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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.)

Definitive chemoradiotherapy (dCRT) is a potentially curative therapy for esophageal cancer. As indications for dCRT differ widely, it is challenging to draw conclusions on outcomes and survival. The aim of this study was to evaluate overall survival (OS) and recurrence patterns according to indications for treatment. Patients who underwent dCRT (50.4 Gy concomitant with carboplatin/paclitaxel) for esophageal cancer between 2012 and 2022 were identified. Indications for dCRT were: cervical tumor, irresectable disease, unfit for surgery, and patient and/or physician preference. The primary endpoint was OS calculated with the Kaplan-Meier method. Secondary endpoints included the proportion of patients that completed the dCRT regimen, 30- and 90-day mortality, and disease recurrence. One hundred and fifty-seven patients were included (72.6% esophageal squamous cell carcinoma) with a median follow-up of 20 months (IQR 10.0-43.9). The full dCRT regimen was completed by 116 patients (73.9%). Thirty- and 90-day mortality were 2.5% and 8.3%, respectively. Median and 5-year OS for all patients were 22.9 months (95% CI 18.0-27.9) and 31.4%, respectively. The median OS per indication was 23.7 months (95% CI 6.5-40.8) for patients with cervical tumors, 10.9 months (95% 0.0-23.2) for irresectable disease, 28.2 months (95% CI 12.3-44.0) for unfit patients, and 22.9 months (95% CI 15.4-30.5) for patients' preference for dCRT (P = 0.11). Disease recurrence was observed in 74 patients (46%), located locoregionally (46%), distant (19%), or combined (35%). Patients who underwent dCRT had a 5-year OS of 31.4%, but OS differed according to indications for treatment with patients who had irresectable disease having the worst prognosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.)

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.)

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.

Objective: Microcystic, elongated fragmented (MELF) pattern of myometrial invasion is a distinct histologic feature occasionally seen in low-grade endometrial carcinomas (EC). The prognostic relevance of MELF invasion was uncertain due to conflicting data, and it had not yet appropriately been studied in the context of the molecular EC classification. We aimed to determine the relation of MELF invasion with clinicopathological and molecular characteristics, and define its prognostic relevance in early-stage low/intermediate risk EC., Methods: Single whole tumor slides of 979 (85.8%) out of 1141 (high)intermediate-risk EC of women who participated in the PORTEC-1/-2 trials were available for review. Clinicopathological and molecular features were compared between MELF invasion positive and negative cases. Time-to-event analyses were done by Kaplan-Meier method, log-rank tests and Cox' proportional hazards models., Results: MELF invasion was found in 128 (13.1%) cases, and associated with grade 1-2 histology, deep myometrial invasion and substantial lymph-vascular space invasion (LVSI). 85.6% of MELF invasion positive tumors were no-specific-molecular-profile (NSMP) EC. NSMP EC with MELF invasion were CTNNB1 wild type in 92.2% and KRAS mutated in 24.4% of cases. Risk of recurrence was lower for MELF invasion positive as compared to MELF invasion negative cases (4.9% vs. 12.7%, p = 0.026). However, MELF invasion had no independent impact on risk of recurrence (HR 0.65, p = 0.30) after correction for clinicopathological and molecular factors., Conclusions: MELF invasion has no independent impact on risk of recurrence in early-stage EC, and is frequently observed in low-grade NSMP tumors. Routine assessment of MELF invasion has no clinical implications and is not recommended., Competing Interests: Declaration of Competing Interest ASVMvdH, NH and CLC report a grant from the Dutch Cancer Society (unrelated). NH reports grant from Varian (unrelated), CLC reports grants from Varian (unrelated) and Elekta (non-financial, unrelated), IDMC membership Merck (unrelated) and chair Endometrial committee CGIG., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Lymphovascular space invasion (LVSI) occurs in a minority of endometrial cancer (EC) cases, and the extent of LVSI is an important risk factor for recurrence and/or metastases. Our aim was to improve the reproducibility of measuring clinically meaningful LVSI by performing a quantitative analysis of the correlation between LVSI and the risk of pelvic lymph node recurrence in EC. EC samples from PORTEC-1 and PORTEC-2 trials were retrieved and used to collect quantitative data, including the number of LVSI-positive vessels per H&E-stained slide. Using a predefined threshold for clinical relevance, the risk of pelvic lymph node recurrence risk was calculated (Kaplan-Meier method, with Cox regression) using a stepwise adjustment for the number of LVSI-positive vessels. This analysis was then repeated in the Danish Gynecological Cancer Database (DGCD) cohort. Among patients in PORTEC-1 and PORTEC-2 trials who did not receive external beam radiotherapy, the 5-yr pelvic lymph node recurrence risk was 3.3%, 6.7% (P=0.51), and 26.3% (P<0.001), respectively when 0, 1 to 3, or ≥4 vessels had LVSI involvement; similar results were obtained for the DGCD cohort. Furthermore, both the average number of tumor cells in the largest embolus and the number of LVSI-positive H&E slides differed significantly between focal LVSI and substantial LVSI. On the basis of these results, we propose a numeric threshold (≥4 LVSI-involved vessels in at least one H&E slide) for defining clinically relevant LVSI in EC, thereby adding supportive data to the semiquantitative approach. This will help guide gynecologic pathologists to differentiate between focal and substantial LVSI, especially in borderline cases., Competing Interests: R.N. reports grants by the Dutch Cancer Society, Dutch Research Council, Elekta, Varian and Accuracy, all unrelated to this work. C.C. reports grants by the Dutch Cancer Society. The remaining authors declare no conflict of interest., (Copyright © 2021 by the International Society of Gynecological Pathologists.)

External beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy is a very effective treatment for locally advanced cervical cancer (LACC). However, treatment-related toxicity is common and reduces the patient's quality of life (QoL) and ability to complete treatment or undergo adjuvant therapies. Intensity modulated proton therapy (IMPT) enables a significant dose reduction in organs at risk (OAR), when compared to that of standard intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). However, clinical studies evaluating whether IMPT consequently reduces side effects for LACC are lacking. The PROTECT trial is a nonrandomized prospective multicenter phase-II-trial comparing clinical outcomes after IMPT or IMRT/VMAT in LACC. Thirty women aged >18 years with a histological diagnosis of LACC will be included in either the IMPT or IMRT/VMAT group. Treatment includes EBRT (45 Gy in 25 fractions of 1.8 Gy), concurrent five weekly cisplatin (40 mg/m 2 ), and 3D image (MRI)-guided adaptive brachytherapy. The primary endpoint is pelvic bones D mean and mean bowel V 15Gy . Secondary endpoints include dosimetric parameters, oncological outcomes, health-related QoL, immune response, safety, and tolerability. This study provides the first data on the potential of IMPT to reduce OAR dose in clinical practice and improve toxicity and QoL for patients with LACC.

Background: Decision making regarding adjuvant therapy for high-risk endometrial cancer is complex. The aim of this study was to determine patients' and clinicians' minimally desired survival benefit to choose chemoradiotherapy over radiotherapy alone. Moreover, influencing factors and importance of positive and negative treatment effects (i.e. attribute) were investigated., Methods: Patients with high-risk endometrial cancer treated with adjuvant pelvic radiotherapy with or without chemotherapy and multidisciplinary gynaecologic oncology clinicians completed a trade-off questionnaire based on PORTEC-3 trial data., Results: In total, 171 patients and 63 clinicians completed the questionnaire. Median minimally desired benefit to make chemoradiotherapy worthwhile was significantly higher for patients versus clinicians (10% vs 5%, p = 0.02). Both patients and clinicians rated survival benefit most important during decision making, followed by long-term symptoms. Older patients (OR 0.92 [95%CI 0.87-0.97]; p = 0.003) with comorbidity (OR 0.34 [95% CI 0.12-0.89]; p = 0.035) had lower preference for chemoradiotherapy, while patients with better numeracy skills (OR 1.2 [95%CI 1.05-1.36], p = 0.011) and chemoradiotherapy history (OR 25.0 [95%CI 8.8-91.7]; p < 0.001) had higher preference for chemoradiotherapy., Conclusions: There is a considerable difference in minimally desired survival benefit of chemoradiotherapy in high-risk endometrial cancer among and between patients and clinicians. Overall, endometrial cancer patients needed higher benefits than clinicians before preferring chemoradiotherapy., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The PORTEC-4a trial investigates molecular-integrated risk profile guided adjuvant treatment for endometrial cancer. The quality assurance programme included a dummy run for vaginal brachytherapy prior to site activation, and annual quality assurance to verify protocol adherence. Aims of this study were to evaluate vaginal brachytherapy quality and protocol adherence., Methods: For the dummy run, institutes were invited to create a brachytherapy plan on a provided CT-scan with the applicator in situ. For annual quality assurance, institutes provided data of one randomly selected brachytherapy case. A brachytherapy panel reviewed and scored the brachytherapy plans according to a checklist., Results: At the dummy run, 15 out of 21 (71.4%) institutes needed adjustments of delineation or planning. After adjustments, the mean dose at the vaginal apex (protocol: 100%; 7 Gy) decreased from 100.7% to 99.9% and range and standard deviation (SD) narrowed from 83.6-135.1 to 96.4-101.4 and 8.8 to 1.1, respectively. At annual quality assurance, 22 out of 27 (81.5%) cases had no or minor and 5 out of 27 (18.5%) major deviations. Most deviations were related to delineation, mean dose at the vaginal apex (98.0%, 74.7-114.2, SD 7.6) or reference volume length., Conclusions: Most feedback during the brachytherapy