Search

Abstract Purpose/objective Currently, there are few prospective data on the tolerability of combining targeted therapies (TT) with radiation therapy (RT). The objective of this prospective study was to assess the feasibility and toxicity of pairing RT with concurrent TT in cancer patients. The aim was to enhance the existing evidence base for the simultaneous administration of targeted substances together with radiotherapy. Methods Prospective study enrollment was conducted at a single institution between March 1, 2020, and December 31, 2021, for all patients diagnosed with histologically confirmed cancer who underwent external beam radiotherapy in combination with targeted therapy. The study, known as the “targeted RT study,” was registered in the German Clinical Trials Register under DRKS00026193. Systematic documentation of the toxicity profiles of different targeted therapies was performed, and the assessment of acute toxicity followed the guidelines of the National Cancer Institute Common Terminology Criteria for Adverse Events Version v5.0. Results A total of 334 patients underwent 683 radiation therapy series. During the course of RT, 51 different TT substances were concurrently administered. External beam radiotherapy was employed for various anatomical sites. The combination of RT and concurrent TT administration was generally well tolerated, with no instances of severe acute toxicity observed. The most commonly reported toxicity was fatigue, ranging from mild to moderate Common Terminology Criteria for Adverse Events (CTCAE) °I-°III. Other frequently observed toxicities included dermatitis, dyspnea, dysphagia, and dry cough. No toxicity greater than moderate severity was recorded at any point. In only 32 patients (4.7% of evaluated RT series), the concurrent substance administration was discontinued due to side effects. However, these side effects did not exceed mild severity according to CTCAE, suggesting that discontinuation was a precautionary measure. Only one patient receiving Imatinib treatment experienced a severe CTCAE °III side effect, leading to discontinuation of the concurrent substance due to the sudden occurrence of melaena during RT. Conclusion In conclusion, the current study did not demonstrate a significant increase or additional toxicity when combining radiotherapy and concurrent targeted therapy. However, additional research is required to explore the specific toxicity profiles of the various substances that can be utilized in this context. Trial registration number DRKS00026193. Date of registration 12/27/2022 (retrospectively registered).

Abstract Background Longitudinal assessments of apparent diffusion coefficients (ADCs) derived from diffusion-weighted imaging (DWI) during intracranial radiotherapy at magnetic resonance imaging-guided linear accelerators (MR-linacs) could enable early response assessment by tracking tumor diffusivity changes. However, DWI pulse sequences are currently unavailable in clinical practice at low-field MR-linacs. Quantifying the in vivo repeatability of ADC measurements is a crucial step towards clinical implementation of DWI sequences but has not yet been reported on for low-field MR-linacs. This study assessed ADC measurement repeatability in a phantom and in vivo at a 0.35 T MR-linac. Methods Eleven volunteers and a diffusion phantom were imaged on a 0.35 T MR-linac. Two echo-planar imaging DWI sequence variants, emphasizing high spatial resolution (“highRes”) and signal-to-noise ratio (“highSNR”), were investigated. A test–retest study with an intermediate outside-scanner-break was performed to assess repeatability in the phantom and volunteers’ brains. Mean ADCs within phantom vials, cerebrospinal fluid (CSF), and four brain tissue regions were compared to literature values. Absolute relative differences of mean ADCs in pre- and post-break scans were calculated for the diffusion phantom, and repeatability coefficients (RC) and relative RC (relRC) with 95% confidence intervals were determined for each region-of-interest (ROI) in volunteers. Results Both DWI sequence variants demonstrated high repeatability, with absolute relative deviations below 1% for water, dimethyl sulfoxide, and polyethylene glycol in the diffusion phantom. RelRCs were 7% [5%, 12%] (CSF; highRes), 12% [9%, 22%] (CSF; highSNR), 9% [8%, 12%] (brain tissue ROIs; highRes), and 6% [5%, 7%] (brain tissue ROIs; highSNR), respectively. ADCs measured with the highSNR variant were consistent with literature values for volunteers, while smaller mean values were measured for the diffusion phantom. Conversely, the highRes variant underestimated ADCs compared to literature values, indicating systematic deviations. Conclusions High repeatability of ADC measurements in a diffusion phantom and volunteers’ brains were measured at a low-field MR-linac. The highSNR variant outperformed the highRes variant in accuracy and repeatability, at the expense of an approximately doubled voxel volume. The observed high in vivo repeatability confirms the potential utility of DWI at low-field MR-linacs for early treatment response assessment.

Abstract Objectives Deep learning-based auto-segmentation of head and neck cancer (HNC) tumors is expected to have better reproducibility than manual delineation. Positron emission tomography (PET) and computed tomography (CT) are commonly used in tumor segmentation. However, current methods still face challenges in handling whole-body scans where a manual selection of a bounding box may be required. Moreover, different institutions might still apply different guidelines for tumor delineation. This study aimed at exploring the auto-localization and segmentation of HNC tumors from entire PET/CT scans and investigating the transferability of trained baseline models to external real world cohorts. Methods We employed 2D Retina Unet to find HNC tumors from whole-body PET/CT and utilized a regular Unet to segment the union of the tumor and involved lymph nodes. In comparison, 2D/3D Retina Unets were also implemented to localize and segment the same target in an end-to-end manner. The segmentation performance was evaluated via Dice similarity coefficient (DSC) and Hausdorff distance 95th percentile (HD95). Delineated PET/CT scans from the HECKTOR challenge were used to train the baseline models by 5-fold cross-validation. Another 271 delineated PET/CTs from three different institutions (MAASTRO, CRO, BERLIN) were used for external testing. Finally, facility-specific transfer learning was applied to investigate the improvement of segmentation performance against baseline models. Results Encouraging localization results were observed, achieving a maximum omnidirectional tumor center difference lower than 6.8 cm for external testing. The three baseline models yielded similar averaged cross-validation (CV) results with a DSC in a range of 0.71–0.75, while the averaged CV HD95 was 8.6, 10.7 and 9.8 mm for the regular Unet, 2D and 3D Retina Unets, respectively. More than a 10% drop in DSC and a 40% increase in HD95 were observed if the baseline models were tested on the three external cohorts directly. After the facility-specific training, an improvement in external testing was observed for all models. The regular Unet had the best DSC (0.70) for the MAASTRO cohort, and the best HD95 (7.8 and 7.9 mm) in the MAASTRO and CRO cohorts. The 2D Retina Unet had the best DSC (0.76 and 0.67) for the CRO and BERLIN cohorts, and the best HD95 (12.4 mm) for the BERLIN cohort. Conclusion The regular Unet outperformed the other two baseline models in CV and most external testing cohorts. Facility-specific transfer learning can potentially improve HNC segmentation performance for individual institutions, where the 2D Retina Unets could achieve comparable or even better results than the regular Unet.

Abstract Background and purpose Magnetic resonance imaging guided radiotherapy (MRgRT) offers treatment plan adaptation to the anatomy of the day. In the current MRgRT workflow, this requires the time consuming and repetitive task of manual delineation of organs-at-risk (OARs), which is also prone to inter- and intra-observer variability. Therefore, deep learning autosegmentation (DLAS) is becoming increasingly attractive. No investigation of its application to OARs in thoracic magnetic resonance images (MRIs) from MRgRT has been done so far. This study aimed to fill this gap. Materials and methods 122 planning MRIs from patients treated at a 0.35 T MR-Linac were retrospectively collected. Using an 80/19/23 (training/validation/test) split, individual 3D U-Nets for segmentation of the left lung, right lung, heart, aorta, spinal canal and esophagus were trained. These were compared to the clinically used contours based on Dice similarity coefficient (DSC) and Hausdorff distance (HD). They were also graded on their clinical usability by a radiation oncologist. Results Median DSC was 0.96, 0.96, 0.94, 0.90, 0.88 and 0.78 for left lung, right lung, heart, aorta, spinal canal and esophagus, respectively. Median 95th percentile values of the HD were 3.9, 5.3, 5.8, 3.0, 2.6 and 3.5 mm, respectively. The physician preferred the network generated contours over the clinical contours, deeming 85 out of 129 to not require any correction, 25 immediately usable for treatment planning, 15 requiring minor and 4 requiring major corrections. Conclusions We trained 3D U-Nets on clinical MRI planning data which produced accurate delineations in the thoracic region. DLAS contours were preferred over the clinical contours.

Abstract Background Patients with locally-advanced non-small-cell lung cancer (LA-NSCLC) are often ineligible for surgery, so that definitive chemoradiotherapy (CRT) represents the treatment of choice. Nevertheless, long-term tumor control is often not achieved. Intensification of radiotherapy (RT) to improve locoregional tumor control is limited by the detrimental effect of higher radiation exposure of thoracic organs-at-risk (OAR). This narrow therapeutic ratio may be expanded by exploiting the advantages of magnetic resonance (MR) linear accelerators, mainly the online adaptation of the treatment plan to the current anatomy based on daily acquired MR images. However, MR-guidance is both labor-intensive and increases treatment times, which raises the question of its clinical feasibility to treat LA-NSCLC. Therefore, the PUMA trial was designed as a prospective, multicenter phase I trial to demonstrate the clinical feasibility of MR-guided online adaptive RT in LA-NSCLC. Methods Thirty patients with LA-NSCLC in stage III A-C will be accrued at three German university hospitals to receive MR-guided online adaptive RT at two different MR-linac systems (MRIdian Linac®, View Ray Inc. and Elekta Unity®, Elekta AB) with concurrent chemotherapy. Conventionally fractioned RT with isotoxic dose escalation up to 70 Gy is applied. Online plan adaptation is performed once weekly or in case of major anatomical changes. Patients are followed-up by thoracic CT- and MR-imaging for 24 months after treatment. The primary endpoint is twofold: (1) successfully completed online adapted fractions, (2) on-table time. Main secondary endpoints include adaptation frequency, toxicity, local tumor control, progression-free and overall survival. Discussion PUMA aims to demonstrate the clinical feasibility of MR-guided online adaptive RT of LA-NSCLC. If successful, PUMA will be followed by a clinical phase II trial that further investigates the clinical benefits of this approach. Moreover, PUMA is part of a large multidisciplinary project to develop MR-guidance techniques. Trial registration ClinicalTrials.gov: NCT05237453 .

