Search

Irradiation log-files store useful information about the plan delivery, and together with independent Monte Carlo dose engine calculations can be used to reduce the time needed for patient-specific quality assurance (PSQA). Nonetheless, machine log-files carry an uncertainty associated to the measurement of the spot position and intensity that can influence the correct evaluation of the quality of the treatment delivery. This work addresses the problem of the inclusion of these uncertainties for the final verification of the treatment delivery. Dedicated measurements performed in an IBA Proteus Plus gantry with a pencil beam scanning (PBS) dedicated nozzle have been carried out to build a ‘room-dependent’ model of the spot position uncertainties. The model has been obtained through interpolation of the look-up tables describing the systematic and random uncertainties, and it has been tested for a clinical case of a brain cancer patient irradiated in a dry-run. The delivered dose has been compared with the planned dose with the inclusion of the errors obtained applying the model. Our results suggest that the accuracy of the treatment delivery is higher than the spot position uncertainties obtained from the log-file records. The comparison in terms of DVHs shows that the log-reconstructed dose is compatible with the planned dose within the 95% confidence interval obtained applying our model. The initial mean dose difference between the calculated dose to the patient based on the plan and recorded data is around 1%. The difference is essentially due to the log-file uncertainties and it can be removed with a correct treatment of these errors. In conclusion our new PSQA protocol allows for a fast verification of the dose delivered after every treatment fraction through the use of machine log-files and an independent Monte Carlo dose engine. Moreover, the inclusion of log-file uncertainties in the dose calculation allows for a correct evaluation of the quality of the treatment plan delivery. [ABSTRACT FROM AUTHOR]

Aim: To evaluate acute toxicity at 6 months after stereotactic body radiotherapy (SBRT) in patients with oligometastatic cancer within the OligoCare cohort., Material and Methods: OligoCare is a prospective, registry-based, single-arm, observational study that aims to report prospective real-world data of patients with oligometastases from solid cancer treated with SBRT (NCT03818503). Primary tumor included non-small cell lung cancer (NSCLC), breast cancer (BC), colorectal cancer (CRC), and prostate cancer (PC). This analysis addresses a secondary endpoint of the trial, acute toxicity within 6 months after SBRT., Results: Out of 1,597registered patients, 1'468 patients were evaluated for acute toxicity. Globally, 290 (20 %) had NSCLC primary disease, 227 (16 %) had BC, 293 (20 %) had CRC, and 658 (45 %) had PC. Concomitant systemic treatment was administered in 527 (35.9 %) patients. According to the EORTC/ESTRO oligometastatic disease (OMD) classification, 828 (56 %) patients had de novo OMD, 464 (32 %) repeat OMD, and 176 (12 %) induced OMD. Acute grade ≥ 3 SBRT related adverse events were reported in 8 (0.5 %) patients, including 2 (0.1 %) fatal AEs. In particular, 6 (0.4 %) grade 3 events were: 1 empyema, 1 pneumonia, 1 radiation pneumonitis, 1 radiation skin injury, 1 decreased appetite, and 1 bone pain. Among those 2 occurred in NSCLC patients, 2 in BC patients, and 1 in CRC and PC patients each. The two (0.1 %) grade 5 toxicity were represented by: pneumonitis and cerebral hemorrhage., Conclusion: OligoCare is the largest prospective registry cohort on oligometastatic disease. Acute toxicity within 6 months was low, confirming the safety of SBRT in the treatment of oligometastases., 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 Elsevier B.V. All rights reserved.)

Online adaptive radiotherapy (oART) uses daily imaging to identify changes in the patient's anatomy and generate a new treatment plan adapted to these changes, and it can be used for treating gastric mucosa-associated lymphoid tissue (MALT) lymphomas. This study aimed to determine the intrafraction motion and planning target volume (PTV) margins required for an oART workflow on a cone beam computed tomography (CBCT)-based dedicated system (Ethos®, Varian Medical Systems, Palo Alto, California, United States) and investigate the potential benefits for patients compared with a non-adaptive workflow. Involving three patients treated for gastric MALT lymphoma with the oART under breath-hold (BH) technique, the study determined a PTV margin for adaptive treatment using CBCT scans performed at the beginning and just before treating the patients for 34 fractions. Different PTVs were made by isotropically extending the clinical target volume (CTV) contoured on the first CBCT (CTV1) at intervals of 1 mm to evaluate intrafraction gastric motion, with the expansion covering the contoured CTV on the second CBCT (CTV2) quantifying the intrafraction motion (adaptive treatment) and the expansion from the CTV delineated on the planning scanner (CTVplanning) that could cover both CTV1 and CTV2 defining the interfraction motion (non-adaptive treatment). PTV margins were then determined as the extension of the CTV allowing coverage of 95% of its volume in 90% of fractions, and the dosimetric impact on dose constraints between an adaptive plan and a non-adaptive plan based on the predetermined margins was evaluated. A total of 68 CBCTs were analyzed, revealing that the PTV margin for oART was 4 mm, while for non-adaptive treatment it was 12 mm, with an average time elapsed between CBCT1 and CBCT2 of 11.62 minutes and no correlation between inter-CBCT timing and PTV margins (Pearson R-coefficient=0.10). All dosimetric constraints were met in both adaptive and non-adaptive plans, but the adaptive plan allowed for reduced organ-at-risk (OAR) doses in each patient. The study concluded that oART could reduce PTV margins in the treatment of gastric MALT lymphoma, especially with a BH strategy, impacting OAR dosimetry, though more prospective studies are required to validate these findings and determine their clinical impact on patients., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: Julien Pierrard declare(s) a grant from Varian, a Siemens Healthineers Company. His PhD project (wich has nothing to do with this work) was partially funded by Varian. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Tison et al.)

Introduction: The international phase II single-arm LungTech trial 22113-08113 of the European Organization for Research and Treatment of Cancer assessed the safety and efficacy of stereotactic body radiotherapy (SBRT) in patients with centrally located early-stage NSCLC., Methods: Patients with inoperable non-metastatic central NSCLC (T1-T3 N0 M0, ≤7cm) were included. After prospective central imaging review and radiation therapy quality assurance for any eligible patient, SBRT (8 × 7.5 Gy) was delivered. The primary endpoint was freedom from local progression probability three years after the start of SBRT., Results: The trial was closed early due to poor accrual related to repeated safety-related pauses in recruitment. Between August 2015 and December 2017, 39 patients from six European countries were included and 31 were treated per protocol and analyzed. Patients were mainly male (58%) with a median age of 75 years. Baseline comorbidities were mainly respiratory (68%) and cardiac (48%). Median tumor size was 2.6 cm (range 1.2-5.5) and most cancers were T1 (51.6%) or T2a (38.7%) N0 M0 and of squamous cell origin (48.4%). Six patients (19.4%) had an ultracentral tumor location. The median follow-up was 3.6 years. The rates of 3-year freedom from local progression and overall survival were 81.5% (90% confidence interval [CI]: 62.7%-91.4%) and 61.1% (90% CI: 44.1%-74.4%), respectively. Cumulative incidence rates of local, regional, and distant progression at three years were 6.7% (90% CI: 1.6%-17.1%), 3.3% (90% CI: 0.4%-12.4%), and 29.8% (90% CI: 16.8%-44.1%), respectively. SBRT-related acute adverse events and late adverse events ≥ G3 were reported in 6.5% (n = 2, including one G5 pneumonitis in a patient with prior interstitial lung disease) and 19.4% (n = 6, including one lethal hemoptysis after a lung biopsy in a patient receiving anticoagulants), respectively., Conclusions: The LungTech trial suggests that SBRT with 8 × 7.5Gy for central lung tumors in inoperable patients is associated with acceptable local control rates. However, late severe adverse events may occur after completion of treatment. This SBRT regimen is a viable treatment option after a thorough risk-benefit discussion with patients. To minimize potentially fatal toxicity, careful management of dose constraints, and post-SBRT interventions is crucial., Competing Interests: Disclosure Dr. Levy reports academic funding from Roche, Beigene, AstraZeneca, and Pharmamar. Dr. Adebahr was supported by the German Cancer Consortium (DKTK) and is now supported by a grant from the Federal Ministry of Education and Research (BMBF). The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Although stereotactic body radiotherapy (SBRT) was progressively adopted in clinical practice in Belgium, a reimbursement request in 2011 was not granted because of remaining clinical and economic uncertainty. A coverage with evidence development (CED) program on SBRT started in 2013, with the aim to assess clinical and technical patterns-of-care in Belgium and monitor survival per indication, in view of supporting inclusion in the reimbursement system., Methods: The Belgian National Institute for Health and Disability Insurance (NIHDI) initiated this prospective observational registry. Participating departments, using SBRT in clinical practice, signed the 'NIHDI convention'. Eligible patients had a primary tumour (PT) or oligometastatic disease (OMD). Patient, tumour, and treatment characteristics were collected through an online module of the Belgian Cancer Registry, prerequisite for financing. Five-year overall survival (5YOS) and 30- and 90-days mortality were primary outcomes, derived from vital status information., Findings: Between 10/2013 and 12/2019, 20 of the 24 accredited radiotherapy departments participated, 6 were academic. Registered cases per department ranged from 21 to 867. Of 5675 registrations analysed, the majority had good performance status and limited number of lesions. Enrolment of PTs remained stable over time, OMDs almost doubled. Peripheral lung lesions dominated in PTs as in OMDs. Other metastases were (para)spinal, 'non-standard' and hepatic. Thirty- and 90-days mortalities remained below 0.5% [95% CI 0.3%-0.8%] respectively 2.1% [95% CI 1.6%-2.7%]. 5YOS varied by indication, primary prostate patients performing best (85%, 95% CI [76%, 96%]), those with liver metastases worst (19%, 95% CI [15%, 24%]). Better OS was observed in academic departments, department size did not significantly impact survival. OMD survival was better in 2018-19., Interpretation: CED can be used to define patterns-of-care and real-life outcome of innovative radiotherapy. As the observed survival for different indications was in line with outcome in emerging literature, SBRT was included in the Belgian reimbursement system as of January 2020., Funding: NIHDI financed participating departments per registered case., Competing Interests: All authors have completed the ICMJE disclosure form and declare: YL is recipient of the HERO-VBHC chair, with payments made to her institution and has unpaid leadership roles in ESTRO (Scientific Committee member and ESTRO-HERO co-chair), the Belgian College of Oncology (Board member) and in the EORTC-ESTRO E2-RADIATE project (PI); DV has research collaboration with RaySearch Laboratories and received speakers fees from BeSTRO and JASTRO and per diem payment as teacher in the ESTRO SBRT course, and reports advisory roles for the Belgian Supreme Health Council and the Medical Jury of the Belgian Federal Agency for Nuclear Control, treasurer of ESTRO and board member of ‘Stand Up Against Cancer’; ML receives a grant of the Foundation Against Cancer for proton radiotherapy in pregnancy (ProPOSE). None of the aforementioned payments or roles are in relation to the submitted work. RW receives fees as president of the College for Physicians of Radiation Oncology Centres, which are paid to her institution; SR is working for the NIHDI, HE was working for the NIHDI during the course of the CED program; SJ and NVD both work for the BCR; but none declare financial or personal interests that could have influenced the submitted work. XG, NJ, LM, VR, KS and CW reported no financial or other relationships that might impact the submitted work., (© 2024 The Authors.)

