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Background The randomized clinical trial ESO-SPARE investigates if oesophagus-sparing radiotherapy (RT) can reduce dysphagia in patients with metastatic spinal cord compression (MSCC). Patient-reported outcome (PRO) is the only follow-up measure. Due to the fragile patient population, low respondent compliance was anticipated. We performed a planned interim analysis of dosimetry and respondent compliance, to ensure that the protocol requirements were met. Methods Patients >18 years referred for cervical/thoracic MSCC radiotherapy in 1-10 fractions were included from two centres. Patients were randomized (1:1) to standard RT or oesophagus-sparing RT, where predefined oesophageal dose constraints were prioritized over target coverage. Patients completed a trial diary with daily reports of dysphagia for 5 weeks (PRO-CTC-AE) and weekly quality of life reports for 9 weeks (QLQ-C30, EQ-5D-5L). According to power calculation, 124 patients are needed for primary endpoint analysis. The sample size was inflated to 200 patients to account for the fragile patient population. The co-primary endpoints, peak patient-reported dysphagia, and preserved ability to walk (EQ-5D-5L), are analysed at 5 and 9 weeks, respectively. The interim analysis was conducted 90 days after the inclusion of patient no 100. Respondent compliance was assessed at 5 and 9 weeks. In all RT plans, oesophagus and target doses were evaluated regarding adherence to protocol constraints. Results From May 2021 to November 2022, 100 patients were included. Fifty-two were randomized to oesophagus-sparing RT. In 23% of these plans, oesophagus constraints were violated. Overall, the dose to both target and oesophagus was significantly lower in the oesophagus-sparing plans. Only 51% and 41% of the patients were evaluable for co-primary endpoint analysis at five and nine weeks, respectively. Mortality and hospitalization rates were significantly larger in patients who completed <4 da, BACKGROUND: The randomized clinical trial ESO-SPARE investigates if oesophagus-sparing radiotherapy (RT) can reduce dysphagia in patients with metastatic spinal cord compression (MSCC). Patient-reported outcome (PRO) is the only follow-up measure. Due to the fragile patient population, low respondent compliance was anticipated. We performed a planned interim analysis of dosimetry and respondent compliance, to ensure that the protocol requirements were met.METHODS: Patients >18 years referred for cervical/thoracic MSCC radiotherapy in 1-10 fractions were included from two centres. Patients were randomized (1:1) to standard RT or oesophagus-sparing RT, where predefined oesophageal dose constraints were prioritized over target coverage. Patients completed a trial diary with daily reports of dysphagia for 5 weeks (PRO-CTC-AE) and weekly quality of life reports for 9 weeks (QLQ-C30, EQ-5D-5L). According to power calculation, 124 patients are needed for primary endpoint analysis. The sample size was inflated to 200 patients to account for the fragile patient population. The co-primary endpoints, peak patient-reported dysphagia, and preserved ability to walk (EQ-5D-5L), are analysed at 5 and 9 weeks, respectively. The interim analysis was conducted 90 days after the inclusion of patient no 100. Respondent compliance was assessed at 5 and 9 weeks. In all RT plans, oesophagus and target doses were evaluated regarding adherence to protocol constraints.RESULTS: From May 2021 to November 2022, 100 patients were included. Fifty-two were randomized to oesophagus-sparing RT. In 23% of these plans, oesophagus constraints were violated. Overall, the dose to both target and oesophagus was significantly lower in the oesophagus-sparing plans. Only 51% and 41% of the patients were evaluable for co-primary endpoint analysis at five and nine weeks, respectively. Mortality and hospitalization rates were significantly larger in patients who completed <4 days PRO quest

Introduction: The prospective TEDDI protocol investigates the feasibility of radiotherapy delivery in deep inspiration breath-hold (DIBH) for pediatric patients. To secure optimal radiotherapy planning, a diagnostic baseline FDG PET/CT in free breathing (FB) and DIBH was acquired. The anatomical changes in the mediastinum and the effect on PET metrics between the two breathing conditions were assessed for pediatric patients with mediastinal lymphoma. Material and methods: Ten patients aged 5–17 were included and had a PET/CT in FB and DIBH. Metabolic active lymphoma volumes were manually delineated with a visually based segmentation method and the PET metrics were extracted. The anatomical lymphoma, lung and heart volumes were delineated on CT. Results: The lung volume increased while the heart was displaced caudally and separated from the lymphoma in DIBH compared to FB. Both the anatomical and the metabolically active lymphoma volumes appeared different regarding shape and configuration in the two breathing conditions. The image quality of the DIBH PET was equal to the FB PET regarding interpretation and delineation of lymphoma lesions. All PET metrics increased on the DIBH PET compared to the FB PET with the highest increase observed for the maximum standardized uptake value (33%, range 7–56%). Conclusion: Diminished respiratory motion together with anatomical changes within the lymphoma increased all PET metrics in DIBH compared to FB. The anatomical changes observed in DIBH compared to FB are expected to reduce radiation doses to the heart and lungs in pediatric patients with mediastinal lymphoma referred for radiotherapy delivery in DIBH and, thereby, reduce their risk of late effects. Trial registration: The Danish Ethical Committee (H-16035870, approved November 24th 2016), the Danish Data Protection Agency (2012-58-0004, approved 1 January 2017). Registered retrospectively at clinicaltrials.gov (NCT03315546, 20 October 2017).