Abstract Background Hybrid devices that combine radiation therapy and MR-imaging have been introduced in the clinical routine for the treatment of lung cancer. This opened up not only possibilities in terms of accurate tumor tracking, dose delivery and adapted treatment planning, but also functional lung imaging. The aim of this study was to show the feasibility of Non-uniform Fourier Decomposition (NuFD) MRI at a 0.35 T MR-Linac as a potential treatment response assessment tool, and propose two signal normalization strategies for enhancing the reproducibility of the results. Methods Ten healthy volunteers (median age 28 ± 8 years, five female, five male) were repeatedly scanned at a 0.35 T MR-Linac using an optimized 2D+t balanced steady-state free precession (bSSFP) sequence for two coronal slice positions. Image series were acquired in normal free breathing with breaks inside and outside the scanner as well as deep and shallow breathing. Ventilation- and perfusion-weighted maps were generated for each image series using NuFD. For intra-volunteer ventilation map reproducibility, a normalization factor was defined based on the linear correlation of the ventilation signal and diaphragm position of each scan as well as the diaphragm motion amplitude of a reference scan. This allowed for the correction of signal dependency on the diaphragm motion amplitude, which varies with breathing patterns. The second strategy, which can be used for ventilation and perfusion, eliminates the dependency on the signal amplitude by normalizing the ventilation/perfusion maps with the average ventilation/perfusion signal within a selected region-of-interest (ROI). The position and size dependency of this ROI was analyzed. To evaluate the performance of both approaches, the normalized ventilation/perfusion-weighted maps were compared and the deviation of the mean ventilation/perfusion signal from the reference was calculated for each scan. Wilcoxon signed-rank tests were performed to test whether the normalization methods can significantly improve the reproducibility of the ventilation/perfusion maps. Results The ventilation- and perfusion-weighted maps generated with the NuFD algorithm demonstrated a mostly homogenous distribution of signal intensity as expected for healthy volunteers regardless of the breathing maneuver and slice position. Evaluation of the ROI’s size and position dependency showed small differences in the performance. Applying both normalization strategies improved the reproducibility of the ventilation by reducing the median deviation of all scans to 9.1%, 5.7% and 8.6% for the diaphragm-based, the best and worst performing ROI-based normalization, respectively, compared to 29.5% for the non-normalized scans. The significance of this improvement was confirmed by the Wilcoxon signed rank test with $$p\,

Abstract Background The management of brain metastases (BM), the major cause of cancer morbidity and mortality, is becoming an emerging area of interest. Surgery, whole brain radiation therapy (WBRT), or stereotactic radiosurgery (SRS), have historically been the main focal treatments for BM. However, the introduction of innovative targeted- and immune-based therapies is progressively changing the paradigm of BM treatment, resulting in an increase in clinical trials investigating new therapeutic strategies. Methods Using ClinicalTrials.gov, the largest clinical trial registry with over 400,000 registered trials, we performed an analysis of phase II and phase III ongoing trials evaluating different systemic therapies, radiotherapy (RT), and surgery given alone or in combination in patients with BM. Results One hundred sixty-eight trials, 133 phase II and 35 phase III; the largest part having primarily the curative treatment of patients with BM from lung cancer, breast cancer and melanoma, were selected. One hundred sixty-three trials used systemic therapies. One hundred thirteen used tyrosine kinase inhibitors, more frequently Osimertinib, Icotinib and Pyrotinib, 50 used monoclonal antibodies, more frequently Trastuzumab, Pembrolizumab, Nivolumab, 20 used conventional chemotherapies whilst no oncological active drugs were used in 6 trials. Ninety-six trials include RT; 54 as exclusive treatment and 42 in combination with systemic therapies. Conclusion Systemic targeted- and/or immune-based therapies, combined or not with RT, are increasingly used in the routine of BM treatment. SRS is progressively replacing WBRT. All these trials intend to address multiple questions on the management of patients with BMs, including the recommended upfront treatment for different cancer histologies and the optimal timing between systemic therapies and radiation regarding brain control and neurocognitive outcome and quality of life.

Abstract Despite intensive basic scientific, translational, and clinical efforts in the last decades, glioblastoma remains a devastating disease with a highly dismal prognosis. Apart from the implementation of temozolomide into the clinical routine, novel treatment approaches have largely failed, emphasizing the need for systematic examination of glioblastoma therapy resistance in order to identify major drivers and thus, potential vulnerabilities for therapeutic intervention. Recently, we provided proof-of-concept for the systematic identification of combined modality radiochemotherapy treatment vulnerabilities via integration of clonogenic survival data upon radio(chemo)therapy with low-density transcriptomic profiling data in a panel of established human glioblastoma cell lines. Here, we expand this approach to multiple molecular levels, including genomic copy number, spectral karyotyping, DNA methylation, and transcriptome data. Correlation of transcriptome data with inherent therapy resistance on the single gene level yielded several candidates that were so far underappreciated in this context and for which clinically approved drugs are readily available, such as the androgen receptor (AR). Gene set enrichment analyses confirmed these results, and identified additional gene sets, including reactive oxygen species detoxification, mammalian target of rapamycin complex 1 (MTORC1) signaling, and ferroptosis/autophagy-related regulatory circuits to be associated with inherent therapy resistance in glioblastoma cells. To identify pharmacologically accessible genes within those gene sets, leading edge analyses were performed yielding candidates with functions in thioredoxin/peroxiredoxin metabolism, glutathione synthesis, chaperoning of proteins, prolyl hydroxylation, proteasome function, and DNA synthesis/repair. Our study thus confirms previously nominated targets for mechanism-based multi-modal glioblastoma therapy, provides proof-of-concept for this workflow of multi-level data integration, and identifies novel candidates for which pharmacological inhibitors are readily available and whose targeting in combination with radio(chemo)therapy deserves further examination. In addition, our study also reveals that the presented workflow requires mRNA expression data, rather than genomic copy number or DNA methylation data, since no stringent correlation between these data levels could be observed. Finally, the data sets generated in the present study, including functional and multi-level molecular data of commonly used glioblastoma cell lines, represent a valuable toolbox for other researchers in the field of glioblastoma therapy resistance.

Abstract Background Quantitative image analysis based on radiomic feature extraction is an emerging field for survival prediction in oncological patients. 18F-Fluorethyltyrosine positron emission tomography (18F-FET PET) provides important diagnostic and grading information for brain tumors, but data on its use in survival prediction is scarce. In this study, we aim at investigating survival prediction based on multiple radiomic features in glioblastoma patients undergoing radio(chemo)therapy. Methods A dataset of 37 patients with glioblastoma (WHO grade 4) receiving radio(chemo)therapy was analyzed. Radiomic features were extracted from pre-treatment 18F-FET PET images, following intensity rebinning with a fixed bin width. Principal component analysis (PCA) was applied for variable selection, aiming at the identification of the most relevant features in survival prediction. Random forest classification and prediction algorithms were optimized on an initial set of 25 patients. Testing of the implemented algorithms was carried out in different scenarios, which included additional 12 patients whose images were acquired with a different scanner to check the reproducibility in prediction results. Results First order intensity variations and shape features were predominant in the selection of most important radiomic signatures for survival prediction in the available dataset. The major axis length of the 18F-FET-PET volume at tumor to background ratio (TBR) 1.4 and 1.6 correlated significantly with reduced probability of survival. Additional radiomic features were identified as potential survival predictors in the PTV region, showing 76% accuracy in independent testing for both classification and regression. Conclusions 18F-FET PET prior to radiation provides relevant information for survival prediction in glioblastoma patients. Based on our preliminary analysis, radiomic features in the PTV can be considered a robust dataset for survival prediction.

Abstract Background Epidermal growth factor receptor (EGFR) is both a driver oncogene and a therapeutic target in advanced head and neck squamous cell carcinoma (HNSCC). However, response to EGFR treatment is inconsistent and lacks markers for treatment prediction. This study investigated EGFR-induced epithelial-to-mesenchymal transition (EMT) as a central parameter in tumor progression and identified novel prognostic and therapeutic targets, and a candidate predictive marker for EGFR therapy response. Methods Transcriptomic profiles were analyzed by RNA sequencing (RNA-seq) following EGFR-mediated EMT in responsive human HNSCC cell lines. Exclusive genes were extracted via differentially expressed genes (DEGs) and a risk score was determined through forward feature selection and Cox regression models in HNSCC cohorts. Functional characterization of selected prognostic genes was conducted in 2D and 3D cellular models, and findings were validated by immunohistochemistry in primary HNSCC. Results An EGFR-mediated EMT gene signature composed of n = 171 genes was identified in responsive cell lines and transferred to the TCGA-HNSCC cohort. A 5-gene risk score comprising DDIT4, FADD, ITGB4, NCEH1, and TIMP1 prognosticated overall survival (OS) in TCGA and was confirmed in independent HNSCC cohorts. The EGFR-mediated EMT signature was distinct from EMT hallmark and partial EMT (pEMT) meta-programs with a differing enrichment pattern in single malignant cells. Molecular characterization showed that ITGB4 was upregulated in primary tumors and metastases compared to normal mucosa and correlated with EGFR/MAPK activity in tumor bulk and single malignant cells. Preferential localization of ITGB4 together with its ligand laminin 5 at tumor-stroma interfaces correlated with increased tumor budding in primary HNSCC tissue sections. In vitro, ITGB4 knock-down reduced EGFR-mediated migration and invasion and ITGB4-antagonizing antibody ASC8 impaired 2D and 3D invasion. Furthermore, a logistic regression model defined ITGB4 as a predictive marker of progression-free survival in response to Cetuximab in recurrent metastatic HNSCC patients. Conclusions EGFR-mediated EMT conveyed through MAPK activation contributes to HNSCC progression upon induction of migration and invasion. A 5-gene risk score based on a novel EGFR-mediated EMT signature prognosticated survival of HNSCC patients and determined ITGB4 as potential therapeutic and predictive target in patients with strong EGFR-mediated EMT.

