Publications by authors named "Steffen Löck"

89 Publications

Identification of patient benefit from proton beam therapy in brain tumour patients based on dosimetric and NTCP analyses.

Radiother Oncol 2021 Apr 16. Epub 2021 Apr 16.

OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany; German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany, Helmholtz Association / Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany. Electronic address:

Background: The limited availability of proton beam therapy (PBT) requires individual treatment selection strategies, such as the model-based approach. In this study, we assessed the dosimetric benefit of PBT compared to photon therapy (XRT), analysed the corresponding changes in normal tissue complication probability (NTCP) on a variety of available models, and illustrated model-based patient selection in an in-silico study for patients with brain tumours.

Methods: For 92 patients treated at two PBT centres, volumetric modulated arc therapy treatment plans were retrospectively created for comparison with the clinically applied PBT plans. Several dosimetric parameters for the brain excluding tumour and margins, cerebellum, brain stem, frontal and temporal lobes, hippocampi, cochleae, chiasm, optic nerves, lacrimal glands, lenses, pituitary gland, and skin were compared between both modalities using Wilcoxon signed-rank tests. NTCP differences (ΔNTCP) were calculated for 11 models predicting brain necrosis, delayed recall, temporal lobe injury, hearing loss, tinnitus, blindness, ocular toxicity, cataract, endocrine dysfunction, alopecia, and erythema. A patient was assumed to be selected for PBT if ΔNTCP exceeded a threshold of 10 percentage points for at least one of the side-effects.

Results: PBT substantially reduced the dose in almost all investigated OARs, especially in the low and intermediate dose ranges and for contralateral organs. In general, NTCP predictions were significantly lower for PBT compared to XRT, in particular in ipsilateral organs. Considering ΔNTCP of all models, 80 patients (87.0%) would have been selected for PBT in this in-silico study, mainly due to predictions of a model on delayed recall (51 patients).

Conclusion: In this study, substantial dose reductions for PBT were observed, mainly in contralateral organs. However, due to the sigmoidal dose response, NTCP was particularly reduced in ipsilateral organs. This underlines that physical dose-volume parameters alone may not be sufficient to describe the clinical relevance between different treatment techniques and highlights potential benefits of NTCP models. Further NTCP models for different modern treatment techniques are mandatory and existing models have to be externally validated in order to implement the model-based approach in clinical practice for cranial radiotherapy.
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http://dx.doi.org/10.1016/j.radonc.2021.04.008DOI Listing
April 2021

Sample-size calculation for preclinical dose-response experiments using heterogeneous tumour models.

Radiother Oncol 2021 Mar 3;158:262-267. Epub 2021 Mar 3.

OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Dresden, Germany. Electronic address:

Background: In preclinical radio-oncological research, local tumour control is considered the most relevant endpoint as it reflects the inactivation of cancer stem cells. Preclinical tumour-control assays may compare dose-response curves between different radiotherapy strategies, e.g., assessing additional targeted drugs and immunotherapeutic interventions, or between different radiation modalities. To mimic the biological heterogeneity of human tumour populations and to accommodate for approaches of personalized oncology, preclinical studies are increasingly performed combining larger panels of tumour models. For designing the study protocols and to obtain reliable results, prospective sample-size planning has to be developed that accounts for such heterogeneous cohorts.

Methods: A Monte-Carlo-based method was developed to estimate the sample size of a comparative 1:1 two-arm prospective tumour-control assay. Based on repeated logistic regression analysis, pre-defined dose levels, assumptions on the dose-response curves of the included tumour models and on the dose-modifying factors (DMF), the power is calculated for a given number of animals per dose group.

Results: Two applications are presented: (i) For a simple tumour-control assay with the head and neck squamous cell carcinoma (HNSCC) model FaDu, 10 animals would be required for each of 7 dose levels per arm to reveal a DMF of 1.25 with a power of 0.82 without drop out (total: 140 animals). (ii) In a more complex experiment combining six different lung tumour models to a heterogeneous population, 21 animals would be required for each of 11 dose levels per arm to reveal a DMF of 1.25 with a power of 0.81 without drop out (total: 462 animals). Analyzing the heterogeneous cohort reduces the required animal number by more than 50% compared to six individual tumour-control assays.

Conclusion: An approach for estimating the required animal number for comparative tumour-control assays in a heterogeneous population is presented, allowing also the inclusion of different treatments as a personalized approach in the experimental arm. The software is publicly available and can be applied to plan comparisons of sigmoidal dose-response curves based on logistic regression.
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http://dx.doi.org/10.1016/j.radonc.2021.02.032DOI Listing
March 2021

Value of functional in-vivo endpoints in preclinical radiation research.

Radiother Oncol 2021 Feb 24;158:155-161. Epub 2021 Feb 24.

Department of Radiation Oncology and OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany; German Cancer Research Center (DKFZ) Heidelberg, Germany.

Background: Cancer research faces the problem of high rates of clinical failure of new treatment approaches after positive preclinical data. We hypothesize that a major confounding factor to this problem in radiooncology is the choice of the preclinical endpoint.

Methods: We present a comprehensive re-evaluation of large-scale preclinical in-vivo data on fractionated irradiation alone or simultaneously with Epidermal Growth Factor Receptor inhibition. Taking the permanent local tumour control assay as a gold standard, we evaluated different tumour volume dependent endpoints that are widely used for preclinical experiments.

Results: The analysis showed the highest correlations between volume related and local tumour control endpoints after irradiation alone. For combined treatments, wide inter-tumoural variations were observed with reduced correlation between the endpoints. Evaluation of growth delay per Gray (GD/Gy) based on two or more dose levels showed closest correlation with local tumour control dose 50% (TCD).

Conclusions: GD/Gy with at least two dose groups correlates with TCD, but cannot replace the latter as the goldstandard.
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http://dx.doi.org/10.1016/j.radonc.2021.02.024DOI Listing
February 2021

Electron dose rate and oxygen depletion protect zebrafish embryos from radiation damage.

Radiother Oncol 2021 Feb 13;158:7-12. Epub 2021 Feb 13.

OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiation Physics, Germany. Electronic address:

Background And Purpose: In consequence of a previous study, where no protecting proton Flash effect was found for zebrafish embryos, potential reasons and requirements for inducing a Flash effect should be investigated with higher pulse dose rate and partial oxygen pressure (pO) as relevant parameters.

Materials And Methods: The experiments were performed at the research electron accelerator ELBE, whose variable pulse structure enables dose delivery as electron Flash and quasi-continuously (reference irradiation). Zebrafish embryos were irradiated with ~26 Gy either continuously at a dose rate of ~6.7 Gy/min (reference) or by 1441 electron pulses within 111 µs at a pulse dose rate of 10 Gy/s and a mean dose rate of 10Gy/s, respectively. Using the OxyLite system to measure the pO a low- (pO ≤ 5 mmHg) and a high-pO group were defined on basis of the oxygen depletion kinetics in sealed embryo samples.

Results: A protective Flash effect was seen for most endpoints ranging from 4 % less reduction in embryo length to about 20-25% less embryos with spinal curvature and pericardial edema, relative to reference irradiation. The reduction of pO below atmospheric levels (148 mmHg) resulted in higher protection, which was however more pronounced in the low-pO group.