Purpose: Radiation therapy for tumors subject to breathing-related motion during breath-holds (BHs) has the potential to substantially reduce the irradiated volume. Mechanically assisted and noninvasive ventilation (MANIV) could ensure the target repositioning accuracy during each BH while facilitating treatment feasibility through oxygen supplementation and a perfectly replicated mechanical support. However, there is currently no clinical evidence substantiating the use of MANIV-induced BH for moving tumors. The aim of this work was, therefore, to evaluate the technique's performance under real treatment conditions., Methods and Materials: Patients eligible for lung or liver stereotactic body radiation therapy were prospectively included in a single-arm trial. The primary endpoint corresponded to the treatment feasibility with MANIV. Secondary outcomes comprised intrafraction geometric uncertainties extracted from real-time imaging, tolerance to BH, and treatment time., Results: Treatment was successfully delivered in 92.9% (13/14) of patients: 1 patient with a liver tumor was excluded because of a mechanically induced gastric insufflation displacing the liver cranially by more than 1 cm. In the left-right/anteroposterior/craniocaudal directions, the recalculated safety margins based on intrafraction positional data were 4.6 mm/5.1 mm/5.6 mm and 4.7 mm/7.3 mm/5.9 mm for lung and liver lesions, respectively. Compared with the free-breathing internal target volume and midposition approaches, the average reduction in the planning target volume with MANIV reached -47.2% ± 15.3%, P < .001, and -29.4% ± 19.2%, P = .007, for intrathoracic tumors and -23.3% ± 12.4%, P < .001, and -9.3% ± 15.3%, P = .073, for upper abdominal tumors, respectively. For 1 liver lesion, large caudal drifts of occasionally more than 1 cm were measured. The total slot time was 53.1 ± 10.6 minutes with a BH comfort level of 80.1% ± 10.6%., Conclusions: MANIV enables high treatment feasibility within a nonselected population. Accurate intrafraction tumor repositioning is achieved for lung tumors. Because of occasional intra-BH caudal drifts, pretreatment assessment of BH stability for liver lesions is, however, recommended., Competing Interests: None., (© 2024 The Author(s).)

Background and Introduction: Optimal dose and fractionation in stereotactic body radiotherapy (SBRT) for oligometastatic cancer patients remain unknown. In this interim analysis of OligoCare, we analyzed factors associated with SBRT dose and fractionation., Materials and Methods: Analysis was based on the first 1,099 registered patients. SBRT doses were converted to biological effective doses (BED) using α/β of 10 Gy for all primaries, and cancer-specific α/β of 10 Gy for non-small cell lung and colorectal cancer (NSCLC, CRC), 2.5 Gy for breast cancer (BC), or 1.5 Gy for prostate cancer (PC)., Results: Of the interim analysis population of 1,099 patients, 999 (99.5 %) fulfilled inclusion criteria and received metastasis-directed SBRT for NSCLC (n = 195; 19.5 %), BC (n = 163; 16.3 %), CRC (n = 184; 18.4 %), or PC (n = 457; 47.5 %). Two thirds of patients were treated for single metastasis. Median number of fractions was 5 (IQR, 3-5) and median dose per fraction was 9.7 (IQR, 7.7-12.4) Gy. The most frequently treated sites were non-vertebral bone (22.8 %), lung (21.0 %), and distant lymph node metastases (19.0 %). On multivariate analysis, the dose varied significantly for primary cancer type (BC: 237.3 Gy BED, PC 300.6 Gy BED, and CRC 84.3 Gy BED), and metastatic sites, with higher doses for lung and liver lesions., Conclusion: This real-world analysis suggests that SBRT doses are adjusted to the primary cancers and oligometastasis location. Future analysis will address safety and efficacy of this site- and disease-adapted SBRT fractionation approach (NCT03818503)., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BAJF received grants from Accuray, AIRC, IBA and Fondazione IEO-CCM, lecture payments/honoraria from Bayer, Accuray, Astellas, IBA, IPSEN, Astra Zeneca, Tecnologie Avanzate, Recordati, and Novartis, and has board appointments at Astra Zeneca, Bayer, and Seagen. MG and PO are PIs of the ESTRO-EORTC 1811-E²-RADIatE OligoCare trial. MG is president-elect of ESTRO., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Most radiotherapy treatments are nowadays delivered with linear accelerators producing photons. This robust radiation technique improved outstandingly during the last three decades, allowing treatments for most tumoural indications with an exquisite accuracy, a formidable effectiveness, a low toxicity, and a very low cost for the society. Therefore, the reasons for using and developing the more expensive hadron therapy and more particularly proton therapy may seem futile. In the current article targeting the general practitioners readership, we look at the principles of this innovative technique, its inherent advantages and limitations, the current and future indications, the challenges and perspectives for the future. We conclude with an overview of the Belgian landscape in terms of installation, operation, access and reimbursement procedures.

