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Background: Chemo-radiotherapy with curative intent for anal cancer has high complete remission rates, but acute treatment-related gastrointestinal (GI) toxicity is significant. Toxicity occurs due to irradiation of surrounding normal tissue. Current radiotherapy requires the addition of large planning margins to the radiation field to ensure target coverage regardless of the considerable organ motion in the pelvic region. This increases the irradiated volume and radiation dose to the surrounding normal tissue and thereby toxicity. Online adaptive radiotherapy uses artificial intelligence to adjust the treatment to the anatomy of the day. This allows for the reduction of planning margins, minimizing the irradiated volume and thereby radiation to the surrounding normal tissue.This study examines if cone beam computed tomography (CBCT)-guided oART with daily automated treatment re-planning can reduce acute gastrointestinal toxicity in patients with anal cancer., Methods/design: The study is a prospective, single-arm, phase II trial conducted at Copenhagen University Hospital, Herlev and Gentofte, Denmark. 205 patients with local only or locally advanced anal cancer, referred for radiotherapy with or without chemotherapy with curative intent, are planned for inclusion. Toxicity and quality of life are reported with Common Terminology Criteria of Adverse Events and patient-reported outcome questionnaires, before, during, and after treatment. The primary endpoint is a reduction in the incidence of acute treatment-related grade ≥ 2 diarrhea from 36 to 25% after daily online adaptive radiotherapy compared to standard radiotherapy. Secondary endpoints include all acute and late toxicity, overall survival, and reduction in treatment interruptions., Results: Accrual began in January 2022 and is expected to finish in January 2026. Primary endpoint results are expected to be available in April 2026., Discussion: This is the first study utilizing online adaptive radiotherapy to treat anal cancer. We hope to determine whether there is a clinical benefit for the patients, with significant reductions in acute GI toxicity without compromising treatment efficacy., Trial Registration: ClinicalTrials.gov Identifier: NCT05438836. Danish Ethical Committee: H-21028093., (© 2024. The Author(s).)

Introduction: It is an ongoing debate how much lung and heart irradiation impact overall survival (OS) after definitive radiotherapy for lung cancer. This study uses a large national cohort of patients with locally advanced NSCLC to investigate the association between OS and irradiation of lung and heart., Methods: Treatment plans were acquired from six Danish radiotherapy centers, and patient characteristics were obtained from national registries. A hybrid segmentation tool automatically delineated the heart and substructures. Dose-volume histograms for all structures were extracted and analyzed using principal component analyses (PCAs). Parameter selection for a multivariable Cox model for OS prediction was performed using cross-validation based on bootstrapping., Results: The population consisted of 644 patients with a median survival of 26 months (95% confidence interval [CI]: 24-29). The cross-validation selected two PCA variables to be included in the multivariable model. PCA1 represented irradiation of the heart and affected OS negatively (hazard ratio, 1.14; 95% CI: 1.04-1.26). PCA2 characterized the left-right balance (right atrium and left ventricle) irradiation, showing better survival for tumors near the right side (hazard ratio, 0.92; 95% CI: 0.84-1.00). Besides the two PCA variables, the multivariable model included age, sex, body-mass index, performance status, tumor dose, and tumor volume., Conclusions: Besides the classic noncardiac risk factors, lung and heart doses had a negative impact on survival, while it is suggested that the left side of the heart is a more radiation dose-sensitive region. The data indicate that overall heart irradiation should be reduced to improve the OS if possible., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors.)

Background and Purpose: The SOFT trial is a prospective, multicenter, phase 2 trial investigating magnetic resonance (MR)-guided stereotactic ablative radiotherapy (SABR) for abdominal, soft tissue metastases in patients with oligometastatic disease (OMD) (clinicaltrials.gov ID NCT04407897). We present the primary endpoint analysis of 1-year treatment-related toxicity (TRAE)., Materials and Methods: Patients with up to five oligometastases from non-hematological cancers were eligible for inclusion. A risk-adapted strategy prioritized fixed organs at risk (OAR) constraints over target coverage. Fractionation schemes were 45-67.5 Gy in 3-8 fractions. The primary endpoint was grade ≥ 4 TRAE within 12 months post-SABR. The association between the risk of gastrointestinal (GI) toxicity and clinical and dosimetric parameters was tested using a normal tissue complication probability model., Results: We included 121 patients with 147 oligometastatic targets, mainly located in the liver (41 %), lymph nodes (35 %), or adrenal glands (14 %). Nearly half of all targets (48 %, n = 71) were within 10 mm of a radiosensitive OAR. No grade 4 or 5 TRAEs, 3.5 % grade 3 TRAEs, and 43.7 % grade 2 TRAEs were reported within the first year of follow-up. We found a significant association between grade ≥ 2 GI toxicity and the parameters GI OAR D 0.1cc, D 1cc, and D 20cc ., Conclusion: In this phase II study of MR-guided SABR of oligometastases in the infra-diaphragmatic region, we found a low incidence of toxicity despite half of the lesions being within 10 mm of a radiosensitive OAR. GI OAR D 0.1cc, D 1cc, and D 20cc were associated with grade ≥ 2 GI toxicity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MF has received research grant from Varian Medical Systems and support from The Danish National Research Centre for Radiotherapy and the Danish Cancer Society. CPB reports institutional research contracts with Brainlab, Varian Medical Systems, Siemens, and ViewRay and teaching contracts with Varian Medical Systems. Research funding from Danish Comprehensive Cancer Center National Thematic Center on radiotherapy (DCCC-RT). UB reports institutional research contracts with Elekta. IVR reports institutional research contracts with Brainlab, Varian Medical Systems, and ViewRay and teaching contracts with Varian Medical Systems. GP has received research grants from Varian Medical Systems, The Danish National Research Centre for Radiotherapy, and the Danish Cancer Society, Herlev & Gentofte Hospitals Internal Research Council, Villadsens Family Foundation. Conference participance from MSD, Daiichi Sankyo, and Pfizer, Pierre Fabre and honoraria for consultancies and lectures from Astra Zeneca. PP has received research grant from Viewray; not relevant to this article; Stock ownership of Nuvaira (COPD device company). MJ have received research support from The Danish National Research Centre for Radiotherapy and the Danish Cancer Society. MP have received honoraria for lectures from Astra Zeneca, BMS, MSD, Pfizer, Roche, Amgen. TS have received honoraria for lectures and travel expenses from Elekta and declares travel assistance from ELEKTA and is member of the MR-L consortium. SB have received research support from The Danish National Research Centre for Radiotherapy. PG reports institutional research contracts with Viewray. PK, ESH, and KJ has nothing to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Stereotactic body radiation therapy for tumors near the central airways implies high-grade toxic effects, as concluded from the HILUS trial. However, the small sample size and relatively few events limited the statistical power of the study. We therefore pooled data from the prospective HILUS trial with retrospective data from patients in the Nordic countries treated outside the prospective study to evaluate toxicity and risk factors for high-grade toxic effects., Methods and Materials: All patients were treated with 56 Gy in 8 fractions. Tumors within 2 cm of the trachea, the mainstem bronchi, the intermediate bronchus, or the lobar bronchi were included. The primary endpoint was toxicity, and the secondary endpoints were local control and overall survival. Clinical and dosimetric risk factors were analyzed for treatment-related fatal toxicity in univariable and multivariable Cox regression analyses., Results: Of 230 patients evaluated, grade 5 toxicity developed in 30 patients (13%), of whom 20 patients had fatal bronchopulmonary bleeding. The multivariable analysis revealed tumor compression of the tracheobronchial tree and maximum dose to the mainstem or intermediate bronchus as significant risk factors for grade 5 bleeding and grade 5 toxicity. The 3-year local control and overall survival rates were 84% (95% CI, 80%-90%) and 40% (95% CI, 34%-47%), respectively., Conclusions: Tumor compression of the tracheobronchial tree and high maximum dose to the mainstem or intermediate bronchus increase the risk of fatal toxicity after stereotactic body radiation therapy in 8 fractions for central lung tumors. Similar dose constraints should be applied to the intermediate bronchus as to the mainstem bronchi., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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

