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Background: The aim is to quantify and analyse tumour motion during a course of treatment for lung SBRT patients. Material and methods: Peak-to-peak motion of 483 tumours in 441 patients treated with peripheral lung SBRT at a single institution over a two year period was measured on planning CT and at all treatment fractions. Planning 4D-CT scans were analysed using our clinical workflow involving deformable propagation of the delineated target to all phases. Similarly, acquisition of the 4D-CBCT data followed the clinical workflow based on XVI 5.0 available on Elekta linacs. Differences and correlations of the peak-to-peak motion on the planning CT and at treatment were analysed. Results: On the planning CT, a total of 81.4% of the tumours had a peak-to-peak motion 7 mm) at the first fraction were evaluated individually, and they all had poor 4DCT image quality. The difference between the first and second/third fractions had a mean and standard deviation of 0.4 mm/0.5 mm and 2.0 mm/1.9 mm. Conclusion: Tumour motion at first treatment was similar to motion at planning, and motion at subsequent treatments was very similar to motion at first treatment. Large tumour motions are located towards the caudal posterior tumour locations. Patients with poor 4D-CT image quality should be closely followed at the first treatment to verify the motion.

BACKGROUND For decades many patients with small cell lung cancer (SCLC) have been offered prophylactic cranial irradiation (PCI) to prevent brain metastases (BM). However, the role of PCI is debated in the modern era of increased brain magnetic resonance imaging (MRI) availability. BM in SCLC patients may respond to chemotherapy, and if a negative MRI is used in the decision to use of PCI in the treatment strategy, the timing of brain MRI may be crucial when evaluating the effect of PCI. This retrospective study investigates the impact of PCI outcomes in patients with SCLC staged with brain MRI prior to chemotherapy. MATERIALS AND METHODS This study included 245 patients diagnosed SCLC/mixed NSCLC-SCLC treated between 2012 and 2019. The population was analyzed separately for limited disease (LS-SCLC) and extensive disease (ES-SCLC). Patients were divided into groups based on baseline brain MRI prior to chemotherapy and PCI. The primary endpoint was time to symptomatic BM. Secondary endpoints were overall survival (OS), and progression-free survival (PFS). RESULTS In patients with LS-SCLC staged with brain MRI the probability of developing symptomatic BM at one year was 4% vs. 22% (p

Introduction: Stereotactic body radiation therapy of thoracic tumors close to the central airways implies risk of severe toxicity. We report a prospective multicenter phase 2 trial for tumors located less than or equal to 1 cm from the proximal bronchial tree with primary end point of local control and secondary end point of toxicity. Methods: Stereotactic body radiation therapy with 7 Gy x 8 was prescribed to the 67% isodose encompassing the planning target volume. The patients were stratified to group A (tumors < 1 cm from the main bronchi and trachea) or group B (all other tumors). Risk factors for treatment-related death were tested in univariate analysis, and a logistic regression model was developed for fatal bronchopulmonary bleeding versus dose to the main bronchi and trachea. Results: A total of 65 patients (group A/group B, n = 39/ 26) were evaluated. The median distance between the tumor and the proximal bronchial tree was 0 mm (0 & ndash;10 mm). The 2-year local control was 83%. Grade 3 to 5 toxicity was noted in 22 patients, including 10 cases of treatment related death (bronchopulmonary hemorrhage, n = 8; pneumonitis, n = 1; fistula, n = 1). Dose to the combined structure main bronchi and trachea and tumor distance to the main bronchi were important risk factors. Dose modeling revealed minimum dose to the & ldquo;hottest & rdquo; 0.2 cc to the structure main bronchi and trachea as the strongest predictor for lethal bronchopulmonary hemorrhage. Conclusions: On the basis of the presented data, 7 Gy x 8, prescribed to the planning target volume-encompassing isodose, should not be used for tumors located within 1 cm from the main bronchi and trachea. Group B-type tumors may be considered for the treatment on the basis of an individual risk-benefit assessment and a maximum dose to the main bronchi and trachea in the order of 70 to 80 Gy (equivalent dose in 2 Gy fractions). (c) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/).