Conclusion: The Flash experiment at ELBE showed that the zebrafish embryo model is appropriate for studying the radiobiological response of high dose rate irradiation. The applied high pulse dose rate was confirmed as important beam parameter as well as the pivotal role of pO during irradiation.
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http://dx.doi.org/10.1016/j.radonc.2021.02.003DOI Listing
February 2021

Modelling of late side-effects following cranial proton beam therapy.

Radiother Oncol 2021 04 19;157:15-23. Epub 2021 Jan 19.

OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany; German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. Electronic address:

Background: The limited availability of proton beam therapy (PBT) requires individual treatment selection strategies that can be based on normal tissue complication probability (NTCP) models. We developed and externally validated NTCP models for common late side-effects following PBT in brain tumour patients to optimise patients' quality of life.

Methods: Cohorts from three PBT centres (216 patients) were investigated for several physician-rated endpoints at 12 and 24 months after PBT: alopecia, dry eye syndrome, fatigue, headache, hearing and memory impairment, and optic neuropathy. Dose-volume parameters of associated normal tissues and clinical factors were used for logistic regression modelling in a development cohort. Statistically significant parameters showing high area under the receiver operating characteristic curve (AUC) values in internal cross-validation were externally validated. In addition, analyses of the pooled cohorts and of time-dependent generalised estimating equations including all patient data were performed.

Results: In the validation study, mild alopecia was related to high dose parameters to the skin [e.g. the dose to 2% of the volume (D2%)] at 12 and 24 months after PBT. Mild hearing impairment at 24 months after PBT was associated with the mean dose to the ipsilateral cochlea. Additionally, the pooled analyses revealed dose-response relations between memory impairment and intermediate to high doses to the remaining brain as well as D2% of the hippocampi. Mild fatigue at 24 months after PBT was associated with D2% to the brainstem as well as with concurrent chemotherapy. Moreover, in generalised estimating equations analysis, dry eye syndrome was associated with the mean dose to the ipsilateral lacrimal gland.

Conclusion: We developed and in part validated NTCP models for several common late side-effects following PBT in brain tumour patients. Validation studies are required for further confirmation.
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http://dx.doi.org/10.1016/j.radonc.2021.01.004DOI Listing
April 2021

Final Results of the Prospective Biomarker Trial PETra: [C]-MET-Accumulation in Postoperative PET/MRI Predicts Outcome after Radiochemotherapy in Glioblastoma.

Clin Cancer Res 2021 Mar 29;27(5):1351-1360. Epub 2020 Dec 29.

Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Purpose: This prospective trial investigates the association of time to recurrence (TTR) in glioblastoma with [C]methionine (MET) tracer uptake before postoperative radiochemotherapy (RCT) aiming to guide radiotherapy boost regions.

Experimental Design: Between 2013 and 2016, 102 patients with glioblastoma were recruited. RCT was performed with concurrent and adjuvant temozolomide to a total dose of 60 Gy. Tumor residues in postresection PET and MRI were together defined as gross tumor volumes for radiotherapy treatment planning. [C]methionine (MET)-PET/MRI was performed before RCT and at each follow-up.

Results: The primary hypothesis of a longer TTR for patients without increased tracer accumulation in postoperative MET-PET was confirmed in 89 patients. With 18.9 months (95% confidence interval, 9.3-28.5 months), median TTR was significantly ( < 0.001) longer for patients without ( = 29, 32.6%) as compared with 6.3 months (3.6-8.9) for patients with MET accumulation ( = 60, 67.4%) in pre-RCT PET. Although MRI often did not detect all PET-positive regions, an unfavorable impact of residual tumor in postsurgical MRI ( = 38, 42.7%) on TTR was observed [4.6 (4.2-5.1) vs. 15.5 months (6.0-24.9), < 0.001]. Significant multivariable predictors for TTR were MRI positivity, PET-positive volume, and O-methylguanine DNA methyltransferase (MGMT) hypermethylation.

Conclusions: Postsurgical amino acid PET has prognostic value for TTR after RCT in glioblastoma. Because of the added value of the metabolic beyond the pure structural information, it should complement MRI in radiotherapy planning if available with reasonable effort, at least in the context of maximal therapy. Furthermore, the spatial correlation of regions of recurrence with PET-positive volumes could provide a bioimaging basis for further trials, for example, testing local radiation dose escalation.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1775DOI Listing
March 2021

Generation of biological hypotheses by functional imaging links tumor hypoxia to radiation induced tissue inflammation/glucose uptake in head and neck cancer.

Radiother Oncol 2021 02 24;155:204-211. Epub 2020 Oct 24.

Department of Radiotherapy and Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany, and German Cancer Research Center (DKFZ) Heidelberg, Germany; OncoRay, National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden, Rossendorf, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology, Dresden, Germany; National Center for Tumour Diseases (NCT), Partner Site Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany, and Helmholtz Association/Helmholtz-Zentrum Dresden, Rossendorf (HZDR), Dresden, Germany.

Background And Purpose: Positron emission tomography (PET) is a functional imaging modality which is able to deliver tracer specific biological information, e.g. about glucose uptake, inflammation or hypoxia of tumors. We performed a proof-of-principle study that used different tracers and expanded the analytical scope to non-tumor structures to evaluate tumor-host interactions.

Materials And Methods: Based on a previously reported prospective imaging study on 50 patients treated with curative intent chemoradiation (CRT) for head and neck squamous cell carcinoma, PET-based hypoxia and normal tissue inflammation measured by repeat 18F-fluoromisonidazole (FMISO) PET and 18F-fluorodesoxyglucose (FDG) PET, respectively, were correlated using the Spearman correlation coefficient R. PET parameters determined before and during CRT (week 1, 2 and 5), were associated with local tumor control and overall survival.

Results: Tumor hypoxia at all measured times showed an inverse correlation with mid-treatment FDG-uptake of non-tumor affected oral (sub-)mucosa with R values between -0.35 and -0.6 (all p < 0.05). Mucosal FDG-uptake and mucosal hypoxia correlated positively but weaker (R values between 0.2 and 0.45). More tumor hypoxia in FMISO-PET (week 2) and less FDG-uptake of (sub-)mucosa in FDG-PET (week 4) were significantly associated with worse LC (FMISO TBR: HR = 1.72, p = 0.030; FDG SUV: HR = 0.23, p = 0.025) and OS (FMISO TBR: HR = 1.71, p = 0.007; FDG SUV: HR = 0.30, p = 0.003). Multivariable models including both parameters showed improved performance, suggesting that these modalities still bear distinct biological information despite their strong inter-correlation.

Conclusion: We report first clinical evidence that tumor hypoxia is inversely correlated with increased FDG-uptake during radiation, potentially expressing inflammation. This observation merits further research and may have important implication for future research on tumor hypoxia and radio-immunology. Our study demonstrates that functional imaging can be utilized to assess complex tumor-host interactions and generate novel biological insights in vivo vero.
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http://dx.doi.org/10.1016/j.radonc.2020.10.030DOI Listing
February 2021

Dual role of ER stress in response to metabolic co-targeting and radiosensitivity in head and neck cancer cells.

Cell Mol Life Sci 2021 Mar 23;78(6):3021-3044. Epub 2020 Nov 23.

