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  • 1
    Keywords: RECEPTOR ; ANGIOGENESIS ; APOPTOSIS ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; IONIZING-RADIATION ; IRRADIATION ; proliferation ; radiotherapy ; SURVIVAL ; tumor ; AGENTS ; CELL ; CELL-PROLIFERATION ; COMBINATION ; FACTOR RECEPTOR ; Germany ; human ; IN-VIVO ; INHIBITION ; KINASE ; PATHWAY ; PROSTATE ; THERAPY ; tumor growth ; VITRO ; DENSITY ; DRUG ; TUMORS ; MICE ; radiation ; PATIENT ; MECHANISM ; INDEX ; TYROSINE KINASE INHIBITOR ; DESIGN ; UP-REGULATION ; prostate cancer ; PROSTATE-CANCER ; DAMAGE ; MUSCLE ; MIGRATION ; experimental design ; CELL-MIGRATION ; TUMOR ANGIOGENESIS ; VEGF ; signaling ; AGENT ; ONCOLOGY ; RE ; antiangiogenesis ; SU5416 ; TUMOR-GROWTH ; THERAPIES ; INCREASE ; cell proliferation ; cell migration ; USA ; vascular endothelial growth factor ; cancer research ; GLIOBLASTOMA ; GROWTH-FACTOR-RECEPTOR ; SMOOTH-MUSCLE-CELLS ; ENDOTHELIAL GROWTH ; MUSCLE-CELLS ; tumor therapy ; radiation dose ; FRACTIONATED-IRRADIATION ; SU6668
    Abstract: Purpose: Investigations on the combination of radiotherapy with vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) antiangiogenic agents, which has the potential to improve the clinical outcome in cancer patients. Experimental Design: Here, we analyze the combined VEGF (SU5416) and PDGF (SU6668) receptor tyrosine kinase inhibition with irradiation in human endothelium (HUVEC), prostate cancer (PC3), and glioblastoma (U87) in vitro and in vivo. Results: Combined inhibition of VEGF and PDGF signaling resulted in enhanced apoptosis, reduced cell proliferation, and clonogenic survival as well as reduced endothelial cell migration and tube formation compared with single pathway inhibition. These effects were further enhanced by additional irradiation. Likewise, in PC3 and U87 tumors growing s.c. on BALB/c nu/nu mice, dual inhibition of VEGF and PDGF signaling significantly increased tumor growth delay versus each monotherapy. Interestingly, radiation at similar to 20% of the dose necessary to induce local tumor control exerts similar tumor growth-inhibitory effects as the antiangiogenic drugs given at their maximum effective dose. Addition of radiotherapy to both mono- as well as dual-antiangiogenic treatment markedly increased tumor growth delay. With respect to tumor angiogenesis, radiation further decreased microvessel density (CD31 count) and tumor cell proliferation (Ki-67 index) in all drug-treated groups. Of note, the slowly growing PC3 tumor responded better to the antiangiogenic drug treatments than the faster-growing U87 tumor. In addition to the beneficial effect of abrogating VEGF survival signaling when combined with radiation, we identified here a novel mechanism for the tumor escape from radiation damage. We found that radiation induced up-regulation of all four isoforms of PDGF (A-D) in endothelial cells supporting adjacent smooth muscle cells resulting in a prosurvival effect of radiation. The addition of SU6668 attenuated this undesirable paracrine radiation effect, which may rationalize the combined application of radiation with PDGF signaling inhibition to increase antitumor effects. Conclusion: A relative low radiation dose markedly enhances local antitumor effects of combined VEGF and PDGF signaling inhibition, suggesting a promising combination regimen for local tumor treatment with radiotherapy remaining an essential element
    Type of Publication: Journal article published
    PubMed ID: 18381963
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  • 2
    Keywords: CANCER ; EXPRESSION ; IRRADIATION ; tumor ; carcinoma ; THERAPY ; MORTALITY ; TUMORS ; T-CELLS ; FREQUENCY ; BONE-MARROW ; MIGRATION ; inflammation ; PANCREATIC-CANCER ; low dose radiation ; colorectal liver metastasis ; ERADICATION ; tumor specific T cells