Abstract Background Magnetic resonance-guided radiotherapy (MRgRT) utilization is rapidly expanding, driven by advanced capabilities including better soft tissue imaging, continuous intrafraction target visualization, automatic triggered beam delivery, and the availability of on-table adaptive replanning. Our objective was to describe patterns of 0.35 Tesla (T)-MRgRT utilization in Europe and Asia among early adopters of this novel technology. Methods Anonymized administrative data from all 0.35T-MRgRT treatment systems in Europe and Asia were extracted for patients who completed treatment from 2015 to 2020. Detailed treatment information was analyzed for all MR-linear accelerators (linac) and -cobalt systems. Results From 2015 through the end of 2020, there were 5796 completed treatment courses delivered in 46,389 individual fractions. 23.5% of fractions were adapted. Ultra-hypofractionated (UHfx) dose schedules (1–5 fractions) were delivered for 63.5% of courses, with 57.8% of UHfx fractions adapted on-table. The most commonly treated tumor types were prostate (23.5%), liver (14.5%), lung (12.3%), pancreas (11.2%), and breast (8.0%), with increasing compound annual growth rates (CAGRs) in numbers of courses from 2015 through 2020 (pancreas: 157.1%; prostate: 120.9%; lung: 136.0%; liver: 134.2%). Conclusions This is the first comprehensive study reporting patterns of utilization among early adopters of a 0.35T-MRgRT system in Europe and Asia. Intrafraction MR image-guidance, advanced motion management, and increasing adoption of on-table adaptive RT have accelerated a transition to UHfx regimens. MRgRT has been predominantly used to treat tumors in the upper abdomen, pelvis and lungs, and increasingly with adaptive replanning, which is a radical departure from legacy radiotherapy practices.

Abstract Background We describe and evaluate a deep network algorithm which automatically contours organs at risk in the thorax and pelvis on computed tomography (CT) images for radiation treatment planning. Methods The algorithm identifies the region of interest (ROI) automatically by detecting anatomical landmarks around the specific organs using a deep reinforcement learning technique. The segmentation is restricted to this ROI and performed by a deep image-to-image network (DI2IN) based on a convolutional encoder-decoder architecture combined with multi-level feature concatenation. The algorithm is commercially available in the medical products “syngo.via RT Image Suite VB50” and “AI-Rad Companion Organs RT VA20” (Siemens Healthineers). For evaluation, thoracic CT images of 237 patients and pelvic CT images of 102 patients were manually contoured following the Radiation Therapy Oncology Group (RTOG) guidelines and compared to the DI2IN results using metrics for volume, overlap and distance, e.g., Dice Similarity Coefficient (DSC) and Hausdorff Distance (HD95). The contours were also compared visually slice by slice. Results We observed high correlations between automatic and manual contours. The best results were obtained for the lungs (DSC 0.97, HD95 2.7 mm/2.9 mm for left/right lung), followed by heart (DSC 0.92, HD95 4.4 mm), bladder (DSC 0.88, HD95 6.7 mm) and rectum (DSC 0.79, HD95 10.8 mm). Visual inspection showed excellent agreements with some exceptions for heart and rectum. Conclusions The DI2IN algorithm automatically generated contours for organs at risk close to those by a human expert, making the contouring step in radiation treatment planning simpler and faster. Few cases still required manual corrections, mainly for heart and rectum.

Abstract Introduction Up to 30% of pancreatic cancer patients initially present locally advanced (LAPC). Stereotactic body radiation therapy (SBRT) may be an additional palliative treatment option when curative resection is no longer achievable. Our systematic review aimed to assess the effect of SBRT on the quality of life in LAPC. Methods We searched five databases until June 29th, 2021, for original articles that reported on SBRT for histologically proven LAPC in adults. Data were extracted on study characteristics, SBRT and additional therapy regimen, pain, biliary complications, nutrition, quality of life and other patient-reported outcomes. Statistical analyses were performed for population and survival data. Results 11 case series studies comprising 292 patients with a median age of 66 (range 34–89) years were included in the final analysis. The weighted average BED2;10 (radiation biologically effective dose, equivalent dose in 2 Gy fractions) was 54 Gy, delivered in 3 to 6 fractions. The individual studies used different scales and endpoints, not allowing a meta-analysis. Pain generally appeared to be improved by SBRT. SBRT significantly reduced jaundice. Local control was achieved in 71.7% of patients. Weight loss and nausea also tended to improve after SBRT. Conclusion SBRT of locally advanced irresectable pancreatic cancer is a promising approach for achieving local control and improving the quality of life. However, randomized controlled trials with larger cohorts are needed to assess the value of SBRT in pancreatic cancer therapy.

Abstract Background Inherent resistance to radio/chemotherapy is one of the major reasons for early recurrence, treatment failure, and dismal prognosis of glioblastoma. Thus, the identification of resistance driving regulators as prognostic and/or predictive markers as well as potential vulnerabilities for combined modality treatment approaches is of pivotal importance. Methods We performed an integrative analysis of treatment resistance and DNA damage response regulator expression in a panel of human glioblastoma cell lines. mRNA expression levels of 38 DNA damage response regulators were analyzed by qRT-PCR. Inherent resistance to radiotherapy (single-shot and fractionated mode) and/or temozolomide treatment was assessed by clonogenic survival assays. Resistance scores were extracted by dimensionality reduction and subjected to correlation analyses with the mRNA expression data. Top-hit candidates with positive correlation coefficients were validated by pharmacological inhibition in clonogenic survival assays and DNA repair analyses via residual γH2AX/53BP1-foci staining. Results Inherent resistance to single-shot and similarly also to fractionated radiotherapy showed strong positive correlations with mRNA expression levels of known vulnerabilities of GBM, including PARP1, NBN, and BLM, as well as ATR and LIG4—two so far underestimated targets. Inhibition of ATR by AZD-6738 resulted in robust and dose-dependent radiosensitization of glioblastoma cells, whereas LIG4 inhibition by L189 had no noticeable impact. Resistance against temozolomide showed strong positive correlation with mRNA expression levels of MGMT as to be expected. Interestingly, it also correlated with mRNA expression levels of ATM, suggesting a potential role of ATM in the context of temozolomide resistance in glioblastoma cells. ATM inhibition exhibited slight sensitization effects towards temozolomide treatment in MGMT low expressing glioblastoma cells, thus encouraging further characterization. Conclusions Here, we describe a systematic approach integrating clonogenic survival data with mRNA expression data of DNA damage response regulators in human glioblastoma cell lines to identify markers of inherent therapy resistance and potential vulnerabilities for targeted sensitization. Our results provide proof-of-concept for the feasibility of this approach, including its limitations. We consider this strategy to be adaptable to other cancer entities as well as other molecular data qualities, and its upscaling potential in terms of model systems and observational data levels deserves further investigation.

Abstract Background Hybrid magnetic resonance (MR)-Linac systems have recently been introduced into clinical practice. The systems allow online adaption of the treatment plan with the aim of compensating for interfractional anatomical changes. The aim of this study was to evaluate the dose volume histogram (DVH)-based dosimetric benefits of online adaptive MR-guided radiotherapy (oMRgRT) across different tumor entities and to investigate which subgroup of plans improved the most from adaption. Methods Fifty patients treated with oMRgRT for five different tumor entities (liver, lung, multiple abdominal lymph nodes, pancreas, and prostate) were included in this retrospective analysis. Various target volume (gross tumor volume GTV, clinical target volume CTV, and planning target volume PTV) and organs at risk (OAR) related DVH parameters were compared between the dose distributions before and after plan adaption. Results All subgroups clearly benefited from online plan adaption in terms of improved PTV coverage. For the liver, lung and abdominal lymph nodes cases, a consistent improvement in GTV coverage was found, while many fractions of the prostate subgroup showed acceptable CTV coverage even before plan adaption. The largest median improvements in GTV near-minimum dose (D98%) were found for the liver (6.3%, p

Abstract Introduction Online MR-guided radiotherapy (MRgRT) is a relatively novel advancement in the field of radiation oncology, ensuring superior soft-tissue visualisation, allowing for online plan adaptation to anatomical and functional interfractional changes and improved motion management. Platinum-based chemoradiation followed by durvalumab is the recommended treatment for stage IIB(N1)/III NSCLC. However, this is only the case for patients with favourable risk factors and sufficient pulmonary function and reserve. Methods Herein, we present a technical report on tumour motion and breathing curve analyses of the first patient with node-positive stage IIB NSCLC and severely compromised pulmonary function and reserve [total lung capacity (TLC) 8.78L/132% predicted, residual volume (RV) 6.35L/271% predicted, vital capacity (VC) max 2.43L/58% predicted, FEV1 1.19L/38% predicted, DLCO-SB corrected for hemoglobin 2.76 mmol/min/kPa/30% predicted] treated in a prospective observational study with moderately hypofractionated MRgRT to a total dose of 48.0 Gy/16 daily fractions on the MRIdian system (Viewray Inc, Oakwood, USA). Results Radiotherapy was well tolerated with no relevant toxicity. First follow-up imaging at 3 months post-radiotherapy showed a partial remission. The distinctive features of this case are the patient’s severely compromised pulmonary function and the first online MR-guided accelerated hypofractionated radiotherapy treatment for primary node-positive NSCLC. Conclusions This technical report describes the first patient treated in a prospective observational study evaluating the feasibility of this relatively novel technology in stage IIB(N1)/III disease, proposing a clinical pathway for the management of high-risk patients.

Abstract Background and purpose Chemoradiotherapy (CRT) followed by a brachytherapy (BT) boost is the standard of care for patients with locally advanced or recurrent gynecological cancer (LARGC). However, not every patient is suitable for BT. Therefore, we investigated the feasibility of an MR-guided SBRT boost (MRg-SBRT boost) following CRT of the pelvis. Material and methods Ten patients with LARGC were analyzed retrospectively. The patients were not suitable for BT due to extensive infiltration of the pelvic wall (10%), other adjacent organs (30%), or both (50%), or ineligibility for anesthesia (10%). Online-adaptive treatment planning was performed to control for interfractional anatomical changes. Treatment parameters and toxicity were evaluated to assess the feasibility of MRg-SBRT boost. Results MRg-SBRT boost was delivered to a median total dose of 21.0 Gy in 4 fractions. The median optimized PTV (PTVopt) size was 43.5ccm. The median cumulative dose of 73.6Gy10 was delivered to PTVopt. The cumulative median D2ccm of the rectum was 63.7 Gy; bladder 72.2 Gy; sigmoid 65.8 Gy; bowel 59.9 Gy (EQD23). The median overall treatment time/fraction was 77 min, including the adaptive workflow in 100% of fractions. The median duration of the entire treatment was 50 days. After a median follow-up of 9 months, we observed no CTCAE ≥ °II toxicities. Conclusion These early results report the feasibility of an MRg-SBRT boost approach in patients with LARGC, who were not candidates for BT. When classical BT-OAR constraints are followed, the therapy was well tolerated. Long-term follow-up is needed to validate the results.

Abstract Background The evaluation of automatic segmentation algorithms is commonly performed using geometric metrics. An analysis based on dosimetric parameters might be more relevant in clinical practice but is often lacking in the literature. The aim of this study was to investigate the impact of state-of-the-art 3D U-Net-generated organ delineations on dose optimization in radiation therapy (RT) for prostate cancer patients. Methods A database of 69 computed tomography images with prostate, bladder, and rectum delineations was used for single-label 3D U-Net training with dice similarity coefficient (DSC)-based loss. Volumetric modulated arc therapy (VMAT) plans have been generated for both manual and automatic segmentations with the same optimization settings. These were chosen to give consistent plans when applying perturbations to the manual segmentations. Contours were evaluated in terms of DSC, average and 95% Hausdorff distance (HD). Dose distributions were evaluated with the manual segmentation as reference using dose volume histogram (DVH) parameters and a 3%/3 mm gamma-criterion with 10% dose cut-off. A Pearson correlation coefficient between DSC and dosimetric metrics, i.e. gamma index and DVH parameters, has been calculated. Results 3D U-Net-based segmentation achieved a DSC of 0.87 (0.03) for prostate, 0.97 (0.01) for bladder and 0.89 (0.04) for rectum. The mean and 95% HD were below 1.6 (0.4) and below 5 (4) mm, respectively. The DVH parameters, V $$_{60/65/70\,{\mathrm{Gy}}}$$ 60 / 65 / 70 Gy for the bladder and V $$_{50/65/70\,{\mathrm{Gy}}}$$ 50 / 65 / 70 Gy for the rectum, showed agreement between dose distributions within $$\pm \, 5\%$$ ± 5 % and $$\pm \,2\%$$ ± 2 % , respectively. The D $$_{98/2\%}$$ 98 / 2 % and V $$_{95\%}$$ 95 % , for prostate and its 3 mm expansion (surrogate clinical target volume) showed agreement with the reference dose distribution within 2% and 3 Gy with the exception of one case. The average gamma pass-rate was 85%. The comparison between geometric and dosimetric metrics showed no strong statistically significant correlation. Conclusions The 3D U-Net developed for this work achieved state-of-the-art geometrical performance. Analysis based on clinically relevant DVH parameters of VMAT plans demonstrated neither excessive dose increase to OARs nor substantial under/over-dosage of the target in all but one case. Yet the gamma analysis indicated several cases with low pass rates. The study highlighted the importance of adding dosimetric analysis to the standard geometric evaluation.

Abstract Hybrid magnetic resonance (MR)-guided linear accelerators represent a new horizon in the field of radiation oncology. By harnessing the favorable combination of on-board MR-imaging with the possibility to daily recalculate the treatment plan based on real-time anatomy, the accuracy in target and organs-at-risk identification is expected to be improved, with the aim to provide the best tailored treatment. To date, two main MR-linac hybrid machines are available, Elekta Unity and Viewray MRIdian. Of note, compared to conventional linacs, these devices raise practical issues due to the positioning phase for the need to include the coil in the immobilization procedure and in order to perform the best reproducible positioning, also in light of the potentially longer treatment time. Given the relative novelty of this technology, there are few literature data regarding the procedures and the workflows for patient positioning and immobilization for MR-guided daily adaptive radiotherapy. In the present narrative review, we resume the currently available literature and provide an overview of the positioning and setup procedures for all the anatomical districts for hybrid MR-linac systems.

Abstract Background Multifocal manifestation of high-grade glioma is a rare disease with very unfavourable prognosis. The pathogenesis of multifocal glioma and pathophysiological differences to unifocal glioma are not fully understood. The optimal treatment of patients suffering from multifocal high-grade glioma is not defined in the current guidelines, therefore individual case series may be helpful as guidance for clinical decision-making. Methods Patients with multifocal high-grade glioma treated with conventionally fractionated radiation therapy (RT) in our institution with or without concomitant chemotherapy between April 2011 and April 2019 were retrospectively analysed. Multifocality was neuroradiologically assessed and defined as at least two independent contrast-enhancing foci in the MRI T1 contrast-enhanced sequence. IDH mutational status and MGMT methylation status were assessed from histopathology records. GTV, PTV as well as the V30Gy, V45Gy and D2% volumes of the brain were analysed. Overall and progression-free survival were calculated from the diagnosis until death and from start of radiation therapy until diagnosis of progression of disease in MRI for all patients. Results 20 multifocal glioma cases (18 IDH wild-type glioblastoma cases, one diffuse astrocytic glioma, IDH wild-type case with molecular features of glioblastoma and one anaplastic astrocytoma, IDH wild-type case) were included into the analysis. Resection was performed in two cases and stereotactic biopsy only in 18 cases before the start of radiation therapy. At the start of radiation therapy patients were 61 years old in median (range 42–84 years). Histopathological examination showed IDH wild-type in all cases and MGMT promotor methylation in 11 cases (55%). Prescription schedules were 60 Gy (2 Gy × 30), 59.4 Gy (1.8 Gy × 33), 55 Gy (2.2 Gy × 25) and 50 Gy (2.5 Gy × 20) in 15, three, one and one cases, respectively. Concomitant temozolomide chemotherapy was applied in 16 cases, combined temozolomide/lomustine chemotherapy was applied in one case and concomitant bevacizumab therapy in one case. Median number of GTVs was three. Median volume of the sum of the GTVs was 26 cm3. Median volume of the PTV was 425.7 cm3 and median PTV to brain ratio 32.8 percent. Median D2% of the brain was 61.5 Gy (range 51.2–62.7) and median V30Gy and V45 of the brain were 59.9 percent (range 33–79.7) and 40.7 percent (range 14.9–64.1), respectively. Median survival was eight months (95% KI 3.6–12.4 months) and median progression free survival after initiation of RT five months (95% CI 2.8–7.2 months). Grade 2 toxicities were detected in eight cases and grade 3 toxicities in four cases consisting of increasing edema in three cases and one new-onset seizure. One grade 4 toxicity was detected, which was febrile neutropenia related to concomitant chemotherapy. Conclusion Conventionally fractionated RT with concomitant chemotherapy could safely be applied in multifocal high-grade glioma in this case series despite large irradiation treatment fields.

Abstract Background The aim of this study was to evaluate and compare the performance of intensity modulated radiation therapy (IMRT) plans, planned for low-field strength magnetic resonance (MR) guided linear accelerator (linac) delivery (labelled IMRT MRL plans), and clinical conventional volumetric modulated arc therapy (VMAT) plans, for the treatment of prostate cancer (PCa). Both plans used the original planning target volume (PTV) margins. Additionally, the potential dosimetric benefits of MR-guidance were estimated, by creating IMRT MRL plans using smaller PTV margins. Materials and methods 20 PCa patients previously treated with conventional VMAT were considered. For each patient, two different IMRT MRL plans using the low-field MR-linac treatment planning system were created: one with original (orig.) PTV margins and the other with reduced (red.) PTV margins. Dose indices related to target coverage, as well as dose-volume histogram (DVH) parameters for the target and organs at risk (OAR) were compared. Additionally, the estimated treatment delivery times and the number of monitor units (MU) of each plan were evaluated. Results The dose distribution in the high dose region and the target volume DVH parameters (D98%, D50%, D2% and V95%) were similar for all three types of treatment plans, with deviations below 1% in most cases. Both IMRT MRL plans (orig. and red. PTV margins) showed similar homogeneity indices (HI), however worse values for the conformity index (CI) were also found when compared to VMAT. The IMRT MRL plans showed similar OAR sparing when the orig. PTV margins were used but a significantly better sparing was feasible when red. PTV margins were applied. Higher number of MU and longer predicted treatment delivery times were seen for both IMRT MRL plans. Conclusions A comparable plan quality between VMAT and IMRT MRL plans was achieved, when applying the same PTV margin. However, online MR-guided adaptive radiotherapy allows for a reduction of PTV margins. With a red. PTV margin, better sparing of the surrounding tissues can be achieved, while maintaining adequate target coverage. Nonetheless, longer treatment delivery times, characteristic for the IMRT technique, have to be expected.

Abstract Background The aim of this work was to investigate the outcome of metastasis-directed radiotherapy (MDT) in prostate cancer patients with bone metastases following current ESTRO/EORTC subclassifications for oligometastatic disease. Methods Clinical data of 80 consecutive oligometastatic patients with 115 bone lesions receiving MDT between 2011 and 2019 were retrospectively evaluated. Hormone-sensitive (77.5%) and castrate-resistant (22.5%) patients were included. MDT was delivered with conventional fractionated or stereotactic body radiotherapy (SBRT) techniques. Kaplan–Meier method, log rank test, as well as Cox regression were used to calculate local control (LC) and biochemical and clinical progression-free survival (bPFS/cPFS). Results At the time of MDT 31% of patients had de-novo synchronous oligometastatic disease, 46% had de-novo metachronous oligorecurrence after primary treatment and 23% had either de-novo oligoprogressive disease, repeat oligometastatic disease or induced oligometastatic disease. The median BED3 was 93.3 Gy (range 75.8–95.3 Gy). Concomitant ADT was administered in 69% of patients. After a median follow-up of 23 months the median bPFS and cPFS were 16.5 and 21.5 months, respectively. The 2-year LC rate was 98.3%. In multivariate analysis, age ≤ 70 (HR = 2.60, 95% CI 1.20–5.62, p = 0.015) and concomitant ADT (HR = 0.26, 95% CI 0.12–0.58, p = 0.001) significantly correlated with cPFS. Category of oligometastatic disease and hormone-sensitivity were predictive for cPFS in univariate analysis. Of 45 patients with biochemical relapse, nineteen patients (42.2%) had repeat oligometastatic disease. Fourteen patients (31%) underwent a second course of MDT. No patients experienced grade ≥ 3 toxicities. Conclusions MDT is safe and offers high local control rates in bone oligometastases of prostate cancer. At 2 years after treatment, more than 2 out of 5 patients are progression-free. Trial registration Retrospectively registered.

Abstract Background In unresectable hepatocellular carcinoma several local ablative treatments are available. Among others, radiation based treatments such as stereotactic body radiotherapy (SBRT) and high-dose rate interstitial brachytherapy (HDR BT) have shown good local control rates. Methods We conducted a dose comparison between actually performed HDR BT versus virtually planned SBRT to evaluate the respective clinically relevant radiation exposure to uninvolved liver tissue. Moreover, dose coverage and conformity indices were assessed. Results Overall, 46 treatment sessions (71 lesions, 38 patients) were evaluated. HDR BT was applied in a single fraction with a dose prescription of 1 × 15 Gy. D98 was 17.9 ± 1.3 Gy, D50 was 41.8 ± 8.1 Gy. The SBRT was planned with a prescribed dose of 3 × 12.5 Gy (65%-Isodose), D98 was 50.7 ± 3.1 Gy, D2 was 57.0 ± 2.3 Gy, and D50 was 55.2 ± 2.3 Gy. Regarding liver exposure Vliver10GyBT was compared to Vliver15.9GySBRT, Vliver16.2GySBRT (EQD2 equivalent doses), and Vliver20GySBRT (clinically relevant dose), all results showed significant differences (p

Abstract Despite complete surgical resection brain metastases are at significant risk of local recurrence without additional radiation therapy. Traditionally, the addition of postoperative whole brain radiotherapy (WBRT) has been considered the standard of care on the basis of randomized studies demonstrating its efficacy in reducing the risk of recurrence in the surgical bed as well as the incidence of new distant metastases. More recently, postoperative stereotactic radiosurgery (SRS) to the surgical bed has emerged as an effective and safe treatment option for resected brain metastases. Published randomized trials have demonstrated that postoperative SRS to the resection cavity provides superior local control compared to surgery alone, and significantly decreases the risk of neurocognitive decline compared to WBRT, without detrimental effects on survival. While studies support the use of postoperative SRS to the resection cavity as the standard of care after surgery, there are several issues that need to be investigated further with the aim of improving local control and reducing the risk of leptomeningeal disease and radiation necrosis, including the optimal dose prescription/fractionation, the timing of postoperative SRS treatment, and surgical cavity target delineation. We provide a clinical overview on current status and recent advances in resection cavity irradiation of brain metastases, focusing on relevant strategies that can improve local control and minimize the risk of radiation-induced toxicity.

Abstract Background Due to improved imaging sensitivity, the term “oligometastatic” prostate cancer disease is diagnosed more often, leading to an increasing interest in metastasis-directed therapy (MDT). There are two types of radiation based MDT applied when treating oligometastatic disease: (1) stereotactic body radiation therapy (SBRT) generally used for bone metastases; or (2) SBRT for isolated nodal oligometastases combined with prophylactic elective nodal radiotherapy. This review aims to summarize current evidence data, which may shed light on the optimal management of this heterogeneous group of patients. Methods A systematic review of the Medline database through PubMed was performed according to PRISMA guidelines. All relevant studies published up to November 2020 were identified and screened. Fifty-six titles were included. Besides outcome parameters, different prognostic and predictive factors were assessed, including site of metastases, time between primary treatment and MDT, use of systemic therapies, hormone sensitivity, as well as pattern of recurrence. Findings Evidence consists largely of retrospective case series and no consistent precise definition of oligometastasis exists, however, most investigators seem to acknowledge the need to distinguish between patients presenting with what is frequently called “synchronous” versus “metachronous” oligometastatic disease. Available data on radiotherapy as MDT demonstrate high local control rates and a small but relevant proportion of patients without progressive disease after 2 years. This holds true for both hormone sensitive and castration resistant prostate cancer diseases. The use of 68Ga-PSMA PET/CT for staging increased dramatically. Radiation doses and field sizes varied considerably among the studies. The search for relevant prognostic and predictive factors is ongoing. Conclusions To our best knowledge this review on oligometastatic prostate cancer included the largest number of original articles. It demonstrates the therapeutic potential and challenges of MDT for oligometastatic prostate cancer. Prospective studies are under way and will provide further high-level evidence.

Abstract Future radiation oncology encompasses a broad spectrum of topics ranging from modern clinical trial design to treatment and imaging technology and biology. In more detail, the application of hybrid MRI devices in modern image-guided radiotherapy; the emerging field of radiomics; the role of molecular imaging using positron emission tomography and its integration into clinical routine; radiation biology with its future perspectives, the role of molecular signatures in prognostic modelling; as well as special treatment modalities such as brachytherapy or proton beam therapy are areas of rapid development. More clinically, radiation oncology will certainly find an important role in the management of oligometastasis. The treatment spectrum will also be widened by the rational integration of modern systemic targeted or immune therapies into multimodal treatment strategies. All these developments will require a concise rethinking of clinical trial design. This article reviews the current status and the potential developments in the field of radiation oncology as discussed by a panel of European and international experts sharing their vision during the “X-Change” symposium, held in July 2019 in Munich (Germany).

Abstract Despite aggressive management consisting of maximal safe surgical resection followed by external beam radiation therapy (60 Gy/30 fractions) with concomitant and adjuvant temozolomide, approximately 90% of WHO grade IV gliomas (glioblastomas, GBM) will recur locally within 2 years. For patients with recurrent GBM, no standard of care exists. Thanks to the continuous improvement in radiation science and technology, reirradiation has emerged as feasible approach for patients with brain tumors. Using stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT), either hypofractionated or conventionally fractionated schedules, several studies have suggested survival benefits following reirradiation of patients with recurrent GBM; however, there are still questions to be answered about the efficacy and toxicity associated with a second course of radiation. We provide a clinical overview on current status and recent advances in reirradiation of GBM, addressing relevant clinical questions such as the appropriate patient selection and radiation technique, optimal dose fractionation, reirradiation tolerance of the brain and the risk of radiation necrosis.

Abstract Purpose Frequency and risk profile of radiation necrosis (RN) in patients with glioma undergoing either upfront stereotactic brachytherapy (SBT) and additional salvage external beam radiotherapy (EBRT) after tumor recurrence or vice versa remains unknown. Methods Patients with glioma treated with low-activity temporary iodine-125 SBT at the University of Munich between 1999 and 2016 who had either additional upfront or salvage EBRT were included. Biologically effective doses (BED) were calculated. RN was diagnosed using stereotactic biopsy and/or metabolic imaging. The rate of RN was estimated with the Kaplan Meier method. Risk factors were obtained from logistic regression models. Results Eighty-six patients (49 male, 37 female, median age 47 years) were included. 38 patients suffered from low-grade and 48 from high-grade glioma. Median follow-up was 15 months after second treatment. Fifty-eight patients received upfront EBRT (median total dose: 60 Gy), and 28 upfront SBT (median reference dose: 54 Gy, median dose rate: 10.0 cGy/h). Median time interval between treatments was 19 months. RN was diagnosed in 8/75 patients. The 1- and 2-year risk of RN was 5.1% and 11.7%, respectively. Tumor volume and irradiation time of SBT, number of implanted seeds, and salvage EBRT were risk factors for RN. Neither of the BED values nor the time interval between both treatments gained prognostic influence. Conclusion The combination of upfront EBRT and salvage SBT or vice versa is feasible for glioma patients. The risk of RN is mainly determined by the treatment volume but not by the interval between therapies.

Abstract Background This long-term retrospective analysis aimed to investigate the outcome and toxicity profile of stereotactic brachytherapy (SBT) in selected low-grade gliomas WHO grade II (LGGII) in a large patient series. Methods This analysis comprised 106 consecutive patients who received SBT with temporary Iodine-125 seeds for histologically verified LGGII at the University of Munich between March 1997 and July 2011. Investigation included clinical characteristics, technical aspects of SBT, the application of other treatments, outcome analyses including malignization rates, and prognostic factors with special focus on molecular biomarkers. Results For the entire study population, the 5- and 10-years overall survival (OS) rates were 79% and 62%, respectively, with a median follow-up of 115.9 months. No prognostic factors could be identified. Interstitial radiotherapy was applied in 51 cases as first-line treatment with a median number of two seeds (range 1–5), and a median total implanted activity of 21.8 mCi (range 4.2–43.4). The reference dose average was 54.0 Gy. Five- and ten-years OS and progression-free survival rates after SBT were 72% and 43%, and 40% and 23%, respectively, with a median follow-up of 86.7 months. The procedure-related mortality rate was zero, although an overall complication rate of 16% was registered. Patients with complications had a significantly larger tumor volume (p = 0.029). Conclusion SBT is a minimally invasive treatment modality with a favorable outcome and toxicity profile. It is both an alternative primary treatment method as well as an adjunct to open tumor resection in selected low-grade gliomas.

Abstract Background Head and neck squamous cell cancer (HNSCC) frequently causes severe symptoms that may be reduced, when the tumor is successfully treated. The SOCCER trial studied the association of treatment response with patient reported tumor symptom burden in first line treatment of recurrent and/or metastatic HNSCC. Methods In this prospective, multi-center, non-interventional trial patients were treated either with platinum-based chemotherapy and cetuximab or radiotherapy and cetuximab. Tumor symptom burden was assessed every four weeks with a questionnaire containing ten visual analogue scales (VAS, range 0–100), which were summarized to the overall VAS score. Results Fourhundred seventy patients were registered in 97 German centers. A total of 315 patients with at least the baseline and one subsequent questionnaire were available for analysis. Changes in the VAS score were rated as absolute differences from baseline. Negative values indicate improvement of symptoms. The overall VAS score improved significantly at the first post-baseline assessment in responders (− 2.13 vs. non-responders + 1.15, p = 0.048), and even more for the best post-baseline assessment (− 7.82 vs. non-responders − 1.97, p = 0.0005). The VAS for pain (− 16.37 vs. non-responders − 8.89, p = 0.001) and swallowing of solid food (− 16.67 vs. non-responders − 5.06, p = 0.002) improved significantly more in responders (best post-baseline assessment). In the multivariable Cox regression analysis, worse overall VAS scores were associated with worse overall survival (hazard ratio for death 1.12 per 10 points increment on the overall VAS scale, 95% CI 1.05–1.20, p = 0.0009). Conclusion In unselected patients beyond randomized controlled trials, treatment response lowers tumor symptom burden in recurrent and/or metastatic HNSCC. Trial registration ClinicalTrials.gov, NCT00122460 . Registered 22 Juli 2005,

Abstract Background and purpose To report on our clinical experience with a newly implemented workflow for radiotherapy (RT) emergency treatments, which allows for a fast treatment application outside the regular working-hours, and its clinical applicability. Methods Treatment planning of 18 emergency RT patients was carried out using diagnostic computed tomography (CT) without a dedicated RT simulation CT. The cone-beam CT (CBCT) deviations of the first RT treatment were analyzed regarding setup accuracy. Furthermore, feasibility of the “fast-track” workflow was evaluated with respect to dose deviations caused by different Hounsfield unit (HU) to relative electron density (rED) calibrations and RT treatment couch surface shapes via 3D gamma index analysis of exemplary treatment plans. The dosimetric uncertainty introduced by different CT calibrations was quantified. Results Mean patient setup vs. CBCT isocenter deviations were (0.49 ± 0.44) cm (x), (2.68 ± 1.63) cm (y) and (1.80 ± 1.06) cm (z) for lateral, longitudinal and vertical directions, respectively. Three out of four dose comparisons between the emergency RT plan calculated on the diagnostic CT and the same plan calculated on the treatment planning CT showed clinically acceptable gamma passing rates, when correcting for surface artifacts. The maximum difference of rED was 0.054, while most parts of the CT calibration curves coincided well. Conclusion In an emergency RT setting, the use of diagnostic CT data for treatment planning might be time-saving and was shown to be suitable for many cases, considering reproducibility of patient setup, accuracy of initial patient setup and accuracy of dose-calculation.

Abstract Lung, breast, and esophageal cancer represent three common malignancies with high incidence and mortality worldwide. The management of these tumors critically relies on radiotherapy as a major part of multi-modality care, and treatment-related toxicities, such as radiation-induced pneumonitis and/or lung fibrosis, are important dose limiting factors with direct impact on patient outcomes and quality of life. In this review, we summarize the current understanding of radiation-induced pneumonitis and pulmonary fibrosis, present predictive factors as well as recent diagnostic and therapeutic advances. Novel candidates for molecularly targeted approaches to prevent and/or treat radiation-induced pneumonitis and pulmonary fibrosis are discussed.

Abstract Background Starting in December 2019, the current pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) confronts the world with an unprecedented challenge. With no vaccine or drug being currently available to control the pandemic spread, prevention and PCR (Polymerase chain reaction) testing becomes a crucial pillar of medical systems. Aim of the present study was to report on the first results of the measures taken in a large German Department of Radiation Oncology, including PCR testing of asymptomatic cancer patients. Methods Pandemic-adapted hygiene regulations and prevention measures for patients and staff were implemented. A visiting ban on both wards was implemented from the beginning and medical staff and patients were required to wear face masks at all times. The waiting rooms were rearranged to ensure distance between patients of at least 1.5 m. Clinical follow up was mainly done by telephone and all patients had to complete a questionnaire regarding symptoms and contacts with COVID-19 patients before entering our department. Educational documents were created for patients to raise awareness of symptoms and avoidance strategies for interactions with other people. Indications for therapy and fractionation schemes were adapted when possible. In a subsequent step, all new asymptomatic patients were tested via nasopharyngeal swab at our screening station shortly before their simulation CT. Results All these measures and implementations have been well accepted semiquantitatively measured by the consent received from patients and staff. Regarding the PCR testing, only 1 out of 139 asymptomatic patients of our cohort so far tested positive for SARS-CoV-2, reflecting a prevalence of 0.72% in this cancer patient population. Up to this point no staff members was tested positive. The start of the treatment for the PCR-positive patient was deferred for 2 weeks. Conclusion Due to the pandemic-adapted implementations, our department seems well prepared during this crisis. The initial screening helps to identify asymptomatic COVID-19 patients in order to protect other patients and our staff from infection and the observed PCR prevalence is in line with comparable studies. A regular PCR testing (e.g. twice a week) of all patients and staff would in principle be desirable but is limited due to testing capacities at present.

Abstract Immune-checkpoint inhibitors (ICI) have dramatically changed the landscape of lung cancer treatment. Preclinical studies investigating combination of ICI with radiation show a synergistic improvement of tumor control probability and have resulted in the development of novel therapeutic strategies. For advanced non-small cell lung cancer (NSCLC), targeting immune checkpoint pathways has proven to be less toxic with more durable treatment response than conventional chemotherapy. In inoperable Stage III NSCLC, consolidation immune checkpoint inhibition with the PD-L1 inhibitor durvalumab after completion of concurrent platinum-based chemoradiotherapy resulted in remarkable improvement of progression-free and overall survival. This new tri-modal therapy has become a new treatment standard. Development of predictive biomarkers and improvement of patient selection and monitoring is the next step in order to identify patients most likely to derive maximal benefit from this new multimodal approach. In this review, we discuss the immunological rationale and current trials investigating chemoradioimmunotherapy for inoperable stage III NSCLC.

Abstract Background Loco-regional and distant failure are common in inoperable stage III non small-cell lung cancer (NSCLC) after chemoradiotherapy (CRT). However, there is limited real-world data on failure pattern, patient prognosis and salvage options. Methods We analysed 99 consecutive patients with inoperable stage III NSCLC treated with CRT between 2011 and 2016. Follow up CT scans from date of the first-site failure were matched with the delivered radiation treatment plans. Intra-thoracic loco-regional relapse was defined as in-field (IFR) vs. out-of-field recurrence (OFR) [in- vs. outside 50Gy isodose line in the involved lung], respectively. Extracranial distant (DMs) and brain metastases (BMs) as first site of recurrence were also evaluated. Using the Kaplan-Meier method, impact of salvage surgery (sS), radiotherapy (sRT), chemotherapy (sCT) and immunotherapy (sIO) on patient survival was assessed. Results Median follow-up was 60.0 months. Median PFS from the end of CRT for the entire cohort was 7.5 (95% CI: 6.0–9.0 months) months. Twenty-six (26%) and 25 (25%) patients developed IFR and OFR. Median time to diagnosis of IFR and OFR was 7.2 and 6.2 months. In the entire cohort, onset of IFR and OFR did not influence patient outcome. However, in 73 (74%) patients who survived longer than 12 months after initial diagnosis, IFR was a significant negative prognostic factor with a median survival of 19.3 vs 40.0 months (p

Abstract Background Prognostic models based on high-dimensional omics data generated from clinical patient samples, such as tumor tissues or biopsies, are increasingly used for prognosis of radio-therapeutic success. The model development process requires two independent discovery and validation data sets. Each of them may contain samples collected in a single center or a collection of samples from multiple centers. Multi-center data tend to be more heterogeneous than single-center data but are less affected by potential site-specific biases. Optimal use of limited data resources for discovery and validation with respect to the expected success of a study requires dispassionate, objective decision-making. In this work, we addressed the impact of the choice of single-center and multi-center data as discovery and validation data sets, and assessed how this impact depends on the three data characteristics signal strength, number of informative features and sample size. Methods We set up a simulation study to quantify the predictive performance of a model trained and validated on different combinations of in silico single-center and multi-center data. The standard bioinformatical analysis workflow of batch correction, feature selection and parameter estimation was emulated. For the determination of model quality, four measures were used: false discovery rate, prediction error, chance of successful validation (significant correlation of predicted and true validation data outcome) and model calibration. Results In agreement with literature about generalizability of signatures, prognostic models fitted to multi-center data consistently outperformed their single-center counterparts when the prediction error was the quality criterion of interest. However, for low signal strengths and small sample sizes, single-center discovery sets showed superior performance with respect to false discovery rate and chance of successful validation. Conclusions With regard to decision making, this simulation study underlines the importance of study aims being defined precisely a priori. Minimization of the prediction error requires multi-center discovery data, whereas single-center data are preferable with respect to false discovery rate and chance of successful validation when the expected signal or sample size is low. In contrast, the choice of validation data solely affects the quality of the estimator of the prediction error, which was more precise on multi-center validation data.

