Purpose The expanded HILUS study showed that bronchial dose and bronchial tumor compression are risk factors for bronchopulmonary bleedings after stereotactic body radiation therapy of centrally located lung tumors. In the current analysis of the same cohort, the aim was to identify the dose-volume histogram (DVH) parameter that best predicts fatal bronchopulmonary bleeding and to develop a predictive model for this endpoint. Methods and Materials The HILUS cohort included 230 patients with 238 central targets treated with stereotactic body radiation therapy of 7 Gy × 8 to the periphery of the planning target volume, where 21 patients developed grade-5 bronchopulmonary bleeding. Cox regression-based normal-tissue complication probability models were developed, accounting for the dose to the main and intermediate bronchi and bronchial tumor compression. Three alternative DVH parameters were explored: the dose to a certain volume (Dv), the volume receiving a certain dose (Vd), and the equivalent uniform dose. Internal validation was performed with the bootstrap method. Results The best fits of the bivariable normal-tissue complication probability models included bronchial tumor compression in combination with the DVH parameters of D0.31 cm3, V82Gy,EQD2 (equivalent dose in 2-Gy fractions), and equivalent uniform dose with n = 0.024, respectively. This indicates that a high dose to a small volume may lead to grade-5 bronchopulmonary bleeding. The probability of fatal bleeding at 2 years without bronchial tumor compression was 10% for a D0.31 cm3 of 107 Gy3 EQD2, and 20% at 165 Gy3 EQD2, whereas the probability with bronchial tumor compression was 10% at 0 Gy3 and 20% at 58 Gy3 EQD2. The model showed good discrimination and calibration. Conclusions Bronchial tumor compression is a strong predictor for grade-5 bleeding, and the most relevant dose parameter appears to be the dose to a small volume of the main and intermediate bronchi.

BACKGROUND:Novel cone-beam computed tomography (CBCT) has become available on standard C-arm linacs, making it widely applicable in photon-based radiotherapy. PURPOSE:To evaluate CT number stability of novel CBCT systems installed on seven C-arm linacs within a single institution, across CBCT systems and over time, and to assess the CBCT-based dose calculation accuracy in head-and-neck, lung, and pelvic cancer patients. METHODS:A Gammex Advanced Electron Density phantom (Sun Nuclear) was scanned at installation of eleven CBCT imaging panels at seven TrueBeam C-arm linacs (Varian Medical Systems, A Siemens Healthineers Company), and after three and six months. Three CBCT protocols were evaluated, a head protocol (tube voltage of 100 kVp, iterative reconstruction, denoted iCBCT), a thorax protocol (tube voltage of 125 kVp; filtered back projection with Feldkamp-Davis-Kress (FDK) algorithm), and a pelvis protocol (tube voltage of 125 kVp; iCBCT). Fifteen tissue-equivalent phantom inserts were scanned individually, placed centrally in the phantom. The mean CT number was extracted, and CT number stability was assessed across imaging panels and timepoints. CT number stability was compared to a previous CBCT detector model. Moreover, routine measurements using four inserts were performed until 18 months after installation. Conversion curves for mass density estimation were generated, following a consensus guide. The spread of the curves due to CT number variation across imaging panels was assessed. Treatment plans created on planning CT (pCT) scans of 10 head-and-neck, 22 lung, and 15 pelvic cancer patients were recalculated on CBCT scans, selected to match the anatomy seen on the pCT. Dose-volume parameters for targets and organs-at-risk were compared between pCT and CBCT. RESULTS:The CT numbers were consistent across the imaging panels and over time for iCBCT reconstruction, but to a lesser degree for FDK reconstruction. The CT number variation increased with the density of the phantom inserts. Still, for the high-density bone insert the range/interquartile range of the CT numbers across imaging panels were 51/29 HU (head protocol), 140/41 HU (thorax protocol), and 27/16 HU (pelvis protocol). For the longitudinal measurements, the median differences were 4 HU, -9 HU, and -8 HU after three months and -8 HU, -32 HU, and -26 HU after six months, for the head, thorax, and pelvis protocol, respectively. For the routine measurements, no clear time dependence was seen for the CT number differences. It was found that a single conversion curve per CBCT protocol could be used for all imaging panels. For iCBCT, median dose differences between pCT and CBCT were within 0.5% for head-and-neck and pelvis and 1.5% for lung, while FDK lung was within 2.5%. The largest deviations with iCBCT were -1.3% for head-and-neck, -1.1% for pelvis, and -3.8% for thorax, but -18.0% for thorax FDK. CONCLUSIONS:The CT number stability was sufficient to allow for a single conversion curve per CBCT protocol to be applied across all CBCT imaging panels. A high dose calculation accuracy was found for 36 patients with iCBCT scans, while larger deviations were seen for eleven thorax FDK scans.