Background and Purpose: Coronary artery calcium score (CACs) is an excellent marker for survival in non-cancer patients, but its role in locally advanced non-small cell lung cancer (LA-NSCLC) patients remains uncertain. In this study, we hypothesize that CACs is a prognostic marker for survival in a competing risk analysis in LA-NSCLC patients treated with definitive radiotherapy., Materials and Methods: We included 644 patients with LA-NSCLC treated in 2014-2015 in Denmark. Baseline patient characteristics were derived from the Danish Lung Cancer Registry. Radiotherapy planning CT scans were used for manual CACs measurements, and the patients were divided into four groups, CACs 0, 1-99, 100-399, and ≥400. A multivariable Cox model utilizing bootstrapping for cross-validation modeled overall survival (OS)., Results: The median follow-up time was seven years, and the median OS was 26 months (95% CI 24-29). Within each CAC group 0, 1-99, 100-399, and ≥400 were 172, 182, 143, and 147 patients, respectively. In the univariable analysis, the survival decreased with increasing CACs. However, after adjustment for age, PS, radiotherapy dose, and logarithmic GTV, CACs did not have a statistically significant impact on OS with hazard ratios of 1.04 (95% CI 0.85-1.28), 1.11 (95%CI 0.89-1.43), and 1.16 (95%CI 0.92-1.47) for CACs 1-99, CACs 100-399 and ≥400, respectively. Elevated CACs was observed in 73 % of the patients suggesting a high risk of cardiac comorbidity before radiotherapy., Conclusion: CACs did not add prognostic information to our population's classical risk factors, such as tumor volume, performance status, and age; the lung cancer has the highest priority despite the risk of baseline cardiac comorbidity., 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.)

Introduction: Immunotherapy with checkpoint inhibitors (CPIs) has revolutionised cancer treatment but has no convincing effect in metastatic castration-resistant prostate cancer (mCRPC). It has been suggested that a combination of CPI and hypofractionated stereotactic body radiotherapy (SBRT) may work synergistically, and recent trials have supported this. We hypothesise that adding SBRT to CPI treatment can improve response rates in patients with mCRPC., Methods and Analysis: The CheckPRO trial is an open-label, randomised, two-stage, phase II trial. We aim to enrol and randomise 80 evaluable patients with mCRPC who progressed following ≥2 lines of treatment. Enrolment started in November 2019 with 38 months expected enrolment period. The participants receive treatment for 52 weeks including four cycles of ipilimumab and nivolumab with or without concomitant SBRT (24 Gray in three fractions) to a single soft tissue or bone metastasis, followed by 10 cycles of nivolumab. Participants are followed until progression, death, or for 12 months after the end of treatment.Co-primary endpoints are the objective response rate and prostate-specific antigen (PSA) response rate. Secondary endpoints include safety, radiographic progression-free survival, clinical benefit rate, duration of response, PSA-progression-free survival beyond 12 weeks, quality of life and overall survival. Exploratory endpoints include translational analyses of tumour biopsies and consecutive blood samples. Biopsies from metastatic sites are collected at baseline, before the third treatment and at the end of treatment. Blood sampling for immune monitoring and circulating tumour DNA is performed consecutively at baseline and every radiographic assessment., Ethics and Dissemination: This study follows the Helsinki Declaration and is approved by the Danish Ethics Committee System (journal no. H-19016100). All participants must receive written and oral information and provide a signed informed consent document prior to inclusion. The study results will be published in an international peer-review journal., Trial Registration Number: EudraCT number: 2018-003461-34., Clinicaltrials: gov ID NCT05655715., Competing Interests: Competing interests: DLN, EVH, GA-F and ST have no conflict of interest. NJS has received conference participation from Pfizer Inc and a research grant from Herlev Hospital and Rigshospitalet, sponsored by Varian Medical Systems. Within the last two years IMS has received honoraria for consultancies and lectures from IO Biotech, Novartis, MSD, Pierre Fabre, BMS, Novo Nordisk, TILT Bio; research grants from IO Biotech, BMS, Lytix, Adaptimmune, TILT Bio. Within the last two years GFP has received conference participance from MSD, Daiichi Sankyo and Pfizer Pierre Fabre. Research grants from Varian Medical Systems and honoraria for consultancies and lectures from Astra Zeneca. RLE has received honoraria for consultancies and lectures from Amgen and received funding of study drugs from Bristol-Myers Squibb in the CheckPRO trial., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: No phase 3 studies have yet been conducted for patients with non-clear cell (CC) renal cell carcinoma (RCC) exclusively due to the rare occurrence of the disease and the heterogenicity in tumor morphology. Consequently, there is no evidence of the optimal treatment, and new approaches are needed. One approach is individualizing treatment based on the gene sequencing of tumor tissue. Additionally, recent studies involving the patient-reported outcomes (PROs) of patients treated for metastatic cancer have shown significant benefits for quality of life, median overall survival, and overall survival. The use of gene sequencing and PROs can be of great importance to patients with rare cancer types, including patients with non-CC RCC, and should be investigated in clinical trials, especially for cases where evidence based on phase 3 studies is difficult to obtain., Objective: We describe the INDIGO study, in which patients, based on gene analyses, will be allocated into 4 treatment arms containing 14 treatments and use electronic PROs. We aim to improve the treatment of patients with non-CC RCC. The end points in the study will be the overall response rate (complete and partial) in the total patient population, which will be based on the RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 criteria, and the time to treatment failure., Methods: INDIGO is a prospective phase 2 trial, and 30 patients will be enrolled. The patients will receive systemic treatment based on genetic analyses of their tumor tissue. All patients will receive electronic questionnaires in a dedicated app-a questionnaire regarding symptoms and side effects and another regarding health-related quality of life. Depending on the treatment regimen, the patients will be seen by a medical doctor every third, fourth, or sixth week, and the effect of the systemic treatment will be evaluated every 6 weeks via a computed tomography scan. The study has been approved by the Danish Medicines Agency and the National Committee on Health Research Ethics (approval number: H-19041833), complies with good clinical practice guidelines, follows the General Data Protection Regulation, and is registered at the Capital Region of Denmark., Results: Recruitment started in March 2020, and at the time of submitting this paper (June 2022), a total of 9 patients have been enrolled., Conclusions: We aim to explore methods for improving the treatment outcomes of patients with non-CC RCC, and the INDIGO study will contribute further data on personalized medicine for rare types of RCC and provide new knowledge on the active use of electronic PROs., Trial Registration: ClinicalTrials.gov NCT04644432, https://clinicaltrials.gov/ct2/show/NCT04644432 ; European Union Drug Regulating Authorities Clinical Trials Database 2019-001316-38, https://tinyurl.com/2p8mb4aw., International Registered Report Identifier (irrid): DERR1-10.2196/36632., (©Ida Marie Lind Rasmussen, Anne Vest Soerensen, Anne Kirstine Møller, Gitte Fredberg Persson, Jesper Andreas Palshof, Gry Assam Taarnhøj, Helle Pappot. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 15.09.2022.)

Background: Palliative radiotherapy for metastatic spinal cord compression (MSCC) is given to halt disease progression and sustain quality of life for patients with advanced cancer. Radiotherapy can however induce toxicity, contradicting treatment intention. Advanced radiotherapy offers possibility of sparing organs at risk (OARs). The purpose of this dosimetric study is to establish the feasibility and potential benefits of dose sparing of the oesophagus., Materials and Methods: 30 patients receiving radiotherapy of 30 Gy/10# for MSCC were retrospectively included and the oesophagus delineated. Two new dose plans were created for each patient (eso-crop and PTV-crop) with the intention of optimising the oesophageal dose. In the eso-crop plan maintaining full target volume coverage was prioritised, for the PTV-crop plan oesophageal dose was further reduced through cropping the planning target volume (PTV) overlapping oesophageal/PTV-area. Time added for delineation was measured. Plans were compared using Wilcoxon signed rank test with p < 0.05 considered statistically significant. Bivariate associations between dose metrics and patient characteristics were quantified using linear regression models., Results: Oesophageal delineation took a mean of 8.6 min. There was significant dose reduction for both V7.7 Gy, D2% and mean oesophageal dose, without significant change in CTV coverage. The mean achievable oesophageal dose reduction was 29.1% and 50.4% for the eso-crop and PTV crop plans, respectively. Minor changes in dose distribution to the lungs was observed, with increased mean and V20Gy for the eso-crop plan and decreased V5Gy to the PTV-crop plan., Conclusion: This study demonstrated the possibility of significant dose sparing of the oesophageal dose using single arc VMAT without impacting on CTV coverage., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sarah Barrett holds a research grant from Varian Medical Systems, not related to this research. Morten Hiul Suppli and Gitte Persson work in departments which hold research agreements with Varian Medical Systems which are unrelated to this research., (© 2022 Published by Elsevier B.V. on behalf of European Society for Radiotherapy & Oncology.)

