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Background and Purpose: Image-guided adaptive brachytherapy (IGABT) is an important modality in the cervical cancer treatment, and plan quality is sensitive to time pressure in the workflow. Patient anatomy-based quality-assurance (QA) with overlap volume histograms (OVHs) has been demonstrated to detect suboptimal plans (outliers). This analysis quantifies the possible improvement of plans detected as outliers, and investigates its suitability as a clinical QA tool in a multi-center setting., Materials and Methods: In previous work OVH-based models were investigated for the use of QA. In this work a total of 160 plans of 68 patients treated in accordance with the current state-of-the-art IGABT protocol from Erasmus MC (EMC) were analyzed, with a model based on 120 plans (60 patients) from UMC Utrecht (UMCU). Machine-learning models were trained to define QA thresholds, and to predict dose D 2cm3 to bladder, rectum, sigmoid and small bowel with the help of OVHs of the EMC cohort. Plans out of set thresholds (outliers) were investigated and retrospectively replanned based on predicted D 2cm3 values., Results: Analysis of replanned plans demonstrated a median improvement of 0.62 Gy for all Organs At Risk (OARs) combined and an improvement for 96 % of all replanned plans. Outlier status was resolved for 36 % of the replanned plans. The majority of the plans that could not be replanned were reported having implantation complications or insufficient coverage due to tumor geometry., Conclusion: OVH-based QA models can detect suboptimal plans, including both unproblematic BT applications and suboptimal planning circumstances in general. OVH-based QA models demonstrate potential for clinical use in terms of performance and user-friendliness, and could be used for knowledge transfer between institutes. Further research is necessary to differentiate between (sub)optimal planning circumstances., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: To investigate relationships between patient-reported acute gastro-intestinal symptoms in a locally advanced cervical cancer (LACC) prospective cohort and clinical and dosimetric parameters, while also taking spatial dose into account., Material and Methods: A total of 103 patients was included, receiving radiotherapy based on a plan-library-based plan-of-the-day protocol, combined either with concurrent chemotherapy or with neo-adjuvant chemotherapy and concomitant hyperthermia. Toxicity endpoints were extracted from questionnaires sent out weekly during treatment and regularly in the acute phase after treatment. Endpoints were defined for symptoms concerning obstipation, diarrhea, fecal leakage, bowel cramps and rectal bleeding. Dose surface maps were constructed for the rectum. Clinical parameters and dosimetric parameters of the bowel bag and rectum were collected for all patients., Results: The use of concomitant chemotherapy and an increase in Planning Target Volume (PTV) resulted in a significant increase in reported diarrhea. The dose-volume parameters V 5Gy -V 25Gy of the rectum were found to be significant, unlike dose-volume parameters of the bowel bag. Additionally, a significantly higher dose to the inferior part of the rectum was found for patients reporting diarrhea. No significance was reached for fecal leakage and bowel cramps., Conclusion: The significance of results for patients reporting diarrhea symptoms found for PTV volume indicates a potential benefit for a plan-of-the-day protocol. Additionally, the results suggest that a reduction of inferior rectum dose could decrease patient-reported diarrhea symptoms, while the administration of concomitant chemotherapy appears to lead to radiosensitizing effects that increase these symptoms., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

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.)

Purpose: To develop and validate fully automated generation of VMAT plan-libraries for plan-of-the-day adaptive radiotherapy in locally-advanced cervical cancer., Material and Methods: Our framework for fully automated treatment plan generation (Erasmus-iCycle) was adapted to create dual-arc VMAT treatment plan libraries for cervical cancer patients. For each of 34 patients, automatically generated VMAT plans (autoVMAT) were compared to manually generated, clinically delivered 9-beam IMRT plans (CLINICAL), and to dual-arc VMAT plans generated manually by an expert planner (manVMAT). Furthermore, all plans were benchmarked against 20-beam equi-angular IMRT plans (autoIMRT). For all plans, a PTV coverage of 99.5% by at least 95% of the prescribed dose (46 Gy) had the highest planning priority, followed by minimization of V45Gy for small bowel (SB). Other OARs considered were bladder, rectum, and sigmoid., Results: All plans had a highly similar PTV coverage, within the clinical constraints (above). After plan normalizations for exactly equal median PTV doses in corresponding plans, all evaluated OAR parameters in autoVMAT plans were on average lower than in the CLINICAL plans with an average reduction in SB V45Gy of 34.6% (p<0.001). For 41/44 autoVMAT plans, SB V45Gy was lower than for manVMAT (p<0.001, average reduction 30.3%), while SB V15Gy increased by 2.3% (p = 0.011). AutoIMRT reduced SB V45Gy by another 2.7% compared to autoVMAT, while also resulting in a 9.0% reduction in SB V15Gy (p<0.001), but with a prolonged delivery time. Differences between manVMAT and autoVMAT in bladder, rectal and sigmoid doses were ≤ 1%. Improvements in SB dose delivery with autoVMAT instead of manVMAT were higher for empty bladder PTVs compared to full bladder PTVs, due to differences in concavity of the PTVs., Conclusions: Quality of automatically generated VMAT plans was superior to manually generated plans. Automatic VMAT plan generation for cervical cancer has been implemented in our clinical routine. Due to the achieved workload reduction, extension of plan libraries has become feasible., Competing Interests: This study is partially funded by Elekta (www.elekta.com), which develops tools and treatment planning systems for radiation therapy, and the Dutch Cancer Society (Grant EMCR 2012-5396).

