated with improved local control and survival and with less morbidity compared with patients with TS BT remaining high (>5) despite initial chemoradiation. TS regression was significant in multivariate analysis for both local control and survival when analyzed in consort with already established prognostic parameters related to the patient, disease, and treatment., Conclusions: TS was validated in a multicenter setting and proven to be a strong multidisciplinary platform for integration of clinical findings and imaging with the ability to quantitate local tumor regression and its prognostic implications regarding BT technique, dose-volume histogram parameters, local control, survival, and morbidity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Approximately 15% of patients with endometrial cancer present with high-risk disease (HREC). Moreover, assessing the extent of lymphovascular space invasion (LVSI) may provide prognostic insight among patients with HREC. The aim of this study was to determine whether the extent of LVSI can serve as a prognostic factor in HREC. All cases of ESMO-ESGO-ESTRO 2016 classified HREC in the Danish Gynecological Cancer Database (DGCD) diagnosed from 2005 to 2012 were reviewed for the presence and extent of LVSI (categorized using a 3-tiered definition). We used the Kaplan-Meier analysis to calculate actuarial survival rates, both adjusted and unadjusted Cox regression analyses were used to calculate the proportional hazard ratio (HR). A total of 376 patients were included in our analysis. Among 305 patients with stage I/II HREC, 8.2% and 6.2% had focal or substantial LVSI, respectively, compared with 12.7% and 38.0% of 71 patients with stage III/IV HREC, respectively. Moreover, the estimated 5-yr recurrence-free survival rate was significantly lower among patients with substantial LVSI compared with patients with no LVSI for both stage I/II (HR: 2.8; P=0.011) and stage III/IV (HR: 2.9; P=0.003) patients. Similarly, overall survival was significantly lower among patients with substantial LVSI for both stage I/II (HR: 3.1; P<0.001) and stage III/IV (HR: 3.2; P=0.020) patients. In patients with HREC, substantial LVSI is an independent adverse prognostic factor for lymph node and distant metastases, leading to reduced survival. Thus, the extent of LVSI should be incorporated into routine pathology reports in order to guide the appropriate choice of adjuvant treatment., Competing Interests: R.A.N. reports grants by the Dutch Cancer Society, Dutch Research Council, Elekta, Varian and Accuracy, all unrelated to this work. C.L.C. reports grants from the Dutch Cancer Society. The remaining authors declare no conflict of interest., (Copyright © 2021 by the International Society of Gynecological Pathologists.)