Aims: The effects of isolated contemporary low-dose breast cancer (BC) radiotherapy (RT) on the heart remain poorly understood. This study aims to assess the long-term impacts of BC-RT on cardiac structure and function., Methods and Results: Seventy-six women (62 ± 7 years) without history of prior heart disease, who had undergone RT for either first left (n = 36) or right (n = 40) BC, without additional medical oncology therapy apart from hormonal treatment 11 ± 1 years earlier, underwent transthoracic echocardiography, cardiac magnetic resonance imaging (CMR), computed tomography coronary angiography (CTCA), NT-proBNP, and a 6-min walk test (6MWT). They were compared with 54 age-matched healthy female controls. By CTCA, 68% of BC patients exhibited no or very mild coronary disease, while only 11% had moderate stenosis (50-69%) and 3% had significant stenosis (>70%). Despite slightly reduced regional echocardiographic midventricular strains, BC patients exhibited similar global left and right ventricular volumes, ejection fractions, and global strains by echocardiography and CMR as controls. Mitral E/e' ratios were slightly higher, and mitral deceleration times were slightly lower, but NT-proBNP was similar to controls. Also, 6MWT was normal. None had late gadolinium enhancement, and extracellular volume fraction was similar in BC (28 ± 3 vs. 29 ± 3, P = 0.15) and controls. No differences were observed relative to dose or side of RT., Conclusion: Aside from minor alterations of regional strains and diastolic parameters, women who received isolated RT for BC had low prevalence of coronary disease, normal global systolic function, NT-proBNP, and exercise capacity and showed no structural changes by CMR, refuting significant long-term cardiotoxicity in such low-risk patients., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective . Radio-opaque markers are recommended for image-guided radiotherapy in liver stereotactic ablative radiotherapy (SABR), but their implantation is invasive. We evaluate in this in-silico study the feasibility of cone-beam computed tomography-guided stereotactic online-adaptive radiotherapy (CBCT-STAR) to propagate the target volumes without implanting radio-opaque markers and assess its consequence on the margin that should be used in that context. Approach . An emulator of a CBCT-STAR-dedicated treatment planning system was used to generate plans for 32 liver SABR patients. Three target volume propagation strategies were compared, analysing the volume difference between the GTV Propagated and the GTV Conventional , the vector lengths between their centres of mass ( l CoM ), and the 95th percentile of the Hausdorff distance between these two volumes (HD95). These propagation strategies were: (1) structure-guided deformable registration with deformable GTV propagation; (2) rigid registration with rigid GTV propagation; and (3) image-guided deformable registration with rigid GTV propagation. Adaptive margin calculation integrated propagation errors, while interfraction position errors were removed. Scheduled plans (Plan Non-adaptive ) and daily-adapted plans (Plan Adaptive ) were compared for each treatment fraction. Main results. The image-guided deformable registration with rigid GTV propagation was the best propagation strategy regarding to l CoM (mean: 4.3 +/- 2.1 mm), HD95 (mean 4.8 +/- 3.2 mm) and volume preservation between GTV Propagated and GTV Conventional . This resulted in a planning target volume (PTV) margin increase (+69.1% in volume on average). Online adaptation (Plan Adaptive ) reduced the violation rate of the most important dose constraints ('priority 1 constraints', 4.2 versus 0.9%, respectively; p < 0.001) and even improved target volume coverage compared to non-adaptive plans (Plan Non-adaptive ). Significance . Markerless CBCT-STAR for liver tumours is feasible using Image-guided deformable registration with rigid GTV propagation. Despite the cost in terms of PTV volumes, daily adaptation reduces constraints violation and restores target volumes coverage., (© 2024 Institute of Physics and Engineering in Medicine.)

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.

Purpose: Ethos proposes a template-based automatic dose planning (Etb) for online adaptive radiotherapy. This study evaluates the general performance of Etb for prostate cancer, as well as the ability to generate patient-optimal plans, by comparing it with another state-of-the-art automatic planning method, i.e., deep learning dose prediction followed by dose mimicking (DP + DM)., Materials: General performances and capability to produce patient-optimal plan were investigated through two studies: Study-S1 generated plans for 45 patients using our initial Ethos clinical goals template (EG&#95;init), and compared them to manually generated plans (MG). For study-S2, 10 patients which showed poor performances at study-S1 were selected. S2 compared the quality of plans generated with four different methods: 1) Ethos initial template (EG&#95;init&#95;selected), 2) Ethos updated template-based on S1 results (EG&#95;upd&#95;selected), 3) DP + DM, and 4) MG plans., Results: EG&#95;init plans showed satisfactory performance for dose level above 50 Gy: reported mean metrics differences (EG&#95;init minus MG) never exceeded 0.6 %. However, lower dose levels showed loosely optimized metrics, mean differences for V30Gy to rectum and V20Gy to anal canal were of 6.6 % and 13.0 %. EG&#95;init&#95;selected showed amplified differences in V30Gy to rectum and V20Gy to anal canal: 8.5 % and 16.9 %, respectively. These dropped to 5.7 % and 11.5 % for EG&#95;upd&#95;selected plans but strongly increased V60Gy to rectum for 2 patients. DP + DM plans achieved differences of 3.4 % and 4.6 % without compromising any V60Gy., Conclusion: General performances of Etb were satisfactory. However, optimizing with template of goals might be limiting for some complex cases. Over our test patients, DP + DM outperformed the Etb approach., 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 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Purpose: Defining dosimetric rules to automatically detect patients requiring adaptive radiotherapy (ART) is not straightforward, and most centres perform ad-hoc ART with no specific protocol. This study aims to propose and analyse different steps to design a protocol for dosimetrically triggered ART of head and neck (H&N) cancer. As a proof-of-concept, the designed protocol was applied to patients treated in TomoTherapy units, using their available software for daily MVCT image and dose accumulation., Methods: An initial protocol was designed by a multidisciplinary team, with a set of flagging criteria based only on dose-volume metrics, including two action levels: (1) surveillance (orange flag), and (2) immediate verification (red flag). This protocol was adapted to the clinical needs following an iterative process. First, the protocol was applied to 38 H&N patients with daily imaging. Automatic software generated the daily contours, recomputed the daily dose and flagged the dosimetric differences with respect to the planning dose. Second, these results were compared, by a sensitivity/specificity test, to the answers of a physician. Third, the physician, supported by the multidisciplinary team, performed a self-analysis of the provided answers and translated them into mathematical rules in order to upgrade the protocol. The upgraded protocol was applied to different definitions of the target volume (i.e. deformed CTV + 0, 2 and 4 mm), in order to quantify how the number of flags decreases when reducing the CTV-to-PTV margin., Results: The sensitivity of the initial protocol was very low, specifically for the orange flags. The best values were 0.84 for red and 0.15 for orange flags. After the review and upgrade process, the sensitivity of the upgraded protocol increased to 0.96 for red and 0.84 for orange flags. The number of patients flagged per week with the final (upgraded) protocol decreased in median by 26% and 18% for red and orange flags, respectively, when reducing the CTV-to-PTV margin from 4 to 2 mm. This resulted in only one patient flagged at the last fraction for both red and orange flags., Conclusion: Our results demonstrate the value of iterative protocol design with retrospective data, and shows the feasibility of automatically-triggered ART using simple dosimetric rules to mimic the physician's decisions. Using a proper target volume definition is important and influences the flagging rate, particularly when decreasing the CTV-to-PTV margin., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Purpose: Automated treatment planning strategies are being widely implemented in clinical routines to reduce inter-planner variability, speed up the optimization process, and improve plan quality. This study aims to evaluate the feasibility and quality of intensity-modulated proton therapy (IMPT) plans generated with four different knowledge-based planning (KBP) pipelines fully integrated into a commercial treatment planning system (TPS)., Materials/methods: A data set containing 60 oropharyngeal cancer patients was split into 11 folds, each containing 47 patients for training, five patients for validation, and five patients for testing. A dose prediction model was trained on each of the folds, resulting in a total of 11 models. Three patients were left out in order to assess if the differences introduced between models were significant. From voxel-based dose predictions, we analyze the two steps that follow the dose prediction: post-processing of the predicted dose and dose mimicking (DM). We focused on the effect of post-processing (PP) or no post-processing (NPP) combined with two different DM algorithms for optimization: the one available in the commercial TPS RayStation (RSM) and a simpler isodose-based mimicking (IBM). Using 55 test patients (five test patients for each model), we evaluated the quality and robustness of the plans generated by the four proposed KBP pipelines (PP-RSM, PP-IBM, NPP-RSM, NPP-IBM). After robust evaluation, dose-volume histogram (DVH) metrics in nominal and worst-case scenarios were compared to those of the manually generated plans., Results: Nominal doses from the four KBP pipelines showed promising results achieving comparable target coverage and improved dose to organs at risk (OARs) compared to the manual plans. However, too optimistic post-processing applied to the dose prediction (i.e. important decrease of the dose to the organs) compromised the robustness of the plans. Even though RSM seemed to partially compensate for the lack of robustness in the PP plans, still 65% of the patients did not achieve the expected robustness levels. NPP-RSM plans seemed to achieve the best trade-off between robustness and OAR sparing., Discussion/conclusions: PP and DM strategies are crucial steps to generate acceptable robust and deliverable IMPT plans from ML-predicted doses. Before the clinical implementation of any KBP pipeline, the PP and DM parameters predefined by the commercial TPS need to be modified accordingly with a comprehensive feedback loop in which the robustness of the final dose calculations is evaluated. With the right choice of PP and DM parameters, KBP strategies have the potential to generate IMPT plans within clinically acceptable levels comparable to plans manually generated by dosimetrists., (© 2023 American Association of Physicists in Medicine.)