quality assurance procedure of the PORTEC-4a trial was related to delineation, dose at the vaginal apex and the reference volume length. Annual quality assurance is essential to promote protocol compliance, ensuring high quality vaginal brachytherapy in all participating institutes., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Vaginal brachytherapy is currently recommended as adjuvant treatment in patients with high-intermediate risk endometrial cancer to maximize local control and has only mild side effects and no or limited impact on quality of life. However, there is still considerable overtreatment and also some undertreatment, which may be reduced by tailoring adjuvant treatment to the patients' risk of recurrence based on molecular tumor characteristics., Primary Objectives: To compare the rates of vaginal recurrence in women with high-intermediate risk endometrial cancer, treated after surgery with molecular-integrated risk profile-based recommendations for either observation, vaginal brachytherapy or external pelvic beam radiotherapy or with standard adjuvant vaginal brachytherapy STUDY HYPOTHESIS: Adjuvant treatment based on a molecular-integrated risk profile provides similar local control and recurrence-free survival as current standard adjuvant brachytherapy in patients with high-intermediate risk endometrial cancer, while sparing many patients the morbidity of adjuvant treatment and reducing healthcare costs., Trial Design: A multicenter, international phase III randomized trial (2:1) of molecular-integrated risk profile-based adjuvant treatment (experimental arm) or adjuvant vaginal brachytherapy (standard arm)., Major Inclusion/exclusion Criteria: Women aged 18 years and over with a histological diagnosis of high-intermediate risk endometrioid endometrial cancer after total abdominal or laparoscopic hysterectomy and bilateral salpingo-oophorectomy. High-intermediate risk factors are defined as: (i) International Federation of Gynecology and Obstetrics stage IA (with invasion) and grade 3; (ii) stage IB grade 1 or 2 with age ≥60 and/or lymph-vascular space invasion; (iii) stage IB, grade 3 without lymph-vascular space invasion; or (iv) stage II (microscopic and grade 1)., Endpoints: The primary endpoint is vaginal recurrence. Secondary endpoints are recurrence-free and overall survival; pelvic and distant recurrence; 5-year vaginal control (including treatment for relapse); adverse events and patient-reported symptoms and quality of life; and endometrial cancer-related healthcare costs., Sample Size: 500 eligible and evaluable patients., Estimated Dates for Completing Accrual and Presenting Results: Estimated date for completing accrual will be late 2021. Estimated date for presentation of (first) results is expected in 2023., Trial Registration: The trial is registered at clinicaltrials.gov (NCT03469674) and ISRCTN (11659025)., Competing Interests: Competing interests: ASVMvdH and NH report a research grant from the Dutch Cancer Society, during the conduct of the PORTEC-4a study. HWN reports non-financial support from Merck, grants from the Dutch Cancer Society, grants from AIMM, outside the submitted work. RAN reports grants from the Dutch Cancer Society, grants from the Dutch Research Council, grants from Elekta, grants from Varian, grants from Accuray, outside the submitted work. CC reports non-financial support from Roche, non-financial support from TherAguix, personal fees from Elekta, personal fees from MSD, personal fees from GSK, outside the submitted work. CLC reports grants from the Dutch Cancer Society, non-financial support from Elekta-Nucletron, during the conduct of the PORTEC-4a study. SK reports personal fees from GSK, personal fees from Roche, personal fees from MSD, personal fees from AstraZeneca, outside the submitted work., (© IGCS and ESGO 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Addition of deep hyperthermia results in improved local control (LC) and overall survival (OS) compared to radiotherapy alone in patients with cervical carcinoma. Previously, we showed that the thermal dose of hyperthermia significantly correlates with LC and disease specific survival (DSS). Over the last decade, new radiation techniques were introduced resulting in improved LC., Aim: To validate the effect of thermal dose in a more recent