Background and Purpose: With the introduction of Intensity Modulated Radiotherapy (IMRT) and image-guided plan-of-the-day strategies, the treatment of cervical cancer has become more sensitive to intra-fraction uncertainties. In this study we quantified intra-fraction changes in cervix-uterus shape, bladder and rectum filling, and patient setup using pre- and post-fraction CBCT scans., Materials and Methods: A total of 632 CBCT scans were analyzed for 16 patients with large tip-of-uterus displacement (>2.5 cm) measured in an empty and full bladder CT scan. In all scans, the bladder, cervix-uterus, and rectum were delineated. For rectum and bladder, intra-fraction volume changes were assessed. Systematic cervix-uterus intra-fraction displacements were obtained by non-rigidly aligning the pre-fraction cervix-uterus to that in the post-fraction CBCT. Intra-fraction patient setup changes were obtained by rigidly aligning pre- and post-CBCTs using the bony anatomy., Results: The mean time between pre- and post-fraction CBCT scan was 20.8 min. The group-mean intra-fraction displacements averaged over the cervix-uterus were 0.1±1.4/1.8±1.5/-2.8±1.8 (LR/CC/AP) mm. The group-mean 5th and 95th percentile intra-fraction displacements were -2.3,2.1/-0.8,4.9/-5.8,0.5 (LR/CC/AP) mm. There was a significant correlation between bladder inflow rate and cervix-uterus motion (r=0.6 and p<0.01). Intra-fraction changes in patient setup were 1.3/0.4/0.6 and 1.4/1.0/1.1 mm (LR/CC/AP), for systematic and random changes, respectively., Conclusion: Intra-fraction cervix-uterus motion can be considerable and should be taken into account using appropriate PTV margins., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: In a published study on cervical cancer, 5-beam IMRT was inferior to single arc VMAT. Here we compare 9, 12, and 20 beam IMRT with single and dual arc VMAT., Material and Methods: For each of 10 patients, automated plan generation with the in-house Erasmus-iCycle optimizer was used to assist an expert planner in generating the five plans with the clinical TPS., Results: For each patient, all plans were clinically acceptable with a high and similar PTV coverage. OAR sparing increased when going from 9 to 12 to 20 IMRT beams, and from single to dual arc VMAT. For all patients, 12 and 20 beam IMRT were superior to single and dual arc VMAT, with substantial variations in gain among the study patients. As expected, delivery of VMAT plans was significantly faster than delivery of IMRT plans., Conclusions: Often reported increased plan quality for VMAT compared to IMRT has not been observed for cervical cancer. Twenty and 12 beam IMRT plans had a higher quality than single and dual arc VMAT. For individual patients, the optimal delivery technique depends on a complex trade-off between plan quality and treatment time that may change with introduction of faster delivery systems., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To evaluate the clinical implementation of an online adaptive plan-of-the-day protocol for nonrigid target motion management in locally advanced cervical cancer intensity modulated radiation therapy (IMRT)., Methods and Materials: Each of the 64 patients had four markers implanted in the vaginal fornix to verify the position of the cervix during treatment. Full and empty bladder computed tomography (CT) scans were acquired prior to treatment to build a bladder volume-dependent cervix-uterus motion model for establishment of the plan library. In the first phase of clinical implementation, the library consisted of one IMRT plan based on a single model-predicted internal target volume (mpITV), covering the target for the whole pretreatment observed bladder volume range, and a 3D conformal radiation therapy (3DCRT) motion-robust backup plan based on the same mpITV. The planning target volume (PTV) combined the ITV and nodal clinical target volume (CTV), expanded with a 1-cm margin. In the second phase, for patients showing >2.5-cm bladder-induced cervix-uterus motion during planning, two IMRT plans were constructed, based on mpITVs for empty-to-half-full and half-full-to-full bladder. In both phases, a daily cone beam CT (CBCT) scan was acquired to first position the patient based on bony anatomy and nodal targets and then select the appropriate plan. Daily post-treatment CBCT was used to verify plan selection., Results: Twenty-four and 40 patients were included in the first and second phase, respectively. In the second phase, 11 patients had two IMRT plans. Overall, an IMRT plan was used in 82.4% of fractions. The main reasons for selecting the motion-robust backup plan were uterus outside the PTV (27.5%) and markers outside their margin (21.3%). In patients with two IMRT plans, the half-full-to-full bladder plan was selected on average in 45% of the first 12 fractions, which was reduced to 35% in the last treatment fractions., Conclusions: The implemented online adaptive plan-of-the-day protocol for locally advanced cervical cancer enables (almost) daily tissue-sparing IMRT., (Copyright © 2014 Elsevier Inc. All rights reserved.)