Background and Purpose: Deep inspiration breath-hold (DIBH) protects critical organs-at-risk (OARs) for adjuvant breast radiotherapy. Guidance systems e.g. surface guided radiation therapy (SGRT) improve the positional breast reproducibility and stability during DIBH. In parallel, OARs sparing with DIBH is enhanced through different techniques e.g. prone position, continuous positive airway pressure (CPAP). By inducing repeated DIBH with the same level of positive pressure, mechanically-assisted and non-invasive ventilation (MANIV) could potentially combine these DIBH optimizations., Materials and Methods: We conducted a randomized, open-label, multicenter and single-institution non-inferiority trial. Sixty-six patients eligible for adjuvant left whole-breast radiotherapy in supine position were equally assigned between mechanically-induced DIBH (MANIV-DIBH) and voluntary DIBH guided by SGRT (sDIBH). The co-primary endpoints were positional breast stability and reproducibility with a non-inferiority margin of 1 mm. Secondary endpoints were tolerance assessed daily via validated scales, treatment time, dose to OARs and their inter-fraction positional reproducibility., Results: Differences between both arms for positional breast reproducibility and stability occurred at a sub-millimetric level (p < 0.001 for non-inferiority). The left anterior descending artery near-max dose (14,6 ± 12,0 Gy vs. 7,7 ± 7,1 Gy, p = 0,018) and mean dose (5,0 ± 3,5 Gy vs. 3,0 ± 2,0 Gy, p = 0,009) were improved with MANIV-DIBH. The same applied for the V 5Gy of the left ventricle (2,4 ± 4,1 % vs. 0,8 ± 1,6 %, p = 0,001) as well as for the left lung V 20Gy (11,4 ± 2,8 % vs. 9,7 ± 2,7 %, p = 0,019) and V 30Gy (8,0 ± 2,6 % vs. 6,5 ± 2,3 %, p = 0,0018). Better heart's inter-fraction positional reproducibility was observed with MANIV-DIBH. Tolerance and treatment time were similar., Conclusion: Mechanical ventilation provides the same target irradiation accuracy as with SGRT while better protecting and repositioning OARs., 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 Elsevier B.V. All rights reserved.)

Objective. To compare a not adapted (NA) robust planning strategy with three fully automated online adaptive proton therapy (OAPT) workflows based on the same optimization method: dose mimicking (DM). The added clinical value and limitations of the OAPT methods are investigated for head and neck cancer (HNC) patients. Approach. The three OAPT strategies aimed at compensating for inter-fractional anatomical changes by mimiking different dose distributions on corrected cone beam CT images (corrCBCTs). Order by complexity, the OAPTs were: (1) online adaptive dose restoration (OADR) where the approved clinical dose on the planning-CT (pCT) was mimicked, (2) online adaptation using DM of the deformed clinical dose from the pCT to corrCBCTs (OADEF), and (3) online adaptation applying DM to a predicted dose on corrCBCTs (OAML). Adaptation was only applied in fractions where the target coverage criteria were not met (D98% < 95% of the prescribed dose). For 10 HNC patients, the accumulated dose distributions over the 35 fractions were calculated for NA, OADR, OADEF, and OAML. Main results. Higher target coverage was observed for all OAPT strategies compared to no adaptation. OADEF and OAML outperformed both NA and OADR and were comparable in terms of target coverage to initial clinical plans. However, only OAML provided comparable NTCP values to those from the clinical dose without statistically significant differences. When the NA initial plan was evaluated on corrCBCTs, 51% of fractions needed adaptation. The adaptation rate decreased significantly to 25% when the last adapted plan with OADR was selected for delivery, to 16% with OADEF, and to 21% with OAML. The reduction was even greater when the best plan among previously generated adapted plans (instead of the last one) was selected. Significance . The implemented OAPT strategies provided superior target coverage compared to no adaptation, higher OAR sparing, and fewer required adaptations., (© 2023 Institute of Physics and Engineering in Medicine.)

Stereotactic body radiotherapy (SBRT) for patients with metastatic cancer, especially when characterised by a low tumour burden (ie, oligometastatic disease), receiving targeted therapy or immunotherapy has become a frequently practised and guideline-supported treatment strategy. Despite the increasing use in routine clinical practice, there is little information on the safety of combining SBRT with modern targeted therapy or immunotherapy and a paucity of high-level evidence to guide clinical management. A systematic literature review was performed to identify the toxicity profiles of combined metastases-directed SBRT and targeted therapy or immunotherapy. These results served as the basis for an international Delphi consensus process among 28 interdisciplinary experts who are members of the European Society for Radiotherapy and Oncology (ESTRO) and European Organisation for Research and Treatment of Cancer (EORTC) OligoCare consortium. Consensus was sought about risk mitigation strategies of metastases-directed SBRT combined with targeted therapy or immunotherapy; a potential need for and length of interruption to targeted therapy or immunotherapy around SBRT delivery; and potential adaptations of radiation dose and fractionation. Results of this systematic review and consensus process compile the best available evidence for safe combination of metastases-directed SBRT and targeted therapy or immunotherapy for patients with metastatic or oligometastatic cancer and aim to guide today's clinical practice and the design of future clinical trials., Competing Interests: Declaration of interests FA declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Varian, Elekta, Brainlabs, outside of this Policy Review. CBe declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis. CBe also declares support for attending meetings and travel from Pfizer and Eli Lilly, unrelated to this Policy Review. CBi declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from SPCC congress, unrelated to this Policy Review. BdB declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Debiopharma, Ipsen, and Astellas; support for attending meetings and travel from Debiopharma and Micropos medical; and leadership or fiduciary role in the board, society, committee, or advocacy group of ESTRO, SAKK, and SASRO, unrelated to this Policy Review. BAJ-F declares grants or contracts from Italian Association for Cancer Research, FIEO-CCM and FUV, Accuray, and IBA Dosimetry; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Bayer, Roche, Astellas, Ipsen, and Accuray; and participation on a data safety monitoring board or advisory board for Bayer, unrelated to this Policy Review. XG declares a grant from Varian paid to their institution; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for Congress Care and Sanofi; and a leadership or fiduciary role in the board, society, committee, or advocacy group for RIZIV–INAMI and FANC–AFCN. YL declares grants or contracts from ImmunoSABR, EU Project, and HERO–VBHC; consulting fees paid to the institution by AstraZeneca; and a leadership or fiduciary role in the board, society, committee, or advocacy group of ESTRO, Belgian College of Oncology, and EORTC–ESTRO Radiation Infrastructure for Europe project, unrelated to this Policy Review. PO declares grants or contracts from Varian and Bayer; consulting fees from Bayer, AAA, Curium, Janssen, Telix, MSD, and Ferring; and support for attending meetings and travel from Ferring, unrelated to this Policy Review. SP declares personal fees from Amgen, AstraZeneca, Bayer, Beigene, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, Guardant Health, Incyte, Janssen, Eli Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and EQRx; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational event from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Sereno, Roche, Takeda, and Pfizer; payment for expert testimony from Roche and Merck Sereno; support for attending meetings and travel from Janssen and Roche; participation on a data safety monitoring board or advisory board for Amgen, AstraZeneca, Bayer, Beigene, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, Guardant Health, Incyte, Janssen, Eli Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, and Seattle Genetics; and leadership or fiduciary role in the board, society, committee, or advocacy group of British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, and ETOP–IBCSG Partners Foundation Board, unrelated to this Policy Review. SR declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD Italia, Genetec, and Istituto Gentili Amgen; and participation on a data safety monitoring board or advisory board for Roche and AstraZeneca, unrelated to this Policy Review. UR declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Elekta and Accuray, unrelated to this Policy Review. MS declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Roche, and Merck; participation on a data safety monitoring board or advisory board for Janssen, Ipsen, and Merck; and a leadership or fiduciary role in the board, society, committee, or advocacy group for ESMO, unrelated to this Policy Review. TZ declares grants or contracts from Varian Medical Systems and Debiopharm; consulting fees from Janssen and Astellas; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Astellas, Debiopharm, Bayer, and Ferring; support for attending meetings and travel from Debiopharm; and participation on a data safety monitoring board or advisory board for SAKK scientific board and GFRU, unrelated to this Policy Review. All other authors report no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective. Protons offer a more conformal dose delivery compared to photons, yet they are sensitive to anatomical changes over the course of treatment. To minimize range uncertainties due to anatomical variations, a new CT acquisition at every treatment session would be paramount to enable daily dose calculation and subsequent plan adaptation. However, the series of CT scans results in an additional accumulated patient dose. Reducing CT radiation dose and thereby decreasing the potential risk of radiation exposure to patients is desirable, however, lowering the CT dose results in a lower signal-to-noise ratio and therefore in a reduced quality image. We hypothesized that the signal-to-noise ratio provided by conventional CT protocols is higher than needed for proton dose distribution estimation. In this study, we aim to investigate the effect of CT imaging dose reduction on proton therapy dose calculations and plan optimization. Approach. To verify our hypothesis, a CT dose reduction simulation tool has been developed and validated to simulate lower-dose CT scans from an existing standard-dose scan. The simulated lower-dose CTs were then used for proton dose calculation and plan optimization and the results were compared with those of the standard-dose scan. The same strategy was adopted to investigate the effect of CT dose reduction on water equivalent thickness (WET) calculation to quantify CT noise accumulation during integration along the beam. Main results. The similarity between the dose distributions acquired from the low-dose and standard-dose CTs was evaluated by the dose-volume histogram and the 3D Gamma analysis. The results on an anthropomorphic head phantom and three patient cases indicate that CT imaging dose reduction up to 90% does not have a significant effect on proton dose calculation and plan optimization. The relative error was employed to evaluate the similarity between WET maps and was found to be less than 1% after reducing the CT imaging dose by 90%. Significance. The results suggest the possibility of using low-dose CT for proton therapy dose estimation, since the dose distributions acquired from the standard-dose and low-dose CTs are clinically equivalent., (© 2022 Institute of Physics and Engineering in Medicine.)

