Heidelberg Institute of Radiation Oncology HIRO
Heidelberg Institute of Radiation Oncology HIRO
Neuholz A.,German Cancer Research Center |
Neuholz A.,Heidelberg Institute of Radiation Oncology HIRO |
Greilich S.,German Cancer Research Center |
Greilich S.,Heidelberg Institute of Radiation Oncology HIRO
Radiation Measurements | Year: 2017
Fluorescent Nuclear Track Detectors (FNTDs) feature superior, submicron spatial resolution that allows for single particle track detection. However, when assessing particle fluence from measured track positions, discrimination of actual fluence patterns from stochastic fluctuations due to spatial randomness in particle arrival can only be done at considerably lower resolution. This work quantifies the spatial limits of fluence-based dosimetry of (heavy) charged particles and presents the tools to detect deviations from homogenous fluence in measured data. It is found that deviations in fluence (and hence dose) on a percent level cannot be detected in a carbon beam on scales smaller than several tenths of a millimeter even when using dose levels of 1 Gy. For typical fluences measured with FNTDs, read-out area side-lengths should be larger than 0.2 mm to detect fluence differences of less than 5%. © 2017 Elsevier Ltd.
Oancea-Castillo L.R.,Johannes Gutenberg University Mainz |
Klein C.,German Cancer Research Center |
Klein C.,Heidelberg Institute of Radiation Oncology HIRO |
Klein C.,Heidelberg Ion Beam Therapy Center |
And 12 more authors.
Cancer Biology and Therapy | Year: 2017
Glioblastoma multiforme (GBM) exhibits high resistance to the standard treatment of temozolomide (TMZ) combined with radiotherapy, due to its remarkable cell heterogeneity. Accordingly, there is a need to target alternative molecules enhancing specific GBM autocrine or paracrine mechanisms and amplifying the effect of standard treatment. Sphingosine 1-phosphate (S1P) is such a lipid target molecule with an important role in cell invasion and proliferation. Sphingosine kinase inhibitors (SKI) prevent S1P formation and induce increased production of reactive oxygen species (ROS), which may potentiate radiation cytotoxicity. We analyzed the effect of SKI singular versus combined treatments with TMZ and radiation on 2 human GBM cell lines characterized by a lack of MGMT expression and low or high expression of the anti-oxidant enzyme, glutathione peroxidase 1 (GPx1). Effects were drug concentration-, cell line-dependent and partly ROS-mediated. Clonogenic survival assay demonstrates that SKI was more effective than TMZ in increasing the sensitivity of U87 cells, which express low GPx1 amount, to a 2 Gy X-ray dose. Addition of both SKI and TMZ drastically decreased U87 cells survival compared with the combination temozolomide/radiation. SKI less effectively than TMZ sensitized LN229 cells to the 2 Gy X-ray dose. Its combination to TMZ in absence of irradiation was as efficient as TMZ combination with X-ray. We provide first evidence for SKI as an alternative or complementary treatment to TMZ, and for efficient combinations of low doses of drugs and X-ray. These may help as novel bi-modal and tri-modal therapies to contend with GBM heterogeneity. © 2017 The Author(s). Published with license by Taylor & Francis Group, LLC
Winter M.,German Cancer Research Center |
Dokic I.,German Cancer Research Center |
Dokic I.,University of Heidelberg |
Schlegel J.,German Cancer Research Center |
And 8 more authors.
Molecular and Cellular Proteomics | Year: 2017
Radiotherapy is a cornerstone of cancer therapy. The recently established particle therapy with raster-scanning protons and carbon ions landmarks a new era in the field of high-precision cancer medicine. However, molecular mechanisms governing radiation induced intracellular signaling remain elusive. Here, we present the first comprehensive proteomic and phosphoproteomic study applying stable isotope labeling by amino acids in cell culture (SILAC) in combination with high-resolution mass spectrometry to decipher cellular response to irradiation with X-rays, protons and carbon ions. At protein expression level limited alterations were observed 2 h post irradiation of human lung adenocarcinoma cells. In contrast, 181 phosphorylation sites were found to be differentially regulated out of which 151 sites were not hitherto attributed to radiation response as revealed by crosscheck with the PhosphoSitePlus database. Radiation-induced phosphorylation of the p(S/T)Q motif was the prevailing regulation pattern affecting proteins involved in DNA damage response signaling. Because radiation doses were selected to produce same level of cell kill and DNA double-strand breakage for each radiation quality, DNA damage responsive phosphorylation sites were regulated to same extent. However, differential phosphorylation between radiation qualities was observed for 55 phosphorylation sites indicating the existence of distinct signaling circuitries induced by X-ray versus particle (proton/carbon) irradiation beyond the canonical DNA damage response. This unexpected finding was confirmed in targeted spike-in experiments using synthetic isotope labeled phosphopeptides. Herewith, we successfully validated uniform DNA damage response signaling coexisting with altered signaling involved in apoptosis and metabolic processes induced by X-ray and particle based treatments. In summary, the comprehensive insight into the radiation-induced phosphoproteome landscape is instructive for the design of functional studies aiming to decipher cellular signaling processes in response to radiotherapy, space radiation or ionizing radiation per se. Further, our data will have a significant impact on the ongoing debate about patient treatment modalities. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
Hauswald H.,University of Heidelberg |
Hauswald H.,Heidelberg Institute of Radiation Oncology HIRO |
Rieken S.,University of Heidelberg |
Rieken S.,Heidelberg Institute of Radiation Oncology HIRO |
And 7 more authors.
BMC Cancer | Year: 2015
Background: The standard trimodal treatment concept in locally advanced and non-metastasized non-small-cell superior sulcus tumors consists of a preoperative chemoradiation followed by surgical resection. High linear energy transfer (LET) radiation as, for example, C12 heavy-ion beam therapy theoretically offers biological advantages compared to high energy x-ray therapy as, for example, higher biological efficiency. Methods/Design: In the present prospective, single-armed, open pilot study performed at the Heidelberg Ion-Beam Therapy Center (HIT) in Heidelberg, the radiation treatment within the standard trimodal concept will be exchanged against C12 heavy-ion beam treatment and apply 39GyE in 13 single fractions in combination with a chemotherapy consisting of cisplatin and vinorelbine (local standard). The primary endpoint is feasibility and safety measured by the incidence of NCI-CTCAE grade 3/4 toxicity and/or discontinuation due to any reason. Secondary endpoint is the degree of regression in the histological specimen. The main inclusion criteria are histologically confirmed non-small-cell superior sulcus tumor, nodal disease stage ≤ N2, Karnofsky performance score ≥70%, patient age between 18 and 75 years as well as written informed consent. The main exclusion criteria include medical contraindications against elements of the trimodal treatment concept, PET confirmed nodal disease stage N3, stage IV disease, prior thoracic irradiation and decompensated diseases of the lung, cardio-vascular system, metabolism, hematopoietic and coagulation system and renal function. Furthermore, patients with implanted active medical devices without certification for ion-beam therapy are not allowed to take part in the study. © Hauswald et al.
Habl G.,Heidelberg Institute of Radiation Oncology HIRO |
Habl G.,TU Munich |
Katayama S.,Heidelberg Institute of Radiation Oncology HIRO |
Uhl M.,Heidelberg Institute of Radiation Oncology HIRO |
And 6 more authors.
BMC Cancer | Year: 2015
Background: Definitive, percutaneous irradiation of the prostate and the pelvic lymph nodes in high-risk prostate cancer is the alternative to prostatectomy plus lymphadenectomy. To date, the role of whole pelvis radiotherapy (WPRT) has not been clarified especially taking into consideration the benefits of high conformal IMRT (intensity modulated radiotherapy) of complex-shaped target volumes. Methods: From 2009 to 2012, 40 patients of high-risk prostate cancer with an increased risk of microscopic lymph node involvement were enrolled into this prospective phase II trial. Patients received at least two months of antihormonal treatment (AT) before radiotherapy continuing for at least 2years. Helical IMRT (tomotherapy) of the pelvic lymph nodes (51.0Gy) with a simultaneous integrated, moderate hypofractionated boost (single dose of 2.25Gy) to the prostate (76.5Gy) was performed in 34 fractions. PSA levels, prostate-related symptoms and quality of life were assessed at regular intervals for 24months. Results: Of the 40 patients enrolled, 38 finished the treatment as planned. Overall acute toxicity rates were low and no acute grade 3 or 4 gastrointestinal (GI) and genitourinary (GU) toxicity occurred. 21.6% of patients experienced acute grade 2 but no late grade ≥2 GI toxicity. Regarding GU side effects, results showed 48.6% acute grade 2 and 6.4% late grade 2 toxicity. After a median observation time of 23.4months the PLATIN 1 trial can be considered as sufficiently safe meeting the prospectively defined aims of the trial. With 34/37 patients free of a PSA recurrence it shows promising efficacy. Conclusion: Tomotherapy of the pelvic lymph nodes with a simultaneous integrated boost to the prostate can be performed safely and without excessive toxicity. The combined irradiation of both prostate and pelvic lymph nodes seems to be as well tolerated as the irradiation of the prostate alone. Trial registration: Trial Numbers: ARO 2009-05, ClinicalTrials.gov: NCT01903408. © 2015 Habl et al.
