Optimization of carbon ion and proton treatment plans using the raster-scanning technique for patients with unresectable pancreatic cancer

Background: The aim of the thesis is to improve radiation plans of patients with locally advanced, unresectable pancreatic cancer by using carbon ion and proton beams. Patients and methods: Using the treatment planning system Syngo RT Planning (Siemens, Erlangen, Germany) a total of 50 treatment plans have been created for five patients with the dose schedule 15 × 3 Gy(RBE). With reference to the anatomy, five field configurations were considered to be relevant. The plans were analyzed with respect to dose distribution and individual anatomy, and compared using a customized index. Results: Within the index the three-field configurations yielded the best results, though with a high variety of score points (field setup 5, carbon ion: median 74 (range 48–101)). The maximum dose in the myelon is low (e.g. case 3, carbon ion: 21.5 Gy(RBE)). A single posterior field generally spares the organs at risk, but the maximum dose in the myelon is high (e.g. case 3, carbon ion: 32.9 Gy(RBE)). Two oblique posterior fields resulted in acceptable maximum doses in the myelon (e.g. case 3, carbon ion: 26.9 Gy(RBE)). The single-field configuration and the two oblique posterior fields had a small score dispersion (carbon ion: median 66 and 58 (range 62–72 and 40–69)). In cases with topographic proximity of the organs at risk to the target volume, the single-field configuration scored as well as the three-field configurations. Conclusion: In summary, the three-field configurations showed the best dose distributions. A single posterior field seems to be robust and beneficial in case of difficult topographical conditions and topographical proximity of organs at risk to the target volume. A setup with two oblique posterior fields is a reasonable compromise between three-field and single-field configurations

The influence of fractionated radiotherapy on the stability of spinal bone metastases: a retrospective analysis from 1047 cases

Background: The effect of radiotherapy, in particular the application of different multi-fraction schedules in the management of unstable spinal bone metastases (SBM), is incompletely understood. This study aims to compare the radiological response regarding various dose and fractionation schedules of radiotherapy in the palliative treatment of SBM. Methods: We retrospectively assessed 1047 patients with osteolytic SBM, treated with palliative radiotherapy at our department between 2000 and 2015. Lung cancer (40.2%), breast (16.7%) and renal cancer (15.2%) were the most common solid tumors in this study. Different common multi-fraction regimen (5x4Gy, 10x3Gy, 14 × 2.5Gy and 20x2Gy) were compared with regard to radiological response and recalcification at 3 and 6 months after radiotherapy. The Taneichi score was used for classification of osteolytic SBM. Results: Median follow up was 6.3 months. The median overall survival (OS) in the short-course radiotherapy (SCR) group using less than 10 treatment fractions was 5.5 months vs. 9.5 months in the long-course radiotherapy (LCR) group using in excess of 10 fractions (log rank p < .0001). Overall survival (OS) in the SCR group after 3 and 6 months was 66.8 and 49.1%, respectively vs 80.9 and 61.5%, respectively in the LCR group. 17.6% (n = 54/306) and 31.1% (n = 89/286) of unstable SBM were classified as stable in the SCR group at 3 and 6 months post radiotherapy, respectively (p < .001 for both). In the LCR group, 24.1% (n = 28/116) and 34.2% (n = 38/111) of unstable SBM were stabilized after 3 and 6 months, respectively (p < .001 for both). Conclusions: Our study shows no significant difference in stabilization achieving recalcification rates between multi-fraction schedules (SCR vs. LCR) in the palliative management of unstable SBM. Both groups with multi-fraction regimen demonstrate a stabilizing effect following 3 and 6 months after radiotherapy

Evaluation of particle radiotherapy for the re-irradiation of recurrent intracranial meningioma