Introduction: The use of definitive radiotherapy (dRT) in unresectable soft-tissue sarcomas (STS) is still controversial and recent data are scarce. We report clinical results of this therapeutic option., Methods: We retrospectively included STS patients treated between 2009 and 2020, with dRT for unresectable or with a measurable residual disease after R2 surgery. Response rate, local failure (LF), progression-free survival (PFS) and overall survival (OS) were evaluated., Results: 116 patients with localized/locally advanced STS were treated from 2009 to 2020, with a median age of 71 years (range 18-92). Most tumors were deep-seated (96.6%), grade 2-3 (85.1%), located in the trunk or extremities (74.2%). Helical tomotherapy, volumetric modulated arc therapy, or stereotactic radiotherapy was performed in 39.7%, 19% and 8.6% of patients, respectively. The median equivalent dose in 2 Gy fractions (EQD2) was 60 Gy (IQR 52-65). At first follow-up, 66 (58.9%) and 25 (22%) patients had stable disease and partial response. After a median follow-up of 54.8 months (IQR 40.3-95.4), 3-year LF, PFS and OS were 43.2%, 16.6% and 34%, respectively. Median OS was 21.4 months (95%CI 14-26). The multivariate analysis identified grade 3 and AJCC T3-T4 stage to be associated with both shorter PFS and OS (all p < 0.001). Macroscopically incomplete resection and EQD2 ≥ 64 Gy were associated with better OS (p = 0.016 and p = 0.007). Acute and late severe adverse events occurred in 24 (19.7%) and 5 (4.3%) patients., Conclusion: In unresectable STS patients, definitive modern radiotherapy is a safe and effective treatment yielding long term control in selected patients., 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 © 2022 Elsevier B.V. All rights reserved.)

Detection and segmentation of abnormalities on medical images is highly important for patient management including diagnosis, radiotherapy, response evaluation, as well as for quantitative image research. We present a fully automated pipeline for the detection and volumetric segmentation of non-small cell lung cancer (NSCLC) developed and validated on 1328 thoracic CT scans from 8 institutions. Along with quantitative performance detailed by image slice thickness, tumor size, image interpretation difficulty, and tumor location, we report an in-silico prospective clinical trial, where we show that the proposed method is faster and more reproducible compared to the experts. Moreover, we demonstrate that on average, radiologists & radiation oncologists preferred automatic segmentations in 56% of the cases. Additionally, we evaluate the prognostic power of the automatic contours by applying RECIST criteria and measuring the tumor volumes. Segmentations by our method stratified patients into low and high survival groups with higher significance compared to those methods based on manual contours., (© 2022. The Author(s).)

Background: Definitive external beam radiotherapy (EBRT) is an unusual treatment of unresectable soft-tissue sarcomas (STS). Recent technical innovations and physical advantages of particle therapies may improve results of this therapeutic option. The role of this review was to report the clinical results of photon- and particle-based EBRT in unresectable STS., Material and Methods: We performed a systematic review of the literature on Pubmed database to identify studies investigating the efficacy and safety of EBRT. The primary endpoint was local control (LC) and secondary endpoints were progression-free survival (PFS), overall survival (OS) and adverse events in a subset of patients with gross disease STS., Results: We identified 29 studies involving 1409 patients (pts) evaluating photon ( n  = 18; 956 pts), proton ( n  = 1; 21 pts), carbon ion ( n  = 2; 152 pts), neutron ( n  = 7; 259 pts) or pion ( n  = 1; 21 pts) therapy. Definitive EBRT achieves valuable 5-year LC rates of 28-73% with photon and 52-69% with particle therapies. Most local failures (66-100%) occurred within 3 years. Long-term disease control can be achieved in a fraction of patients, with 5-year PFS and OS of 0-39% and 24.7-63%, respectively. The rate of severe adverse events was highly variable with photons, <15% in proton and carbon ion therapy, whereas 25 to 50% of patients treated with neutrons and pions presented severe AE. While a dose higher or equal 64 Gy seem to improve the prognosis, delivering a dose higher or equal 68 Gy dramatically increases severe adverse events., Conclusion: Definitive EBRT with dose 64-66 Gy seems to be a safe and efficient treatment for unresectable STS. Future clinical trials should assess the potential of biomarkers of response, thus identifying patients that could benefit from local treatment.

Background: There has been growing evidence of the benefits of high-intensity aerobic interval training (HIIT) and resistance training (RES) for populations with cancer. However, these two modalities have not yet been performed alone in rectal cancer patients undergoing neoadjuvant chemoradiotherapy (NACR T). Therefore, this study aimed to determine the feasibility of HIIT and RES in rectal cancer patients undergoing NACR T., Materials and Methods: Rectal cancer patients set to undergo NACRT were randomly assigned to HIIT intervention, RES intervention, or the usual care. Feasibility of HIIT and RES was assessed by measuring recruitment rate, adherence (retention rate, attendance rate, and exercise sessions duration and intensity), and adverse events. Endpoints (changes in fatigue, health-related quality of life, depression, daytime sleepiness, insomnia, sleep quality, functional exercise capacity, and executive function) were assessed at baseline and at week 5., Results: Among the 20 eligible patients, 18 subjects were enrolled and completed the study, yielding a 90% recruitment rate and 100% retention rate. Attendance at exercise sessions was excellent, with 92% in HIIT and 88% in RES. No exercise-related adverse events occurred., Conclusion: This study demonstrated that HIIT and RES are feasible in rectal cancer patients undergoing NACR T., Trial Registration: www.clinicaltrials.gov, NCT03252821 (date of registration: March 30, 2017)., Competing Interests: Conflict of interest None declared., (© 2022 Greater Poland Cancer Centre.)