Novel medical therapies have revolutionized outcome for patients with melanoma. However, patients with melanoma brain metastases (MBM) still have poor survival. Data are limited as these patients are generally excluded from clinical trials, wherefore real-world data on clinical outcome may support evidence-based treatment choices for patients with MBM. Patients diagnosed with MBM between 2008 and 2020 were included retrospectively. Patient characteristics, treatment, and outcome data were recorded from The Danish Metastatic Melanoma Database, pathology registries, electronic patient files, and radiation plans. Anti-programmed cell death protein 1 antibodies and the combination of BRAF/MEK-inhibitors were introduced in Denmark in 2015, and the cohort was split accordingly for comparison. A total of 527 patients were identified; 148 underwent surgical excision of MBM, 167 had stereotactic radiosurgery (SRS), 270 received whole-brain radiation therapy (WBRT), and 343 received systemic therapies. Median overall survival (mOS) for patients diagnosed with MBM before and after 2015 was 4.4 and 7.6 months, respectively. Patients receiving surgical excision as first choice of treatment had the best mOS of 10.9 months, whereas patients receiving WBRT had the worst outcome (mOS, 3.4 months). Postoperative SRS did not improve survival or local control after surgical excision of brain metastases. Of the 40 patients alive >3 years after diagnosis of MBM, 80% received immunotherapy at some point after diagnosis. Patients with meningeal carcinosis did not benefit from treatment with CPI. Outcome for patients with MBM has significantly improved after 2015, but long-term survivors are rare. Most patients alive >3 years after diagnosis of MBM received immunotherapy., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: SBRT of central lung tumours implies significant risk of toxicity. We are initiating two phase II trials prescribing 56 Gy/eight fractions to PTV, allowing for dose escalation of GTV. We prioritize organs at risk (OAR) constraints over target coverage, making the treatment plans very sensitive to OAR delineation variations. The aim of this study is to quantify the dosimetric impact of contouring variations and to provide a thorough description of pre-trial quality assurance to be used in upcoming trials to provide consistent clinical care., Materials and Methods: Delineation: Seven physicians delineated OAR in three rounds, with evaluations in-between. For each patient case, seven treatment plans, repeatedly using each of the OAR structure sets from the seven physicians, were made and compared to evaluate the dosimetric effect of delineation variability. Treatment planning: Treatment plans for seven cases were made at six departments in two rounds, with discussion in-between., Results: OAR delineation variation between centres resulted in high variabilities in OAR dose for simulated plans and led to potential overdosage of the lobar bronchus (constraint: D 0.03cc  < 45 Gy), with maximum doses ranging between 58 Gy (first round), and 50 Gy (third round). For mediastinal tissue, the constraint (D 0.03cc  < 45 Gy) was violated for the majority of the delineations in all three rounds, with maximum doses of 84 Gy (first round), and 72 Gy (third round).For the treatment planning study, the range of the standard deviation for GTV mean dose was 12.8-18.5 Gy (first round) and 2.8-3.5 Gy (second round)., Conclusions: Even small variations in OAR delineation led to high OAR overdosage. The study demonstrates the importance of having extensive QA procedures in place before initiating clinical trials on dose escalation in SBRT., Competing Interests: Conflict of interest statement The authors have no conflicts of interests to report., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Respiratory motion is one of the major challenges in radiotherapy. In this work, a comprehensive and clinically plausible set of 4D numerical phantoms, together with their corresponding "ground truths," have been developed and validated for 4D radiotherapy applications., Methods: The phantoms are based on CTs providing density information and motion from multi-breathing-cycle 4D Magnetic Resonance imagings (MRIs). Deformable image registration (DIR) has been utilized to extract motion fields from 4DMRIs and to establish inter-subject correspondence by registering binary lung masks between Computer Tomography (CT) and MRI. The established correspondence is then used to warp the CT according to the 4DMRI motion. The resulting synthetic 4DCTs are called 4DCT(MRI)s. Validation of the 4DCT(MRI) workflow was conducted by directly comparing conventional 4DCTs to derived synthetic 4D images using the motion of the 4DCTs themselves (referred to as 4DCT(CT)s). Digitally reconstructed radiographs (DRRs) as well as 4D pencil beam scanned (PBS) proton dose calculations were used for validation., Results: Based on the CT image appearance of 13 lung cancer patients and deformable motion of five volunteer 4DMRIs, synthetic 4DCT(MRI)s with a total of 871 different breathing cycles have been generated. The 4DCT(MRI)s exhibit an average superior-inferior tumor motion amplitude of 7 ± 5 mm (min: 0.5 mm, max: 22.7 mm). The relative change of the DRR image intensities of the conventional 4DCTs and the corresponding synthetic 4DCT(CT)s inside the body is smaller than 5% for at least 81% of the pixels for all studied cases. Comparison of 4D dose distributions calculated on 4DCTs and the synthetic 4DCT(CT)s using the same motion achieved similar dose distributions with an average 2%/2 mm gamma pass rate of 90.8% (min: 77.8%, max: 97.2%)., Conclusion: We developed a series of numerical 4D lung phantoms based on real imaging and motion data, which give realistic representations of both anatomy and motion scenarios and the accessible "ground truth" deformation vector fields of each 4DCT(MRI). The open-source code and motion data allow foreseen users to generate further 4D data by themselves. These numeric 4D phantoms can be used for the development of new 4D treatment strategies, 4D dose calculations, DIR algorithm validations, as well as simulations of motion mitigation and different online image guidance techniques for both proton and photon radiation therapy., (© 2022 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background: Immune checkpoint inhibitors (ICIs) are implemented as standard treatment for patients with advanced non-small cell lung cancer (NSCLC) in first-line and subsequent-line treatment. However, certain subgroups such as patients with older age, poor performance status (PS), and severe comorbidity are underrepresented in the randomized controlled trials (RCTs). This study aimed to assess overall survival (OS), treatment data, and clinical features affecting second- or subsequent-line ICI efficacy in an unselected, Danish, nationwide NSCLC population., Methods: Patients with advanced NSCLC who started nivolumab or pembrolizumab as second-line or subsequent-line treatment between 1 September 2015, and 1 October 2018, were identified from institutional records of all Danish oncology departments. Clinical and treatment data were retrospectively collected. Descriptive statistics and survival analyses were performed., Results: Data were available for 840 patients; 49% females. The median age was 68 years (19% were ≥75 years), 19% had PS ≥2, and 36% had moderate to severe comorbidity. The median OS (mOS) was 12.2 months; 15.1 months and 10.0 months in females and males, respectively. The median time-to-treatment discontinuation (mTTD) and median progression-free survival (mPFS) was 3.2 and 5.2 months, respectively. Patients with PS ≥2 had a mOS of 4.5 months, mTTD of 1.1 month, and mPFS of 2.0 months. In multivariable Cox regression analysis, male sex (HR = 1.35, 95% CI 1.11-1.62), PS >0 (PS 1, HR = 1.88, 95% CI 1.52-2.33; PS ≥2, HR = 4.15, 95% CI 3.13-5.5), liver metastases (HR = 1.72, 95% CI 1.34-2.22), and bone metastases (HR = 1.27, 95% CI 1.03-1.58) were significant poor prognostic OS factors., Conclusions: Danish real-world patients with advanced NSCLC treated with second- or subsequent-line ICI had an OS comparable to results from RCTs. Women, frail and older patients constituted a higher proportion than in previous RCTs. Clinical features associated with poor OS were male sex, PS ≥1 (in particular PS ≥2), bone-, and liver metastases.