Background and purpose: Prophylactic cranial irradiation (PCI) is part of standard treatment for patients with limited disease small cell lung cancer (LD-SCLC), treated with curative intent. However, doubt has been raised about the efficacy of PCI in a modern clinical setting. Therefore, we examined factors impacting PCI receival, the cumulative incidence of symptomatic brain metastases, and overall survival (OS) with and without PCI. Patient/material and methods: Records of 190 patients with LD-SCLC consecutively treated between 2012 and 2021 at our institution were reviewed. Patients were grouped based on whether they received PCI (PCI, n = 119) or not (no PCI, n = 71). Baseline characteristics, Kaplan-Meier estimates of OS, and cumulative incidence of symptomatic brain metastases were compared for the two groups. Results: PCI no patients were older, had a poorer performance status, were more often treated in 2018–2021 and had more frequently a brain magnetic resonance imaging (MRI) at the time of diagnosis. No PCI median OS was 19 months compared to 24 months for PCI, not significantly different (p = 0.40). During follow-up 54 patients (28.4%) developed symptomatic brain metastases, with no statistically significant difference in the numbers of patients with, and cumulative incidence of, symptomatic brain metastases between the two groups (p = 0.35 and p = 0.21, respectively). Interpretation: Despite patients not receiving PCI being older and in poorer performance status, no statistically significant difference in OS or cumulative incidence of brain metastasis were observed compared to patients who received PCI. This supports uncertainty regarding the role of PCI.

Robust quality assurance (QA) of clinical trials in radiotherapy (RT) is paramount for minimising uncertainties in treatment delivery, thereby strengthening the statistical power of the study and increasing the likelihood of accurately answering the research question. As RT techniques evolve and become more complex, establishing an appropriate QA program for a specific clinical trial becomes increasingly challenging, highlighting the importance of clear and standardised recommendations. This study provide such recommendations for Principal Investigators (PIs) to consider when planning and conducting RT Quality Assurance (RTQA) for clinical trials. They arise from experiences with RTQA in the clinical trials conducted in the Danish Multidisciplinary Cancer Groups (DMCGs). The recommendations include a checklist to guide PIs in developing an effective RTQA program.

BACKGROUND:Independent secondary dose calculation (ISDC) is becoming increasingly important for patient specific quality assurance. The most widely used analytical algorithms in ISDC are becoming challenged by Monte Carlo systems, which offer a potentially higher accuracy. PURPOSE:Quantify the benefit of Monte Carlo over analytical algorithms, and of customized beam models over generic beam models, in terms of clinically relevant parameters, action level, and workload. METHODS:A set of 100 patients across 20 case classes, all planned with Acuros XB (Siemens Healthineers) was analyzed with Mobius3D (M3D) (Siemens Healthineers) and SciMoCa (Radialogica LLC), both with custom beam models (SMCcbm) and generic beam models (SMCgen). Gamma pass rate (GPR) and mean target dose difference |ΔD| action levels were determined for various rates of QA failures. RESULTS:At a workload of < 10%, the action level for M3D was GPR (3%, 3 mm) < 90% and |ΔD| > 4.5%. For SMCgen, the action level was GPR (2%, 2 mm) < 95% and |ΔD| > 1.5%. For SMCcbm, it was GPR (2%, 1 mm) < 95% and |ΔD | > 1%. The combination of both criteria reduced the workload to < 5%. SMC failures could be traced back to differences in the patient density model of Acuros XB. Some M3D failures could be traced back to the handling of tissue heterogeneities. The different performance between SMCcbm and SMCgen was due to one (of three) generic beam models. CONCLUSION:Monte Carlo allows substantially stricter acceptance criteria and is sensitive enough to capture TPS commissioning errors. Generic beam models must be validated thoroughly before being put to use in ISDC.

Purpose: To present results from the trial radiotherapy quality assurance (RTQA) programme of the centres involved in the randomised phase-III PROton versus photon Therapy for esophageal Cancer – a Trimodality strategy (PROTECT)-trial, investigating the clinical effect of proton therapy (PT) vs. photon therapy (XT) for patients with oesophageal cancer. Materials and methods: The pre-trial RTQA programme consists of benchmark target and organ at risk (OAR) delineations as well as treatment planning cases, a facility questionnaire and beam output audits. Continuous on-trial RTQA with individual case review (ICR) of the first two patients and every fifth patient at each participating site is performed. Patient-specific QA is mandatory for all patients. On-site visits are scheduled after the inclusion of the first two patients at two associated PT and XT sites. Workshops are arranged annually for all PROTECT participants. Results: Fifteen PT/XT sites are enrolled in the trial RTQA programme. Of these, eight PT/XT sites have completed the entire pre-trial RTQA programme. Three sites are actively including patients in the trial. On-trial ICR was performed for 22 patients. For the delineation of targets and OARs, six major and 11 minor variations were reported, and for six patients, there were no remarks. One major and four minor variations were reported for the treatment plans. Three site visits and two annual workshops were completed. Interpretation: A comprehensive RTQA programme was implemented for the PROTECT phase III trial. All centres adhered to guidelines for pre-trial QA. For on-trial QA, major variations were primarily seen for target delineations (< 30%), and no treatment plans required re-optimisation.

INTRODUCTION:Centrally located early-stage non-small cell lung cancer (ES NSCLC) with tumors close to the bronchi is potentially curable with stereotactic body radiation therapy (SBRT). To evaluate the clinical benefit of the treatment, both the risk of high-grade toxicity as well as the treatment efficacy need to be assessed. MATERIAL AND METHODS:From the expanded HILUS cohorts, 72 patients with T1-T3N0M0 NSCLC were included in the current analysis. All patients had been treated with SBRT in 8 fractions to 56 Gy for a tumor located within 2 cm from the tracheobronchial tree. Primary endpoint was progression free survival (PFS) and secondary endpoints included pattern of failure, local control (LC), lung cancer-specific survival (LCSS), overall survival (OS) and toxicity. The Kaplan-Meier method and Cox regression analysis were used. RESULTS:The median age of the cohort was 73 years and all patients suffered from comorbidities prior to SBRT. T2-T3 tumors were seen in 65 % of the patients. Seventeen patients relapsed after SBRT and distant recurrence was the most common form of relapse. Three-year PFS was 31 % (95 % CI 22-44) and largely explained by the short overall survival (38 % (95 % CI 22-44) at 3 years). Three-year rates of LC and LCSS were 97 % (95 % CI 92-100) and 76 % (95 % CI 65-89), respectively. Twelve patients (17 %) suffered from grade 5 toxicity, of which 9 were bronchopulmonary bleedings. CONCLUSION:The severe toxic profile limits the clinical benefit using SBRT with the investigated approach for patients with centrally located ES NSCLC.

BACKGROUND AND PURPOSE:Standard treatment for esophageal (EC) and gastroesophageal junction (GEJ) cancer includes neoadjuvant chemo-radiotherapy (nCRT), followed by surgery or definitive chemo-radiotherapy (dCRT) for inoperable patients. This study assessed real-world survival and morbidity in EC patients treated with radiotherapy (RT). Patient/material and methods: In this retrospective study, 417 patients with EC or GEJ cancer received nCRT or dCRT between 2012 and 2021 at a single center. We evaluated overall survival (OS), loco-regional control, progression-free survival, failure patterns, and toxicity. Data were sourced from clinical and treatment records. Patients were treated following national guidelines and received intensity-modulated radiotherapy and daily cone-beam Computed Tomography (CT) for setup. Radiotherapy doses were 41.4-66 Gy in 23-33 fractions. RESULTS:Of the patients, 250 received nCRT, and 167 received dCRT. Most (86%) had T3-T4 tumors, and 65% had node-positive disease. Histologies were adenocarcinoma (50%) and squamous cell carcinoma (45%). A total of 88% completed RT, and 92.4% of nCRT patients proceeded to surgery. Median OS was 31 months for nCRT and 24 months for dCRT; 3-year OS was 46% and 38%, respectively. Disease recurrence occurred in 46% with a median interval of 20 months. Multivariable analysis identified OS-associated factors for both nCRT and dCRT. Acute toxicity was common but generally mild; late side effects were not systematically recorded. INTERPRETATION:In clinical practice, OS after nCRT or dCRT was as expected. Most patients undergoing nCRT proceeded to surgery. Toxicity was frequent but manageable.