OncoRay, National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Fetscherstraße 74, 01307, Dresden, Germany.

Arginine deprivation therapy (ADT) is a new metabolic targeting approach with high therapeutic potential for various solid cancers. Combination of ADT with low doses of the natural arginine analog canavanine effectively sensitizes malignant cells to irradiation. However, the molecular mechanisms determining the sensitivity of intrinsically non-auxotrophic cancers to arginine deficiency are still poorly understood. We here show for the first time that arginine deficiency is accompanied by global metabolic changes and protein/membrane breakdown, and results in the induction of specific, more or less pronounced (severe vs. mild) ER stress responses in head and neck squamous cell carcinoma (HNSCC) cells that differ in their intrinsic ADT sensitivity. Combination of ADT with canavanine triggered catastrophic ER stress via the eIF2α-ATF4(GADD34)-CHOP pathway, thereby inducing apoptosis; the same signaling arm was irrelevant in ADT-related radiosensitization. The particular strong supra-additive effect of ADT, canavanine and irradiation in both intrinsically more and less sensitive cancer cells supports the rational of ER stress pathways as novel target for improving multi-modal metabolic anti-cancer therapy.
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http://dx.doi.org/10.1007/s00018-020-03704-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004506PMC
March 2021

Pictures worth more than a thousand words: Prediction of survival in medulloblastoma patients.

EBioMedicine 2020 Dec 21;62:103136. Epub 2020 Nov 21.

OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany; German Cancer Consortium (DKTK), partner site, Dresden, Germany and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.

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http://dx.doi.org/10.1016/j.ebiom.2020.103136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691739PMC
December 2020

Radiotherapy enhances uptake and efficacy of Y-cetuximab: A preclinical trial.

Radiother Oncol 2021 02 21;155:285-292. Epub 2020 Nov 21.

German Cancer Consortium (DKTK), Partner Site Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TU, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, German Cancer Research Center (DKFZ), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany, Helmholtz Association / Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.

Background And Purpose: Systemic molecular radiotherapy utilizes internal irradiation by radionuclide-labeled tumor-targeting agents with the potential to destroy (micro-)metastases. However, doses that are applicable in solid tumors do not reach the levels nessecary for tumor control. Thus, the combination of molecular and external radiotherapy is a promising treatment strategy, as enhanced tumor doses can be delivered with and without minor overlapping toxicities. Here, we combined a Y-labeled anti-EGFR antibody (Cetuximab) with clinically relevant fractionated radiotherapy in a preclinical trial using head and neck squamous cell carcinoma xenograft tumors.

Materials And Methods: To model Y-Cetuximab uptake for treatment schedule optimization, FaDu-bearing mice were injected with near-infrared-labeled-Cetuximab at different time points during radiotherapy with differing doses. Cetuximab uptake was longitudinally followed by in vivo-optical imaging. Tumor control probability experiments with fractionated radiotherapy (30 fx, 6 weeks, 8 dose groups/ arm) in combination with Y-Cetuximab were performed to test the curative potential.

Results: Imaging of near-infrared-labeled-Cetuximab uptake revealed that low to moderate external beam doses can enhance antibody uptake. Using the optimized schedule, combination of molecular and external radiotherapy using Y-Cetuximab at a dose that did not result in permanent tumor inactivation in previous experiments, led to substantially increased tumor control compared to radiotherapy alone.

Conclusion: Our results indicate that combination of radiolabeled therapeutics with clinically relevant fractionated radiotherapy has a remarkable potential to improve curative treatment outcome. Application of some radiation dose prior to injection may improve drug uptake and enable patient stratification and treatment personalization via a corresponding PET-tracer during therapy.
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http://dx.doi.org/10.1016/j.radonc.2020.11.013DOI Listing
February 2021

[Ga]Ga-PSMA-11 PET before and after initial long-term androgen deprivation in patients with newly diagnosed prostate cancer: a retrospective single-center study.

EJNMMI Res 2020 Nov 6;10(1):135. Epub 2020 Nov 6.

OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany.

Purpose: The study aimed to evaluate the effect of androgen deprivation therapy (ADT) on PSMA imaging and its correlation to the PSA concentration by comparing qualitative and quantitative parameters: SUV, SUV, PSMA-derived tumor volume (PSMA-TV), total lesion PSMA (TL-PSMA) and molecular imaging (mi)PSMA score.

Methods: Retrospective analysis of 21 therapy-naïve patients with oligometastatic prostate cancer (median age 70 years) who underwent either [Ga]Ga-PSMA-11-PET/CT or -PET/MRI before initiation of (T1) as well as during ADT (T2). The median duration of ADT was 155 days (range 61-289 days). All lesions were analyzed using several qualitative and quantitative PET parameters.

Results: A total of 109 PSMA-positive lesions (24 intraprostatic, 56 lymphonodal and 29 osseous) were visually detected at any of the examinations, while at T2, two new bone lesions were detected in one patient. During ADT, all patients experienced a decrease in their PSA level (median: 29.1 before vs. 0.71 after; p < 0.001). During long-term ADT, a relevant decrease in lesion count occurred, especially in patients with a T2 PSA value < 1 ng/ml (median: 4 vs. 0.9; p = 0.007) and PSMA expression, which resulted in miN- and/or miM-downstaging in 11 patients (52.7%). All analyzed PET parameters correlated strongly with each other. The PSA level at T2 correlated modestly with the decrease in PSMA expression and its derived volumes.

Conclusion: Post-ADT scans detected, especially in patients with a residual PSA < 1 ng/ml, fewer PSMA-positive lesions with overall lower PSMA expression, regardless of primary tumor site or metastatic sites. None of the PET parameters has proven to be superior, as they all correlated modestly with the PSA value at T2. Thus, the simply acquirable miPSMA score seems to be the most suitable for evaluating the effect of ADT on PSMA expression.
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http://dx.doi.org/10.1186/s13550-020-00723-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647983PMC
November 2020

Comprehensive Analysis of Tumour Sub-Volumes for Radiomic Risk Modelling in Locally Advanced HNSCC.

Cancers (Basel) 2020 Oct 19;12(10). Epub 2020 Oct 19.

OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01307 Dresden, Germany.

Imaging features for radiomic analyses are commonly calculated from the entire gross tumour volume (GTV ). However, tumours are biologically complex and the consideration of different tumour regions in radiomic models may lead to an improved outcome prediction. Therefore, we investigated the prognostic value of radiomic analyses based on different tumour sub-volumes using computed tomography imaging of patients with locally advanced head and neck squamous cell carcinoma. The GTV  was cropped by different margins to define the rim and the corresponding core sub-volumes of the tumour. Subsequently, the best performing tumour rim sub-volume was extended into surrounding tissue with different margins. Radiomic risk models were developed and validated using a retrospective cohort consisting of 291 patients in one of the six Partner Sites of the German Cancer Consortium Radiation Oncology Group treated between 2005 and 2013. The validation concordance index (C-index) averaged over all applied learning algorithms and feature selection methods using the GTVentire achieved a moderate prognostic performance for loco-regional tumour control (C-index: 0.61 ± 0.04 (mean ± std)). The models based on the 5 mm tumour rim and on the 3 mm extended rim sub-volume showed higher median performances (C-index: 0.65 ± 0.02 and 0.64 ± 0.05, respectively), while models based on the corresponding tumour core volumes performed less (C-index: 0.59 ± 0.01). The difference in C-index between the 5 mm tumour rim and the corresponding core volume showed a statistical trend ( = 0.10). After additional prospective validation, the consideration of tumour sub-volumes may be a promising way to improve prognostic radiomic risk models.
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http://dx.doi.org/10.3390/cancers12103047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589463PMC
October 2020

Comparison of patient stratification by computed tomography radiomics and hypoxia positron emission tomography in head-and-neck cancer radiotherapy.

Phys Imaging Radiat Oncol 2020 Jul;15:52-59

Section for Biomedical Physics, Department of Radiation Oncology, University of Tübingen, Germany.

Background And Purpose: Hypoxia Positron-Emission-Tomography (PET) as well as Computed Tomography (CT) radiomics have been shown to be prognostic for radiotherapy outcome. Here, we investigate the stratification potential of CT-radiomics in head and neck cancer (HNC) patients and test if CT-radiomics is a surrogate predictor for hypoxia as identified by PET.

Materials And Methods: Two independent cohorts of HNC patients were used for model development and validation, HN1 (n = 149) and HN2 (n = 47). The training set HN1 consisted of native planning CT data whereas for the validation cohort HN2 also hypoxia PET/CT data was acquired using [F]-Fluoromisonidazole (FMISO). Machine learning algorithms including feature engineering and classifier selection were trained for two-year loco-regional control (LRC) to create optimal CT-radiomics signatures.Secondly, a pre-defined [F]FMISO-PET tumour-to-muscle-ratio (TMR ≥ 1.6) was used for LRC prediction. Comparison between risk groups identified by CT-radiomics or [F]FMISO-PET was performed using area-under-the-curve (AUC) and Kaplan-Meier analysis including log-rank test.

Results: The best performing CT-radiomics signature included two features with nearest-neighbour classification (AUC = 0.76 ± 0.09), whereas AUC was 0.59 for external validation. In contrast, [F]FMISO TMR reached an AUC of 0.66 in HN2. Kaplan-Meier analysis of the independent validation cohort HN2 did not confirm the prognostic value of CT-radiomics (p = 0.18), whereas for [F]FMISO-PET significant differences were observed (p = 0.02).

Conclusions: No direct correlation of patient stratification using [F]FMISO-PET or CT-radiomics was found in this study. Risk groups identified by CT-radiomics or hypoxia PET showed only poor overlap. Direct assessment of tumour hypoxia using PET seems to be more powerful to stratify HNC patients.
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http://dx.doi.org/10.1016/j.phro.2020.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536307PMC
July 2020

2D and 3D convolutional neural networks for outcome modelling of locally advanced head and neck squamous cell carcinoma.

Sci Rep 2020 09 24;10(1):15625. Epub 2020 Sep 24.

OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany.

For treatment individualisation of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with primary radiochemotherapy, we explored the capabilities of different deep learning approaches for predicting loco-regional tumour control (LRC) from treatment-planning computed tomography images. Based on multicentre cohorts for exploration (206 patients) and independent validation (85 patients), multiple deep learning strategies including training of 3D- and 2D-convolutional neural networks (CNN) from scratch, transfer learning and extraction of deep autoencoder features were assessed and compared to a clinical model. Analyses were based on Cox proportional hazards regression and model performances were assessed by the concordance index (C-index) and the model's ability to stratify patients based on predicted hazards of LRC. Among all models, an ensemble of 3D-CNNs achieved the best performance (C-index 0.31) with a significant association to LRC on the independent validation cohort. It performed better than the clinical model including the tumour volume (C-index 0.39). Significant differences in LRC were observed between patient groups at low or high risk of tumour recurrence as predicted by the model ([Formula: see text]). This 3D-CNN ensemble will be further evaluated in a currently ongoing prospective validation study once follow-up is complete.
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http://dx.doi.org/10.1038/s41598-020-70542-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518264PMC
September 2020

Results of a randomized controlled phase III trial: efficacy of polyphenol-containing cystus® tea mouthwash solution for the reduction of mucositis in head and neck cancer patients undergoing external beam radiotherapy.

Strahlenther Onkol 2021 Jan 24;197(1):63-73. Epub 2020 Sep 24.

German Cancer Research Center (DKFZ), Heidelberg, Germany.

Purpose: To determine the effect of Cystus® tea (Naturprodukte Dr. Pandalis GmbH & Co. KG) as mouthwash compared to sage tea on oral mucositis in patients undergoing radio(chemo)therapy for head and neck cancer.

Methods: In this randomized, prospective phase III study, 60 head and neck cancer patients with primary or postoperative radio(chemo)therapy were included between 04/2012 and 06/2014. They received either sage or Cystus® tea for daily mouthwash under therapy. Mucositis was scored twice a week following the Radiation Therapy Oncology Group and the European Organization for Research and Treatment Cancer (RTOG/EORTC) scoring system. Dental parameters were also recorded. Statistical evaluation of the primary endpoint was performed using t‑test and log rank test.

Results: Data from 57 patients could be evaluated. Patient characteristics showed no significant difference between the two groups (n = 27 sage; n = 30 Cystus®). A total of 55 patients received the prescribed dose (60-66 Gy postoperative; 70-76.8 Gy primary). Mucositis grade 3 was observed in 23 patients (n = 11 sage; n = 12 Cystus®) and occurred between day 16 and 50 after start of therapy. There was no significant difference between the two groups in latency (p = 0.75) and frequency (p = 0.85) of the occurrence of mucositis grade 3. The self-assessment of the oral mucosa and the tolerability of the tea also showed no significant differences. Occurrence of dental pathologies appeared to increase over time after radiotherapy.

Conclusion: Cystus® and sage tea have a similar effect on the occurrence of radiation-induced mucositis regarding latency and incidence. Cystus® tea mouthwash solution is tolerated well and can be applied in addition to intensive oral care and hygiene along with the application of fluorides.
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http://dx.doi.org/10.1007/s00066-020-01684-yDOI Listing
January 2021

Dose dependent cerebellar atrophy in glioma patients after radio(chemo)therapy.

Radiother Oncol 2020 09 31;150:262-267. Epub 2020 Jul 31.

Institute of Radiooncology - OncoRay, Helmholtz-Zentrum Dresden-Rossendorf, Germany; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany, and; Helmholtz Association/Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.

Background And Purpose: Radiotherapy is a standard treatment option for high-grade gliomas. Brain atrophy has previously been associated with radiotherapy. The goal of this study was to investigate dose dependent cerebellar atrophy using prospective, longitudinal MR data from adult glioma patients who received radiotherapy.

Materials And Methods: Cerebellar volumes were measured using T1-weighted MR images from 91 glioma patients before radiotherapy (N = 91) and from longitudinal follow-ups acquired in three monthly intervals (N = 349). Relative cerebellar volumes were calculated as ratios to the corresponding baseline values. Univariate mixed effects models were used to determine factors that were significantly associated with relative cerebellar volumes. These factors were subsequently included as fixed effects in a final multivariate linear mixed effects model.