At its core, radiation therapy (RT) requires balancing therapeutic effects against risk of adverse events in cancer survivors. The radiation oncologist weighs numerous disease and patient-level factors when considering the expected risk–benefit ratio of combined treatment modalities. As part of this, RT plan optimization software is used to find a clinically acceptable RT plan delivering a prescribed dose to the target volume while respecting pre-defined radiation dose–volume constraints for selected organs at risk. The obvious limitation to the current approach is that it is virtually impossible to ensure the selected treatment plan could not be bettered by an alternative plan providing improved disease control and/or reduced risk of adverse events in this individual. Outcome-based optimization refers to a strategy where all planning objectives are defined by modeled estimates of a specific outcome’s probability. Noting that various adverse events and disease control are generally incommensurable, leads to the concept of a Pareto-optimal plan: a plan where no single objective can be improved without degrading one or more of the remaining objectives. Further benefits of outcome-based multi objective optimization are that quantitative estimates of risks and benefit are obtained as are the effects of choosing a different trade-off between competing objectives. Furthermore, patient-level risk factors and combined treatment modalities may be integrated directly into plan optimization. Here, we present this approach in the clinical setting of multi modality therapy for malignant lymphoma, a malignancy with marked heterogeneity in biology, target localization, and patient characteristics. We discuss future research priorities including the potential of artificial intelligence.

Purpose: Radiation therapy delivery during deep inspiration breath-hold (DIBH) reduces the irradiation of the heart and lungs and is therefore recommended for adults with mediastinal lymphoma. However, no studies have addressed the use of DIBH in children. This pilot study investigates the feasibility of and compliance with DIBH in children. Methods and Materials: Children from the age of 5 years were recruited to a training session to assess their ability to perform DIBH. No children received radiation therapy. The children were placed in a potential radiation therapy position. The DIBH was voluntary and monitored using an optical surface system providing visual feedback. Children who performed 3 stable DIBHs of 20 seconds each and remained motionless were deemed DIBH compliant. Compliance, equipment suitability, and coaching were further assessed in a semistructured interview. Results: We included 33 children (18 healthy and 15 hospitalized children with cancer) with a mean age of 8.5 years (range, 5-15). A total of 28 (85%) children were DIBH compliant. Twenty children were deemed immediately DIBH compliant, and 8 were deemed conditionally DIBH compliant, as DIBH compliance was presumed with custom-made immobilization and/or additional DIBH training. Mean age of the DIBH-compliant and the non-DIBH-compliant children was 8.9 years (range, 5-15) and 6 years (range, 5-9), respectively. Only 1 of 15 hospitalized children was not DIBH compliant and only 1 of all 33 children was unable to grasp the DIBH concept. The available DIBH equipment was suitable for children, and 94% reported that they were happy with training and performing DIBH. Conclusions: This pilot study demonstrated that children from the age of 5 years can potentially comply with the DIBH technique and perform stable and reproducible DIBHs suitable for radiation therapy. Custom-made immobilization and adequate training will potentially increase DIBH compliance. A prospective clinical trial (NCT033155