Background: The increasing role of exercise training in cancer care is built on evidence that exercise can reduce side effects of treatment, improve physical functioning and quality of life. We and others have shown in mouse tumor models, that exercise leads to an adrenalin-mediated increased influx of T and NK cells into the tumor, altering the tumor microenvironment (TME) and leading to reduced tumor growth. These data suggest that exercise could improve immune responses against cancer cells by increase immune cell infiltration to the tumor and potentially having an impact on disease progression. Additionally, there are data to suggest that infiltration of T and NK cells into the TME is correlates with response to immune checkpoint inhibitors in patients. We have therefore initiated the clinical trial HI AIM, to investigate if high intensity exercise can mobilize and increase infiltration of immune cells in the TME in patients with lung cancer., Methods: HI AIM (NCT04263467) is a randomized controlled trial (70 patients, 1:1) for patients with non-small cell lung cancer. Patients in the treatment arm, receive an exercise-intervention consisting of supervised and group-based exercise training, comprising primarily intermediate to high intensity interval training three times per week over 6 weeks. All patients will also receive standard oncological treatments; checkpoint inhibitors, checkpoint inhibitors combined with chemotherapy or oncological surveillance. Blood samples and biopsies (ultrasound guided), harvested before, during and after the 6-week training program, will form basis for immunological measurements of an array of immune cells and markers. Primary outcome is circulating NK cells. Secondary outcome is other circulating immune cells, infiltration of immune cells in tumor, inflammatory markers, aerobic capacity measured by VO 2 max test, physical activity levels and quality of life measured by questionnaires, and clinical outcomes., Discussion: To our knowledge, HI AIM is the first project to combine supervised and monitored exercise in patients with lung cancer, with rigorous analyses of immune and cancer cell markers over the course of the trial. Data from the trial can potentially support exercise as a tool to mobilize cells of the immune system, which in turn could potentiate the effect of immunotherapy., Trial Registration: The study was prospectively registered at ClinicalTrials.gov on February 10 th 2020, ID: NCT04263467. https://clinicaltrials.gov/ct2/show/NCT04263467., (© 2022. The Author(s).)

Background The selection of patients with non-small cell lung cancer (NSCLC) for immune checkpoint inhibitor (ICI) treatment remains challenging. This real-world study aimed to compare the overall survival (OS) before and after the implementation of ICIs, to identify OS prognostic factors, and to assess treatment data in first-line (1L) ICI-treated patients without epidermal growth factor receptor mutation or anaplastic lymphoma kinase translocation. Methods Data from the Danish NSCLC population initiated with 1L palliative antineoplastic treatment from 1 January 2013 to 1 October 2018, were extracted from the Danish Lung Cancer Registry (DLCR). Long-term survival and median OS pre- and post-approval of 1L ICI were compared. From electronic health records, additional clinical and treatment data were obtained for ICI-treated patients from 1 March 2017 to 1 October 2018. Results The OS was significantly improved in the DLCR post-approval cohort ( n = 2055) compared to the pre-approval cohort ( n = 1658). The 3-year OS rates were 18% (95% CI 15.6-20.0) and 6% (95% CI 5.1-7.4), respectively. On multivariable Cox regression, bone (HR = 1.63) and liver metastases (HR = 1.47), performance status (PS) 1 (HR = 1.86), and PS ≥ 2 (HR = 2.19) were significantly associated with poor OS in ICI-treated patients. Conclusion OS significantly improved in patients with advanced NSCLC after ICI implementation in Denmark. In ICI-treated patients, PS ≥ 1, and bone and liver metastases were associated with a worse prognosis.

Background: Lung cancer incidence and prevalence is increasing worldwide and there is a focus on prevention, early detection, and development of new treatments which will impact the epidemiological patterns of lung cancer. The clinical characteristics and the trends in incidence, mortality, and prevalence of lung cancer in Denmark from 2006 through 2015 are described and a model for predicting the future epidemiological profile of lung cancer through 2030 is introduced., Methods: The study population comprised all cases of lung cancer, registered in the Danish Cancer Registry, who were alive on January 1, 2006 or had a first-time ever diagnosis of lung cancer during 2006 through 2015. Information on morphology, stage of the disease, comorbidity and survival was obtained from other Danish health registers. Based on NORDCAN data and estimated patient mortality rates as well as prevalence proportions for the period 2006 through 2015, future case numbers of annual incidence, deaths, and resulting prevalence were projected., Results: A total of 44.291 patients were included in the study. A shift towards more patients diagnosed with lower stages and with adenocarcinoma was observed. The incidence increased and the patient mortality rate decreased significantly, with a doubling of the prevalence during the observation period. We project that the numbers of prevalent cases of lung cancer in Denmark most likely will increase from about 10,000 at the end of 2015 to about 23,000 at the end of 2030., Conclusions: Our findings support that lung cancer is being diagnosed at an earlier stage, that incidence will stop increasing, that mortality will decrease further, and that the prevalence will continue to increase substantially. Projections of cancer incidence, mortality, and prevalence are important for planning health services and should be updated at regular intervals., (© 2021. The Author(s).)

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 × 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 (0-10 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 "hottest" 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 × 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)., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: A major burden of introducing an online daily adaptive proton therapy (DAPT) workflow is the time and resources needed to correct the daily propagated contours. In this study, we evaluated the dosimetric impact of neglecting the online correction of the propagated contours in a DAPT workflow., Material and Methods: For five NSCLC patients with nine repeated deep-inspiration breath-hold CTs, proton therapy plans were optimised on the planning CT to deliver 60 Gy-RBE in 30 fractions. All repeated CTs were registered with six different clinically used deformable image registration (DIR) algorithms to the corresponding planning CT. Structures were propagated rigidly and with each DIR algorithm and reference structures were contoured on each repeated CT. DAPT plans were optimised with the uncorrected, propagated structures (propagated DAPT doses) and on the reference structures (ideal DAPT doses), non-adapted doses were recalculated on all repeated CTs., Results: Due to anatomical changes occurring during the therapy, the clinical target volume (CTV) coverage of the non-adapted doses reduces on average by 9.7% (V95) compared to an ideal DAPT doses. For the propagated DAPT doses, the CTV coverage was always restored (average differences in the CTV V95 < 1% compared to the ideal DAPT doses). Hotspots were always reduced with any DAPT approach., Conclusion: For the patients presented here, a benefit of online DAPT was shown, even if the daily optimisation is based on propagated structures with some residual uncertainties. However, a careful (offline) structure review is necessary and corrections can be included in an offline adaption., 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 © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: The accuracy of analytical dose calculations (ADC) and dose uncertainties resulting from anatomical changes are both limiting factors in proton therapy. For the latter, rapid plan adaption is necessary; for the former, Monte Carlo (MC) approaches are increasingly recommended. These, however, are inherently slower than analytical approaches, potentially limiting the ability to rapidly adapt plans. Here, we compare the clinical relevance of uncertainties resulting from both., Methods and Materials: Five patients with non-small cell lung cancer with up to 9 computed tomography (CT) scans acquired during treatment and five paranasal (head and neck) patients with 10 simulated anatomical changes (sinus filling) were analyzed. On the initial planning CT scans, treatment plans were optimized and calculated using an ADC and then recalculated with MC. Additionally, all plans were recalculated (non-adapted) and reoptimized (adapted) on each repeated CT using the same ADC as for the initial plan, and the resulting dose distributions were compared., Results: When comparing analytical and MC calculations in the initial treatment plan and averaged over all patients, 94.2% (non-small cell lung cancer) and 98.5% (head and neck) of voxels had differences <±5%, and only minor differences in clinical target volume (CTV) V95 (average <2%) were observed. In contrast, when recalculating nominal plans on the repeat (anatomically changed) CT scans, CTV V95 degraded by up to 34%. Plan adaption, however, restored CTV V95 differences between adapted and nominal plans to <0.5%. Adapted organ-at-risk doses remained the same or improved., Conclusions: Dose degradations caused by anatomic changes are substantially larger than uncertainties introduced by the use of analytical instead of MC dose calculations. Thus, if the use of analytical calculations can enable more rapid and efficient plan adaption than MC approaches, they can and should be used for plan adaption for these patient groups., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To examine the feasibility of automatic data extraction from clinical radiation therapy (RT) databases at four hospitals to investigate the impact of mean lung dose (MLD) and age on the risk of early respiratory-related death and early overall death for patients treated with RT for non-small-cell lung cancer (NSCLC). Material and methods: We included adult patients with NSCLC receiving curatively intended RT between 2002 and 2017 at four hospitals. A script was developed to automatically extract RT-related data. The cause of death for patients deceased within 180 days of the start of RT was retrospectively assessed. Using logistic regression, the risks of respiratory-related death and of overall death within 90 and 180 days were investigated using MLD and age as variables. Results : Altogether, 1785 patients were included in the analysis of early overall mortality and 1655 of early respiratory-related mortality. The respiratory-related mortalities within 90 and 180 days were 0.9% (15/1655) and 3.6% (60/1655). The overall mortalities within 90 and 180 days were 2.5% (45/1785) and 10.6% (190/1785). Higher MLD and older age were associated with an increased risk of respiratory-related death within 180 days and overall death within 90 and 180 days (all p <.05). For example, the risk of respiratory-related death within 180 days and their 95% confidence interval for patients aged 65 and 75 years with MLDs of 20 Gy was according to our logistic model 3.8% (2.6-5.0%) and 7.7% (5.5-10%), respectively. Conclusions: Automatic data extraction was successfully used to pool data from four hospitals. MLD and age were associated with the risk of respiratory-related death within 180 days of the start of RT and with overall death within 90 and 180 days. A model quantifying the risk of respiratory-related death within 180 days was formulated.