Results: In multivariate analysis, cerebellar volume decreased significantly as a function of time (p < 0.001), time × dose (p < 0.001) and patient age (p = 0.007). Considering a 55 year patient receiving a mean cerebellar dose of 0 Gy (10 Gy), the linear mixed effects model predicts a relative cerebellar volume loss of 0.4% (2.0%) after 1 year and 0.7% (3.6%) after 2 years. Compared to patients treated with photons, the cerebellar dose was significantly lower in patients treated with proton therapy (p < 0.001, r = 0.62).

Conclusion: Cerebellar volume decreased significantly and irreversibly after radiotherapy as function of time and mean cerebellar dose. Further work is now needed to correlate these results with cognitive function and motor performance.
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http://dx.doi.org/10.1016/j.radonc.2020.07.044DOI Listing
September 2020

Microenvironmentally-driven Plasticity of CD44 isoform expression determines Engraftment and Stem-like Phenotype in CRC cell lines.

Theranostics 2020 18;10(17):7599-7621. Epub 2020 Jun 18.

OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, and Helmholtz-Zentrum Dresden-Rossendorf, Germany.

Theranostic biomarkers for putative cancer stem-like cells (CSC) in colorectal cancer (CRC) are of particular interest in translational research to develop patient-individualized treatment strategies. Surface proteins still under debate are CD44 and CD133. The structural and functional diversity of these antigens, as well as their plasticity, has only just begun to be understood. Our study aimed to gain novel insight into the plasticity of CD133/CD44, thereby proving the hypothesis of marker-associated tumorigenic and non-tumorigenic phenotypes to be environmentally driven. CD133/CD44 profiles of 20 CRC cell lines were monitored; three models with distinct surface patterns were systematically examined. CD133/CD44 subpopulations were isolated by FACS and analyzed upon growth and/or in limiting dilution engraftment studies. The experimental setup included biomarker analyses on the protein (flow cytometry, Western blotting, immunofluorescence) and mRNA levels (RT-/qPCR) as well as CD44 gene sequencing. In general, we found that (i) the CD133/CD44 pattern never determined engraftment and (ii) the CD133/CD44 population distributions harmonized under conditions. The LS1034 cell line appeared as a unique model due to its presentation of CD44. was identified as main transcript, which was stronger expressed in primary human CRC than in normal colon tissues. Biomarker pattern of LS1034 cells reflected secondary engraftment: the tumorigenic potential was highest in CD133/CD44, intermediate in CD133/CD44 and entirely lost in CD133/CD44 subfractions. Both CD44 and CD44 LS1034 cells gave rise to tumorigenic and non-tumorigenic progeny and were convertible - but only as long as they expressed CD133 . The highly tumorigenic CD133/CD44(v8-10) LS1034 cells were localized in well-oxygenated perivascular but not hypoxic regions. From a multitude of putative modulators, only the direct interaction with stromal fibroblasts triggered an essential, -like enhancement of CD44v8-10 presentation . Environmental conditions modulate CD133/CD44 phenotypes and tumorigenic potential of CRC subpopulations. The identification of fibroblasts as drivers of cancer-specific CD44 expression profile and plasticity sheds light on the limitation of per se dynamic surface antigens as biomarkers. It can also explain the location of putative CD133/CD44-positive CRC CSC in the perivascular niche, which is likely to comprise cancer-associated fibroblasts. The LS1034 model is a valuable tool to unravel the mechanism of stromal-induced CD44v8-10 expression and identify further therapeutically relevant, mutual interrelations between microenvironment and tumorigenic phenotype.
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http://dx.doi.org/10.7150/thno.39893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359088PMC
June 2020

Applying Tissue Slice Culture in Cancer Research-Insights from Preclinical Proton Radiotherapy.

Cancers (Basel) 2020 Jun 16;12(6). Epub 2020 Jun 16.

German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

A challenge in cancer research is the definition of reproducible, reliable, and practical models, which reflect the effects of complex treatment modalities and the heterogeneous response of patients. Proton beam radiotherapy (PBRT), relative to conventional photon-based radiotherapy, offers the potential for iso-effective tumor control, while protecting the normal tissue surrounding the tumor. However, the effects of PBRT on the tumor microenvironment and the interplay with newly developed chemo- and immunotherapeutic approaches are still open for investigation. This work evaluated thin-cut tumor slice cultures (TSC) of head and neck cancer and organotypic brain slice cultures (OBSC) of adult mice brain, regarding their relevance for translational radiooncology research. TSC and OBSC were treated with PBRT and investigated for cell survival with a lactate dehydrogenase (LDH) assay, DNA repair via the DNA double strand break marker γH2AX, as well as histology with regards to morphology. Adult OBSC failed to be an appropriate model for radiobiological research questions. However, histological analysis of TSC showed DNA damage and tumor morphological results, comparable to known in vivo and in vitro data, making them a promising model to study novel treatment approaches in patient-derived xenografts or primary tumor material.
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http://dx.doi.org/10.3390/cancers12061589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352770PMC
June 2020

Individual patient data meta-analysis of FMISO and FAZA hypoxia PET scans from head and neck cancer patients undergoing definitive radio-chemotherapy.

Radiother Oncol 2020 08 15;149:189-196. Epub 2020 May 15.

Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; German Cancer Consortium (DKTK), partner site Tu¨bingen, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Helmholtz Association/Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Germany.

Background And Purpose: Tumor hypoxia plays an important role in head and neck squamous cell carcinomas (HNSCC). Various positron emission tomography (PET) tracers promise non-invasive assessment of tumor hypoxia. So far, the applicability of hypoxia PET is hampered by monocentric imaging trials with few patients.

Materials And Methods: Multicenter individual patient data based meta-analysis of the original PET data from four prospective imaging trials was performed. All patients had localized disease and were treated with curatively intended radio(-chemo)therapy. Hypoxia PET imaging was performed with F-Fluoromisonidazole (FMISO, 102 patients) or F-Fluoroazomycin-arabinoside (FAZA, 51 patients). Impact of hypoxia PET parameters on loco-regional control (LRC) and overall survival (OS) was analyzed by uni- and multivariable Cox regression.

Results: Baseline characteristics between participating centers differed significantly, especially regarding T stage (p < 0.001), tumor volume (p < 0.001) and p16 status (p = 0.009). The commonly used hypoxia parameters, maximal tumor-to-muscle ratio (TMR) and hypoxic volume with 1.6 threshold (HV), showed a strong association with LRC (p = 0.001) and OS (p < 0.001). These findings were irrespective of the radiotracer and the same cut-off values could be applied for FMISO and FAZA (TMR > 2.0 or HV > 1.5 ml). The effect size of TMR was similar for subgroups of patients defined by radiotracer, p16 status and FDG-PET parameters for LRC and OS, respectively.

Conclusion: PET measured hypoxia is robust and has a strong impact on LRC and OS in HNSCC. The most commonly investigated tracers FMISO and FAZA can probably be used equivalently in multicenter trials. Optimal strategies to improve the dismal outcome of hypoxic tumors remain elusive.
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http://dx.doi.org/10.1016/j.radonc.2020.05.022DOI Listing
August 2020

Establishment and Characterisation of Heterotopic Patient-Derived Xenografts for Glioblastoma.