Ibrutinib has now been approved for treatment of chronic lymphocytic leukemia (CLL) in both front-line setting and as later-line treatment. However, knowledge about the outcomes and adverse events (AE) among patients at a population-based level is still limited. Objectives: To report outcomes and AEs in a population-based cohort treated with ibrutinib outside clinical trials. Methods: We conducted a multicenter, retrospective cohort study including all patients with CLL treated with ibrutinib. Results: In total, 205 patients were included of whom 39 (19%) were treatment-naïve. The median follow-up was 21.4 months (interquartile range (IQR), 11.9,32.8), the estimated overall survival at 12 months was 88.8% (95% confidence interval (CI); 84.3%, 93.3%), and the estimated progression-free survival at 12 months was 86.3% (95% CI; 81.3%, 91.2%). During follow-up, 200 (97.6%) patients had at least one AE and 100 (48.8%) patients had at least one grade ≥3 AE. Eighty-six patients (42.0%) discontinued ibrutinib, hereof 47 (54.7%) due to AEs and 19 (22.1%) had progression of CLL or Richter transformation. Conclusions: In our study, we find comparable, though slightly inferior, overall, and progression-free survival, and discontinuation due to toxicity was higher compared with clinical trials. Patient training and information may improve treatment adherence outside clinical trials.

Introduction Ibrutinib is an oral irreversible inhibitor of Bruton's tyrosine kinase for treatment of chronic lymphocytic leukemia (CLL). Ibrutinib has demonstrated superior efficacy for patients with TP53 aberration or relapsed/refractory (R/R) CLL; and more recently superior progression free survival (PFS) has been demonstrated compared to chemoimmunotherapy as first line therapy. However, knowledge about the outcomes and adverse events (AE) upon ibrutinib among patients at a population-based level are still limited. The aim of the here presented study is to explore outcomes of ibrutinib treatment in a population-based cohort of patients with CLL treated with ibrutinib in Denmark. Methods In this retrospective study, patients from 8 hospitals in Denmark, who were diagnosed with CLL and treated with ibrutinib from April 2014 until February 2019 were included. Medical records were retrospectively reviewed to obtain information. Patients receiving ibrutinib within clinical trials were excluded. Overall survival (OS) was defined as time from ibrutinib start to death from any cause while PFS was defined as time from ibrutinib start to progression or death from any cause. PFS and OS were analyzed with the Kaplan-Meier method while cumulative incidence was calculated with the Aalen-Johansen estimator. Results In total, 205 patients with CLL receiving ibrutinib treatment were identified from hospital records and registries. The median follow-up was 21.4 months (IQR, 11.9-32.8) and the median time on ibrutinib was 16.8 months (IQR, 6.0-28.1). The median age at treatment initiation was 72.8 years (IQR, 65.7-77.8), 128 (62.4%) were male, and 111 (63.4%) were Binet stage B/C at treatment initiation out of 175 with available information regarding clinical stage. Thirty-nine (19.0%) received ibrutinib as first-line, and 166 for R/R CLL with a median of 2 (range, 1-8) prior treatment regimens. Information on TP53 aberration was available for 149 and regarding IGHV mutation for 147 patients, 111 (74.5%) had TP53 aberration and 107 (72.8%) were IGHV unmutated. Eighty-six patients (42.0%) discontinued ibrutinib during follow-up with a median time until discontinuation of 9.3 months (IQR, 3.0-23.2). Forty-seven (54.7%) discontinued due to AEs, 19 (22.1%) due to progression (12 had progression of CLL and 7 had Richter's transformation) while the remaining 20 (23.2%) discontinued due to other reasons. The estimated cumulative incidence of discontinuation at 12 months was 24.8% (95% CI: 18.6-30.9). The estimated OS after 12 and 24 months was 88.8% (95%CI: 84.3-93.3) and 76.8% (95%CI: 70.4-83.2) and the estimated PFS after 12 and 24 months was 87.3% (95%CI: 82.5-92.1) and 72.4% (95%CI: 65.5-79.2). One hundred and eighty-eight (91.7%) experienced at least one AE, among these 45 (23.9%) experienced a grade 3+. The most common AEs were hemorrhage (tendency to bruise, epistaxis etc.) which occurred in 86 (42.0%) of all and musculoskeletal and connective tissue disorders (arthralgia, myalgia etc.) which occurred in 82 (40.0%). Thirty-one (15.1%) patients experienced atrial fibrillation while on ibrutinib and 14 (6.8%) developed hypertension. One hundred and thirty-seven patients (66.8%) had at least one infection and among these 80 (58.4%) were hospitalized with an infection. The most common infections were lower respiratory tract infections and urinary tract infections that occurred for 88 (42.9%) and 41 (20.0%). The estimated cumulative incidence for any infection was 58.9% (95%CI: 52.0-65.9) at 12 months. Conclusion This is the first study describing outcomes for a population-based cohort of CLL patients treated with ibrutinib in Denmark. Real-world studies are warranted, to confirm the results from clinical trials. In this study, patients appear to have comparable OS and types of AE compared with the RESONATE trial. Differences in frequency of AEs compared to the clinical trial may reflect the focus of clinicians in routine practice. Discontinuation in this cohort was higher compared to clinical trials but comparable to previously reported real-world studies. While ibrutinib can be safely managed in routine clinical practice, this study demonstrates that a quarter of patients discontinue treatment due to mainly AEs. Further patient training and information, and in some instances personalized treatment with other targeted agents based on adverse event profile, may improve treatment adherence. Disclosures Aarup: Research Committee, Rigshospitalet: Research Funding. Enggaard:Abbie: Other: Advisory board; Gilead: Other: Advisory board; Janssen: Other: Advisory board. Frederiksen:Gilead: Research Funding; Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding; Novartis: Research Funding; Alexion: Research Funding. Niemann:Novo Nordisk Foundation: Research Funding; AstraZeneca: Consultancy, Other: Travel Grant, Research Funding; Sunesis: Consultancy; Acerta: Consultancy; CSL Behring: Consultancy; Roche: Other: Travel Grant; Janssen: Consultancy, Other: Travel Grant, Research Funding; Gilead: Other: Travel Grant; Abbvie: Consultancy, Other: Travel Grant, Research Funding.