Background and Purpose: Non-small cell lung cancer (NSCLC) patients show typically large anatomical changes during treatment, making recalculation or adaption necessary. For report and review, the applied treatment dose can be accumulated on the reference planning CT using deformable image registration (DIR). We investigated the dosimetric impact of using six different clinically available DIR algorithms for dose accumulation in presence of inter-fractional anatomy variations., Materials and Methods: For seven NSCLC patients, proton treatment plans with 66 Gy-RBE to the planning target volume (PTV) were optimised. Nine repeated CTs were registered to the planning CT using six DIR algorithms each. All CTs were acquired in visually guided deep-inspiration breath-hold. The plans were recalculated on the repeated CTs and warped back to the planning CT using the corresponding DIRs. Fraction doses warped with the same DIR were summed up to six different accumulated dose distributions per patient, and compared to the initial dose., Results: The PTV-V95 of accumulated doses decreased by 16% on average over all patients, with variations due to DIR selection of 8.7%. A separation of the dose effects caused by anatomical changes and DIR uncertainty showed a good agreement between the dose degradation caused by anatomical changes and the dose predicted from the average of all DIRs (differences of only 1.6%)., Conclusion: The dose degradation caused by anatomical changes was more pronounced than the uncertainty of employing different DIRs for dose accumulation, with averaged results from several DIRs providing a good representation of dose degradation caused by anatomy. However, accumulated dose variations between DIRs can be substantial, leading to an additional dose uncertainty., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The overall aim was to investigate the change over time in circulating cell free DNA (cfDNA) in patients with locally advanced non-small cell lung cancer (NSCLC) undergoing concurrent chemo-radiotherapy. Furthermore, to assess the possibility of detecting circulating cell free tumor DNA (ctDNA) using shallow whole genome sequencing (sWGS) and size selection., Methods: Ten patients were included in a two-phase study. The first four patients had blood samples taken prior to a radiation therapy (RT) dose fraction and at 30 minutes, 1 hour and 2 hours after RT to estimate the short-term dynamics of cfDNA concentration after irradiation. The remaining six patients had one blood sample taken on six treatment days 30 minutes post treatment to measure cfDNA levels. Presence of ctDNA as indicated by chromosomal aberrations was investigated using sWGS. The sensitivity of this method was further enhanced using in silico size selection., Results: cfDNA concentration from baseline to 120 min after therapy was stable within 95% tolerance limits of +/- 2 ng/ml cfDNA. Changes in cfDNA were observed during therapy with an apparent qualitative difference between adenocarcinoma (average increase of 0.69 ng/ml) and squamous cell carcinoma (average increase of 4.0 ng/ml). Tumor shrinkage on daily cone beam computer tomography scans during radiotherapy did not correlate with changes in concentration of cfDNA., Conclusion: Concentrations of cfDNA remain stable during the first 2 hours after an RT fraction. However, based on the sWGS profiles, ctDNA represented only a minor fraction of cfDNA in this group of patients. The detection sensitivity of genomic alterations in ctDNA strongly increases by applying size selection., Competing Interests: The authors have declared that no competing interests exist.

Purpose: We propose and simulate a model-based methodology to incorporate heterogeneous treatment benefit of proton therapy (PrT) versus photon therapy into randomized trial designs. We use radiation-induced pneumonitis (RP) as an exemplar. The aim is to obtain an unbiased estimate of how predicted difference in normal tissue complications probability (ΔNTCP) converts into clinical outcome on the patient level., Materials and Methods: ΔNTCP data from in silico treatment plans for photon therapy and PrT for patients with locally advanced lung cancer as well as randomly sampled clinical risk factors were included in simulations of trial outcomes. The model used at point of analysis of the trials was an iQUANTEC model. Trial outcomes were examined with Cox proportional hazards models, both in case of a correctly specified model and in a scenario where there is discrepancy between the dose metric used for ΔNTCP and the dose metric associated with the "true" clinical outcome, that is, when the model is misspecified. We investigated how outcomes from such a randomized trial may feed into a model-based estimate of the patient-level benefit from PrT, by creating patient-specific predicted benefit probability distributions., Results: Simulated trials showed benefit in accordance with that expected when the NTCP model was equal to the model for simulating outcome. When the model was misspecified, the benefit changed and we observed a reversal when the driver of outcome was high-dose dependent while the NTCP model was mean-dose dependent. By converting trial results into probability distributions, we demonstrated large heterogeneity in predicted benefit, and provided a randomized measure of the precision of individual benefit estimates., Conclusions: The design allows for quantifying the benefit of PrT referral, based on the combination of NTCP models, clinical risk factors, and traditional randomization. A misspecified model can be detected through a lower-than-expected hazard ratio per predicted ΔNTCP., Competing Interests: Conflicts of Interest: Ivan R. Vogelius, PhD, DMSc, has received grants and educational fees from Varian Medical Systems. Johannes A. Langendijk, MD, PhD, received honoraria from IBA for a consulting and advisory role and from IBA Speakers' Bureau, paid to the UMCG Research B.V. No other author declares conflicts of interest., (© Copyright 2019 International Journal of Particle Therapy.)

Objectives: Patients with locally advanced non-small cell lung cancer (NSCLC) were included in a prospective trial for radiotherapy in deep inspiration breath hold (DIBH). We evaluated DIBH compliance and target position reproducibility., Methods: Voluntary, visually guided DIBHs were performed with optical tracking. Patients underwent three consecutive DIBH CT scans for radiotherapy planning. We evaluated the intrafractional uncertainties in the position of the peripheral tumour, lymph nodes and differential motion between them, enabling PTV margins calculation. Patients who underwent all DIBH imaging and had tumour position reproducibility <8 mm were up-front DIBH compliant. Patients who performed DIBHs throughout the treatment course were overall DIBH compliant. Clinical parameters and DIBH-related uncertainties were validated against our earlier pilot study., Results: 69 of 88 included patients received definitive radiotherapy. 60/69 patients (87%) were up-front DIBH compliant. DIBH plan was not superior in seven patients and three lost DIBH ability during the treatment, leaving 50/69 patients (72%) overall DIBH compliant.The systematic and random errors between consecutive DIBHs were small but differed from the pilot study findings. This led to slightly different PTV margins between the two studies., Conclusions: DIBH compliance and reproducibility was high. Still, this validation study highlighted the necessity of designing PTV margins in larger, representative patient cohorts., Advances in Knowledge: We demonstrated high DIBH compliance in locally advanced NSCLC patients. DIBH does not eliminate but mitigates the target position uncertainty, which needs to be accounted for in treatment margins. Margin design should be based on data from larger representative patient groups.

Introduction: We hypothesized that gross tumor volume (GTV) of primary tumor (GTV T ) and nodal volumes (GTV N ) were predictors of first failure site in non-small cell lung cancer (NSCLC). We aimed at also comparing the prognostic model's complexity to its ability to generate absolute risk predictions with emphasis on variables available at the time of diagnosis. Materials and methods: Three hundred and forty-two patients treated with definitive chemoradiotherapy (CRT) for adenocarcinoma (AC) or squamous cell carcinoma (SCC) in 2009-2017 were analyzed. Clinical data, standardized uptake values on FDG-PET/CT, GTV T and GTV N were analyzed using multivariate competing risk models. Results: One hundred and thirty-seven patients had SCC. As first site of failure 49 had locoregional failure (LRF), 40 had distant metastasis (DM) and 24 died with no evidence of disease (NED). In 205 patients with AC, 34 had LRF, 118 had DM as first failure site and 17 died with NED. Performance status predicted LRF ( p  = .02) and UICC stage risk of DM ( p  = .05 for stage 3, p  < .001 for stage 4). Adding histopathology changed predictions with much reduced risk of LRF in AC compared to SCC (HR = 0.5, 95% CI: (0.3-0.75), p  = .001). Conversely, AC had a higher rate of DM than SCC (HR = 2.1, 95% CI: (1.5-3.0], p  < .001). Addition of FDG metrics and tumor/nodal volume data predicted DM risk ( p  = .001), but with smaller impact on absolute risk compared to histopathology. Separation of GTV in nodal and tumor lesions did not improve risk predictions. Conclusions: We quantified the effect of adding volumetric and quantitative imaging to competing risk models of first failure site, but did not find tumor volume components to be important. Histopathology remains the simplest and most important factor in prognosticating failure patterns in NSCLC.