Cancers (Basel) 2020 Apr 3;12(4). Epub 2020 Apr 3.

OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz- Zentrum Dresden-Rossendorf, 01307 Dresden, Germany.

Glioblastoma is an aggressive brain tumour with a patient median survival of approximately 14 months. The development of innovative treatment strategies to increase the life span and quality of life of patients is hence essential. This requires the use of appropriate glioblastoma models for preclinical testing, which faithfully reflect human cancers. The aim of this study was to establish glioblastoma patient-derived xenografts (PDXs) by heterotopic transplantation of tumour pieces in the axillae of NMRI nude mice. Ten out of 22 patients' samples gave rise to tumours in mice. Their human origin was confirmed by microsatellite analyses, though minor changes were observed. The glioblastoma nature of the PDXs was corroborated by pathological evaluation. Latency times spanned from 48.5 to 370.5 days in the first generation. Growth curve analyses revealed an increase in the growth rate with increasing passages. The methylation status of the promoter in the primary material was maintained in the PDXs. However, a trend towards a more methylated pattern could be found. A correlation was observed between the take in mice and the proportion of Sox2 cells ( = 0.49, = 0.016) and nestin cells ( = 0.55, = 0.007). Our results show that many PDXs maintain key features of the patients' samples they derive from. They could thus be used as preclinical models to test new therapies and biomarkers.
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http://dx.doi.org/10.3390/cancers12040871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226316PMC
April 2020

Comparison of GeneChip, nCounter, and Real-Time PCR-Based Gene Expressions Predicting Locoregional Tumor Control after Primary and Postoperative Radiochemotherapy in Head and Neck Squamous Cell Carcinoma.

J Mol Diagn 2020 06 2;22(6):801-810. Epub 2020 Apr 2.

German Cancer Consortium (DKTK) partner site Dresden, Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg; the OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, and Helmholtz Association/Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.

This article compares the expression and applicability of biomarkers, from single genes and gene signatures, identified in patients with locally advanced head and neck squamous cell carcinoma using the GeneChip Human Transcriptome Array 2.0, nCounter, and real-time PCR analyses. Two multicenter, retrospective cohorts of patients with head and neck squamous cell carcinoma from the German Cancer Consortium Radiation Oncology Group who received postoperative radiochemotherapy or primary radiochemotherapy were considered. Real-time PCR was performed for a limited number of 38 genes of the cohort who received postoperative radiochemotherapy only. Correlations between the methods were evaluated by the Spearman rank correlation coefficient. Patients were stratified based on the expression of putative cancer stem cell markers, hypoxia-associated gene signatures, and a previously developed seven-gene signature. Locoregional tumor control was compared between these patient subgroups using log-rank tests. Gene expressions obtained from nCounter analyses were moderately correlated to GeneChip analyses (median ρ = approximately 0.68). A higher correlation was obtained between nCounter analyses and real-time PCR (median ρ = 0.84). Significant associations with locoregional tumor control were observed for most of the considered biomarkers evaluated by GeneChip and nCounter analyses. In general, all applied biomarkers (single genes and gene signatures) classified approximately 70% to 85% of the patients similarly. Overall, gene signatures seem to be more robust and had a better transferability among different measurement methods.
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http://dx.doi.org/10.1016/j.jmoldx.2020.03.005DOI Listing
June 2020

Specific requirements for translation of biological research into clinical radiation oncology.

Mol Oncol 2020 07 8;14(7):1569-1576. Epub 2020 Apr 8.

Translational Oncogenomics, CRUK Manchester Institute and Centre, Division of Cancer Sciences, University of Manchester, UK.

Radiotherapy has been optimized over the last decades not only through technological advances, but also through the translation of biological knowledge into clinical treatment schedules. Optimization of fractionation schedules and/or the introduction of simultaneous combined systemic treatment have significantly improved tumour cure rates in several cancer types. With modern techniques, we are currently able to measure factors of radiation resistance or radiation sensitivity in patient tumours; the definition of new biomarkers is expected to further enable personalized treatments. In this Review article, we overview important translation paths and summarize the quality requirements for preclinical and translational studies that will help to avoid bias in trial results.
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http://dx.doi.org/10.1002/1878-0261.12671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332213PMC
July 2020

The Image Biomarker Standardization Initiative: Standardized Quantitative Radiomics for High-Throughput Image-based Phenotyping.

Radiology 2020 05 10;295(2):328-338. Epub 2020 Mar 10.

From OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Fetscherstr 74, PF 41, 01307 Dresden, Germany (A.Z., S. Leger, E.G.C.T., C.R., S. Löck); National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany (A.Z.); Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz Association/Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany (A.Z., S. Leger, E.G.C.T.); German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany (A.Z., S. Leger, E.G.C.T., C.R., S. Löck); Medical Physics Unit, McGill University, Montréal, Canada (M.V., I.E.N.); Image Response Assessment Team Core Facility, Moffitt Cancer Center, Tampa, Fla (M.A.A.); Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Harvard University, Boston, Mass (H.J.W.L.A.); Institute of Information Systems, University of Applied Sciences Western Switzerland (HES-SO), Sierre, Switzerland (V.A., A.D., H.M.); Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY (A.A.); Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, Md (S.A.); Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Md (S.A., A.R.); Center for Biomedical image Computing and Analytics (CBICA), University of Pennsylvania, Philadelphia, Pa (S.B., C.D., S.M.H., S.P.); Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (S.B., C.D., S.M.H., S.P.); Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (S.B.); Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen (UMCG), Groningen, the Netherlands (R.J.B., R.B., E.A.G.P.); Radiology and Nuclear Medicine, VU University Medical Centre (VUMC), Amsterdam, the Netherlands (R.B.); Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (M.B., M.Guckenberger, S.T.L.); Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy (L.B., N.D., R.G., J.L., V.V.); Laboratoire d'Imagerie Translationnelle en Oncologie, Université Paris Saclay, Inserm, Institut Curie, Orsay, France (I.B., C.N., F.O.); Cancer Imaging Dept, School of Biomedical Engineering and Imaging Sciences, King's College London, London, United Kingdom (G.J.R.C., V.G., M.M.S.); Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital, Lausanne, Switzerland (A.D.); Laboratory of Medical Information Processing (LaTIM)-team ACTION (image-guided therapeutic action in oncology), INSERM, UMR 1101, IBSAM, UBO, UBL, Brest, France (M.C.D., M.H., T.U.); Department of Radiation Oncology, the Netherlands Cancer Institute (NKI), Amsterdam, the Netherlands (C.V.D.); Department of Radiology, Stanford University School of Medicine, Stanford, Calif (S.E., S.N.); Department of Radiation Oncology, Physics Division, University of Michigan, Ann Arbor, Mich (I.E.N., A.U.K.R.); Surgical Planning Laboratory, Brigham and Women's Hospital and Harvard Medical School, Harvard University, Boston, Mass (A.Y.F.); Department of Cancer Imaging and Metabolism, Moffitt Cancer Center, Tampa, Fla (R.J.G.); Department of Medical Image Computing, German Cancer Research Center (DKFZ), Heidelberg, Germany (M. Götz, F.I., K.H.M.H., J.S.); The D-Lab, Department of Precision Medicine, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands (P.L., R.T.H.L.); Section for Biomedical Physics, Department of Radiation Oncology, University of Tübingen, Germany (F.L., J.S.F., D.T.); Department of Clinical Medicine, University of Bergen, Bergen, Norway (A.L.); Department of Radiation Oncology, University of California, San Francisco, Calif (O.M.); University of Geneva, Geneva, Switzerland (H.M.); Department of Electrical Engineering, Stanford University, Stanford, Calif (S.N.); Department of Medicine (Biomedical Informatics Research), Stanford University School of Medicine, Stanford, Calif (S.N.); Departments of Radiology and Physics, University of British Columbia, Vancouver, Canada (A.R.); Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Mich (A.U.K.R.); Department of Radiation Oncology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, the Netherlands (N.M.S., R.J.H.M.S., L.V.v.D.); School of Engineering, Cardiff University, Cardiff, United Kingdom (E.S., P.W.); Department of Medical Physics, Velindre Cancer Centre, Cardiff, United Kingdom (E.S.); Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany (E.G.C.T., C.R., S. Löck), Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, Dresden, Germany (E.G.C.T., C.R.); Department of Nuclear Medicine, CHU Milétrie, Poitiers, France (T.U.); Department of Radiology, the Netherlands Cancer Institute (NKI), Amsterdam, the Netherlands (J.v.G.); GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands (J.v.G.); Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (J.v.G.); and Department of Radiology, Leiden University Medical Center (LUMC), Leiden, the Netherlands (F.H.P.v.V.).