Introduction: Intensity modulated proton therapy (IMPT) is highly sensitive to anatomical variations which can cause inadequate target coverage during treatment. This study compares not-adapted (NA) robust plans to two adaptive IMPT methods - a fully-offline adaptive (FOA) and a simplified automatic online adaptive strategy (dose restoration (DR)) to determine the benefit of DR, in head and neck cancer (HNC)., Material/methods: Robustly optimized clinical IMPT doses in planning-CTs (pCTs) were available for a cohort of 10 HNC patients. During robust re-optimization, DR used isodose contours, generated from the clinical dose on pCTs, and patient specific objectives to reproduce the clinical dose in every repeated-CT(rCT). For each rCT(n = 50), NA, DR and FOA plans were robustly evaluated., Results: An improvement in DVH-metrics and robustness was seen for DR and FOA plans compared to NA plans. For NA plans, 74%(37/50) of rCTs did not fulfill the CTV coverage criteria (D98%>95%Dprescription). DR improved target coverage, target homogeneity and variability on critical risk organs such as the spinal cord. After DR, 52%(26/50) of rCTs met all clinical goals. Because of large anatomical changes and/or inaccurate patient repositioning, 48%(24/50) of rCTs still needed full offline adaptation to ensure an optimal treatment since dose restoration was not able to re-establish the initial plan quality., Conclusion: Robust optimization together with fully-automatized DR avoided offline adaptation in 52% of the cases. Implementation of dose restoration in clinical routine could ensure treatment plan optimality while saving valuable human and material resources to radiotherapy departments., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Purpose: The Quality Assurance project for stage III non-small cell lung cancer radiotherapy ProCaLung performed a multicentric two-step exercise evaluating mediastinal nodal Target Volume Definition and Delineation (TVD) variability and the opportunity for standardization. The TVD variability before and after providing detailed guidelines and the value of qualitative contour reviewing before applying quantitative measures were investigated., Materials and Methods: The case of a patient with stage III NSCLC and involved mediastinal lymph nodes was used as a basis for this study. Twenty-two radiation oncologists from nineteen centers in Belgium and Luxembourg participated in at least one of two phases of the project (before and after introduction of ProCaLung contouring guidelines). The resulting thirty-three mediastinal nodal GTV and CTV contours were then evaluated using a qualitative-before-quantitative (QBQ) approach. First, a qualitative analysis was performed, evaluating adherence to most recent guidelines. From this, a list of observed deviations was created and these were used to evaluate contour conformity. The second analysis was quantitative, using overlap and surface distance measures to compare contours within qualitative groups and between phases. A 'most robust' reference volume for these analyses was created using the STAPLE-algorithm and an averaging method., Results: Five GTV and seven CTV qualitative groups were identified. Second step contours were more often in higher-conformity groups (p = 0.012 for GTV and p = 0.024 for CTV). Median Residual Mean Square Distances improved from 2.34 mm to 1.36 mm for GTV (p = 0.01) and from 4.53 mm to 1.58 mm for CTV (p < 0.0001). Median Dice coefficients increased from 0.81 to 0.84 for GTV (p = 0.07) and from 0.82 to 0.89 for CTV (p ≤ 0.001). Using HC-contours only to generate references translated in more robust quantitative evaluations., Conclusion: Variability of mediastinal nodal TVD was reduced after providing the ProCaLung consensus guidelines. A qualitative review was essential for providing meaningful quantitative measures., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Y.L.: Personal fees from AstraZeneca (advisory board) and RaySearch (speaker fee), not related to this project. F.C., T.D., L.M., V.R., X.G., M.L.: None., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: Planning target volume (PTV) definition based on Mid-Position (Mid-P) strategy typically integrates breathing motion from tumor positions variances along the conventional axes of the DICOM coordinate system. Tumor motion directionality is thus neglected even though it is one of its stable characteristics in time. We therefore propose the directional MidP approach (MidP dir), which allows motion directionality to be incorporated into PTV margins. A second objective consists in assessing the ability of the proposed method to better take care of respiratory motion uncertainty., Methods: 11 lung tumors from 10 patients with supra-centimetric motion were included. PTV were generated according to the MidP and MidP dir strategies starting from planning 4D CT., Results: PTV MidP dir volume didn't differ from the PTV MidP volume: 31351 mm 3 IC95% [17242-45459] vs. 31003 mm 3 IC95% [ 17347-44659], p = 0.477 respectively. PTV MidP dir morphology was different and appeared more oblong along the main motion axis. The relative difference between 3D and 4D doses was on average 1.09%, p = 0.011 and 0.74%, p = 0.032 improved with directional MidP for D 99% and D 95% . D 2% was not significantly different between both approaches. The improvement in dosimetric coverage fluctuated substantially from one lesion to another and was all the more important as motion showed a large amplitude, some obliquity with respect to conventional axes and small hysteresis., Conclusions: Directional MidP method allows tumor motion to be taken into account more tightly as a geometrical uncertainty without increasing the irradiation volume., (Copyright © 2021 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Background: The role of postoperative radiation therapy (PORT) in stage III N2 NSCLC is controversial. We analyzed decision-making for PORT among European radiation oncology experts in lung cancer., Methods: Twenty-two experts were asked before and after presentation of the results of the LungART trial to describe their decision criteria for PORT in the management of pN+ NSCLC patients. Treatment strategies were subsequently converted into decision trees and analyzed., Results: Following decision criteria were identified: extracapsular nodal extension, incomplete lymph node resection, multistation lymph nodes, high nodal tumor load, poor response to induction chemotherapy, ineligibility to receive adjuvant chemotherapy, performance status, resection margin, lung function and cardiopulmonary comorbidities. The LungART results had impact on decision-making and reduced the number of recommendations for PORT. The only clear indication for PORT was a R1/2 resection. Six experts out of ten who initially recommended PORT for all R0 resected pN2 patients no longer used PORT routinely for these patients, while four still recommended PORT for all patients with pN2. Fourteen experts used PORT only for patients with risk factors, compared to eleven before the presentation of the LungART trial. Four experts stated that PORT was never recommended in R0 resected pN2 patients regardless of risk factors., Conclusion: After presentation of the LungART trial results at ESMO 2020, 82% of our experts still used PORT for stage III pN2 NSCLC patients with risk factors. The recommendation for PORT decreased, especially for patients without risk factors. Cardiopulmonary comorbidities became more relevant in the decision-making for PORT., Competing Interests: 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 © 2021 Elsevier Inc. All rights reserved.)

Background and Purpose: There are several alternatives to the widespread ITV strategy in order to account for breathing-induced motion in PTV margins. The most sophisticated one includes the generation of a motion-compensated CT scan with the CTV placed in its average position - the mid-position approach (MidP). In such configuration, PTV margins integrate breathing as another random error. Despite overall irradiated volume reduction, such approach is barely used in clinical practice because of its dependence to deformable registration and its unavailability in commercial treatment planning systems. As an alternative, the mid-ventilation approach (MidV) selects the phase in the 4D-CT scan that is the closest to the MidP, with a residual error accounted for in the PTV margin. We propose a treatment planning system-integrated strategy, aiming at better approximating the MidP approach without its drawbacks: Hybrid MidV-MidP approach, i.e., the delineation on the MidV-CT and translation at the mid-position coordinates using treatment planning system built-in capabilities., Material and Methods: Forty-five lung lesions treated with stereotactic radiotherapy were selected. PTV was defined using MidP, MidV, Hybrid MidV-MidP and ITV strategies. Margin definitions were adapted and resulting PTVs were compared., Results: Hybrid MidV-MidP showed similar target volume and location than the MidP and confirmed that margin-incorporated tumor motion strategies lead to significantly smaller PTVs than the ITV with mean reduction of 26 ± 7%., Conclusion: We report on the successful implementation of a pseudo-MidP solution without its inherent drawbacks. It answers the need for TPS-embedded tumor motion range identification and related margin's component calculation., Competing Interests: Declaration of Competing Interest The authors declare they have no conflict of interest., (Copyright © 2021 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Background: Exercise training has shown beneficial effects in the management of radiotherapy-related side effects in prostate cancer (PCa) patients undergoing radiation therapy (RT). However, the optimal modality of the exercise programs have not been yet determined. The aim of this randomized controlled trial was to investigate the effects of high-intensity interval training (HIIT) and resistance training (RES) compared to usual care (UC) on cancer-treatment-related fatigue (CTRF) (primary outcome), quality of life, depression, daytime sleepiness, insomnia, sleep quality, functional exercise capacity and executive function in PCa patients during RT., Methods: PCa patients undergoing RT with or without ADT were randomized in HIIT, RES or UC. Both exercise programs included three sessions per week during 5-8 weeks. HIIT consisted of 8-15 × 60 s intervals (≥85% maximal heart rate). RES was performed with 1-3 sets of 8-12 repetitions for each large muscle groups. The primary outcome was changed in CTRF measured with the Functional Assessment of Chronic Illness Therapy-Fatigue., Results: Seventy-two subjects (69.1 ± 8.2 years) completed the study. No exercise-related adverse events occurred. HIIT (p = 0.012) and RES (p = 0.039) training attenuated increases in CTRF compared to UC. Functional exercise capacity, evaluated by the 6-min walk test, increased after HIIT (p = 0 = 0.43) and RES (p = 0.041) compared to UC (+0.1%). No other secondary variables were different between groups., Conclusions: Both intervention groups displayed beneficial effects on CTRF and functional exercise capacity in PCa patients undergoing RT. In addition, HIIT and RES are both safe with an excellent attendance rate to the exercise sessions.

Background: Whole brain radiotherapy (WBRT) is a common treatment option for brain metastases secondary to non-small cell lung cancer (NSCLC). Data from the QUARTZ trial suggest that WBRT can be omitted in selected patients and treated with optimal supportive care alone. Nevertheless, WBRT is still widely used to treat brain metastases secondary to NSCLC. We analysed decision criteria influencing the selection for WBRT among European radiation oncology experts., Methods: Twenty-two European radiation oncology experts in lung cancer as selected by the European Society for Therapeutic Radiation Oncology (ESTRO) for previous projects and by the Advisory Committee on Radiation Oncology Practice (ACROP) for lung cancer were asked to describe their strategies in the management of brain metastases of NSCLC. Treatment strategies were subsequently converted into decision trees and analysed for agreement and discrepancies., Results: Eight decision criteria (suitability for SRS, performance status, symptoms, eligibility for targeted therapy, extra-cranial tumour control, age, prognostic scores and "Zugzwang" (the compulsion to treat)) were identified. WBRT was recommended by a majority of the European experts for symptomatic patients not suitable for radiosurgery or fractionated stereotactic radiotherapy. There was also a tendency to use WBRT in the ALK/EGFR/ROS1 negative NSCLC setting., Conclusion: Despite the results of the QUARTZ trial WBRT is still widely used among European radiation oncology experts., 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 © 2020 Elsevier B.V. All rights reserved.)