    Abstract: BACKGROUND: Insufficient migration and activation of tumor specific effector T cells in the tumor is one of the main reasons for inadequate host anti-tumor immune response. External radiation seems to induce inflammation and activate the immune response. This phase I/II clinical trial aims to evaluate whether low dose single fraction radiotherapy can improve T cell associated antitumor immune response in patients with colorectal liver metastases. METHODS: This is an investigator-initiated, prospective randomised, 4-armed, controlled Phase I /II trial. Patients undergoing elective hepatic resection due to colorectal cancer liver metastasis will be enrolled in the study. Patients will receive 0 Gy, 0.5 Gy, 2 Gy or 5 Gy radiation targeted to their liver metastases. Radiation will be applied by external beam radiotherapy using a 6 MV linear accelerator (Linac) with intensity modulated radiotherapy (IMRT) technique two days prior to surgical resection. All patients admitted to the Department of General-, Visceral-, and Transplantion Surgery, University of Heidelberg for elective hepatic resection are consecutively screened for eligibility into this trial, and written informed consent is obtained before inclusion. The primary objective is to assess the effect of active local external beam radiation dose on tumor infiltrating T cells as a surrogate parameter for antitumor activity. Secondary objectives include radiogenic treatment toxicity, postoperative morbidity and mortality, local tumor control and recurrence patterns, survival and quality of life. Furthermore, frequencies of systemic tumor reactive T cells in blood and bone marrow will be correlated with clinical outcome. DISCUSSION: This is a randomized controlled patient blinded trial to assess the safety and efficiency of low dose radiotherapy on metastases infiltrating T cells and thus potentially enhance the antitumor immune response. Trial registration: ClinicalTrials.gov - NCT01191632.
    Type of Publication: Journal article published
    PubMed ID: 21961577
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  • 3
    Keywords: CANCER ; IRRADIATION ; radiotherapy ; SURVIVAL ; Germany ; LUNG ; THERAPY ; TOXICITY ; lung cancer ; LUNG-CANCER ; SURGERY ; radiation ; PATIENT ; CYCLE ; treatment ; antibodies ; antibody ; STAGE ; TRIAL ; RADIATION-THERAPY ; RATES ; metastases ; chemotherapy ; RESECTION ; CARCINOMAS ; OVEREXPRESSION ; IMRT ; FEASIBILITY ; PHASE-II ; NECK-CANCER ; SUBSET ; CONCURRENT ; ADVANCED HEAD ; INFUSION ; PHASE ; REMISSION ; prospective ; NSCLC ; C225 ; FACTOR RECEPTOR BLOCKADE ; stage III ; surgical resection
    Abstract: Background: Even today, treatment of Stage III NSCLC still poses a serious challenge. So far, surgical resection is the treatment of choice. Patients whose tumour is not resectable or who are unfit to undergo surgery are usually referred to a combined radio-chemotherapy. However, combined radio-chemotherapeutic treatment is also associated with sometimes marked side effects but has been shown to be more efficient than radiation therapy alone. Nevertheless, there is a significant subset of patients whose overall condition does not permit administration of chemotherapy in a combined-modality treatment. It could be demonstrated though, that NSCLCs often exhibit over-expression of EGF-receptors hence providing an excellent target for the monoclonal EGFR-antagonist cetuximab (Erbitux(R)) which has already been shown to be effective in colorectal as well as head-and-neck tumours with comparatively mild side-effects. Methods/design: The NEAR trial is a prospective phase II feasibility study combining a monoclonal EGF-receptor antibody with loco-regional irradiation in patients with stage III NSCLC. This trial aims at testing the combination's efficacy and rate of development of distant metastases with an accrual of 30 patients. Patients receive weekly infusions of cetuximab (Erbitux(R)) plus loco-regional radiation therapy as intensity-modulated radiation therapy. After conclusion of radiation treatment patients continue to receive weekly cetuximab for 13 more cycles. Discussion: The primary objective of the NEAR trial is to evaluate toxicities and feasibility of the combined treatment with cetuximab (Erbitux(R)) and IMRT loco-regional irradiation. Secondary objectives are remission rates, 3-year-survival and local/systemic progression-free survival