Uhl M.,University of Heidelberg |
Uhl M.,Heidelberg Ion Beam Therapy Center |
Uhl M.,German Cancer Research Center |
Herfarth K.,University of Heidelberg |
And 7 more authors.
Cancer Journal (United States) | Year: 2014
Protons and carbon ions currently are the most used charged-particle therapies in the cancer treatment of humans. This review summarizes the physical and biological differences and their impact on clinical use. Furthermore, published data in the treatment of several tumor entities and the use of protons and carbon ions are collected and discussed. © 2014 by Lippincott Williams & Wilkins.
PubMed | Heidelberg Institute of Radiation Oncology HIRO
Type: Clinical Trial, Phase I | Journal: Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al] | Year: 2015
A prospective study to assess toxicity and survival outcomes after intensity-modulated whole-abdominal irradiation (IM-WAI) following surgery and adjuvant intravenous carboplatin/taxane chemotherapy in advanced FIGO stage III ovarian cancer.Between 2006 and 2009, 16 patients with optimally resected FIGO stage III ovarian cancer, who had received six cycles of adjuvant carboplatin/taxane chemotherapy were treated with consolidation IM-WAI. Radiotherapy was delivered to a total dose of 30 Gy in 1.5-Gy fractions, using step-and-shoot (n=3) or helical tomotherapy (n=13). The first 10 patients were treated within a phase I trial; the following patients received the same treatment modality. The target volume included the entire peritoneal cavity, the diaphragm, the liver capsule, and the pelvic and para-aortic node regions. Organs at risk were kidneys, liver, heart, and bone marrow.Median follow-up was 44 months (range 19.2-67.2 months). No grade 4 toxicities occurred during IM-WAI. Common Toxicity Criteria for Adverse Events (CTCAE) grade 3 toxicities were: diarrhea (25%), leucopenia (19%), nausea/vomiting (6%), and thrombocytopenia (6%). No toxicity-related treatment break was necessary. Small bowel obstruction occurred in a total of 6 patients: in 3 cases (19%) due to postsurgical adhesions and in 3 cases due to local tumor recurrence (19%). Median recurrence-free survival (RFS) was 27.6 months (95% confidence interval, CI =24-44 months) and median overall survival (OS) was 42.1 months (95%CI =17-68 months). The peritoneal cavity was the most frequent site of initial failure.Consolidation IM-WAI following surgery and adjuvant chemotherapy is feasible and can be performed with manageable acute and late toxicity. The favorable RFS outcome is promising and justifies further clinical trials.
PubMed | Universitatsklinikum Wurzburg, Heidelberg Institute of Radiation Oncology HIRO, University Hospital Freiburg and Universitasspital Zurich
Type: Journal Article | Journal: Radiation oncology (London, England) | Year: 2016
Current guidelines recommend stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer (NSCLC) in medically inoperable patients. There are excellent outcome and toxicity data for SBRT of peripheral lung tumors. However, the discussion on SBRT for centrally located tumors is controversial. This study evaluated current clinical practice regarding SBRT of centrally located lung tumors, to identify common fractionation schedules and commonly accepted contraindications for SBRT.A questionnaire consisting of two parts was introduced at the annual meeting of the DEGRO working group on stereotactic radiotherapy, representing centers in Germany and Switzerland. The first part of the questionnaire covered general information about the centers, whereas the second part specifically addressed SBRT of centrally located lung tumors, using case examples of nine primary NSCLC patients. Reconstructions of a contrast enhanced CT, as well as PET-Imaging for each case were demonstrated to the participants.Twenty-six centers participated in the meeting. The majority was academic (73%), participated in interdisciplinary thoracic oncology tumorboards (88%) and offered SBRT for lung tumors (96%). Two centers questioned the indication of SBRT for central lung tumors because of lack of evidence. The majority of centers had experience in SBRT for central lung tumors (88%) and half of the centers reported more than ten cases treated during a median period of five years. Most fractionation schedules used PTV encompassing doses of 48-60Gy in eight fractions with maximum doses of 125-150%. A clear indication for SBRT treatment was seen by more than 85% of centers in three of the nine patients in whom tumors were small and not closer than 2cm to the main bronchus. Prior pneumonectomy or immediate adjacency to hilar/mediastinal structures were not considered as contraindications for SBRT. In cases where the tumor exceeded 4cm in diameter or was located closer than 4cm to the carina 50-80% of centers saw an indication for SBRT. One case, with a 7cm tumor reaching to the carina would have been treated with SBRT only by one center.Within DEGRO working group on stereotactic radiotherapy, SBRT for small (<4cm) early stage NSCLC is a common indication, if the minimal distance to the main bronchi is at least 2cm. The controversy on the treatment of larger and more central tumors will hopefully be solved by ongoing prospective clinical trials.