Background: With the advance of modern irradiation techniques, the role of radiotherapy (RT) for intracranial meningioma has increased significantly throughout the past years. Despite that tumor’s generally favorable outcome with local control rates of up to 90% after ten years, progression after RT does occur. In those cases, re-irradiation is often difficult due to the limited radiation tolerance of the surrounding tissue. The aim of this analysis is to determine the value of particle therapy with its better dose conformity and higher biological efficacy for re-irradiating recurrent intracranial meningioma. It was performed within the framework of the “clinical research group heavy ion therapy” and funded by the German Research Council (DFG, KFO 214). Methods: Forty-two patients treated with particle RT (protons (n = 8) or carbon ions (n = 34)) for recurrent intracranial meningioma were included in this analysis. Location of the primary lesion varied, including skull base (n = 31), convexity (n = 5) and falx (n = 6). 74% of the patients were categorized high-risk according to histology with a WHO grading of II (n = 25) or III (n = 6), in the remaining cases histology was either WHO grade I (n = 10) or unknown (n = 1). Median follow-up was 49,7 months. Results: In all patients, re-irradiation could be performed safely without interruptions due to side effects. No grade IV or V toxicities according to CTCAE v4.0 were observed. Particle RT offered good overall local control rates with 71% progression-free survival (PFS) after 12 months, 56,5% after 24 months and a median PFS of 34,3 months (95% CI 11,7–56,9). Histology had a significant impact on PFS yielding a median PFS of 25,7 months (95% CI 5,8–45,5) for high-risk histology (WHO grades II and III) while median PFS was not reached for low-risk tumors (WHO grade I) (p = 0,03). Median time to local progression was 15,3 months (Q1-Q3 8,08–34,6). Overall survival (OS) after re-irradiation was 89,6% after 12 months and 71,4% after 24 months with a median OS of 61,0 months (95% CI 34,2–87,7). Again, WHO grading had an effect, as median OS for low-risk patients was not reached whereas for high-risk patients it was 45,5 months (95% CI 35,6–55,3). Conclusion: Re-irradiation using particle therapy is an effective method for the treatment of recurrent meningiomas. Interdisciplinary decision making is necessary to guarantee best treatment for every patient

Survey in radiation oncology departments in Germany, Austria, and Switzerland: state of digitalization by 2023.

PURPOSE The aim of this work was to assess the current state of digitalization in radiation oncology departments in Germany, Austria, and Switzerland. METHODS A comprehensive survey was conducted in a digital format, consisting of 53 questions that covered various aspects of digitalization including patient workflow, departmental organization, radiotherapy planning, and employee-related aspects. RESULTS Overall, 120 forms were eligible for evaluation. Participants were mainly physicians or medical physicists responsible for digitalization aspects in their departments. Nearly 70% of the institutions used electronic patient records, with 50% being completely paperless. However, the use of smartphone apps for electronic patient reported outcomes (ePROMs) and digital health applications (DIGA) was limited (9% and 4.9%, respectively). In total, 70.8% of the radio-oncology departments had interfaces with diagnostic departments, and 36% had digital interchanges with other clinics. Communication with external partners was realized mainly through fax (72%), e‑mails (55%), postal letters (63%), or other digital exchange formats (28%). Almost half of the institutions (49%) had dedicated IT staff for their operations. CONCLUSION To the best of our knowledge, this survey is the first of its kind conducted in German-speaking radiation oncology departments within the medical field. The findings suggest that there is a varied level of digitalization implementation within these departments, with certain areas exhibiting lower rates of digitalization that could benefit from targeted improvement initiatives

Whole brain radiation therapy alone versus radiosurgery for patients with 1–10 brain metastases from small cell lung cancer (ENCEPHALON Trial): study protocol for a randomized controlled trial

Background: Conventional whole brain radiotherapy (WBRT) has been established as the treatment standard in patients with cerebral metastases from small-cell lung cancer (SCLC), however, it has only modest efficacy and limited prospective data is available for WBRT as well as local treatments such as stereotactic radiosurgery (SRS). Methods/design: The present single-center prospective randomized study, conducted at Heidelberg University Hospital, compares neurocognitive function, as objectively measured by significant deterioration in Hopkins Verbal Learning Test – Revised total recall at 3 months. Fifty-six patients will be randomized to receive either SRS of all brain metastases (up to ten lesions) or WBRT. Secondary endpoints include intracranial progression (local tumor progression and number of new cerebral metastases), extracranial progression, overall survival, death due to brain metastases, local (neurological) progression-free survival, progression-free survival, changes in other cognitive performance measures, quality of life and toxicity. Discussion: Recent evidence suggests that SRS might be a promising treatment option for SCLC patients with brain metastases. The present trial is the first to prospectively investigate the treatment response, toxicity and neurocognition of WBRT and SRS in SCLC patients. Trial registration: Clinicaltrials.gov NCT03297788 . Registered September 29, 2017

Local response and pathologic fractures following stereotactic body radiotherapy versus three-dimensional conformal radiotherapy for spinal metastases - a randomized controlled trial