    Type of Publication: Journal article published
    PubMed ID: 16681848
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  • 4
    Keywords: IRRADIATION ; radiotherapy ; SURVIVAL ; tumor ; Germany ; THERAPY ; TOXICITY ; FOLLOW-UP ; DEATH ; SURGERY ; radiation ; TIME ; PATIENT ; prognosis ; treatment ; MALIGNANCIES ; AGE ; RATES ; chemotherapy ; local control ; ORGANIZATION ; MANAGEMENT ; ONCOLOGY-GROUP ; POSTOPERATIVE RADIOTHERAPY ; GRADE ; LIFE ; SIZE ; function ; TREATMENT TIME ; soft-tissue sarcoma ; ADJUVANT BRACHYTHERAPY ; electron boost radiation ; external beam radiotherapy ; limb-sparing treatment ; PROSPECTIVE RANDOMIZED TRIAL
    Abstract: Purpose: To analyze long-term prognosis and morbidity after limb-sparing treatment of patients with extremity soft-tissue sarcoma, with intraoperative electron boost radiotherapy (IOERT) followed by a moderate dose of external beam radiotherapy (EBRT). Methods and Materials: A total of 153 patients who were treated in a single center from 1991 to 2004 were ovaluated. Median IOERT dose was 15 Gy, mean EBRT dose 43 Gy (range, 40-50.4 Gy) in conventional fractionation (1.8-2 Gy). Median duration of follow-up was 33 months. Acute toxicity was assessed with Common Toxicity Criteria; late toxic effects were scored according to European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group criteria. Results: Five-year overall survival and 5-year local control rates were 77% and 78%.. respectively. Whereas tumor size, patient age, and EBRT dose did not significantly affect outcome, resection status and grading were significant for survival; resection status and IOERT dose were significant for local control. Extremity salvage until death or time of follow-up was achieved in 90% of our patients, 86% of whom showed excellent limb function without impairment in activities of daily life. Acute toxicity Grade 2-4 was observed in 23% and late toxicity Grade 2-4 in 17% of patients. Conclusions: Treatment with IOERT combined with moderate doses of external beam irradiation yields high local control and extremity preservation rates in resected extremity soft-tissue sarcoma. (c) 2006 Elsevier Inc
    Type of Publication: Journal article published
    PubMed ID: 16413697
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  • 5
    Keywords: CELLS ; radiotherapy ; SURVIVAL ; tumor ; CELL ; Germany ; neoplasms ; THERAPY ; TOXICITY ; FOLLOW-UP ; DISEASE ; TUMORS ; SURGERY ; radiation ; MRI ; PROGRESSION ; CONFORMAL RADIOTHERAPY ; EXPERIENCE ; RADIATION-THERAPY ; AGE ; EFFICACY ; REGION ; HEAD ; NECK ; local control ; ONCOLOGY ; overall survival ; radiation therapy ; MENINGIOMAS ; BONE ; SCAN ; INSTITUTION ; CASE SERIES
    Abstract: Background: Giant cell tumors are rare neoplasms, representing less than 5% of all bone tumors. The vast majority of giant cell tumors occurs in extremity sites and is treated by surgery alone. However, a small percentage occurs in pelvis, spine or skull bones, where complete resection is challenging. Radiation therapy seems to be an option in these patients, despite the lack of a generally accepted dose or fractionation concept. Here we present a series of five cases treated with high dose IMRT. Patients and Methods: From 2000 and 2006 a total of five patients with histologically proven benign giant cell tumors have been treated with IMRT in our institution. Two patients were male, three female, and median age was 30 years (range 20 - 60). The tumor was located in the sacral region in four and in the sphenoid sinus in one patient. All patients had measurable gross disease prior to radiotherapy with a median size of 9 cm. All patients were treated with IMRT to a median total dose of 64 Gy (range 57.6 Gy to 66 Gy) in conventional fractionation. Results: Median follow up was 46 months ranging from 30 to 107 months. Overall survival was 100%. One patient developed local disease progression three months after radiotherapy and needed extensive surgical salvage. The remaining four patients have been locally controlled, resulting in a local control rate of 80%. We found no substantial tumor shrinkage after radiotherapy but in two patients morphological signs of extensive tumor necrosis were present on MRI scans. Decline of pain and/or neurological symptoms were seen in all four locally controlled patients. The patient who needed surgical salvage showed markedly reduced pain but developed functional deficits of bladder, rectum and lower extremity due to surgery. No severe acute or late toxicities attributable to radiation therapy were observed so far. Conclusion: IMRT is a feasible option in giant cells tumors not amendable to complete surgical removal. In our case series local control was achieved in four out of five patients with marked symptom relief in the majority of cases. No severe toxicity was observed
    Type of Publication: Journal article published
    PubMed ID: 20187955
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  • 6
    Keywords: CANCER ; IRRADIATION ; radiotherapy ; tumor ; CELL ; Germany ; LUNG ; THERAPY ; TOXICITY ; lung cancer ; LUNG-CANCER ; COHORT ; DISEASE ; HISTORY ; RISK ; radiation ; ASSOCIATION ; CONFORMAL RADIOTHERAPY ; AGE ; smoking ; chemotherapy ; LOCALIZATION ; PREDICTION ; ESCALATION ; ONCOLOGY ; small cell lung cancer ; REGRESSION ; development ; NSCLC ; RADIATION PNEUMONITIS ; MODALITY ; CONCURRENT CHEMOTHERAPY ; Dose-volume constraints
    Abstract: Purpose: To analyze the association of patient- and treatment-related factors with the onset of radiation pneumonitis in a homogeneously treated cohort of patients suffering from small cell Lung cancer (SCLC). Patients and Methods: 242 patients with SCLC staged as limited disease, who had been treated with chemotherapy and three-dimensional conformal radiotherapy, were retrospectively analyzed. Pneumonitis was defined by typical symptoms and radiographic findings and judged clinically relevant, if drug administration and hospitalization were necessary. Patient- (age, gender, smoking history, performance status, tumor Localization, benign lung disease) and treatment-related parameters (V-10-V-40, mean lung dose [MLD]) were analyzed using chi(2)-tests for categorical parameters and Logistic regression for continuous variables. Results: 33 patients (13.6%) developed a clinically relevant pneumonitis, of whom three patients died. ALL cases of pneumonitis developed within 120 days. None of the patient-related parameters correlated significantly with the onset of pneumonitis. Considering treatment-related parameters, a significant correlation of V-30 in regard to total lung and V-40 in regard to ipsilateral, contralateral and total Lung to the risk of pneumonitis was found. So, the estimated risk of a clinically relevant pneumonitis increased from 10% given a V-30 of 13% to 30% given a V-30 of 35%. In contrast, no significant correlation was found for V-10 and V-20 and only a trend for MLD. Conclusion: In this series, high-dose radiation volume parameters, i.e., V-30 and especially V-40, were identified as the most important factors for the development of radiation pneumonitis. Low-dose radiation volume parameters and clinical parameters played an inferior role in predicting the pneumonitis risk
    Type of Publication: Journal article published
    PubMed ID: 20165822
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  • 7
    Keywords: PATIENT ; radiation ; Germany ; THERAPY ; imaging ; CANCER ; RADIATION-THERAPY ; Jun ; pancreatic cancer ; RECURRENT ; ONCOLOGY ; PANCREATIC-CANCER ; radiation therapy
    Type of Publication: Meeting abstract published
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  • 8
    Keywords: RESECTION ; RADIATION-THERAPY ; radiation ; THERAPY
    Type of Publication: Meeting abstract published
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  • 9