Four-dimensional dose evaluation of inhomogeneous dose distributions planned for non-small cell lung cancer patients with lymph node involvement

BACKGROUND AND PURPOSE:Local recurrence is frequent in locally advanced NSCLC and is primarily located in FDG-avid parts of tumour and lymph nodes. Aiming at improving local control without increasing toxicity, we designed a multi-centre phase-III trial delivering inhomogeneous dose-escalation driven by FDG-avid volumes, while respecting normal tissue constraints and requiring no increase in mean lung dose. Dose-escalation driven by FDG-avid volumes, delivering mean doses of 95Gy (tumour) and 74Gy (lymph nodes), was pursued and compared to standard 66Gy/33F plans.MATERIAL AND METHODS:Dose plans for the first thirty patients enroled were analysed. Standard and escalated plans were created for all patients, blinded to randomization, and compared for each patient in terms of the ability to escalate while protecting normal tissue.RESULTS:The median dose-escalation in FDG-avid areas was 93.9Gy (tumour) and 73.0Gy (lymph nodes). Escalation drove the GTV and CTV to mean doses for the tumour of 87.5Gy (GTV-T) and 81.3Gy (CTV-T) in median. No significant differences in mean dose to lung and heart between standard and escalated were found, but small volumes of e.g. the bronchi received doses between 66 and 74Gy due to escalation.CONCLUSIONS:FDG-driven inhomogeneous dose-escalation achieves large increment in tumour and lymph node dose, while delivering similar doses to normal tissue as homogenous standard plans. BACKGROUND AND PURPOSE: Local recurrence is frequent in locally advanced NSCLC and is primarily located in FDG-avid parts of tumour and lymph nodes. Aiming at improving local control without increasing toxicity, we designed a multi-centre phase-III trial delivering inhomogeneous dose-escalation driven by FDG-avid volumes, while respecting normal tissue constraints and requiring no increase in mean lung dose. Dose-escalation driven by FDG-avid volumes, delivering mean doses of 95Gy (tumour) and 74Gy (lymph nodes), was pursued and compared to standard 66Gy/33F plans.MATERIAL AND METHODS: Dose plans for the first thirty patients enroled were analysed. Standard and escalated plans were created for all patients, blinded to randomization, and compared for each patient in terms of the ability to escalate while protecting normal tissue.RESULTS: The median dose-escalation in FDG-avid areas was 93.9Gy (tumour) and 73.0Gy (lymph nodes). Escalation drove the GTV and CTV to mean doses for the tumour of 87.5Gy (GTV-T) and 81.3Gy (CTV-T) in median. No significant differences in mean dose to lung and heart between standard and escalated were found, but small volumes of e.g. the bronchi received doses between 66 and 74Gy due to escalation.CONCLUSIONS: FDG-driven inhomogeneous dose-escalation achieves large increment in tumour and lymph node dose, while delivering similar doses to normal tissue as homogenous standard plans.