Background: This was a prespecified secondary analysis of a randomized trial, which analyzed bone density following stereotactic body radiotherapy (SBRT) versus conventional three-dimensional conformal radiotherapy (3DCRT) as part of palliative management of painful spinal metastases. Methods: Fifty-five patients were enrolled in this single-institutional randomized exploratory trial (NCT02358720). Participants were randomly assigned to receive SBRT (single-fraction 24 Gy) or 3DCRT (30 Gy/10 fractions). Quantitative bone density was evaluated at baseline, 3 and 6 months in both irradiated and unirradiated spinal bodies, along with rates of pathologic fractures and vertebral compression fractures. Results: As compared to baseline, bone density became significantly higher at 3 and 6 months following SBRT by a median of 33.8% and 72.1%, respectively (p < 0.01 for both). These figures in the 3DCRT cohort were 32.9% and 41.2%, respectively (p < 0.01 for both). There were no statistical differences in bone density between SBRT and 3DCRT at 3 (p = 0.629) or 6 months (p = 0.327). Subgroup analysis of osteolytic metastases showed an increase in bone density relative to baseline in the SBRT (but not 3DCRT) arm. Bone density in unaffected vertebrae did not show substantial changes in either group. The 3-month incidence of new pathological fractures was 8.7% in the SBRT arm vs. 4.3% in the 3DCRT arm. Conclusions: Despite high ablative doses in the SBRT arm, the significant increase in bone density after 3 and 6 months was similar to that of 3DCRT. Our trial demonstrated a moderate rate of subsequent pathological fracture after SBRT. Future randomized investigations with larger sample sizes are recommended. Trial registration: www.clinicaltrials.gov : NCT02358720 on 9nd of February 2015

Bone density and pain response following intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy for vertebral metastases - secondary results of a randomized trial

Background: This was a prespecified secondary analysis of a randomized trial that analyzed bone density and pain response following fractionated intensity-modulated radiotherapy (IMRT) versus three-dimensional conformal radiotherapy (3DCRT) for palliative management of spinal metastases. Methods/materials: Sixty patients were enrolled in the single-institutional randomized exploratory trial, randomly assigned to receive IMRT or 3DCRT (30 Gy in 10 fractions). Along with pain response (measured by the Visual Analog Scale (VAS) and Chow criteria), quantitative bone density was evaluated at baseline, 3, and 6 months in both irradiated and unirradiated spinal bodies, along with rates of pathologic fractures and vertebral compression fractures. Results: Relative to baseline, bone density increased at 3 and 6 months following IMRT by a median of 24.8% and 33.8%, respectively (p < 0.01 and p = 0.048). These figures in the 3DCRT cohort were 18.5% and 48.4%, respectively (p < 0.01 for both). There were no statistical differences in bone density between IMRT and 3DCRT at 3 (p = 0.723) or 6 months (p = 0.341). Subgroup analysis of osteolytic and osteoblastic metastases showed no differences between groups; however, mixed metastases showed an increase in bone density over baseline in the IMRT (but not 3DCRT) arm. The 3-month rate of the pathological fractures was 15.0% in the IMRT arm vs. 10.5% in the 3DCRT arm. There were no differences in pathological fractures at 3 (p = 0.676) and 6 (p = 1.000) months. The IMRT arm showed improved VAS scores at 3 (p = 0.037) but not 6 months (p = 0.430). Using Chow criteria, pain response was similar at both 3 (p = 0.395) and 6 (p = 0.732) months. Conclusions: This the first prospective investigation evaluating the impact of IMRT vs. 3DCRT on bone density. Along with pain response and pathologic fracture rates, significant rises in bone density after 3 and 6 months were similar in both cohorts. Future randomized investigations with larger sample sizes are recommended. Trial registration: NCT, NCT02832830. Registered 14 July 201

Identifying core MRI sequences for reliable automatic brain metastasis segmentation

BACKGROUND Many automatic approaches to brain tumor segmentation employ multiple magnetic resonance imaging (MRI) sequences. The goal of this project was to compare different combinations of input sequences to determine which MRI sequences are needed for effective automated brain metastasis (BM) segmentation. METHODS We analyzed preoperative imaging (T1-weighted sequence ± contrast-enhancement (T1/T1-CE), T2-weighted sequence (T2), and T2 fluid-attenuated inversion recovery (T2-FLAIR) sequence) from 339 patients with BMs from seven centers. A baseline 3D U-Net with all four sequences and six U-Nets with plausible sequence combinations (T1-CE, T1, T2-FLAIR, T1-CE + T2-FLAIR, T1-CE + T1 + T2-FLAIR, T1-CE + T1) were trained on 239 patients from two centers and subsequently tested on an external cohort of 100 patients from five centers. RESULTS The model based on T1-CE alone achieved the best segmentation performance for BM segmentation with a median Dice similarity coefficient (DSC) of 0.96. Models trained without T1-CE performed worse (T1-only: DSC = 0.70 and T2-FLAIR-only: DSC = 0.73). For edema segmentation, models that included both T1-CE and T2-FLAIR performed best (DSC = 0.93), while the remaining four models without simultaneous inclusion of these both sequences reached a median DSC of 0.81-0.89. CONCLUSIONS A T1-CE-only protocol suffices for the segmentation of BMs. The combination of T1-CE and T2-FLAIR is important for edema segmentation. Missing either T1-CE or T2-FLAIR decreases performance. These findings may improve imaging routines by omitting unnecessary sequences, thus allowing for faster procedures in daily clinical practice while enabling optimal neural network-based target definitions

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation