TY - JOUR AB - BACKGROUND: We explored the dynamic changes of major leukocyte subsets during definitive treatment of patients with inoperable stage II/III NSCLC lung cancer and correlated it to survival to identify subpopulations associated with maximal patient benefit. METHODS: We analyzed peripheral blood of 20 patients, either treated with thoracic radiotherapy (RT), concurrent chemo-radiotherapy (cCRT), or cCRT with additional immune-checkpoint inhibition therapy. Peripheral blood of 20 patients was collected at 9 timepoints before, during, and up to 1 year post treatment and analyzed by multi-color flow cytometry. Statistical analysis was conducted for leukocyte subpopulations, IL-6, progression-free survival (PFS) and overall survival (OS). RESULTS: Increase of absolute lymphocyte counts (ALC) after the end of RT until 6 months thereafter was a predictor of PFS. Baseline lymphocyte counts showed no significant correlation to PFS or OS. Early recovery of absolute counts (AC) at 3 weeks after RT, total CD3 + T-cells, and CD8 + cytotoxic T-cells distinguished those patients with favorable PFS (≥ 12 months) from all other patients. Discriminant analysis identified B-cells, neutrophil-lymphocyte-ratio (NLR), CD4 + T-helper-cells, and NK-cells as predictors of favorable PFS. High variability in IL-6 plasma concentration of consecutive measurements within 6 months after the end of RT correlated negatively with PFS. CONCLUSION: Our results suggest that two parameters commonly assessed in clinical routine can be used to predict patient outcome. These are: early increase in CD8 + T-cell lymphocyte count and variability in IL-6 plasma concentration, that are correlated to patients with favorable, respectively, poor outcome after definitive therapy independent of treatment regimen. AU - Hofer, T.P. AU - Nieto, A.E.* AU - Käsmann, L.* AU - Pelikan, C. AU - Taugner, J.* AU - Mathur, S. AU - Eze, C.* AU - Belka, C.* AU - Manapov, F.* AU - Nößner, E. C1 - 73730 C2 - 57198 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Early recovery of leukocyte subsets is associated with favorable progression-free survival in patients with inoperable stage II/III NSCLC after multimodal treatment: A prospective explorative study. JO - Radiat. Oncol. VL - 20 IS - 1 PB - Bmc PY - 2025 SN - 1748-717X ER - TY - JOUR AB - BACKGROUND: Lung cancer primarily affects elderly individuals and is the leading cause of cancer-related death in people aged 80 years and older. In addition, the incidence of multiple primary lung cancer (MPLC) is increasing worldwide. Although surgery is recommended as the standard of care, many elderly patients are considered medically unsuitable, or they refuse surgery. The role of stereotactic body radiotherapy (SBRT) as an alternative treatment option for these elderly patients, particularly those with multiple primary lung cancer, has not been fully elucidated. Therefore, the aim of this study was to report the outcome and toxicities associated with SBRT for histologically confirmed early-stage non-small cell lung cancer (NSCLC) and synchronous and metachronous multiple primary lung cancer in patients aged ≥ 80 years. METHODS: This retrospective study included 118 patients aged ≥ 80 years with a total of 141 SBRT-treated primary lung cancers (19 patients with MPLC). We assessed local control (LC), progression-free survival (PFS), overall survival (OS) and cancer-specific survival (CSS). We further evaluated toxicities and factors impacting therapeutic efficacy. RESULTS: The median follow-up after SBRT was 47 months (range 3-169 months). The LC rate was 96.2% (95% CI: 90.1 to 98.6%) two years and 86.4% (71.8 to 93.8%) five years after SBRT for NSCLC/MPLC. The PFS and OS rates were 67.0% (57.4 to - 74.9%) and 74.7% (65.4 to - 81.1%), respectively, after two years and 24.7% (14.5 to 35.6%) and 30.2% (19.4 to 41.7%), respectively, after five years. The CSS rate was 88.6% (80.3-93.6%) at two years and 76.6% (61.4-86.4%) at 5 years after SBRT. Age and the Charlson Comorbidity Index score were found to be independent predictors of OS and PFS. Predictors other than these patient-related factors could not be identified. Toxicities higher than Grade 2 after SBRT of NSCLC and MPLC were not observed. CONCLUSION: This study emphasises the efficacy and safety of SBRT in the treatment of early-stage NSCLC in patients aged ≥ 80 years, including those with MPLC. SBRT proves to be an appropriate treatment modality for this frail patient group, as it provides favourable LC and CSS rates with low toxicity. AU - Vorbach, S.M.* AU - Seppi, T.* AU - Peeken, J.C. AU - Sarcletti, M.* AU - Pointner, M.* AU - Hörmandinger, K.* AU - Mangesius, J.* AU - Nevinny-Stickel, M.* AU - Ganswindt, U.* C1 - 75178 C2 - 57842 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Stereotactic body radiotherapy for single and multiple early-stage non-small cell lung cancer in patients aged ≥ 80 years. JO - Radiat. Oncol. VL - 20 IS - 1 PB - Bmc PY - 2025 SN - 1748-717X ER - TY - JOUR AB - BACKGROUND: Post-Therapy-Pneumonitis (PTP) is a critical side effect of both, thoracic radio(chemo)therapy (R(C)T) and immune checkpoint inhibition (ICI). However, disease characteristics and patient-specific risk factors of PTP after combined R(C)T + ICI are less understood. Given that RT-triggered PTP is strongly dependent on the volume and dose of RT [1], driven by inflammatory mechanisms, we hypothesize that combination therapy of R(C)T with ICI influences the dose-volume-effect correlation for PTP. This study focuses on the development of a method for evaluation of alterations of dosimetric parameters for PTP after R(C)T with and without ICI. METHODS AND MATERIALS: PTP volumes were delineated on the follow-up diagnostic Computed Tomography (CT) and deformably matched to the planning CT for patients with PTP after thoracic R(C)T + ICI or R(C)T. Dose data was converted to 2-Gy equivalent doses (EQD2) and dosimetrically analyzed. Dosimetric and volumetric parameters of the segmented PTP volumes were analyzed. The method was exemplarily tested on an internal patient cohort including 90 patients having received thoracic R(C)T + ICI (39) and R(C)T (51). Thirtytwo patients with PTP were identified for further analysis. Additional data on previous chemotherapy, RT, smoking status and pulmonary co-morbidity were conducted. A matched pair analysis with regard to planning target volumes (PTV) was conducted for curative intended (definitive) and palliative patient cohorts individually. RESULTS: The presented method was able to quantify and compare the dosimetric parameters of PTP for the different therapies. For our study group, no significant differences between R(C)T + ICI and R(C)T only was observed. However, the dosimetric analysis revealed large volumetric fractions (55%) of the PTP volumes to be located outside of high dose (EQD2 < 40 Gy) regions for R(C)T + ICI. There was a non-significant trend towards increased area under the curve of the dose volume histogram (AUC) values for R(C)T + ICI compared to R(C)T only (3743.6 Gy∙% vs. 2848.8 Gy∙%; p-value = 0.171). In contrast to the data for the palliative intended treatment group, for definitive R(C)T + ICI, data tended towards increased volumes with higher doses. CONCLUSIONS: The proposed method was capable to quantify dosimetric differences in the dose-volume-effect relationship of PTP for patients with R(C)T + ICI and patients with R(C)T only. In this exploratory analysis, no significant dosimetric differences within PTP volumes for the different groups could be observed. However, our observations suggest, that for safe application of thoracic R(C)T + ICI, further careful investigation of dosimetric prescription and analysis concepts with larger and conformer study groups is recommendable. AU - Kraus, K.M. AU - Bauer, C.* AU - Steinhelfer, L.* AU - Feuerecker, B.* AU - Martins, J.C.* AU - Fischer, J.C.* AU - Borm, K.J.* AU - Peeken, J.C. AU - Bernhardt, D.* AU - Combs, S.E. C1 - 72480 C2 - 56611 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Pneumonitis after normofractionated radioimmunotherapy: A method for dosimetric evaluation. JO - Radiat. Oncol. VL - 19 IS - 1 PB - Bmc PY - 2024 SN - 1748-717X ER - TY - JOUR AB - BACKGROUND: Approximately 25-50% of patients undergoing radiotherapy (RT) experience psychological distress and anxiety, which can detrimentally affect both their quality of life and treatment outcomes. While previous research has demonstrated that relaxation exercises can enhance the tolerability of RT and alleviate associated stress and anxiety, the specific needs for such therapies in radiation oncology remain under-explored. This study aims to investigate the demand for and preferences toward relaxation exercises among radiotherapy patients, addressing a critical gap in patient-centered care. METHODS: A prospective pseudonymized survey study using a one-time paper-based questionnaire was conducted from 2022 to 2023 among patients undergoing curative-intent RT for breast cancer or patients undergoing palliative RT for bone metastases. Patients were asked in a 11-item questionnaire about their anxiety, pre-existing practice of relaxation exercises/interventions, their interest in relaxation exercises, and preferences on the type and format of instruction. Data were analyzed descriptively. RESULTS: 100 patients (74 female and 26 male) responded, of whom 68 received curative-intent adjuvant RT and 32 palliative RT. Median age was 62 years. 78% of patients indicated a desire to be actively involved in their radiotherapy, but only 27% had used relaxation exercises prior to RT. 44.8% of both curatively and palliatively treated patients who wanted to be actively involved in their therapy desired to learn how to best relax. 56.4% of respondents were willing to spend extra time learning offered exercises. CONCLUSION: The survey indicates that patients undergoing RT, both for curative or palliative intent, desire relaxation exercises to relieve stress and anxiety from RT. It is therefore important to assess the need for relaxation interventions in individual patients and to develop suitable programs or collaborate with other healthcare professionals to meet these needs. AU - Moser, R.* AU - Mayr, N.A.* AU - Nano, J.* AU - Behzadi, S.T.* AU - Kiesl, S.* AU - Combs, S.E. AU - Borm, K.J.* C1 - 70785 C2 - 55893 CY - Campus, 4 Crinan St, London N1 9xw, England TI - A survey of cancer patients' interest in undertaking exercise to promote relaxation during radiotherapy for breast cancer and metastatic cancer. JO - Radiat. Oncol. VL - 19 IS - 1 PB - Bmc PY - 2024 SN - 1748-717X ER - TY - JOUR AB - BACKGROUND: An enhanced aerobic glycolysis ("Warburg effect") associated with an increase in lactic acid in the tumor microenvironment contributes to tumor aggressiveness and resistance to radiation and chemotherapy. We investigated the radiation- and chemo-sensitizing effects of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac in different cancer cell types. METHODS: The effects of a non-lethal concentration of diclofenac was investigated on c-MYC and Lactate Dehydrogenase (LDH) protein expression/activity and the Heat shock Protein (HSP)/stress response in human colorectal (LS174T, LoVo), lung (A549), breast (MDA-MB-231) and pancreatic (COLO357) carcinoma cells. Radiation- and chemo-sensitization of diclofenac was determined using clonogenic cell survival assays and a murine xenograft tumor model. RESULTS: A non-lethal concentration of diclofenac decreases c-MYC protein expression and LDH activity, reduces cytosolic Heat Shock Factor 1 (HSF1), Hsp70 and Hsp27 levels and membrane Hsp70 positivity in LS174T and LoVo colorectal cancer cells, but not in A549 lung carcinoma cells, MDA-MB-231 breast cancer cells and COLO357 pancreatic adenocarcinoma cells. The impaired lactate metabolism and stress response in diclofenac-sensitive colorectal cancer cells was associated with a significantly increased sensitivity to radiation and 5Fluorouracil in vitro, and in a human colorectal cancer xenograft mouse model diclofenac causes radiosensitization. CONCLUSION: These findings suggest that a decrease in the LDH activity and/or stress response upon diclofenac treatment predicts its radiation/chemo-sensitizing capacity. AU - Schwab, M.* AU - Dezfouli, A.B.* AU - Khosravi, M.* AU - Alkotub, Ab. AU - Bauer, L.* AU - Birgani, M.J.T.* AU - Multhoff, G.* C1 - 69828 C2 - 55270 CY - Campus, 4 Crinan St, London N1 9xw, England TI - The radiation- and chemo-sensitizing capacity of diclofenac can be predicted by a decreased lactate metabolism and stress response. JO - Radiat. Oncol. VL - 19 IS - 1 PB - Bmc PY - 2024 SN - 1748-717X ER - TY - JOUR AB - BACKGROUND: Soft tissue sarcomas (STS) are a relatively rare group of malignant tumors. Currently, there is very little published clinical data, especially in the context of curative multimodal therapy with image-guided, conformal, intensity-modulated radiotherapy. METHODS: Patients who received preoperative or postoperative intensity-modulated radiotherapy for STS of the extremities or trunk with curative intent were included in this single centre retrospective analysis. A Kaplan-Meier analysis was performed to evaluate survival endpoints. Multivariable proportional hazard models were used to investigate the association between survival endpoints and tumour-, patient-, and treatment-specific characteristics. RESULTS: 86 patients were included in the analysis. The most common histological subtypes were undifferentiated pleomorphic high-grade sarcoma (UPS) (27) and liposarcoma (22). More than two third of the patients received preoperative radiation therapy (72%). During the follow-up period, 39 patients (45%) suffered from some type of relapse, mainly remote (31%). The two-years overall survival rate was 88%. The median DFS was 48 months and the median DMFS was 51 months. Female gender (HR 0.460 (0.217; 0.973)) and histology of liposarcomas compared to UPS proved to be significantly more favorable in terms of DFS (HR 0.327 (0.126; 0.852)). CONCLUSION: Conformal, intensity-modulated radiotherapy is an effective treatment modality in the preoperative or postoperative management of STS. Especially for the prevention of distant metastases, the establishment of modern systemic therapies or multimodal therapy approaches is necessary. AU - Dapper, H.* AU - Diehl, C.* AU - Knebel, C.* AU - Mogler, C.* AU - Borm, K.* AU - Dobiasch, S. AU - Combs, S.E. AU - Peeken, J.C. C1 - 67559 C2 - 54070 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Outcome of patients with soft tissue sarcomas of the extremities and trunk treated by (neo)adjuvant intensity modulated radiation therapy with curative intent. JO - Radiat. Oncol. VL - 18 IS - 1 PB - Bmc PY - 2023 SN - 1748-717X ER - TY - JOUR AB - 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. AU - Schnöller, L.E.* AU - Piehlmaier, D. AU - Weber, P. AU - Brix, N.* AU - Fleischmann, D.F.* AU - Nieto, A.E.* AU - Selmansberger, M. AU - Heider, T. AU - Hess J. AU - Niyazi, M.* AU - Belka, C. AU - Lauber, K. AU - Unger, K. AU - Orth, M.* C1 - 67734 C2 - 54042 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Systematic in vitro analysis of therapy resistance in glioblastoma cell lines by integration of clonogenic survival data with multi-level molecular data. JO - Radiat. Oncol. VL - 18 IS - 1 PB - Bmc PY - 2023 SN - 1748-717X ER - TY - JOUR AB - Background Current literature lacks a comparison of lymph node metastases and non-pathological lymph nodes distribution in breast cancer patients. The aim of the current retrospective study was to generate a comprehensive atlas of the lymph node system. Methods 143 breast cancer patients underwent F-18-FDG-PET/CT (PET/CT) imaging for staging purposes and were diagnosed with regional lymph node metastases. Based on the PET/CT data set a total of 326 lymph node metastases and 1826 non-pathological lymph nodes were detected and contoured manually in the patient collective. Using rigid and deformable registration algorithms all structures were transferred to a template planning CT of a standard patient. Subsequently, a 3D-atlas of the distribution of lymph node metastases and non-pathological lymph nodes were generated and compared to each other. Results Both, lymph node metastases and non-pathological lymph nodes, accumulated in certain areas ("hot-spots") within the lymphatic drainage system. However large differences regarding the distribution patterns were detected: lymph node metastases hot spots occurred in close proximity to the subclavian vein in level I-III, whereas the non-pathological lymph nodes accumulated mostly (within a wider range) in level I. In level II and III lymph node metastases exceeded clearly the areas in which non-pathological lymph nodes occurred. Conclusion Lymph node metastases and non-pathological lymph node distribution within the lymph node system differ clearly. Based on our results, an individual adjustment of the CTV in order to include visible lymph nodes in level II and III should be discussed. AU - Borm, K.J.* AU - Ernst, L.* AU - Voppichler, J.* AU - Oechsner, M.* AU - Duesberg, M.* AU - Buschner, G.* AU - Weber, W.* AU - Combs, S.E. AU - Duma, M.N.* C1 - 64320 C2 - 52058 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Comparison of the distribution of lymph node metastases compared to healthy lymph nodes in breast cancer. JO - Radiat. Oncol. VL - 17 IS - 1 PB - Bmc PY - 2022 SN - 1748-717X ER - TY - JOUR AB - 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. AU - Schnöller, L.E.* AU - Albrecht, V.* AU - Brix, N.* AU - Nieto, A.E.* AU - Fleischmann, D.F.* AU - Niyazi, M.* AU - Hess J. AU - Belka, C. AU - Unger, K. AU - Lauber, K. AU - Orth, M.* C1 - 64859 C2 - 52519 TI - Integrative analysis of therapy resistance and transcriptomic profiling data in glioblastoma cells identifies sensitization vulnerabilities for combined modality radiochemotherapy. JO - Radiat. Oncol. VL - 17 IS - 1 PY - 2022 SN - 1748-717X ER - TY - JOUR AB - 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). AU - Corradini, S.* AU - Niyazi, M.* AU - Verellen, D.* AU - Valentini, V.* AU - Walsh, S.* AU - Grosu, A.L.* AU - Lauber, K.* AU - Giaccia, A.* AU - Unger, K. AU - Debus, J.* AU - Pieters, B.R.* AU - Guckenberger, M.* AU - Senan, S.* AU - Budach, W.* AU - Rad, R.* AU - Mayerle, J.* AU - Belka, C.* C1 - 61348 C2 - 50178 CY - Campus, 4 Crinan St, London N1 9xw, England TI - X-change symposium: Status and future of modern radiation oncology-from technology to biology. JO - Radiat. Oncol. VL - 16 IS - 1 PB - Bmc PY - 2021 SN - 1748-717X ER - TY - JOUR AB - Background: Invasiveness is a major factor contributing to metastasis of tumour cells. Given the broad variety and plasticity of invasion mechanisms, assessing potential metastasis-promoting effects of irradiation for specific mechanisms is important for further understanding of potential adverse effects of radiotherapy. In fibroblast-led invasion mechanisms, fibroblasts produce tracks in the extracellular matrix in which cancer cells with epithelial traits can follow. So far, the influence of irradiation on this type of invasion mechanisms has not been assessed. Methods: By matrix-embedding coculture spheroids consisting of breast cancer cells (MCF-7, BT474) and normal fibroblasts, we established a model for fibroblast-led invasion. To demonstrate applicability of this model, spheroid growth and invasion behaviour after irradiation with 5 Gy were investigated by microscopy and image analysis. Results: When not embedded, irradiation caused a significant growth delay in the spheroids. When irradiating the spheroids with 5 Gy before embedding, we find comparable maximum migration distance in fibroblast monoculture and in coculture samples as seen in unirradiated samples. Depending on the fibroblast strain, the number of invading cells remained constant or was reduced. Conclusion: In this spheroid model and with the cell lines and fibroblast strains used, irradiation does not have a major invasion-promoting effect. 3D analysis of invasiveness allows to uncouple effects on invading cell number and maximum invasion distance when assessing radiation effects. AU - Mei, J.* AU - Böhland, C.* AU - Geiger, A.* AU - Baur, I.* AU - Berner, K.* AU - Heuer, S. AU - Liu, X. AU - Mataite, L.* AU - Melo-Narváez, M.C.* AU - Özkaya, E.* AU - Rupp, A.* AU - Siebenwirth, C.* AU - Thoma, F.* AU - Kling, M.F.* AU - Friedl, A.A.* C1 - 62843 C2 - 51098 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Development of a model for fibroblast-led collective migration from breast cancer cell spheroids to study radiation effects on invasiveness. JO - Radiat. Oncol. VL - 16 IS - 1 PB - Bmc PY - 2021 SN - 1748-717X ER - TY - JOUR AB - Background: Radiochemotherapy (RCT) has been shown to induce changes in immune cell homeostasis which might affect antitumor immune responses. In the present study, we aimed to compare the composition and kinetics of major lymphocyte subsets in the periphery of patients with non-locoregional recurrent (n = 23) and locoregional recurrent (n = 9) squamous cell carcinoma of the head and neck (SCCHN) upon primary RCT. Methods: EDTA-blood of non-locoregional recurrent SCCHN patients was collected before (t0), after application of 20–30 Gy (t1), in the follow-up period 3 (t2) and 6 months (t3) after RCT. In patients with locoregional recurrence blood samples were taken at t0, t1, t2 and at the time of recurrence (t5). EDTA-blood of age-related, healthy volunteers (n = 22) served as a control (Ctrl). Major lymphocyte subpopulations were phenotyped by multiparameter flow cytometry. Results: Patients with non-recurrent SCCHN had significantly lower proportions of CD19+ B cells compared to healthy individuals before start of any therapy (t0) that dropped further until 3 months after RCT (t2), but reached initial levels 6 months after RCT (t3). The proportion of CD3+ T and CD3+/CD4+ T helper cells continuously decreased between t0 and t3, whereas that of CD8+ cytotoxic T cells and CD3+/CD56+ NK-like T cells (NKT) gradually increased in the same period of time in non-recurrent patients. The percentage of CD4+/CD25+/FoxP3+ regulatory T cells (Tregs) decreased directly after RCT, but increased above initial levels in the follow-up period 3 (t2) and 6 (t3) months after RCT. Patients with locoregional recurrence showed similar trends with respect to B, T cells and Tregs between t0 and t5. CD4+ T helper cells remained stably low between t0 and t5 in patients with locoregional recurrence compared to Ctrl. NKT/NK cell subsets (CD56+/CD69+, CD3−/CD56+, CD3−/CD94+, CD3−/NKG2D+, CD3−/NKp30+, CD3−/NKp46+) increased continuously up to 6 months after RCT (t0-t3) in patients without locoregional recurrence, whereas in patients with locoregional recurrence, these subsets remained stably low until time of recurrence (t5). Conclusion: Monitoring the kinetics of lymphocyte subpopulations especially activatory NK cells before and after RCT might provide a clue with respect to the development of an early locoregional recurrence in patients with SCCHN. However, studies with larger patient cohorts are needed. Trial registration: Observational Study on Biomarkers in Head and Neck Cancer (HNprädBio), NCT02059668. Registered on 11 February 2014, https://clinicaltrials.gov/ct2/show/NCT02059668. AU - Niu, M.* AU - Combs, S.E. AU - Baumann, M.* AU - Tinhofer, I.* AU - Budach, V.* AU - Von der Grün, J.* AU - Rödel, F.* AU - Grosu, A.L.* AU - Multhoff, G.* C1 - 62732 C2 - 51028 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Comparison of the composition of lymphocyte subpopulations in non-relapse and relapse patients with squamous cell carcinoma of the head and neck before, during radiochemotherapy and in the follow-up period: A multicenter prospective study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG). JO - Radiat. Oncol. VL - 16 IS - 1 PB - Bmc PY - 2021 SN - 1748-717X ER - TY - JOUR AB - BACKGROUND: Positron emission tomography-(PET) has evolved as a powerful tool to guide treatment for prostate cancer (PC). The aim of this survey was to evaluate the acceptance and use of PET-especially with prostate-specific membrane antigen (PSMA) targeting tracers-in clinical routine for radiotherapy (RT) and the impact on target volume definition and dose prescription. METHODS: We developed an online survey, which we distributed via e-mail to members of the German Society of Radiation Oncology (DEGRO). The survey included questions on patterns of care of RT for PC with/without PET. For evaluation of doses we used the equivalent dose at fractionation of 2 Gy with α/β = 1.5 Gy [EQD2(1.5 Gy)]. RESULTS: From 109 participants, 78.9% have the possibility to use PET for RT planning. Most centers use PSMA-targeting tracers (98.8%). In 39.5%, PSMA-PET for biochemical relapse after prior surgery is initiated at PSA ≥ 0.5 ng/mL, while 30.2% will perform PET at ≥ 0.2 ng/mL (≥ 1.0 ng/mL: 16.3%, ≥ 2.0 ng/mL: 2.3%, regardless of PSA: 11.7%). In case of PET-positive local recurrence (LR) and pelvic lymph nodes (LNs), 97.7% and 96.5% of the participants will apply an escalated dose. The median total dose in EQD2(1.5 Gy) was 70.00 Gy (range: 56.89-85.71) for LR and 62.00 Gy (range: 52.61-80.00) for LNs. A total number of ≤ 3 (22.0%) or ≤ 5 (20.2%) distant lesions was most often described as applicable for the definition as oligometastatic PC. CONCLUSION: PSMA-PET is widely used among German radiation oncologists. However, specific implications on treatment planning differ among physicians. Therefore, further trials and guidelines for PET-based RT are warranted. AU - Vogel, M.M. AU - Dewes, S.* AU - Sage, E.K.* AU - Devecka, M.* AU - Gschwend, J.E.* AU - Eiber, M.* AU - Combs, S.E. AU - Schiller, K.* C1 - 61957 C2 - 50535 CY - Campus, 4 Crinan St, London N1 9xw, England TI - A survey among German-speaking radiation oncologists on PET-based radiotherapy of prostate cancer. JO - Radiat. Oncol. VL - 16 IS - 1 PB - Bmc PY - 2021 SN - 1748-717X ER - TY - JOUR AB - Background The clonogenic assay is a versatile and frequently used tool to quantify reproductive cell survival in vitro. Current state-of-the-art analysis relies on plating efficiency-based calculations which assume a linear correlation between the number of cells seeded and the number of colonies counted. The present study was designed to test the validity of this assumption and to evaluate the robustness of clonogenic survival results obtained. Methods A panel of 50 established cancer cell lines was used for comprehensive evaluation of the clonogenic assay procedure and data analysis. We assessed the performance of plating efficiency-based calculations and examined the influence of critical experimental parameters, such as cell density seeded, assay volume, incubation time, as well as the cell line-intrinsic factor of cellular cooperation by auto-/paracrine stimulation. Our findings were integrated into a novel mathematical approach for the analysis of clonogenic survival data. Results For various cell lines, clonogenic growth behavior failed to be adequately described by a constant plating efficiency, since the density of cells seeded severely influenced the extent and the dynamics of clonogenic growth. This strongly impaired the robustness of survival calculations obtained by the current state-of-the-art method using plating efficiency-based normalization. A novel mathematical approach utilizing power regression and interpolation of matched colony numbers at different irradiation doses applied to the same dataset substantially reduced the impact of cell density on survival results. Cellular cooperation was observed to be responsible for the non-linear clonogenic growth behavior of a relevant number of cell lines and the impairment of survival calculations. With 28/50 cell lines of different tumor entities showing moderate to high degrees of cellular cooperation, this phenomenon was found to be unexpectedly common. Conclusions Our study reveals that plating efficiency-based analysis of clonogenic survival data is profoundly compromised by cellular cooperation resulting in strongly underestimated assay-intrinsic errors in a relevant proportion of established cancer cell lines. This severely questions the use of plating efficiency-based calculations in studies aiming to achieve more than semiquantitative results. The novel approach presented here accounts for the phenomenon of cellular cooperation and allows the extraction of clonogenic survival results with clearly improved robustness. AU - Brix, N.* AU - Samaga, D. AU - Hennel, R.* AU - Gehr, K.* AU - Zitzelsberger, H. AU - Lauber, K. C1 - 60429 C2 - 49248 CY - Campus, 4 Crinan St, London N1 9xw, England TI - The clonogenic assay: Robustness of plating efficiency-based analysis is strongly compromised by cellular cooperation. JO - Radiat. Oncol. VL - 15 IS - 1 PB - Bmc PY - 2020 SN - 1748-717X ER - TY - JOUR AB - 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. AU - Combs, S.E. AU - Belka, C.* AU - Niyazi, M.* AU - Corradini, S.* AU - Pigorsch, S.U. AU - Wilkens, J.* AU - Grosu, A.-L.* AU - Guckenberger, M.* AU - Ganswindt, U.* AU - Bernhardt, D. C1 - 58809 C2 - 48381 TI - First statement on preparation for the COVID-19 pandemic in large German Speaking University-based radiation oncology departments. JO - Radiat. Oncol. VL - 15 IS - 1 PY - 2020 SN - 1748-717X ER - TY - JOUR AB - 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. AU - Gaasch, A.* AU - Schönecker, S.* AU - Simonetto, C. AU - Eidemüller, M. AU - Pazos, M.* AU - Reitz, D.* AU - Rottler, M.* AU - Freislederer, P.* AU - Braun, M.* AU - Würstlein, R.* AU - Harbeck, N.* AU - Niyazi, M.* AU - Belka, C.* AU - Corradini, S.* C1 - 59245 C2 - 48762 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Heart sparing radiotherapy in breast cancer: The importance of baseline cardiac risks. JO - Radiat. Oncol. VL - 15 IS - 1 PB - Bmc PY - 2020 SN - 1748-717X ER - TY - JOUR AB - 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. AU - Käsmann, L.* AU - Dietrich, A.* AU - Staab-Weijnitz, C.A. AU - Manapov, F.* AU - Behr, J.* AU - Rimner, A.* AU - Jeremic, B.* AU - Senan, S.* AU - De Ruysscher, D.* AU - Lauber, K.* AU - Belka, C.* C1 - 60065 C2 - 49204 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Radiation-induced lung toxicity - cellular and molecular mechanisms of pathogenesis, management, and literature review. JO - Radiat. Oncol. VL - 15 IS - 1 PB - Bmc PY - 2020 SN - 1748-717X ER - TY - JOUR AB - Background: The ESCALOX trial was designed as a multicenter, randomized prospective dose escalation study for head and neck cancer. Therefore, feasibility of treatment planning via different treatment planning systems (TPS) and radiotherapy (RT) techniques is essential. We hypothesized the comparability of dose distributions for simultaneous integrated boost (SIB) volumes respecting the constraints by different TPS and RT techniques. Methods: CT data sets of the first six patients (all male, mean age: 61.3 years) of the pre-study (up to 77 Gy) were used for comparison of IMRT, VMAT, and helical tomotherapy (HT). Oropharynx was the primary tumor location. Normalization of the three step SIB (77 Gy, 70 Gy, 56 Gy) was D95% = 77 Gy. Coverage (CVF), healthy tissue conformity index (HTCI), conformation number (CN), and dose homogeneity (HI) were compared for PTVs and conformation index (COIN) for parotids. Results: All RT techniques achieved good coverage. For SIB77Gy, CVF was best for IMRT and VMAT, HT achieved highest CN followed by VMAT and IMRT. HT reached good HTCI value, and HI compared to both other techniques. For SIB70Gy, CVF was best by IMRT. HTCI favored HT, consequently CN as well. HI was slightly better for HT. For SIB56Gy, CVF resulted comparably. Conformity favors VMAT as seen by HTCI and CN. Dmean of ipsilateral and contralateral parotids favor HT. Conclusion: Different TPS for dose escalation reliably achieved high plan quality. Despite the very good results of HT planning for coverage, conformity, and homogeneity, the TPS also achieved acceptable results for IMRT and VMAT. Trial registration ClinicalTrials.gov Identifier: NCT 01212354, EudraCT-No.: 2010-021139-15. ARO: ARO 14-01 AU - Pigorsch, S.U.* AU - Kampfer, S.* AU - Oechsner, M.* AU - Mayinger, M.C.* AU - Mozes, P.* AU - Devecka, M.* AU - Kessel, K.K.* AU - Combs, S.E. AU - Wilkens, J.J.* C1 - 60470 C2 - 49468 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Report on planning comparison of VMAT, IMRT and helical tomotherapy for the ESCALOX-trial pre-study. JO - Radiat. Oncol. VL - 15 IS - 1 PB - Bmc PY - 2020 SN - 1748-717X ER - TY - JOUR AB - 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. AU - Samaga, D. AU - Hornung, R.* AU - Braselmann, H. AU - Hess J. AU - Zitzelsberger, H. AU - Belka, C. AU - Boulesteix, A.L.* AU - Unger, K. C1 - 59124 C2 - 48576 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Single-center versus multi-center data sets for molecular prognostic modeling: A simulation study. JO - Radiat. Oncol. VL - 15 IS - 1 PB - Bmc PY - 2020 SN - 1748-717X ER - TY - JOUR AB - BACKGROUND: Local hypofractionated stereotactic radiotherapy (HFSRT) of the resection cavity is emerging as the standard of care in the treatment of patients with a limited number of brain metastases as it warrants less neurological impairment compared to whole brain radiotherapy. In periventricular metastases surgical resection can lead to an opening of the ventricles and subsequently carries a potential risk of cerebrospinal tumour cell dissemination. The aim of this study was to assess whether local radiotherapy of the resection cavity is viable in these cases. METHODS: From our institutional database we analyzed the data of 125 consecutive patients with resected brain metastases treated in our institution with HFSRT between 2009 and 2017. The incidence of LMD, overall survival (OS), local recurrence (LC) and distant recurrence were evaluated depending on ventricular opening (VO) during surgery. RESULTS: From all 125 patients, the ventricles were opened during surgery in 14 cases (11.2%). None of the patients with VO and 7 patients without VO during surgery developed LMD (p = 0.371). OS (p = 0.817), LC (p = 0.524) and distant recurrence (p = 0.488) did not differ in relation to VO during surgical resection. However, the incidence of distant intraventricular recurrence was slightly increased in patients with VO (14.3% vs. 2.7%, p < 0.01). CONCLUSION: VO during neurosurgical resection did not affect the outcome after HFSRT of the resection cavity in patients with brain metastases. Particularly, the incidence of LMD was not increased in patients receiving local HFSRT after VO. HFSRT can therefore be offered independently of VO as a local treatment of tumor bed after resection of brain metastases. AU - Scharl, S.* AU - Kessel, K.A. AU - Diehl, C.* AU - Gempt, J.* AU - Meyer, B.* AU - Zimmer, C.* AU - Straube, C.* AU - Combs, S.E. C1 - 60764 C2 - 49534 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Is local radiotherapy a viable option for patients with an opening of the ventricles during surgical resection of brain metastases? JO - Radiat. Oncol. VL - 15 IS - 1 PB - Bmc PY - 2020 SN - 1748-717X ER - TY - JOUR AB - An amendment to this paper has been published and can be accessed via the original article. AU - Schaule, J.* AU - Kroeze, S.G.C.* AU - Blanck, O.* AU - Stera, S.* AU - Kahl, K.H.* AU - Roeder, F.* AU - Combs, S.E. AU - Kaul, D.* AU - Claes, A.* AU - Schymalla, M.M.* AU - Adebahr, S.* AU - Eckert, F.* AU - Lohaus, F.* AU - Abbasi-Senger, N.* AU - Henke, G.* AU - Szuecs, M.* AU - Geier, M.* AU - Sundahl, N.* AU - Buergy, D.* AU - Dummer, R.* AU - Guckenberger, M.* C1 - 60823 C2 - 50224 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Correction to: Predicting survival in melanoma patients treated with concurrent targeted- or immunotherapy and stereotactic radiotherapy: Melanoma brain metastases prognostic score (Radiation Oncology, (2020), 15, 1, (135), 10.1186/s13014-020-01558-8). JO - Radiat. Oncol. VL - 15 IS - 1 PB - Bmc PY - 2020 SN - 1748-717X ER - TY - JOUR AB - Background Melanoma patients frequently develop brain metastases. The most widely used score to predict survival is the molGPA based on a mixed treatment of stereotactic radiotherapy (SRT) and whole brain radiotherapy (WBRT). In addition, systemic therapy was not considered. We therefore aimed to evaluate the performance of the molGPA score in patients homogeneously treated with SRT and concurrent targeted therapy or immunotherapy (TT/IT). Methods This retrospective analysis is based on an international multicenter database (TOaSTT) of melanoma patients treated with TT/IT and concurrent (<= 30 days) SRT for brain metastases between May 2011 and May 2018. Overall survival (OS) was studied using Kaplan-Meier survival curves and log-rank testing. Uni- and multivariate analysis was performed to analyze prognostic factors for OS. Results One hundred ten patients were analyzed. 61, 31 and 8% were treated with IT, TT and with a simultaneous combination, respectively. A median of two brain metastases were treated per patient. After a median follow-up of 8 months, median OS was 8.4 months (0-40 months). The molGPA score was not associated with OS. Instead, cumulative brain metastases volume, timing of metastases (syn- vs. metachronous) and systemic therapy with concurrent IT vs. TT influenced OS significantly. Based on these parameters, the VTS score (volume-timing-systemic therapy) was established that stratified patients into three groups with a median OS of 5.1, 18.9 and 34.5 months, respectively (p = 0.001 and 0.03). Conclusion The molGPA score was not useful for this cohort of melanoma patients undergoing local therapy for brain metastases taking into account systemic TT/IT. For these patients, we propose a prognostic VTS score, which needs to be validated prospectively. AU - Schaule, J.* AU - Kroeze, S.G.C.* AU - Blanck, O.* AU - Stera, S.* AU - Kahl, K.H.* AU - Roeder, F.* AU - Combs, S.E. AU - Kaul, D.* AU - Claes, A.* AU - Schymalla, M.M.* AU - Adebahr, S.* AU - Eckert, F.* AU - Lohaus, F.* AU - Abbasi-Senger, N.* AU - Henke, G.* AU - Szuecs, M.* AU - Geier, M.* AU - Sundahl, N.* AU - Buergy, D.* AU - Dummer, R.* AU - Guckenberger, M.* C1 - 59275 C2 - 48710 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Predicting survival in melanoma patients treated with concurrent targeted- or immunotherapy and stereotactic radiotherapy Melanoma brain metastases prognostic score. JO - Radiat. Oncol. VL - 15 IS - 1 PB - Bmc PY - 2020 SN - 1748-717X ER - TY - JOUR AB - 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. AU - Schüttrumpf, L. AU - Marschner, S. AU - Scheu, K. AU - Hess J. AU - Rietzler, S. AU - Walch, A.K. AU - Baumeister, P. AU - Kirchner, T. AU - Ganswindt, U. AU - Zitzelsberger, H. AU - Belka, C. AU - Maihoefer, C. C1 - 57768 C2 - 48127 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Definitive chemoradiotherapy in patients with squamous cell cancers of the head and neck-results from an unselected cohort of the clinical cooperation group "Personalized Radiotherapy in Head and Neck Cancer". JO - Radiat. Oncol. VL - 15 IS - 1 PB - Bmc PY - 2020 SN - 1748-717X ER - TY - JOUR AB - Background: We present a functional gene association network of the CLIP2 gene, generated byde-novoreconstruction from transcriptomic microarray data. CLIP2 was previously identified as a potential marker for radiation induced papillary thyroid carcinoma (PTC) of young patients in the aftermath of the Chernobyl reactor accident. Considering the rising thyroid cancer incidence rates in western societies, potentially related to medical radiation exposure, the functional characterization of CLIP2 is of relevance and contributes to the knowledge about radiation-induced thyroid malignancies.Methods: We generated a transcriptomic mRNA expression data set from a CLIP2-perturbed thyroid cancer cell line (TPC-1) with induced CLIP2 mRNA overexpression and siRNA knockdown, respectively, followed by gene-association network reconstruction using the partial correlation-based approachGeneNet. Furthermore, we investigated different approaches for prioritizing differentially expressed genes for network reconstruction and compared the resulting networks with existing functional interaction networks from the Reactome, Biogrid and STRING databases. The derived CLIP2 interaction partners were validated on transcript and protein level.Results: The best reconstructed network with regard to selection parameters contained a set of 20 genes in the 1st neighborhood of CLIP2 and suggests involvement of CLIP2 in the biological processes DNA repair/maintenance, chromosomal instability, promotion of proliferation and metastasis. Peptidylprolyl Isomerase Like 3 (PPIL3), previously identified as a potential direct interaction partner of CLIP2, was confirmed in this study by co-expression at the transcript and protein level.Conclusion:In our study we present an optimized preselection approach for genes subjected to gene- association network reconstruction, which was applied to CLIP2 perturbation transcriptome data of a thyroid cancer cell culture model. Our data support the potential carcinogenic role of CLIP2 overexpression in radiation-induced PTC and further suggest potential interaction partners of the gene. AU - Selmansberger, M. AU - Michna, A. AU - Braselmann, H. AU - Höfig, I. AU - Schorpp, K.K. AU - Weber, P. AU - Anastasov, N. AU - Zitzelsberger, H. AU - Hess J. AU - Unger, K. C1 - 59824 C2 - 49059 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Transcriptome network of the papillary thyroid carcinoma radiation marker CLIP2. JO - Radiat. Oncol. VL - 15 IS - 1 PB - Bmc PY - 2020 SN - 1748-717X ER - TY - JOUR AB - Background Radiotherapy treatment of head and neck cancer affects local arteries and increases the risk of stroke. This study aimed at a closer characterization of this damage and its development in time with a longitudinal study set up. Methods Male patients treated between 2011 and 2016 for hypopharyngeal carcinoma were identified from the in-house clinical data base. They were included into the study if besides the planning CT at least one additional CT image was available from follow-up (13 patients) or at least two MRI scans (16 patients of which 2 were already included). All patients received radiotherapy, and chemotherapy was administered to 16 patients. The time from the beginning of radiotherapy to the last available image ranged from 2 months to 4.5 years. For six segments of the carotid arteries, the number and volume of atherosclerotic plaques were determined from the CT scans, and the intima media thickness from the MRI scans. Information on comorbid cardiovascular disease, hypertension and diabetes mellitus was retrieved from medical records. Results Total plaque volume rose from 0.25 cm(3) before to 0.33 cm(3) after therapy but this was not significant (p = 0.26). The mean number of plaques increased from 5.7 to 8.1 (p = 0.002), and the intima media thickened from 1.17 mm to 1.35 mm (p = 0.002). However, the mean intima media thickness practically did not change in patients with comorbid diabetes mellitus (p-value for homogeneity: 0.03). For patients without diabetes mellitus, dynamics of both plaque number and intima media thickness, was consistent with an increase until about one year after therapy and no further progression thereafter. Conclusion Our study confirmed the thickening of artery walls and the increase in the number of plaques. Results imply that definitive radiation damage to the artery walls can be determined not earlier than about one year after radiotherapy and there is no substantial deterioration thereafter. Reasons for the absence of an observable intima media thickening in patients with diabetes are unclear. AU - Simonetto, C. AU - Mayinger, M.* AU - Ahmed, T.* AU - Borm, K.* AU - Kundrát, P. AU - Pigorsch, S.* AU - Kaiser, J.C. AU - Combs, S.E. C1 - 59068 C2 - 48554 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Longitudinal atherosclerotic changes after radio(chemo)therapy of hypopharyngeal carcinoma. JO - Radiat. Oncol. VL - 15 IS - 1 PB - Bmc PY - 2020 SN - 1748-717X ER - TY - JOUR AB - 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. AU - Stegen, B.* AU - Nieto, A.* AU - Albrecht, V.* AU - Maas, J.* AU - Orth, M.* AU - Neumaier, K.* AU - Reinhardt, S.* AU - Weick-Kleemann, M.* AU - Goetz, W.* AU - Reinhart, M.* AU - Parodi, K.* AU - Belka, C. AU - Niyazi, M.* AU - Lauber, K. C1 - 58667 C2 - 48222 TI - Contrast-enhanced, conebeam CT-based, fractionated radiotherapy and follow-up monitoring of orthotopic mouse glioblastoma: A proof-of-concept study. JO - Radiat. Oncol. VL - 15 IS - 1 PY - 2020 SN - 1748-717X ER - TY - JOUR AB - BackgroundOver the past years, several treatment regimens have been recommended for elderly patients with glioblastoma (GBM), ranging from ultrahypofractionated radiotherapy (RT) over monochemotherapy (ChT) to combined radiochemotherapy (RChT). The current guidelines recommend active treatment in elderly patients in cases with a KPS of at least 60%. We established a score for selecting patients with a very poor prognosis from patients with a better prognosis.MethodsOne hundred eighty one patients >= 65years old, histologically diagnosed with GBM, were retrospectively evaluated. Clinical characteristics were analysed for their impact on the overall survival (OS). Factors which were significant in univariate analysis (log-rank test, p<0.05) were included in a multi-variate model (multi-variate Cox regression analysis, MVA). The 9-month OS for the significant factors after MVA (p <0.05) was included in a prognostic score. Score sums with a median OS of < and>6months were summarized as Group A and B, respectively.ResultsAge, KPS, MGMT status, the extent of resection, aphasia after surgery and motor dysfunction after surgery were significantly associated with OS on univariate analysis (p<0.05). On MVA age (p 0.002), MGMT promotor methylation (p 0.013) and Karnofsky performance status (p 0.005) remained significant and were included in the score. Patients were divided into two groups, group A (median OS of 2.7months) and group B (median OS of 7.8months). The score was of prognostic significance, independent of the adjuvant treatment regimen.ConclusionsThe score distinguishes patients with a poor prognosis from patients with a better prognosis. Its inclusion in future retrospective or prospective trials could help enhance the comparability of results. Before its employment on a routine basis, external validation is recommended. AU - Straube, C.* AU - Kessel, K.A.* AU - Antoni, S.* AU - Gempt, J.* AU - Meyer, B.* AU - Schlegel, J.* AU - Schmidt-Graf, F.* AU - Combs, S.E. C1 - 59061 C2 - 48552 CY - Campus, 4 Crinan St, London N1 9xw, England TI - A balanced score to predict survival of elderly patients newly diagnosed with glioblastoma. JO - Radiat. Oncol. VL - 15 IS - 1 PB - Bmc PY - 2020 SN - 1748-717X ER - TY - JOUR AB - Background: The aim of this study was to assess the correlations between the levels of blood glucose (BG) and the dose of radiation therapy (RT) to the central gustatory system (GS) in glioblastoma multiforme (GBM) patients. Methods: Thirty-seven GBM patients with regular blood glucose measurements were investigated retrospectively. 59.5% were female and 40.5% male with a median age of 64.3 years (range 27.4-85.6). Diabetes mellitus type 2 (DM2) history, BG levels and dexamethasone (DEXA) medication were assessed. The analyzed central gustatory structures were: solitary tract and nucleus, ventral posteromedial nucleus of the thalamus, sensory tongue area of the postcentral gyrus, anterior part of the insula, frontal operculum, amygdala, hypothalamus. These structures were delineated on magnetic resonance tomographies (MRIs) registered to planning-CTs. All GS doses were transformed in equivalent doses in 2 Gy fraction (EQD2). Results: Twenty one patients (56.8%) had at least one BG values over 200 mg/dl during RT. There was a difference between average BG in DM2: 192.8 mg/dl (±24.4) and non-DM2 patients: 145.7 mg/dl (±39.5; p = 0.01) but no significant difference in daily DEXA medication - DM2 patients: 7.9 mg/d (±1.9) vs. non-DM2: 9.3 mg/dl (±5.7; p = 0.29). The EQD2 Dmean to the total GS was 36.0Gy (±8.6 Gy). There was a tendency for a higher increase in maximum BG values with more radiation dose to the total GS (b = 1.9, R2 = 0.103, p = 0.06). Conclusion: BG levels in GBM patients are in direct correlation to the dose of RT applied to the central GS. GBM patients that undergo RT should thus be closely monitored for changes in BG levels during and after the radiation. AU - Duma, M.N.* AU - Oszfolk, N.I.* AU - Boeckh-Behrens, T.* AU - Oechsner, M.* AU - Zimmer, C.* AU - Meyer, B.* AU - Pfluger, P.T. AU - Combs, S.E. C1 - 56274 C2 - 46954 TI - Positive correlation between blood glucose and radiotherapy doses to the central gustatory system in Glioblastoma Multiforme patients. JO - Radiat. Oncol. VL - 14 IS - 1 PY - 2019 SN - 1748-717X ER - TY - JOUR AB - PURPOSE/OBJECTIVE(S): Along with breast-conserving surgery (BCS), adjuvant radiotherapy (RT) of patients with early breast cancer plays a crucial role in the oncologic treatment concept. Conventionally, irradiation is carried out with the aid of tangentially arranged fields. However, more modern and more complex radiation techniques such as IMRT (intensity-modulated radio therapy) are used more frequently, as they improve dose conformity and homogeneity and, in some cases, achieve better protection of adjacent risk factors. The use of this technique has implications for the incidental- and thus unintended- irradiation of adjacent loco regional lymph drainage in axillary lymph node levels I-III and internal mammary lymph nodes (IMLNs). A comparison of a homogeneous "real-life" patient collective, treated with helical tomotherapy (TT), patients treated with 3D conformal RT conventional tangentially arranged fields (3DCRT) and deep inspiration breath hold (3DCRT-DIBH), was conducted. MATERIALS/METHODS: This study included 90 treatment plans after BCS, irradiated in our clinic from January 2012 to August 2016 with TT (n = 30) and 3D-CRT (n = 30), 3DCRT DIBH (n = 30). PTVs were contoured at different time points by different radiation oncologists (> 7). TT was performed with a total dose of 50.4 Gy and a single dose of 1.8 Gy with a simultaneous integrated boost (SIB) to the tumor cavity (TT group). Patients irradiated with 3DCRT/3DCRT DIBH received 50 Gy à 2 Gy and a sequential boost. Contouring of lymph drainage routes was performed retrospectively according to RTOG guidelines. RESULTS: Average doses (DMean) in axillary lymph node Level I/Level II/Level III were 31.6 Gy/8.43 Gy/2.38 Gy for TT, 24.0 Gy/11.2 Gy/3.97 Gy for 3DCRT and 24.7 Gy/13.3 Gy/5.59 Gy for 3DCRT-DIBH patients. Internal mammary lymph nodes (IMLNs) Dmean were 27.8 Gy (TT), 13.5 Gy (3DCRT), and 18.7 Gy (3DCRT-DIBH). Comparing TT to 3DCRT-DIBH dose varied significantly in all axillary lymph node levels and the IMLNs. Comparing TT to 3DCRT significant dose difference in Level I and IMLNs was observed. CONCLUSION: Dose applied to locoregional lymph drainage pathways varies comparing tomotherapy plans to conventional tangentially arranged fields. Studies are warranted whether dose variations influence loco-regional spread and must have implications for target volume definition guidelines. AU - Mayinger, M.* AU - Borm, K.J.* AU - Dreher, C.* AU - Dapper, H.* AU - Duma, M.N. AU - Oechsner, M.* AU - Kampfer, S.* AU - Combs, S.E. AU - Habermehl, D. C1 - 56702 C2 - 47250 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Incidental dose distribution to locoregional lymph nodes of breast cancer patients undergoing adjuvant radiotherapy with tomotherapy - is it time to adjust current contouring guidelines to the radiation technique? JO - Radiat. Oncol. VL - 14 IS - 1 PB - Bmc PY - 2019 SN - 1748-717X ER - TY - JOUR AB - PURPOSE: Pathogenesis of brain metastases/meningeal cancer and the emotional and neurological outcomes are not yet well understood. The hypothesis of our study is that patients with leptomeningeal cancer show volumetric differences in brain substructures compared to patients with cerebral metastases. METHODS: Three groups consisting of female breast cancer patients prior to brain radiotherapy were compared. Leptomeningeal cancer patients (LMC Group), oligometastatic patients (1-3 brain metastases) prior to radiosurgery (OMRS Group) and patients prior to whole brain radiation (WB Group) were included. All patients had MRI imaging before treatment. T1 MRI sequences were segmented using automatic segmentation. For each patient, 14 bilateral and 11 central/median subcortical structures were tested. Overall 1127 structures were analyzed and compared between groups using age matched two-sided t-tests. RESULTS: The average age of patients in the OMRS group was 60.8 years (± 14.7), 65.3 (± 10.3) in the LMC group and 62.6 (± 10.2) in the WB group. LMC patients showed a significantly larger fourth ventricle compared to OMRS (p = 0.001) and WB (p = 0.003). The central corpus callosum appeared smaller in the LMC group (LMC vs OMRS p = 0.01; LMC vs WB p = 0.026). The right amygdala in the WB group appeared larger compared with the OMRS (p = 0.035). CONCLUSIONS: Differences in the size of brain substructures of the three groups were found. The results appear promising and should be taken into account for further prospective studies also involving healthy controls. The volumetrically determined size of the fourth ventricle might be a helpful diagnostic marker in the future. AU - Mayinger, M.* AU - Reibelt, A.* AU - Borm, K.J.* AU - Ettl, J.* AU - Wilkens, J.J.* AU - Combs, S.E. AU - Oechsner, M.* AU - Duma, M.N.* C1 - 56967 C2 - 47463 TI - MRI based neuroanatomical segmentation in breast cancer patients: Leptomeningeal carcinomatosis vs. oligometastatic brain disease vs. multimetastastic brain disease. JO - Radiat. Oncol. VL - 14 IS - 1 PY - 2019 SN - 1748-717X ER - TY - JOUR AB - Background: Multimodal treatment with neoadjuvant chemoradiation followed by surgery (nCRT + S) is the treatment of choice for patients with locally advanced or node-positive esophageal squamous cell carcinoma (E-SCC). Those who are unsuitable or who decline surgery can be treated with definitive chemoradiation (dCRT). This study compares the oncologic outcome of nCRT + S and dCRT in E-SCC patients.Methods: Between 2011 and 2017, 95 patients with E-SCC were scheduled for dCRT or nCRT+ S with IMRT at our department Patients undergoing dCRT received at least 50 Gy and those undergoing nCRT + S received at least 41.4 Gy. All patients received simultaneous chemotherapy with either carboplatin and paclitaxel or cisplatin and 5-fluoruracil. We retrospectively compared baseline characteristics and oncologic outcome including overall survival (OS), progression-free survival (PFS) and site of failure between both treatment groups.Results: Patients undergoing dCRT were less likely to have clinically suspected lymph node metastases (85% vs. 100%, p = 0.019) than patients undergoing nCRT + S and had more proximally located tumors (median distance from dental arch to cranial tumor border 20 cm vs. 26 cm, p < 0.001). After a median follow up of 25.6 months for surviving patients, no significant differences for OS and PFS were noticed comparing nCRT + S and dCRT. However, the rate of local tumor recurrence was significantly higher in patients treated with dCRT than in those treated with nCRT + S (38% vs. 10%, p = 0.002). Within a multivariate Cox regression model, age, tumor location, and tumor grading were the only independent parameters affecting OS and PFS. In addition to that, proximal tumor location was the only parameter independently associated with an increased risk for local treatment failure.Conclusion: In E-SCC patients treated with either dCRT or nCRT + 5, a higher rate of local tumor recurrence was seen in patients treated with dCRT than in patients treated with nCRT + S. There was at least a trend towards an improved OS and PFS in patients undergoing nCRT + S. However, this should be interpreted with caution, because proximal tumor location was the only parameter independently affecting the risk of local tumor recurrence. AU - Münch, S.* AU - Pigorsch, S.U.* AU - Devečka, M.* AU - Dapper, H.* AU - Feith, M.* AU - Friess, H.* AU - Weichert, W.* AU - Jesinghaus, M.* AU - Braren, R.* AU - Combs, S.E. AU - Habermehl, D.* C1 - 55909 C2 - 46669 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Neoadjuvant versus definitive chemoradiation in patients with squamous cell carcinoma of the esophagus. JO - Radiat. Oncol. VL - 14 IS - 1 PB - Bmc PY - 2019 SN - 1748-717X ER - TY - JOUR AB - Background: The aim of this study was to compare dose-volume histogram (DVH) with dose-mass histogram (DMH) parameters for treatment of left-sided breast cancer in deep inspiration breath-hold (DIBH) and free breathing (FB). Additionally, lung expansion and anatomical factors were analyzed and correlated to dose differences. Methods: For 31 patients 3D conformal radiation therapy plans were retrospectively calculated on FB and DIBH CTs in the treatment planning system. The calculated doses, structures and CT data were transferred into MATLAB and DVHs and DMHs were calculated. Mean doses (Dmean), volumes and masses receiving certain doses (Vx, Mx) were determined for the left lung and the heart. Additionally, expansion of the left lung was evaluated using deformable image registration. Differences in DVH and DMH dose parameters between FB and DIBH were statistically analyzed and correlated to lung expansion and anatomical factors. Results: DIBH reduced Dmean (DVH) and relative V20 (V20 [%]) of the left lung in all patients, on average by - 19 ± 9% (mean ± standard deviation) and - 24 ± 10%. Dmean (DMH) and M20 [%] were also significantly reduced (- 12 ± 11%, - 16 ± 13%), however 4 patients had higher DMH values in DIBH than in FB. Linear regression showed good correlations between DVH and DMH parameters, e.g. a dosimetric benefit smaller than 8.4% for Dmean (DVH) in DIBH indicated more irradiated lung mass in DIBH than in FB. The mean expansion of the left lung between FB and DIBH was 1.5 ± 2.4 mm (left), 16.0 ± 4.0 mm (anterior) and 12.2 ± 4.6 mm (caudal). No significant correlations were found between expansions and differences in Dmean for the left lung. The heart dose in DIBH was reduced in all patients by 53% (Dmean) and this dosimetric benefit correlated to lung expansion in anterior. Conclusions: Treatment of left-sided breast cancer in DIBH reduced dose to the heart and in most cases the lung dose, relative irradiated lung volume and lung mass. A mass related dosimetric benefit in DIBH can be achieved as long as the volume related benefit is about ≥8-9%. The lung expansion (breathing pattern) showed no impact on lung dose, but on heart dose. A stronger chest breathing (anterior expansion) for DIBH seems to be more beneficial than abdominal breathing. AU - Oechsner, M.* AU - Düsberg, M.* AU - Borm, K.J.* AU - Combs, S.E. AU - Wilkens, J.J.* AU - Duma, M.N.* C1 - 56357 C2 - 47033 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Deep inspiration breath-hold for left-sided breast irradiation: Analysis of dose-mass histograms and the impact of lung expansion. JO - Radiat. Oncol. VL - 14 IS - 1 PB - Bmc PY - 2019 SN - 1748-717X ER - TY - JOUR AB - BackgroundAdvanced radiotherapy (RT) techniques allow normal tissue to be spared in patients with extremity soft tissue sarcoma (STS). This work aims to evaluate toxicity and outcome after neoadjuvant image-guided radiotherapy (IGRT) as helical intensity modulated radiotherapy (IMRT) with reduced margins based on MRI-based target definition in patients with STS.MethodsBetween 2010 to 2014, 41 patients with extremity STS were treated with IGRT delivered as helical IMRT on a tomotherapy machine. The tumor site was in the upper extremity in 6 patients (15%) and lower extremity in 35 patients (85%). Reduced margins of 2.5cm in longitudinal direction and 1.0cm inaxial direction were used to expand the MRI-defined gross tumor volume, including peritumoral edema, to the clinical target volume. An additional margin of 5mm was added to receive the planning target volume. The full total dose of 50Gy in 2Gy fractions was sucessfully applied in 40 patients. Two patients received chemotherapy instead of surgery due to systemic progression. All patients were included into a strict follow-up program and were seen interdisciplinarily by the Departments of Orthopaedic Surgery and Radiation Oncology.ResultsThirty eight patients that received total RT total dose and subsequent resection were analyzed for outcome. After a median follow-up of 38.5months cumulative OS, local PFS and systemic PFS at 2years were determined at 78.2, 85.2 and 54.5%, respectively. Two of 6 local recurrences were proximal marginal misses. Negative resection margins were achieved in 84% of patients. The rate of major wound complications was comparable to previous IMRT studies with 36.8%. RT was overall tolerable with low toxicity rates.ConclusionsIMRT-IGRT offers neoadjuvant treatment for extremity STS with reduced safety margins and thus low toxicity rates. Wound complication rates were comparable to previously reported frequencies. Two reported marginal misses suggest a word of caution for reduction of longitudinal safety margins. AU - Peeken, J.C.* AU - Knie, C.* AU - Kessel, K.A. AU - Habermehl, D.* AU - Kampfer, S.* AU - Dapper, H.* AU - Devecka, M.* AU - von Eisenhart-Rothe, R.* AU - Specht, K.* AU - Weichert, W.* AU - Wörtler, K.* AU - Knebel, C.* AU - Wilkens, J.J. AU - Combs, S.E. C1 - 55161 C2 - 46291 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Neoadjuvant image-guided helical intensity modulated radiotherapy of extremity sarcomas - a single center experience. JO - Radiat. Oncol. VL - 14 IS - 1 PB - Bmc PY - 2019 SN - 1748-717X ER - TY - JOUR AB - BackgroundBreast cancer is the most common invasive tumor in women worldwide and the second cause of cancer-related deaths. After breast conserving surgery the tumor bed gets irradiated. Radiation-induced tumor cell death has been found to be associated with the release of damage-associated molecular patterns (DAMPs) including free Hsp70 that can stimulate inflammatory immune responses. Therefore, Hsp70 serum levels as well as the composition of lymphocyte subpopulations have been measured in breast cancer patients during therapy and in the follow-up period as potential predictors for clinical outcome.MethodsThe serum of 40 breast cancer patients, who received a breast-conserving surgery and adjuvant radiotherapy (RT) was examined for soluble, free Hsp70 using the R&D Human HSP70 DuoSet and lipHsp70 ELISA. Lymphocyte subpopulations and total lymphocyte counts were analysed by multiparameter flow cytometry in the peripheral blood. Blood samples were collected before (t1), after 30Gy (t2) and 60Gy (t3), 6weeks (t4), 6months (t5) and 1year (t6) after RT. Clinical responses were assessed regularly up to 5years after RT.ResultsPatients who developed a contralateral recurrence or metastases within the first 2years after RT had significantly higher serum Hsp70 values at the end of RT (t3; p=0.03) up to 6weeks after RT (t4; p=0.007) compared to patients who either remained disease-free or developed a secondary endometrial carcinoma. Clinicopathological parameters such as age, tumor size, grading and TNM-stage of the resected tumors, adjuvant chemotherapy and irradiation dose did not affect serum Hsp70 levels. Elevated free Hsp70 levels might be indicative for a chronic inflammatory response which could support tumor recurrence. Lymphocyte subpopulation analysis revealed lower NK cell counts after RT in recurrence/metastases patients as compared to disease-free patients. In contrast, no significant changes were observed in the proportion of T and B cells.ConclusionLongitudinal elevated serum levels of free Hsp70 up to 6weeks after RT and dropping NK cell counts might be predictive for an unfavourable prognosis in patients with breast cancer. AU - Rothammer, A.* AU - Sage, E.K.* AU - Werner, C.* AU - Combs, S.E. AU - Multhoff, G.* C1 - 56034 C2 - 46787 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Increased heat shock protein 70 (Hsp70) serum levels and low NK cell counts after radiotherapy - potential markers for predicting breast cancer recurrence? JO - Radiat. Oncol. VL - 14 IS - 1 PB - Bmc PY - 2019 SN - 1748-717X ER - TY - JOUR AB - Background Adjuvant (ART) and salvage radiotherapy (SRT) are two common concepts to enhance biochemical relapse free survival (BCRFS) in patients with prostate cancer (PC). We analyzed differences in outcome between ART and SRT in patients with steep decline of PSA-levels after surgery to compare outcome. Methods We evaluated 253 patients treated with postoperative RT with a median age of 66 years (range 42-85 years) treated between 2004 and 2014. Patients with additive radiotherapy due to PSA persistence and patients in the SRT group, who did not achieve a postoperative PSA level <0.1 ng/mL were excluded. Hence, data of 179 patients was evaluated. We used propensity score matching to build homogenous groups. A Cox regression model was used to determine differences between treatment options. Median follow-up was 32.5 months (range 1.4-128.0 months). Results Early SRT at PSA levels <0.3 ng/mL was associated with significant longer BCRFS than late SRT (HR: 0.32, 95%-CI: 0.14-0.75, p = 0.009). Multiple Cox regression showed pre-RT PSA level, tumor stage, and Gleason score as predictive factors for biochemical relapse. In the overall group, patients treated with either ART or early SRT showed no significant difference in BCRFS (HR: 0.17, 95%-CI: 0.02-1.44, p = 0.1). In patients with locally advanced PC (pT3/4) BCRFS was similar in both groups as well (HR: 0.21, 95%-CI:0.02-1.79, p = 0.15). Conclusion For patients with PSA-triggered follow-up, close observation is essential and early initiation of local treatment at low PSA levels (<0.3 ng/mL) is beneficial. Our data suggest, that SRT administered at early PSA rise might be equieffective to postoperative ART in patients with locally advanced PC. However, the individual treatment decision must be based on any adverse risk factors and the patients' postoperative clinical condition. Study registration The present work is approved by the Ethics Commission of the Technical University of Munich (TUM) and is registered with the project number 320/14. AU - Vogel, M.M. AU - Kessel, K.A. AU - Schiller, K.* AU - Devecka, M.* AU - Gschwend, J.E.* AU - Weichert, W.* AU - Wilkens, J.J.* AU - Combs, S.E. C1 - 57318 C2 - 47684 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Adjuvant versus early salvage radiotherapy: outcome of patients with prostate cancer treated with postoperative radiotherapy after radical prostatectomy. JO - Radiat. Oncol. VL - 14 IS - 1 PB - Bmc PY - 2019 SN - 1748-717X ER - TY - JOUR AB - PurposeThis study was performed to evaluate skin toxicity during modern three-dimensional conformal radiotherapy (3D-CRT) and to evaluate the importance of dose distribution and patient related factors.Material and methodsThis study comprises 255 patients with breast cancer treated with tangential three-dimensional conformal radiotherapy (3D-CRT) after breast conserving surgery between 03/2012 and 05/2017. The median prescribed dose was 50.4Gy (range 50-50.4) and 92.2% of the patients received a sequential boost of 10-16Gy. Adverse skin toxicities (according to CTCAE v. 4.03 and the occurrence of moist desquamations) were assessed at the end of treatment. The dose distribution in the skin (5mm strip from the patient outline) and in the CTV was evaluated and correlated to the CTCAE scores and the occurrence of moist desquamation.Results42.4% of the patients developed grade I, 55.7% grade II and 2% grade III skin toxicities. Moist desquamation was observed in 59 cases (23.1%). Dose distribution within the CTV and skin was homogenous with only small areas receiving 107% of the prescribed dose (median: 0.7cm(3)) in the CTV and 105% (median 0.5cm(3)) in the skin. On univariate analysis breast size as well as V107%(CTV), V105%(skin) and V80%(skin) correlated significantly (p<0.05) with the incidence of skin toxicity. On multivariate analysis only V80%(skin) was confirmed as independent risk factor.ConclusionModern tangential multi-field 3D-CRT allows a homogeneous dose distribution with similar skin toxicity as compared to studies performing IMRT. Dose distribution within the skin (V80%) might have a relevant impact on the severity of skin toxicity and the occurrence of moist desquamation. AU - Borm, K.J.* AU - Loos, M.* AU - Oechsner, M.* AU - Mayinger, M.C.* AU - Paepke, D.* AU - Kiechle, M.B.* AU - Combs, S.E. AU - Duma, M.N. C1 - 54766 C2 - 45862 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Acute radiodermatitis in modern adjuvant 3D conformal radiotherapy for breast cancer - the impact of dose distribution and patient related factors. JO - Radiat. Oncol. VL - 13 IS - 1 PB - Bmc PY - 2018 SN - 1748-717X ER - TY - JOUR AB - Background: The cranial border of the target volume (T/) in rectal cancer patients treated with neoadjuvant chemoradiation (nCRT) is mostly defined at the level of L5/S1. However, current studies have shown that relapse cranially of the target volume after neoadjuvant nCRT and surgery is very rare. A reduction of cranial TV margins could be reasonable to reduce toxicity to the organs at risk (OAR). In this study we compared the dose distribution to the OAR for different cranial longitudinal margins using a dose-volume histogram (DVH) analysis.Methods: Ten patients with loco regional advanced rectal cancer were analysed retrospectively. All patients were planned for Volumetric Arc Therapy Radiation Therapy (VMAT). Next to the original PTV (PTV0), three new planning target volumes (PTV) were defined for each patient: The PTV0 reduced by 1 cm, 2 cm and 3 cm on cranial extension. For each PTV a treatment plan with a total dose of 50.4 Gy with daily doses of 1.8 Gy was calculated. Dose to the OAR were evaluated and compared.Results: For the bone marrow, the small bowel and the peritoneal space all clinically relevant relative dose parameters (V10-V50) as well as the Dmedian could be significantly reduced with every cranial target volume reduction of 1 cm. For V10 of the peritoneal space the dose could be nearly halved with a 3 cm shortened TV. After TV reduction of 3 cm also for the urinary bladder a significant dose reduction of the Dmedian could be achieved.Conclusions: Considering the very low recurrence rates in the TME and IMRT era, the distribution patterns of these relapses as well as the relevant side effects of nCRT, we would agree with existing recommendations of reduction of the cranial target volume in nCRT treated rectal cancer patients. AU - Dapper, H.* AU - Oechsner, M.* AU - Münch, S.* AU - Borm, K.* AU - Peeken, J.C.* AU - Mayinger, M.* AU - Combs, S.E. AU - Habermehl, D.* C1 - 54311 C2 - 45459 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Dosimetric analysis and comparison of reduced longitudinal cranial margins of VMAT-IMRT of rectal cancer. JO - Radiat. Oncol. VL - 13 IS - 1 PB - Bmc PY - 2018 SN - 1748-717X ER - TY - JOUR AB - IntroductionThe ano-inguinal lymphatic drainage (AILD) is located in the subcutaneous adipose tissue of the proximal medial thigh. Currently, there are no recommendations for an inclusion of the true' AILD in the clinical target volume (CTV) of definitive chemoradiation for anal cancer patients. To estimate the relevance of inguinal recurrence, we compared the incidental dose to the AILD in anal cancer (AC) patients who were treated either with Volumetric Arc Therapy - Intensity Modulated Radiation Therapy (VMAT-IMRT) or conventional 3D-radiation technique.MethodsOne VMAT-IMRT-plans and one 3D-plans were calculated on the same target volumes and identical dose prescription in ten patients. We defined the volume of the AILD on the planning CT-scans based on the information of new fluorescence methods. Furthermore, we defined several anatomical subvolumes of interest inside the AILD. We examined and compared absolute and relative dosimetric parameters of the AILD and different anatomical subunits.ResultsThe Dmean of the AILD was 40Gy in the 3D-group and 38Gy in the IMRT-group. Dmean and Dmedian as well as the V30Gy of the AILD and all subvolumes of the caudal AILD were significant higher using 3D-RT compared to IMRT. Even though the absolute differences were small, in the caudal aspect of the ano-inguinal lymphatic drainage the V30Gy could be more than 10% less with VMAT-IMRT.Conclusions3D-RT was slightly superior to IMRT in terms of dose coverage of the AILD. However, the absolute differences were very small. Some relevant caudal parts of the AILD received an insufficient dose for treating potential micrometastases. Particularly in high-risk situations, this may lead to inguinal recurrence and therefore the true deep AILD should be included into the target volume in high risk patients. AU - Dapper, H.* AU - Oechsner, M.* AU - Hirche, C.* AU - Münch, S.* AU - Sauter, C.* AU - Borm, K.* AU - Peeken, J.C.* AU - Combs, S.E. AU - Habermehl, D. C1 - 54861 C2 - 45890 CY - Campus, 4 Crinan St, London N1 9xw, England SP - 227 TI - Dosimetric comparison of different radiation techniques (IMRT vs. 3-dimensional) of the "true" (deep) ano-inguinal lymphatic drainage of anal cancer patients. JO - Radiat. Oncol. VL - 13 IS - 1 PB - Bmc PY - 2018 SN - 1748-717X ER - TY - JOUR AB - BackgroundNeoadjuvant radio- or chemoradiation (nIRT) therapy is the standard treatment for loco-regional advanced rectal cancer patients of the lower or middle third. Currently, intensity modulated radiation therapy (IMRT) is not the recommended radiation technique even though IMRT has advantages compared to 3D-radiation regarding dose sparing to organs at risk like small bowel and urinary bladder. So far, the benefit of IMRT concerning the anal sphincter complex is not examined. With this study we intended to evaluate the dose distribution on the anal sphincters of rectal cancer patients treated with IMRT in comparison with 3D-techniques.MethodsWe selected 16 patients for the IMRT-group and 16 patients for the 3D-group with rectal cancer of the middle third who were treated in our institute. All patients received 45Gy in a chemoradiation protocol. Patients in both groups were matched regarding stage, primary tumor distance to the anal verge and size of the tumor. We delineated the internal and external anal sphincters, the addition of both sphincters and the levator ani muscle in all patients. Subsequently, we evaluated and compared dose parameters of the different sphincters in both groups and analysed the configuration of the isodoses in the area of the caudal radiation field, respectively.ResultsMost of the relevant dose parameters of the caudal sphincters (Dmean, Dmedian, V10-V40) were significantly reduced in the IMRT-group compared to the 3D-group. Accordingly, the isodoses at the caudal edge of the target volume in the IMRT group demonstrated a steep dose fall. The levator ani muscle always was included into the planned target volumes and received the full dose in both groups.ConclusionsThe modern VMAT-IMRT can significantly reduce the dose to the anal sphincters for rectal cancer patients of the middle third who were treated with conventional chemoradiation therapy. AU - Dapper, H.* AU - Rodríguez, I.* AU - Münch, S.* AU - Peeken, J.C.* AU - Borm, K.* AU - Combs, S.E. AU - Habermehl, D.* C1 - 54916 C2 - 45923 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Impact of VMAT-IMRT compared to 3D conformal radiotherapy on anal sphincter dose distribution in neoadjuvant chemoradiation of rectal cancer. JO - Radiat. Oncol. VL - 13 IS - 1 PB - Bmc PY - 2018 SN - 1748-717X ER - TY - JOUR AB - Background: The purpose of this study is to evaluate the tumor movement and accuracy of patient immobilization in stereotactic body radiotherapy of liver tumors with low pressure foil or abdominal compression. Methods: Fifty-four liver tumors treated with stereotactic body radiotherapy were included in this study. Forty patients were immobilized by a vacuum couch with low pressure foil, 14 patients by abdominal compression. We evaluated the ratio of gross tumor volume/internal target volume, the tumor movement in 4D-computed tomography scans and daily online adjustments after cone beam computed tomography scans. Results: The ratio of gross tumor volume/internal target volume was smaller with low pressure foil. The tumor movement in 4D-computed tomography scans was smaller with abdominal compression, the cranial movement even significantly different (p = 0.02). The mean online adjustments and their mean absolute values in the vertical, lateral and longitudinal axis were smaller with abdominal compression. The online adjustments were significantly different (p < 0.013), their absolute values in case of the longitudinal axis (p = 0.043). There was no significant difference of the adjustments' 3D vectors. Conclusions: In comparison to low pressure foil, abdominal compression leads to a reduction of the tumor movement. Online adjustments decreased significantly, thus leading to higher accuracy in patient positioning. AU - Dreher, C.* AU - Oechsner, M.* AU - Mayinger, M.* AU - Beierl, S.* AU - Duma, M.* AU - Combs, S.E. AU - Habermehl, D. C1 - 52954 C2 - 44393 CY - London TI - Evaluation of the tumor movement and the reproducibility of two different immobilization setups for image-guided stereotactic body radiotherapy of liver tumors. JO - Radiat. Oncol. VL - 13 PB - Biomed Central Ltd PY - 2018 SN - 1748-717X ER - TY - JOUR AB - Background: Meningiomas of the skull base account for 25-30% of all meningiomas. Due to the complex structure of the cranial base and its close proximity to critical structures, surgery is often associated with substantial morbidity. Treatment options include observation, aggressive surgical intervention, stereotactic or conventional radiotherapy. In this analysis we evaluate the outcome of 110 patients with meningiomas of the skull base treated with particle therapy. It was performed within the framework of the "clinical research group heavy ion therapy" and supported by the German Research Council (DFG, KFO 214). Methods: Between May 2010 and November 2014, 110 Patients with skull base meningioma were treated with particle radiotherapy at the Heidelberg Ion Therapy Center (HIT). Primary localizations included the sphenoid wing (n = 42), petroclival region (n = 23), cavernous sinus (n = 4), sella (n = 10) and olfactory nerve (n = 4). Sixty meningiomas were benign (WHO degrees I); whereas 8 were high-risk (WHO degrees II (n = 7) and degrees III (n = 1)). In 42 cases histology was not examined, since no surgery was performed. Proton (n = 104) or carbon ion (n = 6) radiotherapy was applied at Heidelberg Ion Therapy Center (HIT) using raster-scanning technique for active beam delivery. Fifty one patients (46.4%) received radiotherapy due to tumor progression, 17 (15.5%) after surgical resection and 42 (38.2%) as primary treatment. Results: Median follow-up in this analysis was 46,8 months (95% CI 39,9-53,7; Q1-Q3 34,3-61,7). Particle radiotherapy could be performed safely without toxicity-related interruptions. No grade IV or V toxicities according to CTCAE v4.0 were observed. Particle RT offered excellent overall local control rates with 100% progression-free survival (PFS) after 36 months and 96.6% after 60 months. Median PFS was not reached due to the small number of events. Histology significantly impacted PFS with superior PFS after 5 years for low-risk tumors (96.6% vs. 75.0%, p = 0,02). Overall survival was 96.2% after 60 months and 92.0% after 72 months from therapy. Of six documented deaths, five were definitely not and the sixth probably not meningioma-related. Conclusion: Particle radiotherapy is an excellent treatment option for patients with meningiomas of the skull base and can lead to long-term tumor control with minimal side effects. Other prospective studies with longer follow-up will be necessary to further confirm the role of particle radiotherapy in skull base meningioma. AU - El Shafie, R.A.* AU - Czech, M.* AU - Kessel, K.A. AU - Habermehl, D. AU - Weber, D.* AU - Rieken, S.* AU - Bougatf, N.* AU - Jaekel, O.* AU - Debus, J.* AU - Combs, S.E. C1 - 53426 C2 - 44729 CY - London TI - Clinical outcome after particle therapy for meningiomas of the skull base: Toxicity and local control in patients treated with active rasterscanning. JO - Radiat. Oncol. VL - 13 PB - Biomed Central Ltd PY - 2018 SN - 1748-717X ER - TY - JOUR AB - Background: With the advance of modern irradiation techniques, the role of radiotherapy (RT) for intracranial meningioma has increased significantly throughout the past years. Despite that tumor's generally favorable outcome with local control rates of up to 90% after ten years, progression after RT does occur. In those cases, re-irradiation is often difficult due to the limited radiation tolerance of the surrounding tissue. The aim of this analysis is to determine the value of particle therapy with its better dose conformity and higher biological efficacy for re-irradiating recurrent intracranial meningioma. It was performed within the framework of the "clinical research group heavy ion therapy" and funded by the German Research Council (DFG, KFO 214). Methods: Forty-two patients treated with particle RT (protons (n = 8) or carbon ions (n = 34)) for recurrent intracranial meningioma were included in this analysis. Location of the primary lesion varied, including skull base (n = 31), convexity (n = 5) and falx (n = 6). 74% of the patients were categorized high-risk according to histology with a WHO grading of II (n = 25) or III (n = 6), in the remaining cases histology was either WHO grade I (n = 10) or unknown (n = 1). Median follow-up was 49,7 months. Results: In all patients, re-irradiation could be performed safely without interruptions due to side effects. No grade IV or V toxicities according to CTCAE v4.0 were observed. Particle RT offered good overall local control rates with 71% progression-free survival (PFS) after 12 months, 56,5% after 24 months and a median PFS of 34,3 months (95% CI 11,7-56,9). Histology had a significant impact on PFS yielding a median PFS of 25,7 months (95% CI 5,8-45,5) for high-risk histology (WHO grades II and III) while median PFS was not reached for low-risk tumors (WHO grade I) (p = 0,03). Median time to local progression was 15,3 months (Q1-Q3 8,08-34,6). Overall survival (OS) after re-irradiation was 89,6% after 12 months and 71,4% after 24 months with a median OS of 61,0 months (95% CI 34,2-87,7). Again, WHO grading had an effect, as median OS for low-risk patients was not reached whereas for high-risk patients it was 45,5 months (95% CI 35,6-55,3). Conclusion: Re-irradiation using particle therapy is an effective method for the treatment of recurrent meningiomas. Interdisciplinary decision making is necessary to guarantee best treatment for every patient. AU - El Shafie, R.A.* AU - Czech, M.* AU - Kessel, K.A. AU - Habermehl, D. AU - Weber, D.* AU - Rieken, S.* AU - Bougatf, N.* AU - Jaekel, O.* AU - Debus, J.* AU - Combs, S.E. C1 - 53566 C2 - 44752 TI - Evaluation of particle radiotherapy for the re-irradiation of recurrent intracranial meningioma. JO - Radiat. Oncol. VL - 13 IS - 1 PY - 2018 SN - 1748-717X ER - TY - JOUR AB - BackgroundCancer cachexia is a prevalent symptom of head and neck neoplasms. The reduction in skeletal muscle mass is one of the main characteristics which can lead to poor physical functioning. The purposes of this pilot randomized controlled trial were to determine the feasibility of progressive resistance training in cachectic head and neck cancer patients during radiotherapy and to explore possible risks and benefits.MethodsTwenty cachectic participants with head and neck cancer receiving radiation were randomized to obtain either a machine supported progressive resistance training (n=10) or usual care (n=10). The training took place 3 times weekly for 30min. Intervention included 3 exercises for major muscle groups with 8-12 repetition maximum for 3 sets each. Bioelectrical impedance analysis, hand-held dynamometry, Six-Minute Walk Test and standardized questionnaires for fatigue and quality of life were used for evaluating outcomes at baseline before radiotherapy (t1), after 7weeks of radiotherapy (t2) and 8weeks after the end of radiotherapy (t3).ResultsAll participants (n=20) completed the trial. No serious adverse events occurred. At the initial assessment the cachectic patients had already lost 7.15.2% of their body weight. General fatigue (score 10.73.3) and reduced quality of life (score 71.3 +/- 20.6) were prevalent in cachectic head and neck cancer patients even before radiotherapy. An average improvement of weight loading for leg press (+19.0%), chest press (+29.8%) and latissimus pull-down (+22.8%) was possible in the intervention group. Participants had at least 13 training sessions. The outcome measures showed nonsignificant changes at t2 and t3, but a trend for a better course of general fatigue and quality of life at t2 in the intervention group.Conclusions Despite advanced tumor stage and burdensome treatment the intervention adherence is excellent. Progressive resistance training in cachectic head and neck cancer patients during radiotherapy seems to be safe and feasible and may have beneficial effects of general fatigue and quality of life.Trial registration ClinicalTrials.gov, NCT03524755. Registered 15 May 2018 - Retrospectively registered. AU - Grote, M.* AU - Maihöfer, C. AU - Weigl, M.* AU - Davies-Knorr, P.* AU - Belka, C. C1 - 54723 C2 - 45779 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Progressive resistance training in cachectic head and neck cancer patients undergoing radiotherapy: A randomized controlled pilot feasibility trial. JO - Radiat. Oncol. VL - 13 IS - 1 PB - Bmc PY - 2018 SN - 1748-717X ER - TY - JOUR AB - Background: Proton radiotherapy is a form of charged particle therapy that is preferentially applied for the treatment of tumors positioned near to critical structures due to their physical characteristics, showing an inverted depth-dose profile. The sparing of normal tissue has additional advantages in the treatment of pediatric patients, in whom the risk of secondary cancers and late morbidity is significantly higher. Up to date, a fixed relative biological effectiveness (RBE) of 1.1 is commonly implemented in treatment planning systems with protons in order to correct the physical dose. This value of 1.1 comes from averaging the results of numerous in vitro experiments, mostly conducted in the middle of the spread-out Bragg peak, where RBE is relatively constant. However, the use of a constant RBE value disregards the experimental evidence which clearly demonstrates complex RBE dependency on dose, cell- or tissue type, linear energy transfer and biological endpoints. In recent years, several in vitro studies indicate variations in RBE of protons which translate to an uncertainty in the biological effective dose delivery to the patient. Particularly for regions surrounding the Bragg peak, the more localized pattern of energy deposition leads to more complex DNA lesions. These RBE variations of protons bring the validity of using a constant RBE into question. Main body: This review analyzes how RBE depends on the dose, different biological endpoints and physical properties. Further, this review gives an overview of the new insights based on findings made during the last years investigating the variation of RBE with depth in the spread out Bragg peak and the underlying differences in radiation re sponse on the molecular and cellular levels between proton and photon irradiation. Research groups such as the Klinische Forschergruppe Schwerionentherapie funded by the German Research Foundation (DFG, KFO 214) have included work on this topic and the present manuscript highlights parts of the preclinical work and summarizes the research activities in this context. Short conclusion: In summary, there is an urgent need for more coordinated in vitro and in vivo experiments that concentrate on a realistic dose range of in clinically relevant tissues like lung or spinal cord. AU - Ilicic, K. AU - Combs, S.E. AU - Schmid, T.E. C1 - 52790 C2 - 44295 CY - London TI - New insights in the relative radiobiological effectiveness of proton irradiation. JO - Radiat. Oncol. VL - 13 IS - 1 PB - Biomed Central Ltd PY - 2018 SN - 1748-717X ER - TY - JOUR AB - In the original publication [1] two author names were missing the middle names. The corrected versions can be found in this Erratum. The original article was updated to rectify these errors. Incorrect author name 1: Stephanie Combs. Correct author name 1: Stephanie E. Combs. Incorrect author name 2: Andra Krauze. Correct author name 2: Andra V. Krauze. AU - Krauze, A.V.* AU - Attia, A.* AU - Braunstein, S.* AU - Chan, M.* AU - Combs, S.E. AU - Fietkau, R.* AU - Fiveash, J.* AU - Flickinger, J.* AU - Grosu, A.-L.* AU - Howard, S.* AU - Nieder, C.* AU - Niyazi, M.* AU - Rowe, L.* AU - Smart, D.D.* AU - Tsien, C.* AU - Camphausen, K.* C1 - 52789 C2 - 44432 CY - London TI - Correction to expert consensus on re-irradiation for recurrent glioma. JO - Radiat. Oncol. VL - 13 IS - 1 PB - Biomed Central Ltd PY - 2018 SN - 1748-717X ER - TY - JOUR AB - Background: Postoperative (chemo) radiation improves tumor control and survival in high-risk patients with head and neck squamous cell carcinoma based on established risk factors. The clinical cooperation group "Personalized Radiotherapy in Head and Neck Cancer" focuses on the identification and validation of new biomarkers, which are aimed at eventually stratifying and personalizing the therapy concept. Hence, we reviewed all patients with head and neck squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx, treated with postoperative (chemo) radiation from 06/2008 until 06/2015 at the Department of Radiation Oncology in the University Hospital, LMU Munich. Here we report the clinical results of the cohort, laying the foundation for further research within the framework of a clinical cooperation group.Methods: Patient data were retrospectively (until 2013) and prospectively (from 2013) collected and analyzed for outcome and treatment failures with regard to previously described and established risk factors.Results: We identified 302 patients (median follow-up 45 months, average age 60.7 years), having received postoperative (chemo) radiation (median 64 Gy). Chemotherapy was added in 58% of cases, mostly Cisplatin/5-Fluorouracil in concordance with the ARO 96-3 study. The 3-year overall survival, local, locoregional and distant failure estimates were 70.5, 9.7, 12.2 and 13.5%, respectively. Human papillomavirus-associated oropharyngeal cancer was associated with a significant improved overall survival, locoregional, distant and overall tumor control rates in multivariate analysis. Additionally, in multivariate analysis, for local failure, resection status and perineural invasion, for locoregional and distant failure extracapsular extension and for overall survival the presence of nodal disease were significant adverse factors. Moreover, 138 patients have been treated in concordance with the ARO 96-3 protocol, corroborating the results of this study.Conclusions: Our cohort represents a large unselected cohort of patients with head and neck squamous cell carcinoma treated with postoperative (chemo) radiation. Tumor control rates and survival rates are consistent with the results of previously reported data. AU - Maihoefer, C. AU - Schüttrumpf, L. AU - Macht, C.* AU - Pflugradt, U. AU - Hess J. AU - Schneider, L. AU - Woischke, C. AU - Walch, A.K. AU - Baumeister, P. AU - Kirchner, T. AU - Zitzelsberger, H. AU - Belka, C. AU - Ganswindt, U. C1 - 53870 C2 - 45041 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Postoperative (chemo) radiation in patients with squamous cell cancers of the head and neck - clinical results from the cohort of the clinical cooperation group "Personalized Radiotherapy in Head and Neck Cancer". JO - Radiat. Oncol. VL - 13 IS - 1 PB - Bmc PY - 2018 SN - 1748-717X ER - TY - JOUR AB - Background: While neoadjuvant chemoradiation therapy (nCRT) with subsequent surgery is the treatment of choice for patients with locally advanced or node-positive squamous cell carcinoma of the esophagus (SCC) suitable for surgery, patients who are unsuitable for surgery or who refuse surgery should be treated with definite chemoradiation therapy (dCRT). Purpose of this study was to compare toxicity and oncologic outcome of dCRT with either cisplatin and 5-fluoruracil (CDDP/5FU) or carboplatin and paclitaxel (Carb/TAX) in patients with SCC.Methods: Twenty-two patients who received dCRT with carboplatin (AUC2, weekly) and paclitaxel (50 mg per square meter of body-surface area, weekly) were retrospectively compared to 25 patients who were scheduled for dCRT with cisplatin (20 mg/m(2)/d) and 5-fluoruracil (500 mg/m(2)/d) on day 1-5 and day 29-33. For the per-protocol (PP) analysis, PP treatment was defined as complete radiation therapy with at least 54Gy and at least three complete cycles of Carb/TAX or complete radiation therapy with at least 54Gy and at least one complete cycle of CDDP/5FU. While patients who were scheduled for dCRT with Carb/TAX received a significantly higher total radiation dose (median dose 59.4Gy vs. 54Gy, p < 0.001) than patients who were scheduled for dCRT with CDDP/5FU, no significant differences were seen for other parameters (age, sex, TNM-stage, grading and tumor extension).Results: Forty-seven patients (25 patients treated with CDDP/5FU and 22 patients treated with Carb/TAX) were evaluated for the intention-to-treat (ITT) analysis and 41 of 47 patients (23 patients treated with CDDP/5FU and 18 patients treated with Carb/TAX) were evaluated for the PP analysis. Severe myelotoxicity (>= III degrees) was seen in 52% (CDDP/5FU) and 55% of patients (Carb/TAX), respectively (p = 1.000). In the univariate binary logistic regression analysis, patients age was the only factor associated with an increased risk of >= III degrees myelotoxicity (hazard ratio 1.145, 95% CI 1.035; 1.266; p = 0.009). Regarding treatment efficiency, no significant differences were seen for overall survival (OS) and freedom from relapse (FFR) between both treatment groups.Conclusion: Myelotoxicity and oncologic outcome under dCRT were not different for patients with SCC of the esophagus treated with either CDDP/5FU or Carb/TAX. The putative equivalence of dCRT with Carb/TAX in this setting should be further investigated in prospective trials. However, our data reveal that the risk of significant myelotoxicity increases with patient age and therefore other chemotherapy regimens might be evaluated in elderly patients. AU - Münch, S.* AU - Pigorsch, S.U.* AU - Devečka, M.* AU - Dapper, H.* AU - Weichert, W.* AU - Friess, H.* AU - Braren, R.* AU - Combs, S.E. AU - Habermehl, D.* C1 - 54115 C2 - 45308 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Comparison of definite chemoradiation therapy with carboplatin/paclitaxel or cisplatin/5-fluoruracil in patients with squamous cell carcinoma of the esophagus. JO - Radiat. Oncol. VL - 13 IS - 1 PB - Bmc PY - 2018 SN - 1748-717X ER - TY - JOUR AB - Background: 68 Ga-PSMA-PET-imaging has proven to be a highly sensitive and specific diagnostic element for patients with prostate cancer (PC). Does the standard clinical target volume (CTV) cover the majority of 68 Ga-PSMA-PET detected lymph nodes (LNs) in a primary setting? Methods: 25 out of 159 patients with primary PC who underwent 68 Ga-PSMA-PET-imaging were analyzed in the process of this study. These 25 high-risk patients had a total of 126 LNs with positive 68 Ga-PSMA-ligand uptake. A standard CTV according to the 'Radiation Therapy Oncology Group' consensus was delineated and LNs were judged whether they were in- or outside of this target volume. With a Pearson correlation we additionally evaluated whether the Gleason score, the prostate-specific antigen (PSA) value or the risk according to the Roach formula correlate with a higher chance of LNs being outside of the CTV in uncommon LN locations. Results: 81 (64.3%) of 126 LNs were covered by the CTV with a complete coverag e of all positive LNs inside the respective radiation volume in 11 of 25 patients (44%). LNs that were not covered by the CTV included (para-aortic,) common-iliac, pre-sacral, obturatoric, para-rectal, para-vesical and pre-acetabular locations. In a statistical analysis neither the Gleason score, nor the PSA value, nor the calculated risk with the Roach formula correlated with LNs being inside or outside of the CTV in this patient group. Conclusion: 68 Ga-PSMA-PET-imaging proves to be a valuable asset for patients and physicians for primary diagnosis and treatment planning. In our study, trusting the RTOG consensus for CTV delineation would have led to up to 35.7% of all LNs not to be included in the clinical radiation volume, which might have resulted in insufficient radiation dose coverage. AU - Schiller, K.* AU - Devecka, M.* AU - Maurer, T.* AU - Eiber, M.* AU - Gschwend, J.E.* AU - Schwaiger, M.* AU - Combs, S.E. AU - Habl, G. C1 - 53235 C2 - 44790 TI - Impact of68Ga-PSMA-PET imaging on target volume definition and guidelines in radiation oncology - a patterns of failure analysis in patients with primary diagnosis of prostate cancer. JO - Radiat. Oncol. VL - 13 IS - 1 PY - 2018 SN - 1748-717X ER - TY - JOUR AB - Background: To evaluate the impact of68Ga-DOTATOC-PET on treatment planning and sparing of normal tissue in the treatment of skull base meningioma with advanced photons and protons. Methods: From the institutional database consisting of 507 skull base meningiomas 10 patients were chosen randomly for the present analysis. Target volume definition was performed based on CT and MRI only, as well as with additional68Ga-DOTATOC-PET. Treatment plans were performed for Intensity Modulated Radiotherapy (IMRT) and proton therapy using active raster scanning on both target volumes. We calculated doses to relevant organs at risk (OAR), conformity indices as well as differences in normal tissue sparing between both radiation modalities based on CT/MRI planning as well as CT/MRI/PET planning. Results: For photon treatment plans, PET-based treatment plans showed a reduction of brain stem Dmaxand Dmedianfor different levels of total dose. At the optic chiasm, use of68Ga-DOTATOC significantly reduces Dmax; moreover, the Dmedianis reduced in most cases, too. For both right and left optic nerve, reduction of dose by addition of68Ga-DOTATOC-PET is minimal and depends on the anatomical location of the meningioma. In protons, the impact of68Ga-DOTATOC-PET is minimal compared to photons. Conclusion: Addition of68Ga-DOTATOC-PET information into treatment planning for skull base meningiomas has a significant impact on target volumes. In most cases, PET-planning leads to significant reductions of the treatment volumes. Subsequently, reduced doses are applied to OAR. Using protons, the benefit of additional PET is smaller since target coverage is more conformal and dose to OAR is already reduced compared to photons. Therefore, PET-imaging has the greatest margin of benefit in advanced photon techniques, and combination of PET-planning and high-precision treatment leads to comparable treatment plans as with protons. AU - Stade, F.* AU - Dittmar, J.O.* AU - Jaekel, O.* AU - Kratochwil, C.* AU - Haberkorn, U.* AU - Debus, J.* AU - Combs, S.E. C1 - 53422 C2 - 44727 CY - London TI - Influence of68Ga-DOTATOC on sparing of normal tissue for radiation therapy of skull base meningioma: Differential impact of photon and proton radiotherapy. JO - Radiat. Oncol. VL - 13 IS - 1 PB - Biomed Central Ltd PY - 2018 SN - 1748-717X ER - TY - JOUR AB - Background: Tumor-Treating Fields (TTFields) are a novel treatment strategy for glioblastoma (GBM) that is approved for the use concomitantly to adjuvant chemotherapy. Preclinical data suggest a synergistic interaction of TTFields and radiotherapy (RT). However, the dosimetric uncertainties caused by the highly dense arrays have led to caution of applying the TTF setup during RT. Methods: In a RW3 slab phantom we compared the MV-and kV-CT based planned dose with the measured dose. VMAT-plans were optimized on MV-CTs of an Alderson head phantom without TTF arrays and then re-calculated on the same phantom equipped with TTF arrays. Dose at organs at risk (OAR) and target volumes (PTVs) were compared. Results: Measurements at a depth of 2, 3 and 4 cm of a RW 3 slab phantom show an attenuation due to TTField arrays of 3.4, 3.7 and 2.7% respectively. This was in-line with calculated attenuations based on MV-CT (1.2, 2.5 and 2.5%) but not with the attenuation expected from kV-CT based calculations (7.1, 8.2 and 8.6%). Consecutive MV-CT based VMAT planning and re-calculation reveals, that the conformity and homogeneity are not affected by the presence of TTField arrays. The dose at organs at risk (OAR) can show increases or decreases by < 0.5 Gy, which should be considered especially in cases next to the scull base. Conclusion: MV-CT based dose calculation results in reliable dose distributions also in the presence of TTField arrays. There is a small but clinically not relevant interaction between the TTField arrays and VMAT dose application. Thus, daily replacement of TTField arrays is not necessary in regard to deeply located OARs. RT is feasible, when a VMAT treatment plan is optimized to an array free planning CT. As the biologic effect of a concomitant treatment especially on OARs is currently unknown, a concomitant treatment should be performed only within clinical trials. AU - Straube, C.* AU - Oechsner, M.* AU - Kampfer, S.* AU - Scharl, S.* AU - Schmidt-Graf, F.* AU - Wilkens, J.J. AU - Combs, S.E. C1 - 53077 C2 - 44469 CY - London TI - Dosimetric impact of tumor treating field (TTField) transducer arrays onto treatment plans for glioblastomas - a planning study. JO - Radiat. Oncol. VL - 13 IS - 1 PB - Biomed Central Ltd PY - 2018 SN - 1748-717X ER - TY - JOUR AB - 68Gallium prostate specific membrane antigen (PSMA) ligand positron emission tomography (PET) is an increasingly used imaging modality in prostate cancer, especially in cases of tumor recurrence after curative intended therapy. Owed to the novelty of the PSMA-targeting tracers, clinical evidence on the value of PSMA-PET is moderate but rapidly increasing. State of the art imaging is pivotal for radiotherapy treatment planning as it may affect dose prescription, target delineation and use of concomitant therapy. This review summarizes the evidence on PSMA-PET imaging from a radiation oncologist's point of view. Additionally a short survey containing twelve examples of patients and 6 additional questions was performed in seven mayor academic centers with experience in PSMA ligand imaging and the findings are reported here. AU - Zschaeck, S.* AU - Lohaus, F.* AU - Beck, M.* AU - Habl, G. AU - Kroeze, S.* AU - Zamboglou, C.* AU - Koerber, S.A.* AU - Debus, J.* AU - Hoelscher, T.* AU - Wust, P.* AU - Ganswindt, U.* AU - Baur, A.D.J.* AU - Zoephel, K.* AU - Cihoric, N.* AU - Guckenberger, M.* AU - Combs, S.E. AU - Grosu, A.-L.* AU - Ghadjar, P.* AU - Belka, C.* C1 - 53564 C2 - 44754 TI - PSMA-PET based radiotherapy: A review of initial experiences, survey on current practice and future perspectives. JO - Radiat. Oncol. VL - 13 IS - 1 PY - 2018 SN - 1748-717X ER - TY - JOUR AB - Background: For irradiation treatment planning of meningiomas the use of PET-scans is well established. The most frequently used tracers are either based on amino acids or the somatostatin receptor ligand DOTATOC. Since up to now no inter-institutionally accepted standard PET-tracer has been defined, the aim of this study was to evaluate the influence of these different types of PET-tracers on the GTV-definition. Methods: Twenty-one patients suffering from intracranial meningiomas underwent CT, MRI, FET- and DOTATOC-PET. First, tumour extension was delineated after image-fusion of CT and MRI (GTV CT/MRI ). Then distinct GTVs based either on FET- or DOTATOC-PET were contoured and compared with each other as well with GTV CT/MRI . Results: Every tumour showed typical enhancement of DOTATOC, but two meningiomas remained FET-negative. The mean relative overlap volume of GTV FET and GTV DOTATOC was only 41.9% and there was a significantly stronger correlation between GTV CT/MRI and GTV DOTATOC than between GTV CT/MRI and GTV FET . Conclusions: Further investigations are necessary to clarify the minor conformity of DOTATOC- and FET-PET in meningiomas. Because of the receptor targeting, DOTATOC is known to be more specific for meningiomas and will remain the standard in our institution with the known limitation in areas nearby the pituitary gland. AU - Dittmar, J.O.* AU - Kratochwil, C.* AU - Dittmar, A.* AU - Welzel, T.* AU - Habermehl, D. AU - Rieken, S.* AU - Giesel, F.L.* AU - Haberkorn, U.* AU - Debus, J.* AU - Combs, S.E.* C1 - 52325 C2 - 43877 CY - London TI - First intraindividual comparison of contrast-enhanced MRI, FET- and DOTATOC- PET in patients with intracranial meningiomas. JO - Radiat. Oncol. VL - 12 IS - 1 PB - Biomed Central Ltd PY - 2017 SN - 1748-717X ER - TY - JOUR AB - Pancreatic cancer, especially in case of locally advanced stage has a poor prognosis. Radiotherapy in general can lead to tumor volume reduction, but further improvements, such as ion beam therapy have to be promoted in order to enable dose escalation, which in turn results in better local control rates and downsizing of the tumor itself. Ion beam therapy with its highly promising physical properties is also accompanied by distinct inter- and intrafractional challenges in case of robustness. First clinical results are promising, but further research in motion mitigation and biological treatment planning is necessary, in order to determine the best clinical rationales and conditions of ion beam therapy of pancreatic cancer. This review summarizes the current knowledge and studies on ion beam therapy of pancreatic cancer. AU - Dreher, C.* AU - Habermehl, D. AU - Jäkel, O.* AU - Combs, S.E. C1 - 52696 C2 - 44103 CY - London TI - Effective radiotherapeutic treatment intensification in patients with pancreatic cancer: Higher doses alone, higher RBE or both? JO - Radiat. Oncol. VL - 12 IS - 1 PB - Biomed Central Ltd PY - 2017 SN - 1748-717X ER - TY - JOUR AB - Purpose: We report our experience of using helical tomotherapy (HT) to treat large and irregular shaped loco-regional advanced breast cancer target volumes embracing various organs at risk. Patients and methods: We retrospectively analyzed 26 patients treated for very large, irregular shaped breast cancers. Patients were treated either with the intent to achieve local control in a primary setting (n = 14) or in a reirradiation setting (n = 12). The recurrence group was heavily pretreated with systemic therapy. Tumors were characterized by wide infiltration of the skin, encompassing mostly a complete hemithorax. The primary group underwent irradiation of supraclavicular, infraclavicular, axillary and parasternal lymphonodal region. Radiotherapy was combined with chemotherapy (n = 11). We assessed the PTV volume and its craniocaudal extension, the dose to the organs at risk, acute toxicity and survival. Results: Median PTV was 2276 cm3 (1476-6837 cm3) with a median cranio-caudal extension of 28 cm (15-52 cm). The median dose to PTV was 40 Gy (32-60Gy). HT could be carried out in all patients without interruption. The acute toxicities were mild to moderate. The median LRFS and OS after radiotherapy was 21 and 57 months for the primary group versus 10 and 11 months for the recurrence group. Median PFS was 18 months (primary group) and 7 months (recurrence group). Conclusions: HT is feasible for advanced thorax embracing target volumes with acceptable acute toxicity. Both curative and palliative indications can be considered good indications based on treatment volume and anatomical constellation. AU - Duma, M.N. AU - Heinrich, C.* AU - Schönknecht, C.* AU - Chizzali, B.* AU - Mayinger, M.* AU - Devecka, M.* AU - Kampfer, S.* AU - Combs, S.E. C1 - 50446 C2 - 42211 CY - London TI - Helical TomoTherapy for locally advanced or recurrent breast cancer. JO - Radiat. Oncol. VL - 12 PB - Biomed Central Ltd PY - 2017 SN - 1748-717X ER - TY - JOUR AB - BACKGROUND: To investigate the risk of second cancer and radiation induced second cancer following prostate cancer radiotherapy. METHODS: We compared men with radiotherapy only with those treated with radical prostatectomy only and those with radiotherapy after radical prostatectomy. Cumulative incidences of second cancers were calculated. Cox analyses were performed to identify determinants influencing second cancer incidence. RESULTS: Nineteen thousand five hundred thirty eight patients were analyzed. Age and median follow-up differed significantly with radiotherapy only patients having the highest median age (70.3 years) and radical prostatectomy only patients the longest median follow-up (10.2 years). Ten-year cumulative incidence of second cancer was 15.9%, 13.2% and 10.5% for patients with radiotherapy only, radiotherapy after radical prostatectomy and radical prostatectomy only (p <0.0001). Increasing age and belonging to the radiotherapy only group were associated with a higher risk of second cancer-no significant increase was seen in radiotherapy after radical prostatectomy patients. A significantly higher rate of smoking related malignancies, like lung, bladder and non-melanoma skin cancer, was seen in radiotherapy only patients. CONCLUSIONS: No clear increase in radiation induced second cancer was found in patients after radiotherapy for prostate cancer. Whereas the rate of second cancer was increased in radiotherapy only patients, no such increase was seen in patients with radiotherapy after radical prostatectomy. The increase of second cancer following radiotherapy only is highly likely to reflect advanced age and lifestyle habits and comorbidities. AU - Hegemann, N.S.* AU - Schlesinger-Raab, A.* AU - Ganswindt, U.* AU - Hörl, C.* AU - Combs, S.E. AU - Hölzel, D.* AU - Gschwend, J.E.* AU - Stief, C.* AU - Belka, C.* AU - Engel, J.* C1 - 52780 C2 - 44159 TI - Risk of second cancer following radiotherapy for prostate cancer: A population-based analysis. JO - Radiat. Oncol. VL - 12 IS - 1 PY - 2017 SN - 1748-717X ER - TY - JOUR AB - Purpose: To investigate radiation oncologists' opinions on important considerations to offering re-irradiation (re-RT) as a treatment option for recurrent glioma. Materials and methods: A survey was conducted with 13 radiation oncologists involved in the care of central nervous system tumor patients. The survey was comprised of 49 questions divided into 2 domains: a demographic section (10 questions) and a case section (5 re-RT cases with 5 to 6 questions representing one or several re-RT treatment dilemmas as may be encountered in the clinic). Respondents were asked to rate the relevance of various factors to offering re-RT, respond to the cases with a decision to offer re-RT vs. not, volume to be treated, margins to be employed, dose/fractionation suggested and any additional comments with respect to rationale in each scenario. Results: Sixty nine percent of responders have been practicing for greater than 10years and 61% have re-RT 20 to 100 patients to date, with 54% seeing 2-5 re-RT cases per month and retreating 1-2 patients per month. Recurrent tumor volume, time since previous radiation therapy, previously administered dose to organs at risk and patient performance status were rated by the majority of responders (85%, 92%, 77%, and 69% respectively) as extremely relevant or very relevant to offering re-RT as an option. Conclusion: The experts' practice of re-RT is still heterogeneous, reflecting the paucity of high-quality prospective data available for decision-making. Nevertheless, practicing radiation oncologists can support own decisions by referring to the cases found suitable for re-RT in this survey. AU - Krauze, A.* AU - Attia, A.* AU - Braunstein, S.* AU - Chan, M.* AU - Combs, S.E. AU - Fietkau, R.* AU - Fiveash, J.* AU - Flickinger, J.* AU - Grosu, A.-L.* AU - Howard, S.* AU - Nieder, C.* AU - Niyazi, M.* AU - Rowe, L.* AU - Smart, D.D.* AU - Tsien, C.* AU - Camphausen, K.* C1 - 52546 C2 - 44063 CY - London TI - Expert consensus on re-irradiation for recurrent glioma. JO - Radiat. Oncol. VL - 12 IS - 1 PB - Biomed Central Ltd PY - 2017 SN - 1748-717X ER - TY - JOUR AB - Purpose: Neoadjuvant chemoradiation (nCRT) is the treatment of choice for patients with locally advanced squamous cell carcinoma of the esophagus (SCC). Today radiation oncologists can choose between two different therapy regimes including chemoradiation with cisplatin and 5-fluoruracil (CDDP/5FU) and chemoradiation analogue to the CROSS-regime with carboplatin and paclitaxel (Carb/TAX). However, there is a lack of studies comparing these regimes, especially for the subgroup of patients with SCC. In this study, we want to compare nCRT with CDDP/5FU and nCRT with Carb/TAX for patients with locally advanced SCC. Patients and methods: We retrospectively compared 20 patients who were scheduled for nCRT with a total radiation dose of 41.4Gy (daily dose of 1.8Gy) and weekly chemotherapy with carboplatin (Area under the curve 2) and Paclitaxel (50mg per square meter of body-surface area) according to the CROSS-regime to 31 patients who were scheduled for nCRT with a total radiation dose of 45Gy (daily dose of 1.8Gy) and simultaneous chemotherapy with cisplatin (20mg/m 2 /d) and 5-fluoruracil (500mg/m 2 /d) on day 1-5 and day 29-33. For the per-protocol (PP) analysis, per protocol treatment was defined as either complete radiation with 41.4Gy, at least three complete cycles of Carb/TAX and subsequent surgery or complete radiation with 45Gy, at least one complete cycle of CDDP/5FU and subsequent surgery. Results: Fifty-one patients (31 patients treated with CDDP/5FU and 20 patients treated with Carb/TAX) were evaluated for the intention-to-treat (ITT) analysis and 44 patients (26 patients treated with CDDP/5FU and 18 patients treated with Carb/TAX) were evaluated for the PP analysis. No significant differences were seen for baseline and tumor characteristics like age, sex, TNM-stage, grading and tumor extension between patients treated with Carb/TAX and patients treated with CDDP/5FU. The most common tumor regression grade after nCRT was grade I as classified by Becker et al., which was observed in 84 and 79% of patients. No significant differences in tumor regression grades were seen between both regimes. Postoperative insufficiency of the anastomosis was seen in 6 patients (33%) who were treated with Carb/TAX and 4 patients (15%) who were treated with CDDP/5FU (p=0.273). Patients treated with CDDP/5FU developed significantly more cumulative hematologic III° (CTCAE) toxicities (58% vs 20%; p=0.010) than patients treated with Carb/TAX. In contrast to that, there was no significant difference for overall survival (OS) and freedom from relapse (FFR) between treatment groups. Conclusion: In this retrospective analysis, no significant difference was seen for OS and FFR between nCRT with CDDP/5FU and nCRT with Carb/TAX. However, the application of CDDP/5FU was associated with significantly more hematologic III°- toxicities compared to Carb/TAX. Future prospective trials should investigate if these results are reproducible in randomized patient cohorts. AU - Münch, S.* AU - Pigorsch, S.U.* AU - Feith, M.* AU - Slotta-Huspenina, J.* AU - Weichert, W.* AU - Friess, H.* AU - Combs, S.E. AU - Habermehl, D. C1 - 52459 C2 - 43998 CY - London TI - Comparison of neoadjuvant chemoradiation with carboplatin/ paclitaxel or cisplatin/ 5-fluoruracil in patients with squamous cell carcinoma of the esophagus. JO - Radiat. Oncol. VL - 12 IS - 1 PB - Biomed Central Ltd PY - 2017 SN - 1748-717X ER - TY - JOUR AB - Purpose: To cover the microscopic tumor spread in squamous cell carcinoma of the esophagus (SCC), longitudinal margins of 3-4cm are used for radiotherapy (RT) protocols. However, smaller margins of 2-3cm might be reasonable when advanced diagnostic imaging is integrated into target volume delineation. Purpose of this study was to compare the dose distribution and deposition to the organs at risk (OAR) for different longitudinal margins using a DVH- and NTCP-based approach. Methods: Ten patients with SCC of the middle or lower third were retrospectively selected. Three planning target volumes (PTV) with longitudinal margins of 4cm, 3cm and 2cm and an axial margin of 1.5cm to the gross target volume (GTV) were defined for each patient. For each PTV two treatment plans with total doses of 41.4Gy (neoadjuvant treatment) and 50.4Gy (definite treatment) were calculated. Dose to the lungs, heart, myelon and liver were then evaluated and compared between different PTVs. Results: Whe n using a longitudinal margin of 3cm instead of 4cm, all dose parameters (Dmin, Dmean, Dmedian and V5-V35), except Dmax could be significantly reduced for the lungs. Regarding the heart, a significant reduction was seen for Dmean and V5, but not for Dmin, Dmax, Dmedian and V10-V35. When comparing a longitudinal margin of 4cm to a longitudinal margin of 2cm, a significant difference was calculated for Dmin, Dmean, Dmedian and V5-V35 of the lungs and for Dmax, Dmean and V5-V35 of the heart. Nevertheless, no difference was seen for median heart dose. An additional dose reduction for V10 of the heart was achieved for definite treatment plans when using a longitudinal margin of 3cm. The NTCP-based risk of pneumonitis was significantly reduced by a margin reduction to 2cm for neoadjuvant and definite treatment plans. Conclusion: Reduction of longitudinal margins from 4cm to 3cm can significantly reduce the dose to lungs and Dmean of the heart. Despite clinical benefit and oncologic outcome remain unclear, reduction of the longitudinal margins might provide the opportunity to reduce side effects of chemoradiation (CRT) for SCC in upcoming studies. AU - Münch, S.* AU - Oechsner, M.* AU - Combs, S.E. AU - Habermehl, D. C1 - 51752 C2 - 43435 CY - London TI - DVH- and NTCP-based dosimetric comparison of different longitudinal margins for VMAT-IMRT of esophageal cancer. JO - Radiat. Oncol. VL - 12 IS - 1 PB - Biomed Central Ltd PY - 2017 SN - 1748-717X ER - TY - JOUR AB - Background: Standard of care primary treatment of carcinoma of locally advanced squamous cell head and neck cancer (LAHNSCC) consists of platinum-based concomitant chemo-irradiation. Despite progress in the treatment of LAHNSCC using modern radiotherapy techniques the outcome remains still poor. Using IMRT with SIB the escalation of total dose to the GTV is possible with the aim to improve clinical outcome. This study tests the hypothesis if radiation dose escalation to the GTV improves 2-year-LRC and -OS after concomitant chemo-irradiation. Methods: The ESCALOX trial is a prospective randomized phase III study using cisplatin chemo-irradiation and the SIB-IMRT concept in patients with LAHNSCC of the oral cavity, oropharynx or hypopharynx to escalate the total dose to the GTV up to 80.5 Gy. Chemotherapy is planned either in the 1st and 5th week (cisplatin 20 mg/m2/d d 1-5 and d 29-33) or weekly (cisplatin 40 mg/m2/d) during RT. RT is delivered as SIB with total doses of 80.5 Gy/70.0 Gy/56.0 Gy with 2.3 Gy/2.0 Gy and 1.6 Gy in the experimental arm and in the control arm with 70.0 Gy/56.0 Gy with 2.0 Gy and 1.6 Gy. A pre-study with dose escalation up to 77.0 Gy/70.0 Gy/56.0 Gy with 2.2 Gy/2.0 Gy and 1.6 Gy is demanded by the German federal office of radiation protection (BfS). In the translational part of the trial 100 of the randomised patients will be investigated by 18-F-FMiso-PET-CT for the presence and behaviour of tumor hypoxia twice in the week before treatment start. Discussion: The primary endpoint of the pre-study is acute radiation induced toxicity. Primary endpoint of the main trial is 2-year-LRC. By using the dose escalation up to 80.5 Gy to the GTV of the primary tumor and lymph nodes > 2 cm a LRC benefit of 15% at 2 years should be expected. The ESCALOX trial is supported by Deutsche Forschungsgemeinschaft (DFG); Grant No.: MO-363/4-1. Trial registration: ClinicalTrials.gov Identifier: NCT 01212354 , EudraCT-No.: 2010-021139-15 AU - Pigorsch, S.U. AU - Wilkens, J.J. AU - Kampfer, S. AU - Kehl, V.* AU - Hapfelmeier, A.* AU - Schläger, C.* AU - Bier, H.* AU - Schwaiger, M.* AU - Combs, S.E. C1 - 50700 C2 - 42631 TI - Do selective radiation dose escalation and tumour hypoxia status impact the loco-regional tumour control after radio-chemotherapy of head & neck tumours? The ESCALOX protocol. JO - Radiat. Oncol. VL - 12 IS - 1 PY - 2017 SN - 1748-717X ER - TY - JOUR AB - BACKGROUND: Glioblastoma is usually diagnosed around the age of 60-70 years. Patients older than 65 years are frequently described as "elderly". Several trials with monotherapy have established treatment regimens that offer therapies with reduced side effects but reduced efficacy. We analysed the outcome of elderly glioblastoma patients treated at our facility. METHODS: We performed a retrospective analysis of 62 consecutive patients older than 65 years treated for a primary glioblastoma at our facility from 2009 to 2015. RESULTS: Median age was 69.6 years (range 65.1-85.6 years); median OS of the entire cohort was 10.9 months. ECOG, MGMT and extent of resection but not age and the time from surgery to radiotherapy were associated with longer survival. Patients treated with adjuvant chemotherapy had a significantly longer survival (20.5 vs. 7.8 months). Furthermore, salvage therapies were associated with significant improved survival when compared to Best Supportive Care (22.3 vs. 8.8 months). CONCLUSION: Also elderly patients are likely to benefit from an aggressive treatment after primary diagnosis of glioblastoma. AU - Straube, C.* AU - Scherb, H. AU - Gempt, J.* AU - Bette, S.* AU - Zimmer, C.* AU - Schmidt-Graf, F.* AU - Schlegel, J.* AU - Meyer, B.* AU - Combs, S.E. C1 - 51012 C2 - 43088 TI - Does age really matter? Radiotherapy in elderly patients with glioblastoma, the Munich experience. JO - Radiat. Oncol. VL - 12 IS - 1 PY - 2017 SN - 1748-717X ER - TY - JOUR AB - BACKGROUND: Acquired and inherent radioresistance of tumor cells is related to tumor relapse and poor prognosis - not only in head and neck squamous cell carcinoma (HNSCC). The underlying molecular mechanisms are largely unknown. Therefore, systemic in-depth analyses are needed to identify key regulators of radioresistance. In the present study, subclones of the CAL-33 HNSCC cell line with different radiosensitivity were analyzed to identify signaling pathways related to the different phenotypes. METHODS: Subclones with altered radiosensitivity were generated by fractionated irradiation of the parental CAL-33 cells. Differences in radiosensitivity were confirmed in colony formation assays. Selected subclones were characterized at the genomic and transcriptomic level by SKY, array CGH, and mRNA-microarray analyses. Time-course gene expression analyses upon irradiation using a natural cubic spline regression model identified temporally differentially expressed genes. Moreover, early and late responding genes were identified. Gene association networks were reconstructed using partial correlation. The Reactome pathway database was employed to conduct pathway enrichment analyses. RESULTS: The characterization of two subclones with enhanced radiation resistance (RP) and enhanced radiosensitivity (SP) revealed distinct genomic and transcriptomic changes compared to the parental cells. Differentially expressed genes after irradiation shared by both subclones pointed to important pathways of the early and late radiation response, including senescence, apoptosis, DNA repair, Wnt, PI3K/AKT, and Rho GTPase signaling. The analysis of the most important nodes of the gene association networks revealed pathways specific to the radiation response in different phenotypes of radiosensitivity. Exemplarily, for the RP subclone the senescence-associated secretory phenotype (SASP) together with GPCR ligand binding were considered as crucial. Also, the expression of endogenous retrovirus ERV3-1in response to irradiation has been observed, and the related gene association networks have been identified. CONCLUSIONS: Our study presents comprehensive gene expression data of CAL-33 subclones with different radiation sensitivity. The resulting networks and pathways associated with the resistant phenotype are of special interest and include the SASP. The radiation-associated expression of ERV3-1 also appears highly attractive for further studies of the molecular mechanisms underlying acquired radioresistance. The identified pathways may represent key players of radioresistance, which could serve as potential targets for molecularly designed, therapeutical intervention. AU - Michna, A. AU - Schötz, U.* AU - Selmansberger, M. AU - Zitzelsberger, H. AU - Lauber, K.* AU - Unger, K. AU - Hess J. C1 - 49165 C2 - 41695 CY - London TI - Transcriptomic analyses of the radiation response in head and neck squamous cell carcinoma subclones with different radiation sensitivity: Time-course gene expression profiles and gene association networks. JO - Radiat. Oncol. VL - 11 IS - 1 PB - Biomed Central Ltd PY - 2016 SN - 1748-717X ER - TY - JOUR AB - Background: The aim of this study was to analyze differences in couch shifts (setup errors) resulting from image registration of different CT datasets with free breathing cone beam CTs (FB-CBCT). As well automatic as manual image registrations were performed and registration results were correlated to tumor characteristics. Methods: FB-CBCT image registration was performed for 49 patients with lung lesions using slow planning CT (PCT), average intensity projection (AIP), maximum intensity projection (MIP) and mid-ventilation CTs (MidV) as reference images. Both, automatic and manual image registrations were applied. Shift differences were evaluated between the registered CT datasets for automatic and manual registration, respectively. Furthermore, differences between automatic and manual registration were analyzed for the same CT datasets. The registration results were statistically analyzed and correlated to tumor characteristics (3D tumor motion, tumor volume, superior-inferior (SI) distance, tumor environment). Results: Median 3D shift differences over all patients were between 0.5 mm (AIPvsMIP) and 1.9 mm (MIPvsPCT and MidVvsPCT) for the automatic registration and between 1.8 mm (AIPvsPCT) and 2.8 mm (MIPvsPCT and MidVvsPCT) for the manual registration. For some patients, large shift differences (>5.0 mm) were found (maximum 10.5 mm, automatic registration). Comparing automatic vs manual registrations for the same reference CTs, Delta AIP achieved the smallest (1.1 mm) and Delta MIP the largest (1.9 mm) median 3D shift differences. The standard deviation (variability) for the 3D shift differences was also the smallest for Delta AIP (1.1 mm). Significant correlations (p < 0.01) between 3D shift difference and 3D tumor motion (AIPvsMIP, MIPvsMidV) and SI distance (AIPvsMIP) (automatic) and also for 3D tumor motion (Delta PCT, Delta MidV; automatic vs manual) were found. Conclusions: Using different CT datasets for image registration with FB-CBCTs can result in different 3D couch shifts. Manual registrations achieved partly different 3D shifts than automatic registrations. AIP CTs yielded the smallest shift differences and might be the most appropriate CT dataset for registration with 3D FB-CBCTs. AU - Oechsner, M.* AU - Chizzali, B.* AU - Devecka, M.* AU - Combs, S.E. AU - Wilkens, J.J. AU - Duma, M.N. C1 - 49916 C2 - 41910 CY - London TI - Registration uncertainties between 3D cone beam computed tomography and different reference CT datasets in lung stereotactic body radiation therapy. JO - Radiat. Oncol. VL - 11 PB - Biomed Central Ltd PY - 2016 SN - 1748-717X ER - TY - JOUR AB - BACKGROUND: Especially elderly and frail patients have a limited ability to compensate for side effects of a radical treatment of head and neck malignancies. Limiting the target volume to the macroscopic disease, without prophylactic nodal irradiation, might present a feasible approach for these patients. The present work therefore aims evaluating an IMRT/IGRT -SIB concept for safety and efficacy. METHODS: The study retrospectively enrolled 27 patients with head and neck cancers treated between 01/2012 and 05/2015. We evaluated patient files for clinical status, concomitant diseases, treatment side, and treatment volumes as well as for side effects and tumor responses. To describe efficacy and risk factors for worse outcome and higher grade toxicities, we performed cox regression analysis as well as Kaplan-Meier survival time analysis. RESULTS: Median survival was 181 days, 75 % patients showed an early local response at six weeks of follow up. Most patients developed mild to moderate acute toxicities, only one patient with grade IV mucositis was seen. The grade of toxicities was correlated to the size of the PTV. Concomitant diseases, metastatic disease, and G3 Grading were indicators for worse prognosis. CONCLUSION: The IMRT/IGRT SIB concept is a safe and feasible radiotherapy concept for patients not able or not willing to undergo radical treatment. AU - Straube, C.* AU - Pigorsch, S.U.* AU - Scherb, H. AU - Wilkens, J.J.* AU - Bier, H.* AU - Combs, S.E. C1 - 49694 C2 - 40868 CY - London TI - Reduced volume SIB-IMRT/IGRT to head and neck cancer in elderly and frail patients: Outcome and toxicity. JO - Radiat. Oncol. VL - 11 PB - Biomed Central Ltd PY - 2016 SN - 1748-717X ER - TY - JOUR AB - Background: The most frequently used method to quantitatively describe the response to ionizing irradiation in terms of clonogenic survival is the linear-quadratic (LQ) model. In the LQ model, the logarithm of the surviving fraction is regressed linearly on the radiation dose by means of a second-degree polynomial. The ratio of the estimated parameters for the linear and quadratic term, respectively, represents the dose at which both terms have the same weight in the abrogation of clonogenic survival. This ratio is known as the aα/β ratio. However, there are plausible scenarios in which the aα/β ratio fails to sufficiently reflect differences between dose-response curves, for example when curves with similar aα/β ratio but different overall steepness are being compared. In such situations, the interpretation of the LQ model is severely limited. Methods: Colony formation assays were performed in order to measure the clonogenic survival of nine human pancreatic cancer cell lines and immortalized human pancreatic ductal epithelial cells upon irradiation at 0-10 Gy. The resulting dataset was subjected to LQ regression and non-linear log-logistic regression. Dimensionality reduction of the data was performed by cluster analysis and principal component analysis. Results: Both the LQ model and the non-linear log-logistic regression model resulted in accurate approximations of the observed dose-response relationships in the dataset of clonogenic survival. However, in contrast to the LQ model the non-linear regression model allowed the discrimination of curves with different overall steepness but similar aα/β ratio and revealed an improved goodness-of-fit. Additionally, the estimated parameters in the non-linear model exhibit a more direct interpretation than the aα/β ratio. Dimensionality reduction of clonogenic survival data by means of cluster analysis was shown to be a useful tool for classifying radioresistant and sensitive cell lines. More quantitatively, principal component analysis allowed the extraction of scores of radioresistance, which displayed significant correlations with the estimated parameters of the regression models. Conclusions: Undoubtedly, LQ regression is a robust method for the analysis of clonogenic survival data. Nevertheless, alternative approaches including non-linear regression and multivariate techniques such as cluster analysis and principal component analysis represent versatile tools for the extraction of parameters and/or scores of the cellular response towards ionizing irradiation with a more intuitive biological interpretation. The latter are highly informative for correlation analyses with other types of data, including functional genomics data that are increasingly being generated. AU - Unkel, S.* AU - Belka, C. AU - Lauber, K. C1 - 47865 C2 - 39759 TI - On the analysis of clonogenic survival data: Statistical alternatives to the linear-quadratic model. JO - Radiat. Oncol. VL - 11 IS - 1 PY - 2016 SN - 1748-717X ER - TY - JOUR AB - BACKGROUND: Colony formation assay is the gold standard to determine cell reproductive death after treatment with ionizing radiation, applied for different cell lines or in combination with other treatment modalities. Associated linear-quadratic cell survival curves can be calculated with different methods. For easy code exchange and methodological standardisation among collaborating laboratories a software package CFAssay for R (R Core Team, R: A Language and Environment for Statistical Computing, 2014) was established to perform thorough statistical analysis of linear-quadratic cell survival curves after treatment with ionizing radiation and of two-way designs of experiments with chemical treatments only. METHODS: CFAssay offers maximum likelihood and related methods by default and the least squares or weighted least squares method can be optionally chosen. A test for comparision of cell survival curves and an ANOVA test for experimental two-way designs are provided. RESULTS: For the two presented examples estimated parameters do not differ much between maximum-likelihood and least squares. However the dispersion parameter of the quasi-likelihood method is much more sensitive for statistical variation in the data than the multiple R (2) coefficient of determination from the least squares method. CONCLUSION: The dispersion parameter for goodness of fit and different plot functions in CFAssay help to evaluate experimental data quality. As open source software interlaboratory code sharing between users is facilitated. AVAILABILITY: The package is available at http://www.bioconductor.org/packages/release/bioc/html/CFAssay.html . AU - Braselmann, H. AU - Michna, A. AU - Hess J. AU - Unger, K. C1 - 47217 C2 - 39186 TI - CFAssay: Statistical analysis of the colony formation assay. JO - Radiat. Oncol. VL - 10 IS - 1 PY - 2015 SN - 1748-717X ER - TY - JOUR AB - Introduction: Recently, information availability has become more elaborate and widespread, and treatment decisions are based on a multitude of factors. Gathering relevant data, also referred to as Big Data, is therefore critical for reaching the best patient care, and enhancing interdisciplinary and clinical research. Combining patient data from all involved systems is essential to prepare unstructured data for analyses. This demands special coordination in data management. Our study aims to characterize current developments in German-speaking hospital departments and practices. We successfully conducted the survey with the members of the Deutsche Gesellschaft für Radioonkologie (DEGRO). Methods: A questionnaire was developed consisting of 17 questions related to data management, documentation and clinical trial analyses, reflecting the clinical topics such as basic patient information, imaging, follow-up information as well as connection of documentation tools with radiooncological treatment planning machines. Results: A total of 44 institutions completed the online survey (University hospitals n = 17, hospitals n = 13, practices/institutes n = 14). University hospitals, community hospitals and private practices are equally equipped concerning IT infrastructure for clinical use. However, private practices have a low interest in research work. All respondents stated the biggest obstacles about introducing a documentation system into their unit lie in funding and support of the central IT departments. Only 27 % (12/44) of responsible persons are specialists for documentation and data management. Conclusion: Our study gives an understanding of the challenges and solutions we need to be looking at for medical data storage. In the future, inter-departmental cross-links will enable the radiation oncology community to generate large-scale analyses. AU - Kessel, K.A. AU - Combs, S.E. C1 - 47353 C2 - 40509 TI - Data management, documentation and analysis systems in radiation oncology: A multi-institutional survey. JO - Radiat. Oncol. VL - 10 IS - 1 PY - 2015 SN - 1748-717X ER - TY - JOUR AB - BACKGROUND: The major stress-inducible heat shock protein 70 (Hsp70) is frequently overexpressed in the cytosol and integrated in the plasma membrane of tumor cells via lipid anchorage. Following stress such as non-lethal irradiation Hsp70 synthesis is up-regulated. Intracellular located Hsp70 is known to exert cytoprotective properties, however, less is known about membrane (m)Hsp70. Herein, we investigate the role of mHsp70 in the sensitivity towards irradiation in tumor sublines that differ in their cytosolic and/or mHsp70 levels. METHODS: The isogenic human colon carcinoma sublines CX(+) with stable high and CX(-) with stable low expression of mHsp70 were generated by fluorescence activated cell sorting, the mouse mammary carcinoma sublines 4 T1 (4 T1 ctrl) and Hsp70 knock-down (4 T1 Hsp70 KD) were produced using the CRISPR/Cas9 system, and the Hsp70 down-regulation in human lung carcinoma sublines H1339 ctrl/H1339 HSF-1 KD and EPLC-272H ctrl/EPLC-272H HSF-1 KD was achieved by small interfering (si)RNA against Heat shock factor 1 (HSF-1). Cytosolic and mHsp70 was quantified by Western blot analysis/ELISA and flow cytometry; double strand breaks (DSBs) and apoptosis were measured by flow cytometry using antibodies against γH2AX and real-time PCR (RT-PCR) using primers and antibodies directed against apoptosis related genes; and radiation sensitivity was determined using clonogenic cell surviving assays. RESULTS: CX(+)/CX(-) tumor cells exhibited similar cytosolic but differed significantly in their mHsp70 levels, 4 T1 ctrl/4 T1 Hsp70 KD cells showed significant differences in their cytosolic and mHsp70 levels and H1339 ctrl/H1339 HSF-1 KD and EPLC-272H ctrl/EPLC-272H HSF-1 KD lung carcinoma cell sublines had similar mHsp70 but significantly different cytosolic Hsp70 levels. γH2AX was significantly up-regulated in irradiated CX(-) and 4 T1 Hsp70 KD with low basal mHsp70 levels, but not in their mHsp70 high expressing counterparts, irrespectively of their cytosolic Hsp70 content. After irradiation γH2AX, Caspase 3/7 and Annexin V were up-regulated in the lung carcinoma sublines, but no significant differences were observed in H1339 ctrl/H1339 HSF-1 KD, and EPLC-272H ctrl/EPLC-272H HSF-1 KD that exhibit identical mHsp70 but different cytosolic Hsp70 levels. Clonogenic cell survival was significantly lower in CX(-) and 4 T1 Hsp70 KD cells with low mHsp70 expression, than in CX+ and 4 T1 ctrl cells, whereas no difference in clonogenic cell survival was observed in H1339 ctrl/H1339 HSF-1 KD and EPLC-272H ctrl/ EPLC-272H HSF-1 KD sublines with identical mHsp70 but different cytosolic Hsp70 levels. CONCLUSION: In summary, our results indicate that mHsp70 has an impact on radiation resistance. AU - Murakami, N.* AU - Kühnel, A.* AU - Schmid, T.E.* AU - Ilicic, K.* AU - Stangl, S.* AU - Braun, I.S.* AU - Gehrmann, M.* AU - Molls, M.* AU - Itami, J.* AU - Multhoff, G. C1 - 46539 C2 - 37620 CY - London TI - Role of membrane Hsp70 in radiation sensitivity of tumor cells. JO - Radiat. Oncol. VL - 10 IS - 1 PB - Biomed Central Ltd PY - 2015 SN - 1748-717X ER - TY - JOUR AB - Background: The purpose of this study was to assess the impact on dose to the planning target volume (PTV) and organs at risk (OAR) by using four differently generated CT datasets for dose calculation in stereotactic body radiotherapy (SBRT) of lung and liver tumors. Additionally, dose differences between 3D conformal radiotherapy and volumetric modulated arc therapy (VMAT) plans calculated on these CT datasets were determined. Methods: Twenty SBRT patients, ten lung cases and ten liver cases, were retrospectively selected for this study. Treatment plans were optimized on average intensity projection (AIP) CTs using 3D conformal radiotherapy (3D-CRT) and volumetric modulated arc therapy (VMAT). Afterwards, the plans were copied to the planning CTs (PCT), maximum intensity projection (MIP) and mid-ventilation (MidV) CT datasets and dose was recalculated keeping all beam parameters and monitor units unchanged. Ipsilateral lung and liver volumes and dosimetric parameters for PTV (Dmean, D2, D98, D95), ipsilateral lung and liver (Dmean, V30, V20, V10) were determined and statistically analysed using Wilcoxon test. Results: Significant but small mean differences were found for PTV dose between the CTs (lung SBRT: ≤2.5 ; liver SBRT: ≤1.6 %). MIPs achieved the smallest lung and the largest liver volumes. OAR mean doses in MIP plans were distinctly smaller than in the other CT datasets. Furthermore, overlapping of tumors with the diaphragm results in underestimated ipsilateral lung dose in MIP plans. Best agreement was found between AIP and MidV (lung SBRT). Overall, differences in liver SBRT were smaller than in lung SBRT and VMAT plans achieved slightly smaller differences than 3D-CRT plans. Conclusions: Only small differences were found for PTV parameters between the four CT datasets. Larger differences occurred for the doses to organs at risk (ipsilateral lung, liver) especially for MIP plans. No relevant differences were observed between 3D-CRT or VMAT plans. MIP CTs are not appropriate for OAR dose assessment. PCT, AIP and MidV resulted in similar doses. If a 4DCT is acquired PCT can be omitted using AIP or MidV for treatment planning. AU - Oechsner, M.* AU - Odersky, L.* AU - Berndt, J.* AU - Combs, S.E. AU - Wilkens, J.J.* AU - Duma, M.N. C1 - 47528 C2 - 40647 TI - Dosimetric impact of different CT datasets for stereotactic treatment planning using 3D conformal radiotherapy or volumetric modulated arc therapy. JO - Radiat. Oncol. VL - 10 PY - 2015 SN - 1748-717X ER - TY - JOUR AU - Summerer, I. AU - Niyazi, M.* AU - Unger, K. AU - Pitea, A. AU - Zangen, V. AU - Hess J. AU - Atkinson, M.J. AU - Belka, C. AU - Mörtl, S. AU - Zitzelsberger, H. C1 - 44478 C2 - 36961 CY - London TI - Erratum: Changes in circulating microRNAs after radiochemotherapy in head and neck cancer patients. JO - Radiat. Oncol. VL - 10 IS - 1 PB - Biomed Central Ltd PY - 2015 SN - 1748-717X ER - TY - JOUR AB - Background: Tumor hypoxia is a known risk factor for reduced response to radiotherapy. The evaluation of noninvasive methods for the detection of hypoxia is therefore of interest. Osteopontin (OPN) has been discussed as an endogenous hypoxia biomarker. It is overexpressed in many cancers and is involved in tumor progression and metastasis. Methods: To examine the influence of hypoxia and irradiation on osteopontin expression we used different cell lines (head and neck cancer (Cal27 and FaDu) and glioblastoma multiforme (U251 and U87)). Cells were treated with hypoxia for 24 h and were then irradiated with doses of 2 and 8 Gy. Osteopontin expression was analyzed on mRNA level by quantitative real-time RT-PCR (qPCR) and on protein level by western blot. Cell culture supernatants were evaluated for secreted OPN by ELISA. Results: Hypoxia caused an increase in osteopontin protein expression in all cell lines. In Cal27 a corresponding increase in OPN mRNA expression was observed. In contrast the other cell lines showed a reduced mRNA expression under hypoxic conditions. After irradiation OPN mRNA expression raised slightly in FaDu and U87 cells while it was reduced in U251 and stable in Cal27 cells under normoxia. The combined treatment (hypoxia and irradiation) led to a slight increase of OPN mRNA after 2 Gy in U251 (24 h) and in U87 (24 and 48 h) cell lines falling back to base line after 8 Gy. This effect was not seen in Cal27 or in FaDu cells. Secreted OPN was detected only in the two glioblastoma cell lines with reduced protein levels under hypoxic conditions. Again the combined treatment resulted in a minor increase in OPN secretion 48 hours after irradiation with 8 Gy. Conclusion: Osteopontin expression is strongly modulated by hypoxia and only to a minor extent by irradiation. Intracellular OPN homeostasis seems to vary considerably between cell lines. This may explain the partly conflicting results concerning response prediction and prognosis in the clinical setting. AU - Wohlleben, G.