cohort of patients treated with modern radiotherapy techniques, including image guided brachytherapy (IGBT)., Methods: We analyzed primary cervical carcinoma patients treated with a combination of radiotherapy and deep hyperthermia between 2005 and 2016 at our institute. Data on patient, tumor and treatment were collected including the thermal dose parameters TRISE and CEM43T90. Follow-up data on LC, disease free survival, DSS, OS as well as late toxicity data were collected. Data were analyzed using the Cox proportional hazard and Kaplan-Meier analyses., Results: 227 patients were included. In multivariate analysis, histology, FIGO stage, lymphadenopathy, TRISE, CEM43T90 and IGBT had a significant effect on LC. In the patients treated with IGBT, the thermal dose parameter TRISE remained to have a significant effect on LC in univariate analysis., Conclusions: The positive association between thermal dose and clinical outcome is replicated in an independent, recent cohort of cervical carcinoma patients. Importantly, in patients receiving IGBT, the effect of thermal dose on clinical outcome is still observed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Addition of deep hyperthermia to radiotherapy results in improved local control (LC) and overall survival compared to radiotherapy alone in cervical carcinoma patients. Based on preclinical data, the time interval between radiotherapy, and hyperthermia is expected to influence treatment outcome. Clinical studies addressing the effect of time interval are sparse. The repercussions for clinical applications are substantial, as the time between radiotherapy and hyperthermia should be kept as short as possible. In this study, we therefore investigated the effect of the time interval between radiotherapy and hyperthermia on treatment outcome. Methods: We analyzed all primary cervical carcinoma patients treated between 1996 and 2016 with thermoradiotherapy at our institute. Data on patients, tumors and treatments were collected, including the thermal dose parameters TRISE and CEM43T90. Follow-up data on tumor status and survival as well as late toxicity were collected. Data was analyzed using Cox proportional hazards analysis and Kaplan Meier analysis. Results: 400 patients were included. Kaplan Meier and univariate Cox analysis showed no effect of the time interval (range 30-230 min) on any clinical outcome measure. Besides known prognostic factors, thermal dose parameters TRISE and CEM43T90 had a significant effect on LC. In multivariate analysis, the thermal dose parameter TRISE (HR 0.649; 95% CI 0.501-0.840) and the use of image guided brachytherapy (HR 0.432; 95% CI 0.214-0.972), but not the time interval, were significant predictors of LC and disease specific survival. Conclusions: The time interval between radiotherapy and hyperthermia, up to 4 h, has no effect on clinical outcome. These results are re-ensuring for our current practice of delivering hyperthermia within maximal 4 h after radiotherapy.

Background: PORTEC-2 was a randomised trial for women with high-intermediate risk (HIR) endometrial cancer, comparing pelvic external beam radiotherapy (EBRT) with vaginal brachytherapy (VBT). We evaluated long-term outcomes combined with the results of pathology review and molecular analysis., Methods: 427 women with HIR endometrial cancer were randomised between 2002-2006 to VBT or EBRT. Primary endpoint was vaginal recurrence (VR). Pathology review was done in 97.4%, combined with molecular analysis., Results: Median follow-up was 116 months; 10-year VR was 3.4% versus 2.4% for VBT vs. EBRT (p = 0.55). Ten-year pelvic recurrence (PR) was more frequent in the VBT group (6.3% vs. 0.9%, p = 0.004), mostly combined with distant metastases (DM). Ten-year isolated PR was 2.5% vs. 0.5%, p = 0.10, and DM 10.4 vs. 8.9% (p = 0.45). Overall survival for VBT vs. EBRT was 69.5% vs. 67.6% at 10 years (p = 0.72). L1CAM and p53-mutant expression and substantial lymph-vascular space invasion were risk factors for PR and DM. EBRT reduced PR in cases with these risk factors., Conclusion: Long-term results of the PORTEC-2 trial confirm VBT as standard adjuvant treatment for HIR endometrial cancer. Molecular risk assessment has the potential to guide adjuvant therapy. EBRT provided better pelvic control in patients with unfavourable risk factors.