Background and Purpose: Motion management in the treatment of lung cancer is necessary to assure highest quality of the delivered radiation therapy. In this study, the breath-hold technique is experimentally investigated for pencil beam scanned (PBS) proton therapy, with respect to the dosimetric effect of residual breath-hold motion., Material and Methods: Three-dimensional (3D)-printed tumours extracted from CT scans of three patients were inserted into a dynamic anthropomorphic breathing phantom. The target was set up to move with the individual patient's tumour motion during breath-hold as previously assessed on fluoroscopy. Target dose was measured with radio-chromic film, and both single field uniform dose (SFUD) and intensity-modulated proton therapy (IMPT) plans were delivered. Experiments were repeated for each patient without any motion, to compute the relative dose deviation between static and breath-hold cases., Results: SFUD plans showed small dose deviations between static and breath-hold cases, as evidenced by the gamma pass rate (3%, 3 mm) of 85% or higher. Dose deviation was more evident for IMPT plans, with gamma pass rate reduced to 50-70%., Conclusions: The breath-hold technique is robust to residual intra-breath-hold motion for SFUD treatment plans, based on our experimental study. IMPT was less robust with larger detected dose deviations., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective:: To evaluate the feasibility of a new liquid fiducial marker for use in image-guided radiotherapy for oesophageal cancer., Methods:: Liquid fiducial markers were implanted in patients with metastatic or inoperable locally advanced oesophageal or gastro-oesophageal junction cancer receiving radiotherapy. Markers were implanted using a conventional gastroscope equipped with a 22 G Wang needle. Marker visibility was evaluated on fluoroscopy, CT, MRI and cone beam CT scans., Results:: Liquid markers (n = 16) were injected in four patients. No Grade 2 or worse adverse events were observed in relation to the implantation procedure, during treatment or in the follow-up period. 12/16 (75%) markers were available at the planning CT-scan and throughout the treatment- and follow-up period. The implanted markers were adequately visible in CT and cone beam CT but were difficult to distinguish in fluoroscopy and MRI without information from the corresponding CT image., Conclusion:: Liquid fiducial marker placement in the oesophagus proved safe and clinically feasible., Advances in Knowledge:: This paper presents the first clinical use of a new liquid fiducial marker in patients with oesophageal cancer and demonstrates that marker implantation using standard gastroscopic equipment and subsequent use in three-dimensional image-guided radiation therapy is safe and clinically feasible.

Purpose: Evaluating performance of modern dose calculation algorithms in SBRT and locally advanced lung cancer radiotherapy in free breathing (FB) and deep inspiration breath hold (DIBH)., Methods: For 17 patients with early stage and 17 with locally advanced lung cancer, a plan in FB and in DIBH were generated with Anisotropic Analytical Algorithm (AAA). Plans for early stage were 3D-conformal SBRT, 45 Gy in 3 fractions, prescribed to 95% isodose covering 95% of PTV and aiming for 140% dose centrally in the tumour. Locally advanced plans were volumetric modulated arc therapy, 66 Gy in 33 fractions, prescribed to mean PTV dose. Calculation grid size was 1 mm for SBRT and 2.5 mm for locally advanced plans. All plans were recalculated with AcurosXB with same MU as in AAA, for comparison on target coverage and dose to risk organs., Results: Lung volume increased in DIBH, resulting in decreased lung density (6% for early and 13% for locally-advanced group). In SBRT, AAA overestimated mean and near-minimum PTV dose (p-values < 0.01) compared to AcurosXB, with largest impact in DIBH (differences of up to 11 Gy). These clinically relevant differences may be a combination of small targets and large dose gradients within the PTV. In locally advanced group, AAA overestimated mean GTV, CTV and PTV doses by median less than 0.8 Gy and near-minimum doses by median 0.4-2.7 Gy. No clinically meaningful difference was observed for lung and heart dose metrics between the algorithms, for both FB and DIBH., Conclusions: AAA overestimated target coverage compared to AcurosXB, especially in DIBH for SBRT., (Copyright © 2018 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Safety and clinical feasibility of injecting a novel liquid fiducial marker for use in image guided radiotherapy in 15 patients with non-small cell lung cancer are reported. No major safety or toxicity issues were encountered. Markers present at start of radiotherapy remained visible in cone beam computed tomography and fluoroscopy images throughout the treatment course and on computed tomography images during follow-up (0-38 months). Marker volume reduction was seen until 9 months after treatment, after which no further marker breakdown was found. No post-treatment migration or marker related complications were found.

We measured the repeatability of FDG PET/CT uptake metrics when acquiring scans in free breathing (FB) conditions compared with deep inspiration breath hold (DIBH) for locally advanced lung cancer. Twenty patients were enrolled in this prospective study. Two FDG PET/CT scans per patient were conducted few days apart and in two breathing conditions (FB and DIBH). This resulted in four scans per patient. Up to four FDG PET avid lesions per patient were contoured. The following FDG metrics were measured in all lesions and in all four scans: Standardized uptake value (SUV) peak , SUV max , SUV mean , metabolic tumor volume (MTV) and total lesion glycolysis (TLG), based on an isocontur of 50% of SUV max . FDG PET avid volumes were delineated by a nuclear medicine physician. The gross tumor volumes (GTV) were contoured on the corresponding CT scans. Nineteen patients were available for analysis. Test-retest standard deviations of FDG uptake metrics in FB and DIBH were: SUV peak FB/DIBH: 16.2%/16.5%; SUV max : 18.2%/22.1%; SUV mean : 18.3%/22.1%; TLG: 32.4%/40.5%. DIBH compared to FB resulted in higher values with mean differences in SUV max of 12.6%, SUV peak 4.4% and SUV mean 11.9%. MTV, TLG and GTV were all significantly smaller on day 1 in DIBH compared to FB. However, the differences between metrics under FB and DIBH were in all cases smaller than 1 SD of the day to day repeatability. FDG acquisition in DIBH does not have a clinically relevant impact on the uptake metrics and does not improve the test-retest repeatability of FDG uptake metrics in lung cancer patients., Competing Interests: None.