* AU - Scherzad, A.* AU - Guettler, A.* AU - Vordermark, D.* AU - Kuger, S. AU - Flentje, M.* AU - Polat, B.* C1 - 46589 C2 - 37694 CY - London TI - Influence of hypoxia and irradiation on osteopontin expression in head and neck cancer and glioblastoma cell lines. JO - Radiat. Oncol. VL - 10 IS - 1 PB - Biomed Central Ltd PY - 2015 SN - 1748-717X ER - TY - JOUR AB - BACKGROUND: Tumor but not normal cells frequently overexpress heat shock protein 70 (Hsp70) and present it on their cell surface (mHsp70) from where it can be actively released. Therefore, membrane (mHsp70) and soluble Hsp70 (sHsp70) were investigated as potential tumor biomarkers and for monitoring the outcome of radiation therapy. METHODS: Biopsies and blood were collected from patients with squamous cell carcinoma of the head and neck (SCCHN) at different time points (before, during therapy and in the follow-up period). Hsp70 membrane expression was determined on single cell suspensions of tumor biopsies and reference tissues by flow cytometry, sHsp70 protein and antibody levels were determined in the serum of patients and healthy donors by ELISA and NK cell markers that are related to the presence of sHsp70 were analyzed in the patient's peripheral blood lymphocytes (PBL). RESULTS: Tumor biopsies exhibited significantly increased mHsp70 expression levels compared to the reference tissue. Soluble Hsp70 levels were significantly higher in SCCHN patients compared to healthy human volunteers and high mHsp70 expression levels on tumor cells were associated with high sHsp70 levels in the serum of patients. Following surgery and radiotherapy sHsp70 levels in patients dropped in patients without tumor relapse in the follow-up period. In contrast to sHsp70 protein, anti-Hsp70 antibody levels remained nearly unaltered in the serum of SCCHN patients before and after therapy. Furthermore, sHsp70 protein but not anti-Hsp70 antibody levels were found to be associated with the tumor volume in SCCHN patients before start of therapy. The expression densities of the activatory NK cell markers CD56, CD94, NKG2D, NKp30, Nkp44, and NKp46 differed in patients following therapeutic intervention. A significant increase in the density of NKG2D was observed in SCCHN patients in the follow-up period after surgery and radiotherapy. CONCLUSION: We suggest sHsp70 as a potential biomarker for detecting tumors and for monitoring the clinical outcome of radiotherapy in SCCHN patients. AU - Gehrmann, M.* AU - Specht, H.M.* AU - Bayer, C.* AU - Brandstetter, M.* AU - Chizzali, B.* AU - Duma, M.* AU - Breuninger, S.* AU - Hube, K.* AU - Lehnerer, S.* AU - van Phi, V.* AU - Sage, E.H.* AU - Schmid, T.E.* AU - Sedelmayr, M.* AU - Schilling, D. AU - Sievert, W. AU - Stangl, S.* AU - Multhoff, G. C1 - 31717 C2 - 34682 CY - London TI - Hsp70 - a biomarker for tumor detection and monitoring of outcome of radiation therapy in patients with squamous cell carcinoma of the head and neck. JO - Radiat. Oncol. VL - 9 IS - 1 PB - Biomed Central Ltd PY - 2014 SN - 1748-717X ER - TY - JOUR AB - BACKGROUND: Radiation-induced alterations in posttranslational histone modifications (PTMs) may affect the cellular response to radiation damage in the DNA. If not reverted appropriately, altered PTM patterns may cause long-term alterations in gene expression regulation and thus lead to cancer. It is therefore important to characterize radiation-induced alterations in PTM patterns and the factors affecting them. METHODS: A lymphoblastoid cell line established from a normal donor was used to screen for alterations in methylation levels at H3K4, H3K9, H3K27, and H4K20, as well as acetylation at H3K9, H3K56, H4K5, and H4K16, by quantitative Western Blot analysis at 15 min, 1 h and 24 h after irradiation with 2 Gy and 10 Gy. The variability of alterations in acetylation marks was in addition investigated in a panel of lymphoblastoid cell lines with differing radiosensitivity established from lung cancer patients. RESULTS: The screening procedure demonstrated consistent hypomethylation at H3K4me3 and hypoacetylation at all acetylation marks tested. In the panel of lymphoblastoid cell lines, however, a high degree of inter-individual variability became apparent. Radiosensitive cell lines showed more pronounced and longer lasting H4K16 hypoacetylation than radioresistant lines, which correlates with higher levels of residual gamma-H2AX foci after 24 h. CONCLUSION: So far, the factors affecting extent and duration of radiation-induced histone alterations are poorly defined. The present work hints at a high degree of inter-individual variability and a potential correlation of DNA damage repair capacity and alterations in PTM levels.   AU - Maroschik, B.* AU - Gürtler, A.* AU - Krämer, A.* AU - Rößler, U.* AU - Gomolka, M.* AU - Hornhardt, S.* AU - Mörtl, S. AU - Friedl, A.A. C1 - 28954 C2 - 33591 CY - London TI - Radiation-induced alterations of histone post-translational modification levels in lymphoblastoid cell lines. JO - Radiat. Oncol. VL - 9 IS - 1 PB - BioMed Central PY - 2014 SN - 1748-717X ER - TY - JOUR AB - Maximisation of the ratio of normal tissue preservation and tumour cell reduction is the main concept of radiotherapy alone or combined with chemo-, immuno- or biologically targeted therapy. The foremost parameter influencing this ratio is radiation sensitivity and its modulation towards a more efficient killing of tumour cells and a better preservation of normal tissue at the same time is the overall aim of modern therapy schemas. Nevertheless, this requires a deep understanding of the molecular mechanisms of radiation sensitivity in order to identify its key players as potential therapeutic targets. Moreover, the success of conventional approaches that tried to statistically associate altered radiation sensitivity with any molecular phenotype such as gene expression proofed to be somewhat limited since the number of clinically used targets is rather sparse. However, currently a paradigm shift is taking place from pure frequentistic association analysis to the rather holistic systems biology approach that seeks to mathematically model the system to be investigated and to allow the prediction of an altered phenotype as the function of one single or a signature of biomarkers. Integrative systems biology also considers the data from different molecular levels such as the genome, transcriptome or proteome in order to partially or fully comprehend the causal chain of molecular mechanisms. An example for the application of this concept currently carried out at the Clinical Cooperation Group "Personalized Radiotherapy in Head and Neck Cancer" of the Helmholtz-Zentrum M?nchen and the LMU Munich is described. This review article strives for providing a compact overview on the state of the art of systems biology, its actual challenges, potential applications, chances and limitations in radiation oncology research working towards improved personalised therapy concepts using this relatively new methodology. AU - Unger, K. C1 - 28903 C2 - 33573 CY - London TI - Integrative radiation systems biology. JO - Radiat. Oncol. VL - 9 IS - 1 PB - Biomed Central Ltd PY - 2014 SN - 1748-717X ER - TY - JOUR AB - NTRODUCTION: Circulating microRNAs (miRNAs) are easily accessible and have already proven to be useful as prognostic markers in cancer patients. However, their origin and function in the circulation is still under discussion. In the present study we analyzed changes in the miRNAs in blood plasma of head and neck squamous cell carcinoma (HNSCC) patients in response to radiochemotherapy and compared them to the changes in a cell culture model of primary HNSCC cells undergoing simulated anti-cancer therapy. MATERIALS AND METHODS: MiRNA-profiles were analyzed by qRT-PCR arrays in paired blood plasma samples of HNSCC patients before therapy and after two days of treatment. Candidate miRNAs were validated by single qRT-PCR assays. An in vitro radiochemotherapy model using primary HNSCC cell cultures was established to test the possible tumor origin of the circulating miRNAs. Microarray analysis was performed on primary HNSCC cell cultures followed by validation of deregulated miRNAs via qRT-PCR. RESULTS: Unsupervised clustering of the expression profiles using the six most regulated miRNAs (miR-425-5p, miR-21-5p, miR-106b-5p, miR-590-5p, miR-574-3p, miR-885-3p) significantly (p = 0.012) separated plasma samples collected prior to treatment from plasma samples collected after two days of radiochemotherapy. MiRNA profiling of primary HNSCC cell cultures treated in vitro with radiochemotherapy revealed differentially expressed miRNAs that were also observed to be therapy-responsive in blood plasma of the patients (miR-425-5p, miR-21-5p, miR-106b-5p, miR-93-5p) and are therefore likely to stem from the tumor. Of these candidate marker miRNAs we were able to validate by qRT-PCR a deregulation of eight plasma miRNAs as well as miR-425-5p and miR-93-5p in primary HNSCC cultures after radiochemotherapy. CONCLUSION: Changes in the abundance of circulating miRNAs during radiochemotherapy reflect the therapy response of primary HNSCC cells after an in vitro treatment. Therefore, the responsive miRNAs (miR-425-5p, miR-93-5p) may represent novel biomarkers for therapy monitoring. The prognostic value of this exciting observation requires confirmation using an independent patient cohort that includes clinical follow-up data. AU - Summerer, I. AU - Niyazi, M.* AU - Unger, K. AU - Pitea, A. AU - Zangen, V. AU - Hess J. AU - Atkinson, M.J. AU - Belka, C. AU - Mörtl, S. AU - Zitzelsberger, H. C1 - 28904 C2 - 33574 CY - London TI - Changes in circulating microRNAs after radiochemotherapy in head and neck cancer patients. JO - Radiat. Oncol. VL - 8 IS - 1 PB - Biomed Central Ltd PY - 2013 SN - 1748-717X ER - TY - JOUR AB - BACKGROUND: There is evidence that the extent of the G2/M arrest following irradiation is correlated with tumour cell survival and hence therapeutic success. We studied the regulation of cellular response to radiation treatment by miR-21-mediated modulation of cell cycle progression in breast cancer cells and analysed miR-21 expression in breast cancer tissue samples with long-term follow up. METHODS: The miR-21 expression levels were quantified (qRT-PCR) in a panel of 86 cases of invasive breast carcinomas in relation to metastasis free survival. The cellular radiosensitivity of human breast cancer cells after irradiation was determined comparing two cell lines (T47D and MDA-MB-361) by cell proliferation and colony forming assays. The influence of miR-21 overexpression or downregulation on cell cycle progression and G2/M checkpoint arrest after irradiation was assessed by flow cytometric analysis. RESULTS: The expression of miR-21 was transiently increased 8 hours after irradiation in the radioresistant T47D cells and significantly changed with lower extent in radiosensitive MDA-MB-361 cells. Anti-miR-21 treated breast cancer cells failed to exhibit the DNA damage-G2 checkpoint increase after irradiation. Apoptotic activity was significantly enhanced from 7% to 27% in T47D cells and from 18% to 30% in MDA-MB-361 cells 24 hours after 5 Gy irradiation. Additionally, we characterized expression of miR-21 in invasive breast carcinomas. In comparison to non-cancerous adjacent breast tissue, tumours samples had increased miR-21 expression that inversely correlated with the distant metastases-free survival of patients (p=0.029). CONCLUSIONS: Our data indicate that miR-21 expression in breast cancer cells contributes to radiation resistance by compromising cell cycle progression. These data point to the potential of combining radiotherapy with an anti-miR-21 as a potent G2/M check point inhibitor in overcoming radiation resistance of tumours. AU - Anastasov, N. AU - Höfig, I. AU - Vasconcellos, I.G. AU - Rappl, K. AU - Braselmann, H. AU - Ludyga, N. AU - Auer, G.* AU - Aubele, M. AU - Atkinson, M.J. C1 - 11616 C2 - 30716 TI - Radiation resistance due to high expression of miR-21 and G2/M checkpoint arrest in breast cancer cells. JO - Radiat. Oncol. VL - 7 IS - 1 PB - Biomed Central Ltd. PY - 2012 SN - 1748-717X ER - TY - JOUR AB - BACKGROUND: The Monte Carlo code GEANT4 was used to implement first steps towards a treatment planning program for fast-neutron therapy at the FRM II research reactor in Garching, Germany. Depth dose curves were calculated inside a water phantom using measured primary neutron and simulated primary photon spectra and compared with depth dose curves measured earlier. The calculations were performed with GEANT4 in two different ways, simulating a simple box geometry and splitting this box into millions of small voxels (this was done to validate the voxelisation procedure that was also used to voxelise the human body). RESULTS: In both cases, the dose distributions were very similar to those measured in the water phantom, up to a depth of 30 cm. In order to model the situation of patients treated at the FRM II MEDAPP therapy beamline for salivary gland tumors, a human voxel phantom was implemented in GEANT4 and irradiated with the implemented MEDAPP neutron and photon spectra. The 3D dose distribution calculated inside the head of the phantom was similar to the depth dose curves in the water phantom, with some differences that are explained by differences in elementary composition. The lateral dose distribution was studied at various depths. The calculated cumulative dose volume histograms for the voxel phantom show the exposure of organs at risk surrounding the tumor. CONCLUSIONS: In order to minimize the dose to healthy tissue, a conformal treatment is necessary. This can only be accomplished with the help of an advanced treatment planning system like the one developed here. Although all calculations were done for absorbed dose only, any biological dose weighting can be implemented easily, to take into account the increased radiobiological effectiveness of neutrons compared to photons. AU - Garny, S. AU - Rühm, W. AU - Zankl, M. AU - Wagner, F.M.* AU - Paretzke, H.G. C1 - 7184 C2 - 29529 TI - First steps towards a fast-neutron therapy planning program. JO - Radiat. Oncol. VL - 6 IS - 1 PB - Biomed Central Ltd. PY - 2011 SN - 1748-717X ER - TY - JOUR AB - Radiotherapists are highly interested in optimizing doses especially for patients who tend to suffer from side effects of radiotherapy (RT). It seems to be helpful to identify radiosensitive individuals before RT. Thus we examined aberrations in FISH painted chromosomes in in vitro irradiated blood samples of a group of patients suffering from breast cancer. In parallel, a follow-up of side effects in these patients was registered and compared to detected chromosome aberrations. METHODS: Blood samples (taken before radiotherapy) were irradiated in vitro with 3 Gy X-rays and analysed by FISH-painting to obtain aberration frequencies of first cycle metaphases for each patient. Aberration frequencies were analysed statistically to identify individuals with an elevated or reduced radiation response. Clinical data of patients have been recorded in parallel to gain knowledge on acute side effects of radiotherapy. RESULTS: Eight patients with a significantly elevated or reduced aberration yield were identified by use of a t-test criterion. A comparison with clinical side effects revealed that among patients with elevated aberration yields one exhibited a higher degree of acute toxicity and two patients a premature onset of skin reaction already after a cumulative dose of only 10 Gy. A significant relationship existed between translocations in vitro and the time dependent occurrence of side effects of the skin during the therapy period. CONCLUSIONS: The results suggest that translocations can be used as a test to identify individuals with a potentially elevated radiosensitivity. AU - Huber, R. AU - Braselmann, H. AU - Geinitz, H.* AU - Jaehnert, I. AU - Baumgartner, A. AU - Thamm, R.* AU - Figel, M. AU - Molls, M.* AU - Zitzelsberger, H. C1 - 6441 C2 - 28695 TI - Chromosomal radiosensitivity and acute radiation side effects after radiotherapy in tumour patients - a follow-up study. JO - Radiat. Oncol. VL - 6 IS - 1 PB - Biomed Cental Ltd PY - 2011 SN - 1748-717X ER - TY - JOUR AB - In order to define new prognostic subgroups in patients with glioblastoma a miRNA screen (> 1000 miRNAs) from paraffin tissues followed by a bio-mathematical analysis was performed. 35 glioblastoma patients treated between 7/2005 - 8/2008 at a single institution with surgery and postoperative radio(chemo)therapy were included in this retrospective analysis. For microarray analysis the febit biochip "Geniom® Biochip MPEA homo-sapiens" was used. Total RNA was isolated from FFPE tissue sections and 1100 different miRNAs were analyzed. It was possible to define a distinct miRNA expression pattern allowing for a separation of distinct prognostic subgroups. The defined miRNA pattern was significantly associated with early death versus long-term survival (split at 450 days) (p = 0.01). The pattern and the prognostic power were both independent of the MGMT status. At present, this is the first dataset defining a prognostic role of miRNA expression patterns in patients with glioblastoma. Having defined such a pattern, a prospective validation of this observation is required. AU - Niyazi, M.* AU - Zehentmayr, F.* AU - Niemöller, O.M.* AU - Eigenbrod, S.* AU - Kretzschmar, H.* AU - Osthoff, K.S.* AU - Tonn, J.C.* AU - Atkinson, M.J. AU - Mörtl, S. AU - Belka, C.* C1 - 6898 C2 - 29420 TI - MiRNA expression patterns predict survival in glioblastoma. JO - Radiat. Oncol. VL - 6 IS - 1 PB - BioMed Central PY - 2011 SN - 1748-717X ER - TY - JOUR AB - Alkylphosphocholines represent promising antineoplastic drugs that induce cell death in tumor cells by primary interaction with the cell membrane. Recently we could show that a combination of radiotherapy with Erufosine, a paradigmatic intravenously applicable alkylphosphocholine, in vitro leads to a clear increase of irradiation-induced cell death. In view of a possible combination of Erufosine and radiotherapy in vivo we determined the pharmacokinetics and bioavailability as well as the tolerability of Erufosine in nude mice. Methods: NMRI (nu/nu) nude mice were treated by intraperitoneal or subcutaneous injections of 5 to 40 mg/kg body weight Erufosine every 48 h for one to three weeks. Erufosine-concentrations were measured in brain, lungs, liver, small intestine, colon, spleen, kidney, stomach, adipoid tissue, and muscle by tandem-mass spectroscopy. Weight course, blood cell count and clinical chemistry were analyzed to evaluate general toxicity. Results: Intraperitoneal injections were generally well tolerated in all dose groups but led to a transient loss of the bodyweight (< 10%) in a dose dependent manner. Subcutaneous injections of high-dose Erufosine caused local reactions at the injection site. Therefore, this regimen at 40 mg/kg body weight Erufosine was stopped after 14 days. No gross changes were observed in organ weight, clinical chemistry and white blood cell count in treated compared to untreated controls except for a moderate increase in lactate dehydrogenase and aspartate-aminotransferase after intensive treatment. Repeated Erufosine injections resulted in drug-accumulation in different organs with maximum concentrations of about 1000 nmol/g in spleen, kidney and lungs. Conclusion: Erufosine was well tolerated and organ-concentrations surpassed the cytotoxic drug concentrations in vitro. Our investigations establish the basis for a future efficacy testing of Erufosine in xenograft tumor models in nude mice alone and in combination with chemo-or radiotherapy. AU - Henke, G.* AU - Lindner, L.H. AU - Vogeser, M.* AU - Eibl, H.J.* AU - Worner, J.* AU - Müller, A.C.* AU - Bamberg, M.* AU - Wachholz, K.* AU - Belka, C.* AU - Jendrossek, V.* C1 - 992 C2 - 26664 TI - Pharmacokinetics and biodistribution of Erufosine in nude mice - implications for combination with radiotherapy. JO - Radiat. Oncol. VL - 4 IS - 1 PB - Biomed Central Ltd PY - 2009 SN - 1748-717X ER -