Background Radiomic features may quantify characteristics present in medical imaging. However, the lack of standardized definitions and validated reference values have hampered clinical use. Purpose To standardize a set of 174 radiomic features. Materials and Methods Radiomic features were assessed in three phases. In phase I, 487 features were derived from the basic set of 174 features. Twenty-five research teams with unique radiomics software implementations computed feature values directly from a digital phantom, without any additional image processing. In phase II, 15 teams computed values for 1347 derived features using a CT image of a patient with lung cancer and predefined image processing configurations. In both phases, consensus among the teams on the validity of tentative reference values was measured through the frequency of the modal value and classified as follows: less than three matches, weak; three to five matches, moderate; six to nine matches, strong; 10 or more matches, very strong. In the final phase (phase III), a public data set of multimodality images (CT, fluorine 18 fluorodeoxyglucose PET, and T1-weighted MRI) from 51 patients with soft-tissue sarcoma was used to prospectively assess reproducibility of standardized features. Results Consensus on reference values was initially weak for 232 of 302 features (76.8%) at phase I and 703 of 1075 features (65.4%) at phase II. At the final iteration, weak consensus remained for only two of 487 features (0.4%) at phase I and 19 of 1347 features (1.4%) at phase II. Strong or better consensus was achieved for 463 of 487 features (95.1%) at phase I and 1220 of 1347 features (90.6%) at phase II. Overall, 169 of 174 features were standardized in the first two phases. In the final validation phase (phase III), most of the 169 standardized features could be excellently reproduced (166 with CT; 164 with PET; and 164 with MRI). Conclusion A set of 169 radiomics features was standardized, which enabled verification and calibration of different radiomics software. © RSNA, 2020 See also the editorial by Kuhl and Truhn in this issue.
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http://dx.doi.org/10.1148/radiol.2020191145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193906PMC
May 2020

Neurocognitive function and quality of life after proton beam therapy for brain tumour patients.

Radiother Oncol 2020 02 8;143:108-116. Epub 2020 Feb 8.

OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany, and; Helmholtz Association / Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.

Background: Neurocognitive function of adult patients with brain tumours may deteriorate after radiotherapy. Proton beam therapy (PBT) reduces the volume of irradiated healthy brain tissue and could potentially preserve neurocognition and quality of life (QoL). As present data are still limited, the impact of clinical factors and dosimetric parameters on neurocognitive function and QoL during recurrence-free follow-up after PBT is investigated.

Methods: The current study includes 62 brain tumour patients treated with PBT between 2015 and 2017. Neurocognition and QoL were assessed at baseline and every 3 months after PBT using the Montreal Cognitive Assessment (MoCA) test together with EORTC-QLQ-C30 and BN20 questionnaires, respectively. Objective and self-reported measures of neurocognitive functions were correlated. During two years of follow-up, the impact of clinical co-factors as well as dosimetric parameters of several brain structures were analysed using a mixed-model approach.

Results: At baseline, mean MoCA total score was 24.8/30 and self-reported cognitive function was 68.9/100. Both remained stable over time. Patients with impaired neurocognition on the MoCA test reported significantly lower global health status, cognitive, physical and role function as well as more fatigue, pain, headache and communication deficits compared to normal performing patients. For most follow-up time points, the majority of MoCA subitems correlated significantly to QoL items regarding neurocognition. Slight deterioration of the MoCA score was associated with tumours located in the left hemisphere and with an increase in relative volume of the anterior cerebellum that received doses of 30-40 Gy(RBE).

Conclusion: Self-reported and objectively measured neurocognition and most other QoL domains remained largely stable over time during recurrence-free follow-up for brain tumour patients treated with PBT. The association between reduced cognitive function and irradiated volume of the anterior cerebellum requires validation in larger studies and comparison to patients treated with photon therapy.
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http://dx.doi.org/10.1016/j.radonc.2019.12.024DOI Listing
February 2020

Photons or protons for reirradiation in (non-)small cell lung cancer: Results of the multicentric ROCOCO study.

Br J Radiol 2020 Mar 20;93(1107):20190879. Epub 2019 Dec 20.

Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.

Objective: Locally recurrent disease is of increasing concern in (non-)small cell lung cancer [(N)SCLC] patients. Local reirradiation with photons or particles may be of benefit to these patients. In this multicentre in trial performed within the Radiation Oncology Collaborative Comparison (ROCOCO) consortium, the doses to the target volumes and organs at risk (OARs) were compared when using several photon and proton techniques in patients with recurrent localised lung cancer scheduled to undergo reirradiation.

Methods: 24 consecutive patients with a second primary (N)SCLC or recurrent disease after curative-intent, standard fractionated radio(chemo)therapy were included in this study. The target volumes and OARs were centrally contoured and distributed to the participating ROCOCO sites. Remaining doses to the OARs were calculated on an individual patient's basis. Treatment planning was performed by the participating site using the clinical treatment planning system and associated beam characteristics.

Results: Treatment plans for all modalities (five photon and two proton plans per patient) were available for 22 patients ( = 154 plans). 3D-conformal photon therapy and double-scattered proton therapy delivered significantly lower doses to the target volumes. The highly conformal techniques, ., intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), CyberKnife, TomoTherapy and intensity-modulated proton therapy (IMPT), reached the highest doses in the target volumes. Of these, IMPT was able to statistically significantly decrease the radiation doses to the OARs.

Conclusion: Highly conformal photon and proton beam techniques enable high-dose reirradiation of the target volume. They, however, significantly differ in the dose deposited in the OARs. The therapeutic options, ., reirradiation or systemic therapy, need to be carefully weighed and discussed with the patients.