Introduction: The aim of the study was to build a model of first failure site- and lesion-specific failure probability after definitive chemoradiotherapy for inoperable NSCLC., Methods: We retrospectively analyzed 251 patients receiving definitive chemoradiotherapy for NSCLC at a single institution between 2009 and 2015. All patients were scanned by fludeoxyglucose positron emission tomography/computed tomography for radiotherapy planning. Clinical patient data and fludeoxyglucose positron emission tomography standardized uptake values from primary tumor and nodal lesions were analyzed by using multivariate cause-specific Cox regression. In patients experiencing locoregional failure, multivariable logistic regression was applied to assess risk of each lesion being the first site of failure. The two models were used in combination to predict probability of lesion failure accounting for competing events., Results: Adenocarcinoma had a lower hazard ratio (HR) of locoregional failure than squamous cell carcinoma (HR = 0.45, 95% confidence interval [CI]: 0.26-0.76, p = 0.003). Distant failures were more common in the adenocarcinoma group (HR = 2.21, 95% CI: 1.41-3.48, p < 0.001). Multivariable logistic regression of individual lesions at the time of first failure showed that primary tumors were more likely to fail than lymph nodes (OR = 12.8, 95% CI: 5.10-32.17, p < 0.001). Increasing peak standardized uptake value was significantly associated with lesion failure (OR = 1.26 per unit increase, 95% CI: 1.12-1.40, p < 0.001). The electronic model is available at http://bit.ly/LungModelFDG., Conclusions: We developed a failure site-specific competing risk model based on patient- and lesion-level characteristics. Failure patterns differed between adenocarcinoma and squamous cell carcinoma, illustrating the limitation of aggregating them into NSCLC. Failure site-specific models add complementary information to conventional prognostic models., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Two techniques for metal artefact reduction for computed tomography were studied in order to identify their impact on tumour delineation in radiotherapy., Materials and Methods: Using specially designed phantoms containing metal implants (dental, spine and hip) as well as patient images, we investigated the impact of two methods for metal artefact reduction on (A) the size and severity of metal artefacts and the accuracy of Hounsfield Unit (HU) representation, (B) the visual impact of metal artefacts on image quality and (C) delineation accuracy. A metal artefact reduction algorithm (MAR) and two types of dual energy virtual monochromatic (DECT VM) reconstructions were used separately and in combination to identify the optimal technique for each implant site., Results: The artefact area and severity was reduced (by 48-76% and 58-79%, MAR and DECT VM respectively) and accurate Hounsfield-value representation was increased by 22-82%. For each energy, the observers preferred MAR over non-MAR reconstructions (p < 0.01 for dental and hip cases, p < 0.05 for the spine case). In addition, DECT VM was preferred for spine implants (p < 0.01). In all cases, techniques that improved target delineation significantly (p < 0.05) were identified., Conclusions: DECT VM and MAR techniques improve delineation accuracy and the optimal of reconstruction technique depends on the type of metal implant., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: We evaluated the feasibility of treating patients with locally advanced non-small cell lung cancer (NSCLC) with pencil beam scanned intensity modulated proton therapy (IMPT) in breath-hold., Methods and Materials: Fifteen NSCLC patients who had previously received 66 Gy in 33 fractions with image guided photon radiation therapy were included in the present simulation study. In addition to a planning breath-hold computed tomography (CT) scan before the treatment start, a median of 6 (range 3-9) breath-hold CT scans per patient were acquired prospectively throughout the radiation therapy course. Three-field IMPT plans were constructed using the planning breath-hold CT scan, and the four-dimensional dose distributions were simulated, with consideration of both patient intra- and interfraction motion, in addition to dynamic treatment delivery., Results: The median clinical target volume receiving 95% of the prescribed dose was 99.8% and 99.7% for the planned and simulated dose distributions, respectively. For 3 patients (20%), the dose degradation was >5%, and plan adjustment was needed. Dose degradation correlated significantly with the change in water-equivalent path lengths (P<.01) in terms of the percentage of voxels with 3-mm or more undershoot on repeat CT scans. The dose to the organs at risk was similar for the planned and simulated dose distributions. Three or fewer breath-holds per field would be required for 12 of the 15 patients, which was clinically feasible., Conclusions: For 9 of 15 NSCLC patients, IMPT in breath-hold was both dosimetrically robust and feasible to deliver regarding the treatment time. Three patients would have required plan adaption to meet the dosimetric criteria. The change in water-equivalent path length is an indicator of plan robustness and should be considered for the selection of patients for whom the plan would require adaptation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: The breath-hold technique inter alia has been suggested to mitigate the detrimental effect of motion on pencil beam scanned (PBS) proton therapy dose distributions. The aim of this study was to evaluate the robustness of incident proton beam angles to day-to-day anatomical variations in breath-hold., Materials and Methods: Single field PBS plans at five degrees increments in the transversal plane were made and water-equivalent path lengths (WEPLs) were derived on the planning breath-hold CT (BHCT) for 30 patients diagnosed with locally-advanced non-small cell lung cancer (NSCLC), early stage NSCLC or lung metastasis. Our treatment planning system was subsequently used to recalculate the plans and derive WEPL on a BHCT scan acquired at the end of the treatment. Changes to the V 95% , D 95 and mean target dose were evaluated., Results: The difference in WEPL as a function of the beam angle was highly patient specific, with a median of 3.3 mm (range: 0.0-41.1 mm). Slightly larger WEPL differences were located around the lateral or lateral anterior/posterior beam angles. Linear models revealed that changes in dose were associated to the changes in WEPL and the tumor baseline shift (p < 0.05)., Conclusions: WEPL changes and tumor baseline shift can serve as reasonable surrogates for dosimetric uncertainty of the target coverage and are well-suited for routine evaluation of plan robustness. The two lateral beam angles are not recommended to use for PBS proton therapy of lung cancer patients treated in breath-hold, due to the poor robustness for several of the patients evaluated.

Objective: We investigated the impact of deep inspiration breath-hold (DIBH) and tumour baseline shifts on image quality and registration uncertainty in image-guided DIBH radiotherapy (RT) for locally advanced lung cancer., Methods: Patients treated with daily cone beam CT (CBCT)-guided free-breathing (FB) RT had an additional CBCT in DIBH at three fractions. These CBCT scans were offline rigidly registered (on tumour) to FB and DIBH CT scans acquired at planning. All registrations were repeated to evaluate the intraobserver uncertainty. CBCT scans were scored on degree of streak artefacts and visualization of tumour and anatomical structures. We examined the impact of tumour baseline shift between consecutive DIBHs on CBCT image quality., Results: CBCT scans from 15 patients were analysed. Intraobserver image registration uncertainty was approximately 2 mm in both FB and DIBH, except for the craniocaudal direction in FB, where it was >3 mm. On the 31st fraction, the intraobserver uncertainty increased compared with the second fraction. This increase was more pronounced in FB. Image quality scores improved in DIBH compared with FB for all parameters in all patients. Simulated tumour baseline shifts ≤2 mm did not affect the CBCT image quality considerably., Conclusion: DIBH CBCT improved image quality and reduced registration uncertainty in the craniocaudal direction in image-guided RT of locally advanced lung cancer. Baseline shifts ≤2 mm in DIBH during CBCT acquisition did not affect image quality. Advances in knowledge: DIBH RT has dosimetric advantages over FB; this work demonstrates an additional benefit of DIBH in terms of registration accuracy because of improved image quality.