Background: Tumor hypoxia increases resistance to radiotherapy and systemic therapy. Our aim was to develop and validate a disease-agnostic and disease-specific CT (+FDG-PET) based radiomics hypoxia classification signature., Material and Methods: A total of 808 patients with imaging data were included: N = 100 training/N = 183 external validation cases for a disease-agnostic CT hypoxia classification signature, N = 76 training/N = 39 validation cases for the H&N CT signature and N = 62 training/N = 36 validation cases for the Lung CT signature. The primary gross tumor volumes (GTV) were manually defined by experts on CT. In order to dichotomize between hypoxic/well-oxygenated tumors a threshold of 20% was used for the [ 18 F]-HX4-derived hypoxic fractions (HF). A random forest (RF)-based machine-learning classifier/regressor was trained to classify patients as hypoxia-positive/ negative based on radiomic features., Results: A 11 feature "disease-agnostic CT model" reached AUC's of respectively 0.78 (95% confidence interval [CI], 0.62-0.94), 0.82 (95% CI, 0.67-0.96) and 0.78 (95% CI, 0.67-0.89) in three external validation datasets. A "disease-agnostic FDG-PET model" reached an AUC of 0.73 (0.95% CI, 0.49-0.97) in validation by combining 5 features. The highest "lung-specific CT model" reached an AUC of 0.80 (0.95% CI, 0.65-0.95) in validation with 4 CT features, while the "H&N-specific CT model" reached an AUC of 0.84 (0.95% CI, 0.64-1.00) in validation with 15 CT features. A tumor volume-alone model was unable to significantly classify patients as hypoxia-positive/ negative. A significant survival split (P = 0.037) was found between CT-classified hypoxia strata in an external H&N cohort (n = 517), while 117 significant hypoxia gene-CT signature feature associations were found in an external lung cohort (n = 80)., Conclusion: The disease-specific radiomics signatures perform better than the disease agnostic ones. By identifying hypoxic patients our signatures have the potential to enrich interventional hypoxia-targeting trials., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Radiotherapy (RT) plays a major role in the treatment of small cell lung cancer (SCLC). Therefore, the ACROP committee was asked by ESTRO to provide recommendations on target volume delineation for standard clinical scenarios in definitive (chemo)-radiotherapy (CRT), adjuvant RT for stages I-III SCLC and consolidation thoracic RT for stage IV disease. The aim of these guidelines is to standardise and optimise the process of RT treatment planning for clinical practice and prospective studies. The process for the development of the guidelines included the evaluation of a structured questionnaire followed by a consensus discussion, voting and writing process within the committee. Firstly, we provide recommendations for both the imaging to be performed as part of the diagnostic work-up and for the RT planning process. Secondly, recommendations are made for target volume delineation including delineation of the primary gross tumour volume (GTV) and lymph node GTV and clinical tumour volume (CTV) expansion in the context of definitive and adjuvant RT. With regard to internal target volume (ITV) and planning target volume (PTV) definitions, we make recommendations about the management of geometric uncertainties and target motion. Finally, we provide our opinions on organ at risk (OAR) delineation and organisational issues to be considered., (Copyright © 2020. Published by Elsevier B.V.)

Kilovoltage intrafraction monitoring (KIM) is a method allowing to precisely infer the tumour trajectory based on cone beam computed tomography (CBCT) 2D-projections. However, its accuracy is deteriorated in the case of highly mobile tumours involving hysteresis. A first adaptation of KIM consisting of a prior amplitude based binning step has been developed in order to minimize the errors of the original model (phase-KIM). In this work, we propose enhanced methods (KIM sub-arc optim and phase-KIM sub-arc optim ) to improve the accuracy of KIM and phase-KIM which relies on the selection of the optimal starting CBCT gantry angle. Aiming at demonstrating the interest of our approach, we carried out a simulation study and an experimental study: we compared the accuracy of the conventional versus sub-arc optim methods on simulated realistic tumour motions with amplitudes ranging from 5 to 30 mm in 1 mm increments. The same approach was performed using a lung dynamic phantom generating a 30 mm amplitude sinusoidal motion. The results show that for in-silico simulated motions of 10, 20 and 30 mm amplitude, the three-dimensional root mean square error (3D-RMSE) can be reduced by 0.67 mm, 0.91 mm, 0.94 mm and 0.18 mm, 0.25 mm, 0.28 mm using KIM sub-arc optim and phase-KIM sub-arc optim respectively. Considering all in-silico simulated trajectories, the percentage of errors larger than 1 mm decreases from 21.9% down to 1.6% for KIM (p < 0.001) and from 6.6% down to 1.2% for phase-KIM (p < 0.001). Experimentally, the 3D-RMSE is lowered by 0.5732 mm for KIM and by 0.1 mm for phase-KIM. The percentage of errors larger than 1 mm falls from 39.7% down to 18.5% for KIM and from 23.2% down to 11.1% for phase-KIM. In conclusion, our method efficiently anticipates CBCT gantry angles associated with a significantly better accuracy by using KIM and phase-KIM., (© 2020 IOP Publishing Ltd.)

Background and Purpose: In proton therapy, inter-fractional density changes can severely compromise the effective delivery of the planned dose. Such dose distortion effects can be accounted for by treatment plan adaptation, that requires considerable automation for widespread implementation in clinics. In this study, the clinical benefit of an automatic online adaptive strategy called dose restoration (DR) was investigated. Our objective was to assess to what extent DR could replace the need for a comprehensive offline adaptive strategy., Materials and Methods: The fully automatic and robust DR workflow was evaluated in a cohort of 14 lung IMPT patients that had a planning-CT and two repeated 4D-CTs (rCT1,rCT2). Initial plans were generated using 4D-robust optimization (including breathing-motion, setup and range errors). DR relied on isodose contours generated from the initial dose and associated patient specific weighted objectives to mimic this initial dose in repeated-CTs. These isodose contours, with their corresponding objectives, were used during re-optimization to compensate proton range distortions disregarding re-contouring. Robustness evaluations were performed for the initial, not-adapted and restored (adapted) plans., Results: The resulting DVH-bands showed overall improvement in DVH metrics and robustness levels for restored plans, with respect to not-adapted plans. According to CTV coverage criteria (D95%>95%Dprescription) in not-adapted plans, 35% (5/14) of the cases needed offline adaptation. After DR, Median(D95%) was increased by 1.1 [IQR,0.4] Gy and only one patient out of 14 (7%) still needed offline adaptation because of important anatomical changes., Conclusions: DR has the potential to improve CTV coverage and reduce offline adaptation rate., Competing Interests: 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., (© 2020 The Authors.)

Background: About 50% of non-small cell lung cancer (NSCLC) patients have metastatic disease at initial diagnosis, which limits their treatment options and, consequently, the 5-year survival rate (15%). Immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, have become standard of care (SOC) for most good performance status patients. However, most patients will not obtain long-term benefit and new treatment strategies are therefore needed. We previously demonstrated clinical safety of the tumour-selective immunocytokine L19-IL2, consisting of the anti-ED-B scFv L19 antibody coupled to IL2, combined with stereotactic ablative radiotherapy (SABR)., Methods: This investigator-initiated, multicentric, randomised controlled open-label phase II clinical trial will test the hypothesis that the combination of SABR and L19-IL2 increases progression free survival (PFS) in patients with limited metastatic NSCLC. One hundred twenty-six patients will be stratified according to their metastatic load (oligo-metastatic: ≤5 or poly-metastatic: 6 to 10) and randomised to the experimental-arm (E-arm) or the control-arm (C-arm). The C-arm will receive SOC, according to the local protocol. E-arm oligo-metastatic patients will receive SABR to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consists of irradiation of one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC). The accrual period will be 2.5-years, starting after the first centre is initiated and active. Primary endpoint is PFS at 1.5-years based on blinded radiological review, and secondary endpoints are overall survival, toxicity, quality of life and abscopal response. Associative biomarker studies, immune monitoring, CT-based radiomics, stool collection, iRECIST and tumour growth rate will be performed., Discussion: The combination of SABR with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients in 14 centres located in 6 countries. This bimodal and trimodal treatment approach is based on the direct cytotoxic effect of radiotherapy, the tumour selective immunocytokine L19-IL2, the abscopal effect observed distant from the irradiated metastatic site(s) and the memory effect. The first results are expected end 2023., Trial Registration: ImmunoSABR Protocol Code: NL67629.068.18; EudraCT: 2018-002583-11; Clinicaltrials.gov: NCT03705403; ISRCTN ID: ISRCTN49817477; Date of registration: 03-April-2019.