BACKGROUND:Radiotherapy of the prostate and the pelvic lymph nodes (LN) is a part of the standard of care treatment for high-risk prostate cancer. The independent translational and rotational (i.e., six-degrees-of-freedom, [6DoF]) motion of the prostate and LN target during and between fractions can perturb the dose distribution. However, no standard dose reconstruction method accounting for differential 6DoF target motion is available. PURPOSE:We present a framework for monitoring motion-induced dose perturbations for two independently moving target volumes in 6DoF. The framework was used to determine the dose perturbation for the prostate and the LN target caused by differential 6DoF motion for a cohort of high-risk prostate cancer patients. As a potential first step toward real-time dose-guided high-risk prostate radiotherapy, we furthermore investigated if the dose reconstruction was fast enough for real-time application for both targets. METHODS:Twenty high-risk prostate cancer patients were treated with 3-arc volumetric modulated arc therapy (VMAT). Kilovoltage intrafraction monitoring (KIM) with triggered kilovoltage (kV) images acquired every 3 throughout 7-10 fractions per patient was used for retrospective 6DoF intrafraction prostate motion estimation. The 6DoF interfraction LN motion was determined from a pelvic bone match between the planning CT and a post-treatment cone beam CT (CBCT). Using the retrospectively extracted motion, real-time 6DoF motion-including dose reconstruction was simulated using the in-house developed software DoseTracker. A data stream with the 6DoF target positions and linac parameters was broadcasted at a 3-Hz frequency to DoseTracker. In a continuous loop, DoseTracker calculated the target dose increments including the specified motion and, for comparison, without motion. The motion-induced change in D99.5% for the prostate CTV (ΔD99.5%) and in D98% for the LN CTV (ΔD98%) was calculated using the final cumulative dose of each fraction and averaged over all imaged fractions. The real-time reconstructed dose distribution of DoseTracker was benchmarked against a clinical treatment planning system (TPS) and it was investigated whether the calculation speed was fast enough to keep up with the incoming data stream. RESULTS:Translational motion was largest in cranio-caudal (CC) direction (prostate: [-5.9, +8.4] mm; LN: [-9.9; +11.0] mm) and anterior-posterior (AP) direction (prostate:[-5.6; +6.9] mm; LN: [-9.6; +11.0] mm). The pitch was the largest rotation (prostate: [-22.5; +25.2] deg; LN: [-3.9; +5.5] deg). The prostate CTV ΔD99.5% was [-16.2; +2.5]% for single fractions and [-3.0; +1.7]% when averaged over all imaged fractions. The LN CTV ΔD98% was [-19.8; +1.2]% for single fractions and [-3.1; +0.9]% after averaging. Mean (Standard deviation) absolute dose errors in DoseTracker of 107.8% (Std: 1.9%) for the prostate and 105.5% (Std:1.4%) for the LN were corrected during dose reconstruction by automatically calculated normalization factors. It resulted in accurate calculation of the motion-induced dose errors with relative differences between DoseTracker and TPS dose calculations of -0.1% (Std: 0.5%) (prostate CTV ΔD99.5%) and -0.2% (Std: 0.5%) (LN CTV ΔD98%). The DoseTracker calculation was fast enough to keep up with the incoming inputs for all but two out of 107 184 dose calculations. CONCLUSION:Using the developed framework for dose perturbation monitoring, we found that the differential 6DoF target motion caused substantial dose perturbation for individual fractions, which largely averaged out after several fractions. The framework was shown to provide reliable dose calculations and a sufficiently high-dose reconstruction speed to be applicable in real-time.