Purpose: To investigate differences in calculated doses and normal tissue complication probability (NTCP) values between different dose algorithms. Methods: Six dose algorithms from four different treatment planning systems were investigated: Eclipse AAA, Oncentra MasterPlan Collapsed Cone and Pencil Beam, Pinnacle Collapsed Cone and XiO Multigrid Superposition, and Fast Fourier Transform Convolution. Twenty NSCLC patients treated in the period 2001-2006 at the same accelerator were included and the accelerator used for treatments were modeled in the different systems. The treatment plans were recalculated with the same number of monitor units and beam arrangements across the dose algorithms. Dose volume histograms of the GTV, PTV, combined lungs (excluding the GTV), and heart were exported and evaluated. NTCP values for heart and lungs were calculated using the relative seriality model and the LKB model, respectively. Furthermore, NTCP for the lungs were calculated from two different model parameter sets. Calculations and evaluations were performed both including and excluding density corrections. Results: There are found statistical significant differences between the calculated dose to heart, lung, and targets across the algorithms. Mean lung dose and V-20 are not very sensitive to change between the investigated dose calculation algorithms. However, the different dose levels for the PTV averaged over the patient population are varying up to 11%. The predicted NTCP values for pneumonitis vary between 0.20 and 0.24 or 0.35 and 0.48 across the investigated dose algorithms depending on the chosen model parameter set. The influence of the use of density correction in the dose calculation on the predicted NTCP values depends on the specific dose calculation algorithm and the model parameter set. For fixed values of these, the changes in NTCP can be up to 45%. Conclusions: Calculated NTCP values for pneumonitis are more sensitive to the choice of algorithm than mean lung dose and V-20 which are also commonly used for plan evaluation. The NTCP values for heart complication are, in this study, not very sensitive to the choice of algorithm. Dose calculations based on density corrections result in quite different NTCP values than calculations without density corrections. It is therefore important when working with NTCP planning to use NTCP parameter values based on calculations and treatments similar to those for which the NTCP is of interest. (C) 2011 American Association of Physicists in Medicine. [DOI: 10.1118/1.3575418]

Delineation accuracy of target shape and position depends on the image quality. This study investigates whether the image quality on standard 4D systems has an influence comparable to the overall delineation uncertainty. A moving lung target was imaged using a dynamic thorax phantom on three different 4D computed tomography (CT) systems and a 4D cone beam CT (CBCT) system using pre-defined clinical scanning protocols. Peak-to-peak motion and target volume were registered using rigid registration and automatic delineation, respectively. A spatial distribution of the imaging uncertainty was calculated as the distance deviation between the imaged target and the true target shape. The measured motions were smaller than actual motions. There were volume differences of the imaged target between respiration phases. Imaging uncertainties of >0.4 cm were measured in the motion direction which showed that there was a large distortion of the imaged target shape. Imaging uncertainties of standard 4D systems are of similar size as typical GTV-CTV expansions (0.5-1 cm) and contribute considerably to the target definition uncertainty. Optimising and validating 4D systems is recommended in order to obtain the most optimal imaged target shape.