Purpose: Library-of-plans ART is used to manage daily anatomy changes in locally advanced cervical cancer. In our institute, the library contains 2 VMAT plans for patients with large cervix-uterus motion. Increasing this number could be beneficial for tissue sparing, but is burdensome while the dosimetric gain is yet unclear. This study's aim is to determine the optimal number of plans at an individual patient level., Material and Methods: Data of 14 treated patients were analyzed. Plan libraries were created containing 1-4 VMAT plans. Pre-treatment extent of uterus motion was defined by the 99th percentile of the Hausdorff distance (HD99). For dosimetric evaluations, OARs were contoured in daily CBCT scans, plan selection was simulated, and the V 45Gy and V 40Gy parameters were recorded., Results: Moderate to strong correlations were found between HD99 and the volume of spared OARs. All patients benefitted from adding a 2nd plan, as is the clinical practice. For patients with a HD99 between 30 and 50mm, a 3-plan library reduced the composite V 40Gy with 11-21ml compared to a 2-plan library., Conclusion: Patients with large uterus motion (HD99>30mm) would benefit from an extension of the plan library to 3. HD99 is an easy-to-implement criteria to select those patients pre-treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: For locally advanced cervical cancer patients, treated with External Beam Radiotherapy (EBRT), Quality of Life (QoL) questionnaires arefrequently used to evaluate treatment-related symptoms and functioning scales. Currently, it is unknown how those evolve during the radiation treatment course. In this prospective study we report on weekly-captured patient-reported QoL and symptoms during image-guided adaptive radiotherapy (IGART) of cervical cancer patients., Material and Methods: Between January 2012 and September 2016, all locally advanced cervical cancer patients treated with IGART and brachytherapy with or without chemotherapy or hyperthermia, were eligible. QoL was assessed at baseline; weekly during the first five weeks of treatment; 1week, 1 and 3months after treatment, using the EORTC QLQ-C30 and the QLQ-CX24 questionnaires. Comparisons were made with an age-matched norm population., Results: Among the 138 (70%) responders, most symptoms showed a moderate-to-large increase, reaching a maximum at the end of treatment, or first week after treatment with return to baseline value at 3months after treatment. While most symptoms gradually increased during the first five weeks, diarrhea and bowel cramps already markedly increased within the first three weeks to reach a plateau at the 5th week of treatment. Global health and functioning were temporarily decreased and returned to a plateau at baseline level 3months after treatment, except for cognitive functioning., Conclusion: A profound impact on QoL was observed during the radiation treatment course, temporarily affecting functioning. The maximum impaired was reached at the end of EBRT., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose/objective: It is unknown whether the historically found dosimetric advantages of treating gynecologic cancer with the patient in a prone position with use of a small-bowel displacement device (belly-board) remain when volumetric arc therapy (VMAT) is used and whether these advantages depend on the necessary margin between clinical target volume (CTV) and planning target volume (PTV). The aim of this study is to determine the best patient position (prone or supine) in terms of sparing organs at risk (OAR) for various CTV-to-PTV margins and VMAT dose delivery., Methods and Materials: In an institutional review board-approved study, 26 patients with gynecologic cancer scheduled for primary (9) or postoperative (17) radiation therapy were scanned in a prone position on a belly-board and in a supine position on the same day. The primary tumor CTV, nodal CTV, bladder, bowel, and rectum were delineated on both scans. The PTVs were created each with a different margin for the primary tumor and nodal CTV. The VMAT plans were generated with our in-house system for automated treatment planning. For all margin combinations, the supine and prone plans were compared with consideration of all OAR dose-volume parameters but with highest priority given to bowel cavity V45Gy (cm(3))., Results: For both groups, the prone position reduced the bowel cavity V45Gy, in particular for nodal margins ≥10 mm (ΔV45Gy = 23.9 ± 10.6 cm(3)). However, for smaller margins, the advantage was much less pronounced (ΔV45Gy = 6.5 ± 3.0 cm(3)) and did not reach statistical significance. The rectum mean dose (Dmean) was significantly lower (ΔDmean = 2.5 ± 0.3 Gy) in the prone position for both patient groups and for all margins, and the bladder Dmean was significantly lower in the supine position (ΔDmean = 2.6 ± 0.4 Gy) only for the postoperative group. The advantage of the prone position was not present if it needed a larger margin than the supine position., Conclusion: For patients with gynecologic cancer, the historically found dosimetric advantages for the prone position remain for modern dose delivery techniques if large margins are needed. However, the advantage is lost for small margins and if the prone position needs a larger margin than the supine position., (Copyright © 2016 Elsevier Inc. All rights reserved.)