    Keywords: RECEPTOR ; CANCER ; CANCER CELLS ; CELLS ; GROWTH ; GROWTH-FACTOR ; radiotherapy ; AGENTS ; COMBINATION ; FACTOR RECEPTOR ; Germany ; INHIBITION ; THERAPY ; TOXICITY ; DEATH ; radiation ; TIME ; PATIENT ; MECHANISM ; prognosis ; GROWTH-FACTOR RECEPTOR ; TRIAL ; IDENTIFICATION ; LESIONS ; PROGRESSION ; RADIATION-THERAPY ; resistance ; NUMBER ; WOMEN ; CLINICAL-TRIALS ; MEN ; chemotherapy ; CANCER-CELLS ; CARCINOMA-CELLS ; RECRUITMENT ; STRATEGIES ; SAFETY ; adenocarcinoma ; TARGETS ; QUESTIONNAIRE ; pancreatic cancer ; IMRT ; EPIDERMAL-GROWTH-FACTOR ; PHASE-II ; AGENT ; targeting ; molecular ; GEMCITABINE ; pancreas ; RE ; PANCREATIC-CANCER ; DETERMINANTS ; targeted ; PROTOCOL ; LIFE ; intensity ; QUALITY-OF-LIFE ; quality of life ; radiation therapy ; INTERVAL ; PHASE ; NEED ; EUROPEAN-ORGANIZATION ; phase II ; Molecular targets ; ADJUVANT COMBINED RADIATION ; COMBINED-MODALITY THERAPY ; CURATIVE RESECTION
    Abstract: Background: Pancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor ( EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR. Methods/design: The PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy ( IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patient's enrolment. Discussion: The primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with chemoradiation therapy with gemcitabine and intensity modulated radiation therapy (IMRT) and EGFR-targeted therapy using cetuximab and to compare between two different methods of cetuximab treatment schedules ( concomitant versus concomitant and sequential cetuximab treatment). Secondary objectives are to determine the role and the mechanism of cetuximab in patient's chemoradiation regimen, the response rate, the potential of this combined modality treatment to concert locally advanced lesions to potentially resectable lesions, the time to progression interval and the quality of life
    Type of Publication: Journal article published
    PubMed ID: 16219105
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  • 10
    Keywords: radiotherapy ; SURVIVAL ; Germany ; THERAPY ; CLASSIFICATION ; FOLLOW-UP ; radiation ; TIME ; PATIENT ; SKIN ; T cell ; T-CELL ; STAGE ; LYMPHOMA ; RADIATION-THERAPY ; AGE ; EFFICIENT ; ELECTRON ; FRANCE ; BEAM ; CTCL ; non-hodgkin's lymphoma ; MANAGEMENT ; MYCOSIS-FUNGOIDES ; THERAPIES ; overall survival ; GRADE ; T-CELL LYMPHOMA ; cutaneous T-cell lymphoma ; radiation therapy ; REMISSION ; SYMPTOMS ; mycosis fungoides ; PROGRESSION-FREE SURVIVAL ; response ; non-Hodgkin ; CORRELATE ; COURSES ; EORTC ; total skin radiotherapy ; TSEBT
    Abstract: Our aim was to analyze the effectiveness of palliative total skin electron beam therapy (TSEBT) in the management of advanced cutaneous T-cell non-Hodgkin's lymphoma (CTCL). Eighteen patients (median age 59 Years) with advanced and therapy-refractory CTCL in stages IIB-IV were treated with TSEBT for the first time. The most common histological subtype was Mycosis fungoides (72%). All patients suffered from lymphoma-associated symptoms. Median daily fractions of 1 Gy were administered up to a median total dose of 25 Gy. The median follow-up period. was 11 months. Nine patients (50%) achieved a complete response and seven patients (39%) had a limited response. The actuarial one-Year progression-free survival was 24%. Four patients (22%) had continuing remission over a median period of six months. Lymphoma associated symptoms were improved in 16 patients (89%). The median overall survival after receiving TSEBT was 12 months, resulting in an actuarial one-year overall survival of 48%. Treatment related acute effects (grade 1 or 2) were observed in all patients during radiation therapy. Transient grade 3 epitheliolyses developed in five patients (28%), late skin effects (grade 1 and 2) in 16 patients (89%), and hypohidrosis was seen in six patients (33%). We conclude that TSEBT is a very efficient and tolerable palliative treatment for patients with advanced CTCL
    Type of Publication: Journal article published
    PubMed ID: 18474461
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