PubMed | Heidelberg Institute of Radiation Oncology HIRO and German Cancer Research Center
Type: | Journal: BMC cancer | Year: 2015
Definitive, percutaneous irradiation of the prostate and the pelvic lymph nodes in high-risk prostate cancer is the alternative to prostatectomy plus lymphadenectomy. To date, the role of whole pelvis radiotherapy (WPRT) has not been clarified especially taking into consideration the benefits of high conformal IMRT (intensity modulated radiotherapy) of complex-shaped target volumes.From 2009 to 2012, 40 patients of high-risk prostate cancer with an increased risk of microscopic lymph node involvement were enrolled into this prospective phase II trial. Patients received at least two months of antihormonal treatment (AT) before radiotherapy continuing for at least 2 years. Helical IMRT (tomotherapy) of the pelvic lymph nodes (51.0 Gy) with a simultaneous integrated, moderate hypofractionated boost (single dose of 2.25 Gy) to the prostate (76.5 Gy) was performed in 34 fractions. PSA levels, prostate-related symptoms and quality of life were assessed at regular intervals for 24 months.Of the 40 patients enrolled, 38 finished the treatment as planned. Overall acute toxicity rates were low and no acute grade 3 or 4 gastrointestinal (GI) and genitourinary (GU) toxicity occurred. 21.6% of patients experienced acute grade 2 but no late grade 2 GI toxicity. Regarding GU side effects, results showed 48.6% acute grade 2 and 6.4% late grade 2 toxicity. After a median observation time of 23.4 months the PLATIN 1 trial can be considered as sufficiently safe meeting the prospectively defined aims of the trial. With 34/37 patients free of a PSA recurrence it shows promising efficacy.Tomotherapy of the pelvic lymph nodes with a simultaneous integrated boost to the prostate can be performed safely and without excessive toxicity. The combined irradiation of both prostate and pelvic lymph nodes seems to be as well tolerated as the irradiation of the prostate alone.Trial Numbers: ARO 2009-05, ClinicalTrials.gov: NCT01903408.
Uhl M.,University of Heidelberg |
Uhl M.,Heidelberg Ion Beam Therapy Center |
Welzel T.,University of Heidelberg |
Jensen A.,University of Heidelberg |
And 13 more authors.
Strahlentherapie und Onkologie | Year: 2015
Purpose: The purpose of this work was to evaluate the results of high-dose radiation treatment using carbon ion therapy, alone or combined with intensity-modulated radiation treatment (IMRT), in patients with sacral chordoma. Materials and methods: Between 2009 and 2012, 56 patients with sacral chordoma were treated in our center. The tumor was located above S3 in 33 patients and in S3 or below in 23 patients. In all, 41 patients received radiation therapy for the primary tumor, while 15 patients were treated for the recurrent tumor. Toxicity was measured using NCI CTCAE v.4.03. Local control (LC) and overall survival (OS) were evaluated with the Kaplan–Meier method. Results: A total of 23 patients were irradiated with carbon ions in combination with photon IMRT, while 33 received carbon ion therapy only. Forty-three patients had a macroscopic tumor at treatment start with a median tumor size (GTV) of 244 ml (range 5–1188 ml). The median total dose was 66 Gy (range 60–74 Gy; RBE). After a median follow-up time of 25 months, the 2- and 3-year local control probability was 76 % and 53 %, respectively. The overall survival rate was 100 %. Treatment for primary tumor and male patients resulted in significant better local control. No higher toxicity occurred within the follow-up time. Conclusion: High-dose photon/carbon ion beam radiation therapy is safe and, especially for primary sacral chordomas, highly effective. A randomized trial is required to evaluate the role of primary definitive hypofractionated particle therapy compared with surgery with or without adjuvant radiotherapy. © 2015, Springer-Verlag Berlin Heidelberg.