Abstract Background Patients with left-sided breast cancer have an increased risk of cardiovascular disease (CVD) after radiotherapy (RT). While the awareness of cardiac toxicity has increased enormously over the last decade, the role of individual baseline cardiac risks has not yet been systematically investigated. Aim of the present study was to evaluate the impact of baseline CVD risks on radiation-induced cardiac toxicity. Methods Two hundred ten patients with left-sided breast cancer treated in the prospective Save-Heart Study using a deep inspiration breath-hold (DIBH) technique were analysed regarding baseline risk factors for CVD. Three frequently used prediction tools (Procam, Framingham and Reynolds score) were applied to evaluate the individual CVD risk profiles. Moreover, 10-year CVD excess absolute risks (EAR) were estimated using the individual mean heart dose (MHD) of treatment plans in free breathing (FB) and DIBH. Results The individual baseline CVD risk factors had a strong impact on the 10-year cumulative CVD risk. The mean baseline risks of the non-diabetic cohort (n = 200) ranged from 3.11 to 3.58%, depending on the risk estimation tool. A large number of the non-diabetic patients had a very low 10-year CVD baseline risk of ≤1%; nevertheless, 8–9% of patients reached ≥10% baseline 10-year CVD risk. In contrast, diabetic patients (n = 10) had significantly higher baseline CVD risks (range: 11.76–24.23%). The mean 10-year cumulative risk (Framingham score) following RT was 3.73% using the DIBH-technique (MHD:1.42Gy) and 3.94% in FB (MHD:2.33Gy), after adding a 10-year-EAR of + 0.34%(DIBH) and + 0.55%(FB) to the baseline risks, respectively. Smoking status was one of the most important and modifiable baseline risk factors. After DIBH-RT, the 182 non-smoking patients had a mean 10-year cumulative risk of 3.55% (3.20% baseline risk, 0.35% EAR) as compared to 6.07% (5.60% baseline risk, 0.47% EAR) for the 28 smokers. Conclusion In the present study, all CVD prediction tools showed comparable results and could easily be integrated into daily clinical practice. A systematic evaluation and screening helps to identify high-risk patients who may benefit from primary prevention. This could result in an even higher benefit than from heart-sparing irradiation techniques alone.

Abstract Background A substantial number of patients will develop further biochemical progression after radical prostatectomy (RP) and salvage radiotherapy (sRT). Recently published data using prostate-specific membrane antigen ligand positron emission tomography (PSMA - PET) for re-staging suggest that those recurrences are often located outside the prostate fossa and most of the patients have a limited number of metastases, making them amenable to metastasis-directed treatment (MDT). Methods We analyzed 78 patients with biochemical progression after RP and sRT from a retrospective European multicenter database and assessed the biochemical recurrence-free survival (bRFS; PSA

Abstract The COVID-19 pandemic is challenging modern radiation oncology. At University Hospitals, we have a mandate to offer high-end treatments to all cancer patients. However, in times of crisis we must learn to prioritize resources, especially personnel. Compromising oncological outcome will blur all statistics, therefore all measures must be taken with great caution. Communication with our neighboring countries, within societies and between departments can help meet the challenge. Here, we report on our learning system and preparation measures to effectively tackle the COVID-19 challenge in University-Based Radiation Oncology Departments.

Abstract Purpose To compare treatment plans for interstitial high dose rate (HDR) liver brachytherapy with 192Ir calculated according to current-standard TG-43U1 protocol with model-based dose calculation following TG-186 protocol. Methods We retrospectively evaluated dose volume histogram (DVH) parameters for liver, organs at risk (OARs) and clinical target volumes (CTVs) of 20 patient cases diagnosed with hepatocellular carcinoma (HCC) or metastatic colorectal cancer (mCRC). Dose calculations on a homogeneous water geometry (TG-43U1 surrogate) and on a computed tomography (CT) based geometry (TG-186) were performed using Monte Carlo (MC) simulations. The CTs were segmented based on a combination of assigning TG-186 recommended tissues to fixed Hounsfield Unit (HU) ranges and using organ contours delineated by physicians. For the liver, V 5Gy and V 10Gy were analysed, and for OARs the dose to 1 cubic centimeter (D 1cc). Target coverage was assessed by calculating V 150, V 100, V 95 and V 90 as well as D 95 and D 90. For every DVH parameter, median, minimum and maximum values of the deviations of TG-186 from TG-43U1 were analysed. Results TG-186-calculated dose was found to be on average lower than dose calculated with TG-43U1. The deviation of highest magnitude for liver parameters was -6.2% of the total liver volume. For OARs, the deviations were all smaller than or equal to -0.5 Gy. Target coverage deviations were as high as -1.5% of the total CTV volume and -3.5% of the prescribed dose. Conclusions In this study we found that TG-43U1 overestimates dose to liver tissue compared to TG-186. This finding may be of clinical importance for cases where dose to the whole liver is the limiting factor.

Abstract Background There is limited data on the use of targeted or immunotherapy (TT/IT) in combination with single fraction stereotactic radiosurgery (SRS) in patients with melanoma brain metastasis (MBM). Therefore, we analyzed the outcome and toxicity of SRS alone compared to SRS in combination with TT/IT. Methods Patients with MBM treated with single session SRS at our department between 2014 and 2017 with a minimum follow-up of 3 months after first SRS were included. The primary endpoint of this study was local control (LC). Secondary endpoints were distant intracranial control, radiation necrosis-free survival (RNFS), and overall survival (OS). The local/ distant intracranial control rates, RNFS and OS were analyzed using the Kaplan-Meier method. The log-rank test was used to test differences between groups. Cox proportional hazard model was performed for univariate continuous variables and multivariate analyses. Results Twenty-eight patients (17 male and 11 female) with 52 SRS-lesions were included. The median follow-up was 19 months (range 14–24 months) after first SRS. Thirty-six lesions (69.2%) were treated with TT/IT simultaneously (4 weeks before and 4 weeks after SRS), while 16 lesions (30.8%) were treated with SRS alone or with sequential TT/IT. The 1-year local control rate was 100 and 83.3% for SRS with TT/IT and SRS alone (p = 0.023), respectively. The estimated 1-year RNFS was 90.0 and 82.1% for SRS in combination with TT/IT and SRS alone (p = 0.935). The distant intracranial control rate after 1 year was 47.7 and 50% for SRS in combination with TT/IT and SRS alone (p = 0.933). On univariate analysis, the diagnosis-specific Graded Prognostic Assessment including the BRAF status (Melanoma-molGPA) was associated with a significantly improved LC. Neither gender nor SRS-PTV margin had a prognostic impact on LC. V10 and V12 were significantly associated with RNFS (p

Abstract Background Three-dimensional Surface Imaging (3DSI) is a well-established method to objectively monitor morphological changes in the female breast in the field of plastic surgery. In contrast, in radiation oncology we are still missing effective tools, which can objectively and reproducibly assess and document adverse events in breast cancer radiotherapy within the framework of clinical studies. The aim of the present study was to apply structured-light technology as a non-invasive and objective approach for the documentation of cosmetic outcome and early effects of breast radiotherapy as a proof of principle. Methods Weekly 3DSI images of patients receiving either conventionally fractionated radiation treatment (CF-RT) or hypofractionated radiation treatment (HF-RT) were acquired during the radiotherapy treatment and clinical follow-up. The portable Artec Eva scanner (Artec 3D Inc., Luxembourg) recorded 3D surface images for the analysis of breast volumes and changes in skin appearance. Statistical analysis compared the impact of the two different fractionation regimens and the differences between the treated and the contralateral healthy breast. Results Overall, 38 patients and a total of 214 breast imaging sessions were analysed. Patients receiving CF-RT showed a significantly higher frequency of breast erythema compared to HF-RT (93.3% versus 34.8%, p = 0.003) during all observed imaging sessions. Moreover, we found a statistically significant (p

Abstract Background/aim mmune checkpoint inhibition (CPI) has an increasing impact in the multimodal treatment of locally advanced non-small cell lung cancer (LA-NSCLC). Increasing evidence suggests treatment outcome depending on tumor cell PD-L1 expression. The purpose of this retrospective study was to investigate the prognostic value of PD-L1 expression on tumor cells in combination with CD8+ tumor stroma-infiltrating lymphocyte (TIL) density in inoperable LA-NSCLC treated with concurrent chemoradiotherapy (CRT). Patients and method We retrospectively assessed clinical characteristics and initial tumor biopsy samples of 31 inoperable LA-NSCLC patients treated with concurrent CRT. Prognostic impact of tumor cell PD-L1 expression (0% versus ≥1%) and CD8+ TIL density (0–40% vs. 41–100%) for local control, progression-free (PFS) and overall survival (OS) as well as correlations with clinicopathological features were evaluated. Results Median OS was 14 months (range: 3–167 months). The OS rates at 1- and 2 years were 68 and 20%. Local control of the entire cohort at 1 and 2 years were 74 and 61%. Median PFS, 1-year and 2-year PFS were 13 ± 1.4 months, 58 and 19%. PD-L1 expression

Abstract Background Definitive chemoradiotherapy (dCRT) is a standard treatment for patients with locally advanced head and neck cancer. There is a clinical need for a stratification of this prognostically heterogeneous group of tumors in order to optimize treatment of individual patients. We retrospectively reviewed all patients with head and neck squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, hypopharynx, or larynx, treated with dCRT from 09/2008 until 03/2016 at the Department of Radiation Oncology, LMU Munich. Here we report the clinical results of the cohort which represent the basis for biomarker discovery and molecular genetic research within the framework of a clinical cooperation group. Methods Patient data were collected and analyzed for outcome and treatment failures with regard to previously described and established risk factors. Results We identified 184 patients with a median follow-up of 65 months and a median age of 64 years. Patients received dCRT with a median dose of 70 Gy and simultaneous chemotherapy in 90.2% of cases, mostly mitomycin C / 5-FU in concordance with the ARO 95–06 trial. The actuarial 3-year overall survival (OS), local, locoregional and distant failure rates were 42.7, 29.8, 34.0 and 23.4%, respectively. Human papillomavirus-associated oropharynx cancer (HPVOPC) and smaller gross tumor volume were associated with significantly improved locoregional tumor control rate, disease-free survival (DFS) and OS in multivariate analysis. Additionally, lower hemoglobin levels were significantly associated with impaired DFS und OS in univariate analysis. The extent of lymph node involvement was associated with distant failure, DFS and OS. Moreover, 92 patients (50%) of our cohort have been treated in concordance with the ARO 95–06 study, corroborating the results of this study. Conclusion Our cohort is a large unselected monocentric cohort of HNSCC patients treated with dCRT. Tumor control rates and survival rates compare favorably with the results of previously published reports. The clinical data, together with the available tumor samples from biopsies, will allow translational research based on molecular genetic analyses.