Advances In Knowledge: Highly conformal photon and proton beam techniques enable high-dose reirradiation of the target volume. In light of the abilities of the various highly conformal techniques to spare specific OARs, the therapeutic options need to be carefully weighed and patients included in the decision-making process.
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http://dx.doi.org/10.1259/bjr.20190879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066965PMC
March 2020

Dose-volume predictors of early esophageal toxicity in non-small cell lung cancer patients treated with accelerated-hyperfractionated radiotherapy.

Radiother Oncol 2020 02 22;143:44-50. Epub 2019 Nov 22.

OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background And Purpose: Early radiation-induced esophageal toxicity (RIET) is one of the major side effects in patients with non-small cell lung cancer (NSCLC) and can be a reason for treatment interruptions. As the age of patients with NSCLC and corresponding comorbidities continue to increase, primary radiotherapy alone is a commonly used alternative treatment in these cases. The aim of the present study is to compare dosimetric and clinical parameters from the previously reported CHARTWEL trial for their ability to predict esophagitis and investigate potential differences in the accelerated and conventional fractionation arm.

Material And Methods: 146 patients of the Dresden cohort of the randomized phase III CHARTWEL trial were included in this post-hoc analysis. Side effects were prospectively scored weekly during the first 8 weeks from start of radiotherapy. To compare both treatment arms, recorded dose-volume parameters were adjusted for the different fractionation schedules. Logistic regression was performed to predict early RIET for the entire study group as well as for the individual treatment arms. Different dosimetric and clinical parameters were tested.

Results: Patients receiving the accelerated CHARTWEL schedule experienced earlier and more severe esophagitis (e.g. 20.5% vs. 9.6% ≥grade 2 at week 3, respectively). In contrast, the median time period for recovery of grade 1 esophagitis was significantly longer for patients with conventional fractionation compared to the CHARTWEL group (median [range]: 21 [12-49] days vs. 15 [7-84] days, p = 0.028). In univariable logistic regression none of the dose-volume parameters showed a significant correlation with early RIET grade ≥ 2 in the conventional irradiation group. In contrast, for patients receiving CHARTWEL, the physical dose-volumes parameters V and V; and re-scaled values V and V were significant predictors of early RIET grade ≥ 2. Dose-volume parameters remained different between CHARTWEL and conventional fractionation even after biological rescaling.

Conclusion: Our results show a more dominant dose-volume effect in the CHARTWEL arm compared to conventional fractionation, especially for higher esophageal doses. These findings support the notion that dose-volume parameters for radiation esophagitis determined in a specific and time dependent setting of field arrangements can not be easily transferred to another setting. In clinical practice esophageal volumes receiving 40 Gy or more should be strictly limited in hyperfractionated-accelerated fraction schemes.
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http://dx.doi.org/10.1016/j.radonc.2019.11.002DOI Listing
February 2020

Analysing Tumour Growth Delay Data from Animal Irradiation Experiments with Deviations from the Prescribed Dose.

Cancers (Basel) 2019 Aug 31;11(9). Epub 2019 Aug 31.

OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany.

The development of new radiotherapy technologies is a long-term process, which requires proof of the general concept. However, clinical requirements with respect to beam quality and controlled dose delivery may not yet be fulfilled. Exemplarily, the necessary radiobiological experiments with laser-accelerated electrons are challenged by fluctuating beam intensities. Based on tumour-growth data and dose values obtained in an in vivo trial comparing the biological efficacy of laser-driven and conventional clinical Linac electrons, different statistical approaches for analysis were compared. In addition to the classical averaging per dose point, which excludes animals with high dose deviations, multivariable linear regression, Cox regression and a Monte-Carlo-based approach were tested as alternatives that include all animals in statistical analysis. The four methods were compared based on experimental and simulated data. All applied statistical approaches revealed a comparable radiobiological efficacy of laser-driven and conventional Linac electrons, confirming the experimental conclusion. In the simulation study, significant differences in dose response were detected by all methods except for the conventional method, which showed the lowest power. Thereby, the alternative statistical approaches may allow for reducing the total number of required animals in future pre-clinical trials.
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http://dx.doi.org/10.3390/cancers11091281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769440PMC
August 2019

The prevalence of extramedullary acute myeloid leukemia detected by FDG-PET/CT: final results from the prospective PETAML trial.

Haematologica 2020 06 29;105(6):1552-1558. Epub 2019 Aug 29.

Department of Nuclear Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Extramedullary (EM) disease in patients with acute myeloid leukemia (AML) is a known phenomenon. Since the prevalence of EM AML has so far only been clinically determined on examination, we performed a prospective study in patients with AML. The aim of the study was to determine the prevalence of metabolically active EM AML using total body Fluorodesoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) imaging at diagnosis prior to initiation of therapy. In order to define the dynamics of EM AML throughout treatment, PET-positive patients underwent a second FDG-PET/CT imaging series during follow up by the time of remission assessment. A total of 93 patients with AML underwent FDG-PET/CT scans at diagnosis. The prevalence of PET-positive EM AML was 19% with a total of 65 EM AML manifestations and a median number of two EM manifestations per patient (range, 1-12), with a median maximum standardized uptake value of 6.1 (range, 2-51.4). When adding those three patients with histologically confirmed EM AML who were FDG-PET/CT negative in the FDG-PET/CT at diagnosis, the combined prevalence for EM AML was 22%, resulting in 77% sensitivity and 97% specificity. Importantly, 60% (6 of 10) patients with histologically confirmed EM AML still had active EM disease in their follow up FDG-PET/CT. FDG-PET/CT reveals a high prevalence of metabolically active EM disease in AML patients. Metabolic activity in EM AML may persist even beyond the time point of hematologic remission, a finding that merits further prospective investigation to explore its prognostic relevance. (Trial registered ).
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http://dx.doi.org/10.3324/haematol.2019.223032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271590PMC
June 2020

Comparable radiation response of ex vivo and in vivo irradiated tumor samples determined by residual γH2AX.

Radiother Oncol 2019 10 21;139:94-100. Epub 2019 Aug 21.

OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Purpose: a) To investigate if an ex vivo cultured and irradiated tumor biopsy reflects and predicts the radiation response of the corresponding in vivo irradiated tumor measured with the DNA double strand break marker γH2AX foci.

Materials And Methods: Five human head and neck squamous cell carcinoma (hHNSCC) xenograft models were used. Fine needle biopsies were taken from anesthetized tumor-bearing NMRI nude mice prior to in vivo single dose irradiation (0, 2, 4, or 8 Gy) under ambient blood flow. Biopsies were ex vivo reoxygenated and irradiated with equivalent doses. Tumors and biopsies were fixed 24 h post irradiation, and γH2AX foci were assessed in oxygenated tumor regions.

Results: Linear regression analysis showed comparable slopes of the residual γH2AX foci dose-response curves in four out of five hHNSCC models when in vivo and ex vivo cohorts were compared. The slopes from ex vivo biopsies and in vivo tumors could classify the respective tumor model as sensitive or resistant according to the intrinsic radiation sensitivity (TCD).

Conclusion: The ability of ex vivo irradiated tumor biopsies to reflect and predict the intrinsic radiation response of in vivo tumors increases the translational potential of the ex vivo γH2AX foci assay as a diagnostic tool for clinical practice.
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http://dx.doi.org/10.1016/j.radonc.2019.06.038DOI Listing
October 2019