Background and Purpose: We analysed the positional and structural stability of a long-term biodegradable liquid fiducial marker (BioXmark) for radiotherapy in patients with locally advanced lung cancer., Material and Methods: Markers were injected via endoscopic- or endobronchial ultrasound in lymph nodes and reachable primary tumours. Marker volume and Hounsfield Units (HU) changing rates were estimated using breath-hold CBCT. Inter-fraction variation in marker position relative to gross tumour volume (GTV) position was established, as well as the inter-fraction variation in mediastinal marker registration relative to a carina registration through the treatment., Results: Fifteen patients were included and 29 markers analysed. All markers that were in situ at planning were visible through the treatment. Mean HU was 902±165HU for lymph node and 991±219HU for tumour markers. Volume degradation rates were -5% in lymph nodes and -23% in primary tumours. Three-dimensional inter-fraction variation for marker position relative to the GTV position was -0.1±0.7mm in lymph nodes and -1.5±2.3mm in primary tumours. Inter-fraction variations in marker registration relative to carina registration were -0.4±1.2mm in left-right, 0.2±2.0mm in anterior-posterior and -0.5±2.0mm in cranio-caudal directions., Conclusions: The liquid fiducial markers were visible and stable in size and position throughout the treatment course., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The safe clinical implementation of pencil beam scanning (PBS) proton therapy for lung tumors is complicated by the delivery uncertainties caused by breathing motion. The purpose of this feasibility study was to investigate whether a voluntary breath-hold technique could limit the delivery uncertainties resulting from interfractional motion., Methods and Materials: Data from 15 patients with peripheral lung tumors previously treated with stereotactic radiation therapy were included in this study. The patients had 1 computed tomographic (CT) scan in voluntary breath-hold acquired before treatment and 3 scans during the treatment course. PBS proton treatment plans with 2 fields (2F) and 3 fields (3F), respectively, were calculated based on the planning CT scan and subsequently recalculated on the 3 repeated CT scans. Recalculated plans were considered robust if the V95% (volume receiving ≥95% of the prescribed dose) of the gross target volume (GTV) was within 5% of what was expected from the planning CT data throughout the simulated treatment., Results: A total of 14/15 simulated treatments for both 2F and 3F met the robustness criteria. Reduced V95% was associated with baseline shifts (2F, P=.056; 3F, P=.008) and tumor size (2F, P=.025; 3F, P=.025). Smaller tumors with large baseline shifts were also at risk for reduced V95% (interaction term baseline/size: 2F, P=.005; 3F, P=.002)., Conclusions: The breath-hold approach is a realistic clinical option for treating lung tumors with PBS proton therapy. Potential risk factors for reduced V95% are small targets in combination with large baseline shifts. On the basis of these results, the baseline shift of the tumor should be monitored (eg, through image guided therapy), and appropriate measures should be taken accordingly. The intrafractional motion needs to be investigated to confirm that the breath-hold approach is robust., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Purpose: Deep inspiration breath hold (DIBH) increases lung volume and can potentially reduce treatment-related toxicity in locally advanced lung cancer. We estimated geometric uncertainties in visually guided voluntary DIBH and derived the appropriate treatment margins for different image-guidance strategies., Material and Methods: Seventeen patients were included prospectively. An optical marker-based respiratory monitoring with visual guidance enabled comfortable DIBHs, adjusted to each patient's performance. All patients had three consecutive DIBH CTs at each of the treatment fractions 2, 16 and 31. DIBH reproducibility was evaluated as inter- and intra-fractional variations in lung volume, tumour position and differential motion between primary tumour and mediastinal lymph nodes., Results: Lung volume increased by median 60% in DIBH. Inter- and intra-fractional lung volume variations were median 2.1% and 1.1%, respectively. Inter- and intra-fractional uncertainties in 3D tumour position were 4.8 ± 2.8 mm and 1.7 ± 1.4 mm (mean ± SD). Inter- and intra-fractional differential motion was 4.8 ± 3.3 mm and 0.0 ± 1.1 mm., Conclusions: For single targets, visually guided voluntary DIBH radiotherapy is highly reproducible provided an image-guidance strategy with tumour registration is performed. If the primary tumour is separated from the mediastinal lymph nodes, inter-fractional differential motion remains a challenge and margins must be adapted to reflect the image registration strategy., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: We hypothesize that the lesion-to-lesion variability in FDG-PET response after one cycle of chemotherapy for NSCLC in an individual patient may inform radiation dose redistribution. To test this hypothesis, we investigate if time to lesion-progression in patients with multiple lesions is dependent on lesion-specific response to chemotherapy., Materials and Methods: We analyzed 81 patients with 184 lesions referred to curative chemo-radiotherapy for NSCLC 2010-2012. (18)F-FDG PET scans were performed at diagnosis and after one series of chemotherapy. Response of each lesion was assessed as the change in FDG peak standardized uptake value. Variance of lesion response was compared within and between patients. Time to progression for each lesion was analyzed using the Kaplan-Meier method and the Cox proportional hazards model., Results: Within-patient variability in lesion responses was of the same magnitude as the between-patient variability. Lesion-specific time to progression was longer in lesions with a better response (log-rank p=0.038). Nodal lesions had a much lower risk of progression than T-site lesions (HR=0.09, p<0.0001)., Conclusions: Recording an overall patient response involves a loss of biological information on heterogeneity between lesions. Poor lesion-specific response after one cycle chemotherapy may identify lesions that would benefit from an individualized radiotherapy strategy., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The prognostic value of 18F-Fludeoxyglucose (FDG) uptake could be due to its association with already known clinical risk factors., Methods: Correlation between FDG uptake metrics and other known risk factors from 287 patients were analyzed. Time to any failure was analyzed using Cox proportional hazards model stratified by tumor subsite. The resulting multivariate prognostic model was used to generate a table of 2-year freedom from failure estimates with confidence intervals (CIs)., Results: Increasing values of standardized uptake value maximum (SUVmax) correlated with other known risk factors. The reduced Cox model included SUVmax (hazard ratio [HR] = 1.34), cisplatin (HR = 0.37), smoking status (HR = 1.49), and gross target volume (GTV; HR = 1.74) as significant prognostic factors. Including SUVmax in the model changed the 2-year failure estimate by more than 10% for a quarter of the patients (23%)., Conclusion: FDG uptake retains statistical significance in a multivariate analysis and has clinically relevant prognostic impact. We developed a prognostic model for risk stratification of patients in a clinical setting., (© 2014 Wiley Periodicals, Inc.)

Background: With 4DCT the risk of introducing positional systematic errors in lung cancer radiotherapy can be minimised. A common approach is to plan on the phase bin of the 4DCT best representing the tumour's time-weighted mean position also called the midventilation scan. However breathing irregularities can introduce uncertainties and potentially misrepresent both the tumour trajectory and the determination of the midventilation phase. In this study we evaluated the robustness of the midventilation approach in the presence of irregular breathing patterns., Methods: A LEGO Mindstorms(®) phantom with compact balls simulating lung tumours was constructed. The breathing curves loaded in the phantom were either acquired from a human volunteer or constructed with various magnitudes (ranging from 12 to 29 mm) as well as various irregularities of motion pattern. Repeated 4DCT scans were performed while tumour trajectories were recorded with two motion tracking systems., Results: The time-weighted mean tumour position is accurately represented in 4DCT scans, even for irregular breathing patterns: the position presentation in the midventilation scan was always within in one standard deviation of the global position presentation (3 mm and 2 mm for regular and irregular breathing patterns, respectively). The displacement representation tended to be underestimated in 4DCT scans., Conclusion: The midventilation approach is robust even in the presence of breathing irregularity. The representation of the tumour trajectory in 4DCT scans is affected by breathing irregularity and the extent of tumour motion can be underestimated, which will affect the calculation of patient-individualised margins based on the 4DCT scan., (Copyright © 2013 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Background: In lung cancer radiotherapy, planning on the midventilation (MidV) bin of a four-dimensional (4D) CT scan can reduce the systematic errors introduced by respiratory tumour motion compared to conventional CT. In this study four different methods for MidV bin selection are evaluated., Material and Methods: The study is based on 4DCT scans of 19 patients with a total of 23 peripheral lung tumours having peak-to-peak displacement ≥ 5 mm in at least one of the left-right (LR), anterior-posterior (AP) or cranio-caudal (CC) directions. For each tumour, the MidV bin was selected based on: 1) visual evaluation of tumour displacement; 2) rigid registration of tumour position; 3) diaphragm displacement in the CC direction; and 4) carina displacement in the CC direction. Determination of the MidV bin based on the displacement of the manually delineated gross tumour volume (GTV) was used as a reference method. The accuracy of each method was evaluated by the distance between GTV position in the selected MidV bin and the time-weighted mean position of GTV throughout the bins (i.e. the geometric MidV error)., Results: Median (range) geometric MidV error was 1.4 (0.4-5.4) mm, 1.4 (0.4-5.4) mm, 1.9 (0.5-6.9) mm, 2.0 (0.5-12.3) mm and 1.1 (0.4-5.4) mm for the visual, rigid registration, diaphragm, carina, and reference method. Median (range) absolute difference between geometric MidV error for the evaluated methods and the reference method was 0.0 (0.0-1.2) mm, 0.0 (0.0-1.7) mm, 0.7 (0.0-3.9) mm and 1.0 (0.0-6.9) mm for the visual, rigid registration, diaphragm and carina method., Conclusion: The visual and semi-automatic rigid registration methods were equivalent in accuracy for selecting the MidV bin of a 4DCT scan. The methods based on diaphragm and carina displacement cannot be recommended without modifications.

The purpose of this study was to evaluate the stability of complex markers implanted into lung tumors throughout a course of stereotactic body radiotherapy (SBRT). Fifteen patients referred for lung SBRT were prospectively included. Radio-opaque markers were implanted percutaneously, guided by computed tomography (CT). Deep inspiration breath-hold CT scans (BHCT) were acquired at planning and on three treatment days. The treatment days' BHCTs were registered to the planning BHCT. Intraobserver uncertainty in both tumor and marker registration was determined. Deviations in the difference between tumor and marker-based image registrations of the BHCT scans during treatment quantified the marker stability. Marker position deviation relative to tumor position of less than 2 mm in all three dimensions was considered acceptable for treatment delivery precision. Intra observer uncertainties for image registration in the left-right (LR), anterior-posterior (AP), craniocaudal (CC) directions and three-dimensional vector (3D) were 0.9 mm, 0.9 mm, 1.0 mm, and 1.1 mm (SD) for tumor registration and 0.3 mm, 0.5 mm, 0.7 mm, and 0.7 mm (SD) for marker registration. Mean 3D differences for tumor registrations on all days were significantly larger than for 3D marker registrations (p = 0.007). Overall median differences between tumor and marker position were 0.0 mm (range -2.9 to 2.6 mm) in LR, 0.0 mm (-1.8 to 1.5 mm) in AP, and -0.2 mm (-2.6 to 2.8 mm) in CC directions. Four patients had deviations exceeding 2 mm in one or more registrations throughout the SBRT course. This is the first study to evaluate stability of complex markers implanted percutaneously into lung tumors for image guidance in SBRT. We conclude that the observed stability of marker position within the tumor indicates that complex markers can be used as surrogates for tumor position during a short course of SBRT as long as the uncertainties related to their position within the tumor are incorporated into the planning target volume.