Abstract Background Despite aggressive treatment regimens comprising surgery and radiochemotherapy, glioblastoma (GBM) remains a cancer entity with very poor prognosis. The development of novel, combined modality approaches necessitates adequate preclinical model systems and therapy regimens that closely reflect the clinical situation. So far, image-guided, fractionated radiotherapy of orthotopic GBM models represents a major limitation in this regard. Methods GL261 mouse GBM cells were inoculated into the right hemispheres of C57BL/6 mice. Tumor growth was monitored by contrast-enhanced conebeam CT (CBCT) scans. When reaching an average volume of approximately 7 mm3, GBM tumors were irradiated with daily fractions of 2 Gy up to a cumulative dose of 20 Gy in different beam collimation settings. For treatment planning and tumor volume follow-up, contrast-enhanced CBCT scans were performed twice per week. Daily repositioning of animals was achieved by alignment of bony structures in native CBCT scans. When showing neurological symptoms, mice were sacrificed by cardiac perfusion. Brains, livers, and kidneys were processed into histologic sections. Potential toxic effects of contrast agent administration were assessed by measurement of liver enzyme and creatinine serum levels and by histologic examination. Results Tumors were successfully visualized by contrast-enhanced CBCT scans with a detection limit of approximately 2 mm3, and treatment planning could be performed. For daily repositioning of the animals, alignment of bony structures in native CT scans was well feasible. Fractionated irradiation caused a significant delay in tumor growth translating into significantly prolonged survival in clear dependence of the beam collimation setting and margin size. Brain sections revealed tumors of similar appearance and volume on the day of euthanasia. Importantly, the repeated contrast agent injections were well tolerated, as liver enzyme and creatinine serum levels were only subclinically elevated, and liver and kidney sections displayed normal histomorphology. Conclusions Contrast-enhanced, CT-based, fractionated radiation of orthotopic mouse GBM represents a versatile preclinical technique for the development and evaluation of multimodal radiotherapeutic approaches in combination with novel therapeutic agents in order to accelerate translation into clinical testing.

Abstract Background Small inter- and intrafractional prostate motion was shown to be a prerequisite for precise radiotherapy (RT) of prostate cancer (PCa) to achieve good local control and low rectal toxicity. As rectal gas and rectal volume are known to have a relevant effect on prostate motion, this study aims to reduce these parameters by using a Low FODMAP Diet (LFD) and to show feasibility of this intervention. Methods We compared a prospective intervention group (IG, n = 25) which underwent RT for PCa and whose patients were asked to follow a LFD during RT with a retrospective control group (CG, n = 25) which did not get any dietary advice. In the planning CT scan and all available cone beam CT scans rectal gas was classified based on a semiquantitative score (scale from 1 to 5) and rectal volume was measured. Furthermore, patients’ compliance was evaluated by a self-assessment questionnaire. Results Clinical and treatment characteristics were well balanced between both groups. A total of 266 (CG, 10.6 per patient) and 280 CT scans (IG, 11.2 per patient), respectively, were analysed. The frequency distribution of gas scores differed significantly from each other (p

Abstract Background Volumetric Modulated Arc Therapy (VMAT) techniques have recently been implemented in clinical practice for total-body irradiation (TBI). To date, most techniques still use special couches, translational tables, or other self-made immobilization devices for dose delivery. Aim of the present study was to report the first results of a newly developed rotatable tabletop designed for VMAT-TBI. Methods The VMAT-TBI technique theoretically allows the use of any standard positioning device at the linear accelerator. Nevertheless, the main problem is that patients taller than 120 cm cannot be treated in one position due to the limited cranial-caudal couch shift capacities of the linac. Therefore, patients are usually turned from a head-first supine position (HFS) to a feet-first supine position (FFS) to overcome this limitation. The newly developed rotatable tabletop consists completely of carbon fiber, including the ball bearing within the base plate of the rotation unit. The patient can be turned 180° from a HFS to a FFS position within a few seconds, without the need of repositioning. Results The first 20 patients had a median age of 47 years, and received TBI before bone marrow transplantation for acute myeloid leukemia. Most patients (13/20) received a TBI dose of 4 Gy in 2 fractions, twice daily. The mean number of applied monitor units (MU) was 6476 MU using a multi-arcs and multi-isocenter VMAT-TBI technique. The tabletop has been successfully used in daily clinical practice and helped to keep the treatment times at an acceptable level. During the first treatment fraction, the mean overall treatment time (OTT) was 57 min. Since no additional image guidance was used in fraction 2 of the same day, the OTT was reduced to mean 38 min. Conclusions The easy and reproducible rotation of the patient on the treatment couch using the rotatable tabletop, is time-efficient and overcomes the need of repositioning the patient after turning from a HFS to a FFS position during VMAT TBI. Furthermore, it prevents couch-gantry collisions, incorrect isocenter shifts and beam mix-up due to predicted absolute table coordinates, which are recorded to the R + V system with the corresponding beams.

Abstract Objectives Postradiogenic wound healing disorders are an important clinical problem. While a variety of treatment modalities are available, there is no strategy to objectively judge treatment success. The aim of this study was to evaluate a 2D luminescence imaging system for pH and oxygen in non-healing wounds after radiotherapy. Methods Luminescence 2D imaging was performed with the VisiSens (Presens, Regensburg, Germany) 2D imaging systems A1 and A2 for oxygen and pH, respectively. Biocompatible planar luminescent sensor foils were applied to non-irradiated and irradiated skin as well as to radiogenic wounds of five patients and the pH and the oxygen saturation was determined. Results pH measurements showed significant differences between non-irradiated skin (6.46 ± 0.18) and irradiated skin (6.96 ± 0.26). Radiogenic wounds exhibited the highest pH values (7.53 ± 0.26). Oxygen measurements revealed a mean oxygen saturation of non-irradiated skin of 6.19 ± 0.83 mmHg. The highest value of oxygen saturation (28.4 ± 2.4 mmHg) was found on irradiated skin while irradiated wounds had a poor oxygen saturation (9.4 ± 2.2 mmHg) (mean ± s.e.m.). Conclusion We found that routine measurement of pH and pO2 in patients could be easily integrated into the clinical routine. The results of the measurements show unfavorable pH and oxygen saturation conditions for wound healing in irradiated wounds. Interestingly, irradiated wounds exhibit a more pronounced hypoxia than irradiated skin which is reflected by an altered pH and pO2 compared to unirradiated skin, which has the potential to serve as a prognostic marker in the future. In addition to the objectification of the treatment success of postradiogenic wound healing disorders, the extent of skin toxicity could already be predicted during radiotherapy with this method.

Abstract Background To determine the feasibility of PET/CT-based image-guided moderate hypofractionated thoracic irradiation (Hypo-IGRT) in locally advanced node-positive non-small cell lung cancer patients with highly compromised pulmonary function. Method Eight highly-selected and closely monitored patients with highly diminished pulmonary function (FEV1 ≤ 1.0 L and/or DLCO-SB ≤ 40% and/or on long-term oxygen therapy) were treated with Hypo-IGRT. Planning was based on 18F-FDG-PET/CT and 4D-CT in the treatment position. Hypo-IGRT was delivered to a total dose of 45 Gy (ICRU) in 15 daily fractions under strict image-guidance. Vital capacity (VC), forced expiratory volume in 1 s (FEV1), and single-breath diffusing capacity of the lung for CO (DLCO-SB) were analyzed prior to, 3 and 6 months after Hypo-IGRT. Result Eight patients with stage IIIA-C NSCLC (8th TNM Ed.) completed Hypo-IGRT. The median follow-up was 29.4 months. The median age was 64 years. Four, three and one patient(s) presented with COPD GOLD IV, III and II, respectively and 5 patients (63%) were on long-term oxygen therapy. The median PTV was 226.9 cc (range: 100.17–379.80 cc). Median PFS and OS were 19 and 34.3 months. The 6 months and 1-year OS rates were 100, 87.5%, respectively. The 6- and 12- months PFS rates were 87.5 and 52.5%. Three patients developed local failure. Median initial VC, FEV1 and DLCO-SB was 1.69 L/64.8% predicted (range: 1.36–2.66 L/33–80%), 1 L/39.4% predicted (range:0.78–1.26 L/28–60% predicted) and 33.3% (range: 13.3–54%) predicted, respectively. Median values for VC, FEV1, DLCO-SB 3 and 6 months after Hypo-IGRT were 2.05 L/56.35% predicted (range: 1.34–2.33 L/47–81.5%), 1.08 L/47.5% predicted (range: 0.74–1.60 L/30.8–59.59%), 38.55% (range: 24–68%) and 1.64 L/66% predicted (range: 1.41–2.79/35.5–75.5%), 1.0 L/47% predicted (range: 0.65–1.28 L/24.5–54.10%), 31% (range: 27–43%), respectively. Mean lung dose was 9.4 Gy (range: 5.3–11.6 Gy) and V20 for both lungs was 15% (range: 6–19%). Mean esophageal dose was 12.76 Gy (range: 2.1–26.7 Gy). There was no case of grade 2 or higher radiation pneumonitis. Four patients developed grade 2 radiation esophagitis. Conclusion Hypo-IGRT can be considered for individual and closely monitored patients with locally advanced node-positive NSCLC with highly compromised pulmonary function. No severe pulmonary toxicity and significant decline of pulmonary function parameters was observed in our cohort. Currently, this protocol is being assessed in an ongoing single-centre prospective study.