Purpose: The purpose of this study was to address the dosimetric accuracy of synthetic computed tomography (sCT) images of patients with brain tumor generated using a modified generative adversarial network (GAN) method, for their use in magnetic resonance imaging (MRI)-only treatment planning for proton therapy., Methods: Dose volume histogram (DVH) analysis was performed on CT and sCT images of patients with brain tumor for plans generated for intensity-modulated proton therapy (IMPT). All plans were robustly optimized using a commercially available treatment planning system (RayStation, from RaySearch Laboratories) and standard robust parameters reported in the literature. The IMPT plan was then used to compute the dose on CT and sCT images for dosimetric comparison, using RayStation analytical (pencil beam) dose algorithm. We used a second, independent Monte Carlo dose calculation engine to recompute the dose on both CT and sCT images to ensure a proper analysis of the dosimetric accuracy of the sCT images., Results: The results extracted from RayStation showed excellent agreement for most DVH metrics computed on the CT and sCT for the nominal case, with a mean absolute difference below 0.5% (0.3 Gy) of the prescription dose for the clinical target volume (CTV) and below 2% (1.2 Gy) for the organs at risk (OARs) considered. This demonstrates a high dosimetric accuracy for the generated sCT images, especially in the target volume. The metrics obtained from the Monte Carlo doses mostly agreed with the values extracted from RayStation for the nominal and worst-case scenarios (mean difference below 3%)., Conclusions: This work demonstrated the feasibility of using sCT generated with a GAN-based deep learning method for MRI-only treatment planning of patients with brain tumor in intensity-modulated proton therapy., (© 2020 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Background and Purpose: Current motion mitigation strategies, like margins, gating, and tracking, deal with geometrical uncertainties in the tumour position, induced by breathing during radiotherapy (RT). However, they often overlook motion variability in amplitude, respiratory rate, or baseline position, when breathing spontaneously. Consequently, this may negatively affect the delivered dose conformality in comparison to the plan. We previously demonstrated on volunteers that 3 different modes of mechanically-assisted and non-invasive ventilation (MANIV) may reduce variability in breathing motion. The volume-controlled mode (VC) constraints the amplitude and respiratory rate (RR) in physiologic condition. The shallow-controlled mode (SH), derived from VC, increases the RR and decreases amplitude. The slow-controlled mode (SL) induces repeated breath holds with constrained ventilation pressure. In this study, we compared these mechanical ventilation modes to spontaneous breathing or breath hold and assessed their tolerance and effects on internal tumour motion in patients receiving RT., Material and Methods: The VC and SH modes were evaluated in ten patients with lung or liver cancers (cohort A). The SL mode was evaluated in 12 left breast cancer patients (cohort B). After a training and simulation session, the patients underwent 2 MRI sessions to analyze the internal motion of breast and tumour., Results: MANIV was well tolerated, without any adverse events or oxymetric changes, even in patients with respiratory comorbidities. In cohort A, when compared to spontaneous breathing (SP), VC reduced significantly inter-session variations of the tumour motion amplitude (p = 0.01), as well as intra- and inter-session variations of the RR (p < 0.05). As to SH, the RR increased, while its variations within and across sessions decreased when compared to SP (p < 0.001). SH reduced the median amplitude of the tumour motion by 6.1 mm or 38.2% (p ≤ 0.01) compared to VC. In cohort B, breast position stability over the end-inspiratory plateaus obtained spontaneously or with SL remained similar. Median duration of the plateaus in SL was 16.6 s., Conclusion: MANIV is a safe and well tolerated ventilation technique for patients receiving radiotherapy. MANIV could thus make current motion mitigation strategies less critical and more robust. Clinical implementation might be considered, provided the ventilation mode is carefully selected with respect to the treatment indication and patient individualities., (Copyright © 2019 Elsevier B.V. All rights reserved.)

We developed a training protocol based on Intrapulmonary Percussive Ventilation in order to prolong breath-hold while nearly suppressing the thorax motion. This protocol allowed ten subjects to achieve a 20-minutes-breath-hold, while reducing the residual surface motion to 1 mm around its mean position for more than 95% of the breath-hold duration., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: The use of neural networks to directly predict three-dimensional dose distributions for automatic planning is becoming popular. However, the existing methods use only patient anatomy as input and assume consistent beam configuration for all patients in the training database. The purpose of this work was to develop a more general model that considers variable beam configurations in addition to patient anatomy to achieve more comprehensive automatic planning with a potentially easier clinical implementation, without the need to train specific models for different beam settings., Methods: The proposed anatomy and beam (AB) model is based on our newly developed deep learning architecture, and hierarchically densely connected U-Net (HD U-Net), which combines U-Net and DenseNet. The AB model contains 10 input channels: one for beam setup and the other 9 for anatomical information (PTV and organs). The beam setup information is represented by a 3D matrix of the non-modulated beam's eye view ray-tracing dose distribution. We used a set of images from 129 patients with lung cancer treated with IMRT with heterogeneous beam configurations (4-9 beams of various orientations) for training/validation (100 patients) and testing (29 patients). Mean squared error was used as the loss function. We evaluated the model's accuracy by comparing the mean dose, maximum dose, and other relevant dose-volume metrics for the predicted dose distribution against those of the clinically delivered dose distribution. Dice similarity coefficients were computed to address the spatial correspondence of the isodose volumes between the predicted and clinically delivered doses. The model was also compared with our previous work, the anatomy only (AO) model, which does not consider beam setup information and uses only 9 channels for anatomical information., Results: The AB model outperformed the AO model, especially in the low and medium dose regions. In terms of dose-volume metrics, AB outperformed AO by about 1-2%. The largest improvement was found to be about 5% in lung volume receiving a dose of 5Gy or more (V 5 ). The improvement for spinal cord maximum dose was also important, that is, 3.6% for cross-validation and 2.6% for testing. The AB model achieved Dice scores for isodose volumes as much as 10% higher than the AO model in low and medium dose regions and about 2-5% higher in high dose regions., Conclusions: The AO model, which does not use beam configuration as input, can still predict dose distributions with reasonable accuracy in high dose regions but introduces large errors in low and medium dose regions for IMRT cases with variable beam numbers and orientations. The proposed AB model outperforms the AO model substantially in low and medium dose regions, and slightly in high dose regions, by considering beam setup information through a cumulative non-modulated beam's eye view ray-tracing dose distribution. This new model represents a major step forward towards predicting 3D dose distributions in real clinical practices, where beam configuration could vary from patient to patient, from planner to planner, and from institution to institution., (© 2019 American Association of Physicists in Medicine.)

Irradiation log-files store useful information about the plan delivery, and together with independent Monte Carlo dose engine calculations can be used to reduce the time needed for patient-specific quality assurance (PSQA). Nonetheless, machine log-files carry an uncertainty associated to the measurement of the spot position and intensity that can influence the correct evaluation of the quality of the treatment delivery. This work addresses the problem of the inclusion of these uncertainties for the final verification of the treatment delivery. Dedicated measurements performed in an IBA Proteus Plus gantry with a pencil beam scanning (PBS) dedicated nozzle have been carried out to build a 'room-dependent' model of the spot position uncertainties. The model has been obtained through interpolation of the look-up tables describing the systematic and random uncertainties, and it has been tested for a clinical case of a brain cancer patient irradiated in a dry-run. The delivered dose has been compared with the planned dose with the inclusion of the errors obtained applying the model. Our results suggest that the accuracy of the treatment delivery is higher than the spot position uncertainties obtained from the log-file records. The comparison in terms of DVHs shows that the log-reconstructed dose is compatible with the planned dose within the 95% confidence interval obtained applying our model. The initial mean dose difference between the calculated dose to the patient based on the plan and recorded data is around 1%. The difference is essentially due to the log-file uncertainties and it can be removed with a correct treatment of these errors. In conclusion our new PSQA protocol allows for a fast verification of the dose delivered after every treatment fraction through the use of machine log-files and an independent Monte Carlo dose engine. Moreover, the inclusion of log-file uncertainties in the dose calculation allows for a correct evaluation of the quality of the treatment plan delivery.

Background and Purpose: When using highly conformal radiotherapy techniques, a stabilized breathing pattern could greatly benefit the treatment of mobile tumours. Therefore, we assessed the feasibility of Mechanically-assisted non-invasive ventilation (MANIV) on unsedated volunteers, and its ability to stabilize and modulate the breathing pattern over time., Materials and Methods: Twelve healthy volunteers underwent 2 sessions of dynamic MRI under 4 ventilation modes: spontaneous breathing (SP), volume-controlled mode (VC) that imposes regular breathing in physiologic conditions, shallow-controlled mode (SH) that intends to lower amplitudes while increasing the breathing rate, and slow-controlled mode (SL) that mimics end-inspiratory breath-holds. The last 3 modes were achieved under respirator without sedation. The motion of the diaphragm was tracked along the breathing cycles on MRI images and expressed in position, breathing amplitude, and breathing period for intra- and inter-session analyses. In addition, end-inspiratory breath-hold duration and position stability were analysed during the SL mode., Results: MANIV was well-tolerated by all volunteers, without adverse event. The MRI environment led to more discomfort than MANIV itself. Compared to SP, VC and SH modes improved the inter-session reproducibility of the amplitude (by 43% and 47% respectively) and significantly stabilized the intra- and inter-session breathing rate (p < 0.001). Compared to VC, SH mode significantly reduced the intra-session mean amplitude (36%) (p < 0.002), its variability (42%) (p < 0.001), and the intra-session baseline shift (26%) (p < 0.001). The SL mode achieved end-inspiratory plateaus lasting more than 10 s., Conclusion: MANIV offers exciting perspectives for motion management. It improves its intra- and inter-session reproducibility and should facilitate respiratory tracking, gating or margin techniques for both photon and proton treatments., (Copyright © 2019 Elsevier B.V. All rights reserved.)