Purpose: In current radiotherapy (RT) planning and delivery, population-based dose-volume constraints are used to limit the risk of toxicity from incidental irradiation of organs at risks (OARs). However, weighing tradeoffs between target coverage and doses to OARs (or prioritizing different OARs) in a quantitative way for each patient is challenging. We introduce a novel RT planning approach for patients with mediastinal Hodgkin lymphoma (HL) that aims to maximize overall outcome for each patient by optimizing on tumor control and mortality from late effects simultaneously. Material and Methods: We retrospectively analyzed 34 HL patients treated with conformal RT (3DCRT). We used published data to model recurrence and radiation-induced mortality from coronary heart disease and secondary lung and breast cancers. Patient-specific doses to the heart, lung, breast, and target were incorporated in the models as well as age, sex, and cardiac risk factors (CRFs). A preliminary plan of candidate beams was created for each patient in a commercial treatment planning system. From these candidate beams, outcome-optimized (O-OPT) plans for each patient were created with an in-house optimization code that minimized the individual risk of recurrence and mortality from late effects. O-OPT plans were compared to VMAT plans and clinical 3DCRT plans. Results: O-OPT plans generally had the lowest risk, followed by the clinical 3DCRT plans, then the VMAT plans with the highest risk with median (maximum) total risk values of 4.9 (11.1), 5.1 (17.7), and 7.6 (20.3)%, respectively (no CRFs). Compared to clinical 3DCRT plans, O-OPT planning reduced the total risk by at least 1% for 9/34 cases assuming no CRFs and 11/34 cases assuming presence of CRFs. Conclusions: We developed an individualized, outcome-optimized planning technique for HL. Some of the resulting plans were substantially different from clinical plans. The results varied depending on how risk models were defined or prioriti

While radiotherapy damages tumor cells, it can also harm the surrounding healthy tissue. This damage can lead to acute and/or late toxicities. For patients with mediastinal tumors like Hodgkin lymphoma and thymic cancer, this could include pneumonitis, esophagitis, secondary cancers, or cardiac toxicity. The purpose of this thesis was to investigate how to best apply modern techniques in radiotherapy to reduce the dose to normal tissue and therefore the risk of toxicity for patients treated for cancer in the mediastinum. The aims of this thesis ranged from applied to more exploratory. The first aim was to calculate the treatment margins for patients with mediastinal lymphoma treated at our institution with the modern techniques of deep inspiration breath hold (DIBH) and daily image guidance. The second aim was to investigate the impact of the two modern techniques of DIBH and proton therapy, relative to treatment in free breathing and photon therapy, for patients with Hodgkin lymphoma and thymic cancer. The third aim was to investigate biological uncertainties in proton therapy due to the linear energy transfer (LET) of the protons at the end of their range for pediatric patients with Hodgkin lymphoma. And finally, the fourth aim was to create photon therapy treatment plansthat minimized the risk of both tumor recurrence and mortality from late toxicity from radiotherapy for patients with Hodgkin lymphoma. The methods for these aims included a retrospective analysis of set-up uncertainties, treatment planning comparisons for different combinations of techniques, Monte Carlo simulations for proton therapy plans, and using an in-house optimizer. For aim 1, we found that a margin of approximately 1 cm was needed to include uncertainties from contouring, setup, and intra-fractional motion for the lymphoma patients treated at our institution with DIBH and daily image guidance. For aim 2, we found that both proton therapy and DIBH reduced the dose to normal tissues, but t

PURPOSE: Current radiation therapy planning uses a set of defined dose-volume constraints to ensure a specified level of tumor coverage while constraining the dose distribution in the organs at risk. Such constraints are aggregated, population-based quantities that do not adequately consider patient-specific risk factors. Furthermore, these constraints are calculated for each organ independently and it is therefore not guaranteed that the optimal trade-off between organs is achieved. We introduce a novel radiotherapy planning approach where a patient-specific all-cause mortality risk is minimized using inverse plan optimization. As illustration of concept, our outcome risk model incorporates patient age, sex, cardiac risk factor (CRF), and smoking.METHODS AND MATERIALS: We retrospectively analyzed a left-sided breast cancer case and a Hodgkin's lymphoma case, both clinically treated with three-dimensional conformal radiotherapy (3D-CRT). Our objective function for inverse plan optimization was an equally weighted summation of risk models for cancer recurrence and mortality from radiation-induced coronary heart disease and secondary lung and breast cancers incorporating patient age, sex, CRF, and smoking. We allowed the optimization algorithm to choose from a large set of gantry angles. The optimization task was to choose beams and optimize monitor units (MUs) so that overall survival was maximized (and the total risk of cancer recurrence and mortality from radiation-induced causes were minimized). The sensitivity analysis was performed in the lymphoma case by changing the tumor control probability model from using mean dose (Model 1) to using generalized equivalent uniform dose (Model 2).RESULTS: For the breast case in this study, the 3D-CRT clinical plan used eight beams while the proposed 3D-CRT outcome-optimized plan used five beams, reducing the total risk - summation of the risks of recurrence and secondary disease mortality - from 3% to 2%. Th