Background. Higher doses to NSCLC tumours are required to increase the low control rates obtained with conventional dose prescriptions. This study presents the concept of inhomogeneous dose distributions as a general way to increase local control probability, not only for isolated lung tumours but also for patients with involved lymph nodes. Material and methods. Highly modulated IMRT plans with homogeneous dose distributions with a prescribed dose of 66Gy/33F were created for 20 NSCLC patients, staged T1b-T4 N0-N3, using standard PTV dose coverage of 95–107%. For each patient, an inhomogeneous dose distribution was created with dose constraints of: PTV-coverage ≥ 95%, same mean lung dose as obtained in the homogeneous dose plan, maximum doses of 45 and 66 Gy to spinal canal and oesophagus, respectively, and V74Gy < 1 cm3 for each of: aorta, trachea + bronchi, the connective tissue in mediastinum, and the thorax wall. The dose was escalated using a TCP model implemented into the planning system. The difference in TCP values between the homogeneous and inhomogeneous plans were evaluated using two different TCP models. Results. Dose escalation was possible for all patients. TCP values based on assumed homogeneous distribution of clonogenic cells either in the GTV, CTV or PTV showed absolute TCP increases of approximately 15, 10 and 5 percentage points, respectively. This increase in local control was obtained without increasing the mean lung dose. However, small increases in maximum doses to the mediastinum were observed: 2.5 Gy for aorta, 4.4 Gy for the connective tissue, 1.6 Gy for the heart, and 2.6 Gy for trachea + bronchi. Conclusion. Increased target doses and TCP values using inhomogeneous dose distributions could be achieved for all patients, regardless of lymph node involvement, tumour stage, location, and size. These new treatment plans have the potential to increase the local tumour control by 10–15 percentage points without compromising the clinically acceptable lung toxicity level.

The aim of immobilisation in radiotherapy is to secure the patient is in the same position at each treatment fraction. This is required in order to deliver the planned radiation doses accurately. S...

To investigate differences in calculated doses and normal tissue complication probability (NTCP) values between different dose algorithms.Six dose algorithms from four different treatment planning systems were investigated: Eclipse AAA, Oncentra MasterPlan Collapsed Cone and Pencil Beam, Pinnacle Collapsed Cone and XiO Multigrid Superposition, and Fast Fourier Transform Convolution. Twenty NSCLC patients treated in the period 2001-2006 at the same accelerator were included and the accelerator used for treatments were modeled in the different systems. The treatment plans were recalculated with the same number of monitor units and beam arrangements across the dose algorithms. Dose volume histograms of the GTV, PTV, combined lungs (excluding the GTV), and heart were exported and evaluated. NTCP values for heart and lungs were calculated using the relative seriality model and the LKB model, respectively. Furthermore, NTCP for the lungs were calculated from two different model parameter sets. Calculations and evaluations were performed both including and excluding density corrections.There are found statistical significant differences between the calculated dose to heart, lung, and targets across the algorithms. Mean lung dose and V20 are not very sensitive to change between the investigated dose calculation algorithms. However, the different dose levels for the PTV averaged over the patient population are varying up to 11%. The predicted NTCP values for pneumonitis vary between 0.20 and 0.24 or 0.35 and 0.48 across the investigated dose algorithms depending on the chosen model parameter set. The influence of the use of density correction in the dose calculation on the predicted NTCP values depends on the specific dose calculation algorithm and the model parameter set. For fixed values of these, the changes in NTCP can be up to 45%.Calculated NTCP values for pneumonitis are more sensitive to the choice of algorithm than mean lung dose and V20 which are also commonly used for plan evaluation. The NTCP values for heart complication are, in this study, not very sensitive to the choice of algorithm. Dose calculations based on density corrections result in quite different NTCP values than calculations without density corrections. It is therefore important when working with NTCP planning to use NTCP parameter values based on calculations and treatments similar to those for which the NTCP is of interest.

Background and purpose To compare setup uncertainties at two different institutions by using identical imaging and analysis techniques for thoracic patients with different fixation equipments. Methods and materials Patient registration results from Cone-Beam CT (CBCT) scans of 174 patients were evaluated (1068 CBCT scans). Patients were fixated using a standard or custom made fixation at Royal Marsden Hospital and Odense University Hospital, respectively. Five imaging protocols were retrospectively simulated to compare the fixation equipments. Systematic and random setup uncertainties were calculated to estimate sufficient treatment margins. Results The setup uncertainties are of similar sizes at the two institutions and there is no observable drift in the precision of the fixation equipments during the treatment course. When a correcting imaging protocol is performed there is a significant increase of the systematic setup uncertainties in between imaging fractions. A margin reduction of ⩾0.2 cm can be achieved for patients with peak-to-peak respiration amplitudes of ⩾1.2 cm when changing from 4D-CT to Active Breathing Coordinator™ (ABC). Conclusions The setup uncertainties at the two institutions are the same despite different fixation equipments. Hence margins cannot be reduced by changing fixating equipment.

Massive B type pulsators such as beta Cep and slowly pulsating B (SPB) stars pulsate due to layers of increased opacity caused by partial ionization. The increased opacity blocks the energy flux to the surface of the stars which causes the layers to rise and the opacity to drop. This cyclical behavior makes the star act as a heat engine and the star will thus pulsate. For beta Cep and SPB stars the increased opacity is believed to be caused by partial ionization of iron and these stars should therefore contain non-insignificant quantities of the metal. A good test of this theory is to search for beta Cep and SPB stars in low-metallicity environments. If no stars are found the theory is supported, but on the other hand if a substantial number of beta Cep and SPB stars are found in these environments then the theory is not supported and a solutions needed. With a growing number of identified beta Cep and SPB stars in the low-metallicity Magellanic Clouds we seem to be left with the second case. We will in this context discuss recent findings of beta Cep and SPB stars in the Magellanic Clouds and some possible solutions to the discrepancy between these observations and the theory. We also describe an ambitious project that we have initiated on the Small Magellanic Cloud open cluster NGC 371 which will help to evaluate these solutions., Comment: 7 pages, 1 figure, submitted to Comm. in Asteroseismology, Proceedings of the 38th LIAC/HELAS-ESTA/BAG, 2008

When implementing new technology into clinical practice, there will always be a need for large knowledge gain. The aim of this study was twofold, (I) audit the treatment planning and dose delivery of Flattening Filter Free (FFF) beam technology for Stereotactic Body Radiation Therapy (SBRT) of lung tumours across a range of treatment planning systems compared to the conventional Flatting Filter (FF) beams, (II) investigate how sharing knowledge between centres of different experience can improve plan quality. All vendor/treatment planning system (TPS) combinations investigated were able to produce acceptable treatment plans and the dose accuracy was clinically acceptable for all plans. By sharing knowledge between the different centres, the minor protocol violations (MPV) could be significantly reduced, from an average of 1.9 MPV per plan to 0.6 after such sharing of treatment planning knowledge. In particular, for the centres with less SBRT and/or volumetric- modulated arc therapy (VMAT) experience the MPV average per plan improved. All vendor/TPS combinations were also able to successfully deliver the FF and FFF SBRT VMAT plans. The plan quality and dose accuracy were found to be clinically acceptable.

Relative large variations in DVH values are observed between respiration phases. However, only a small systematic effect is seen in changing between the midventilation phase and the expiration or inspiration phase. The changes are thus not directly related to changes between these phases but simply to small image differences (artefacts) between the different respiration phases. The position and extension of the tumour is a main uncertainty in stereotactic lung cancer treatment. It is therefore important that the images exactly reflect the tumour and surroundings. Image artefacts are less in the expiration phase in which the respiration induced motion is minimal. It is therefore beneficial to perform delineation and plan calculations in the expiration phase, as long as the actual treatment delivery is based on the mid-ventilation phase.