Center for Translational Research in Radiation Oncology

Tel Aviv, Israel

Center for Translational Research in Radiation Oncology

Tel Aviv, Israel
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Den R.B.,Thomas Jefferson University | Kamrava M.,U.S. National Cancer Institute | Sheng Z.,University of Massachusetts Medical School | Werner-Wasik M.,Thomas Jefferson University | And 12 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2013

Purpose: Despite recent advances in the management of high-grade and recurrent gliomas, survival remains poor. Antiangiogenic therapy has been shown to be efficacious in the treatment of high-grade gliomas both in preclinical models and in clinical trials. We sought to determine the safety and maximum tolerated dose of sorafenib when combined with both radiation and temozolomide in the primary setting or radiation alone in the recurrent setting. Methods and Materials: This was a preclinical study and an open-label phase I dose escalation trial. Multiple glioma cell lines were analyzed for viability after treatment with radiation, temozolomide, or sorafenib or combinations of them. For patients with primary disease, sorafenib was given concurrently with temozolomide (75 mg/m2) and 60 Gy radiation, for 30 days after completion of radiation. For patients with recurrent disease, sorafenib was combined with a hypofractionated course of radiation (35 Gy in 10 fractions). Results: Cell viability was significantly reduced with the combination of radiation, temozolomide, and sorafenib or radiation and sorafenib. Eighteen patients (11 in the primary cohort, 7 in the recurrent cohort) were enrolled onto this trial approved by the institutional review board. All patients completed the planned course of radiation therapy. The most common toxicities were hematologic, fatigue, and rash. There were 18 grade 3 or higher toxicities. The median overall survival was 18 months for the entire population. Conclusions: Sorafenib can be safely combined with radiation and temozolomide in patients with high-grade glioma and with radiation alone in patients with recurrent glioma. The recommended phase II dose of sorafenib is 200 mg twice daily when combined with temozolomide and radiation and 400 mg with radiation alone. To our knowledge, this is the first publication of concurrent sorafenib with radiation monotherapy or combined with radiation and temozolomide. © 2013 Elsevier Inc. All rights reserved.

Gutovich J.M.,Drexel University | Den R.B.,Thomas Jefferson University | Werner-Wasik M.,Thomas Jefferson University | Dicker A.P.,Thomas Jefferson University | And 2 more authors.
Journal of the American College of Radiology | Year: 2013

Purpose: Academic research is an essential part of residency training, yet resident productivity in research seems to be highly variable. The aim of this study was to determine the factors, both individual and institutional, that contribute to research output among radiation oncology residents. Methods: Newly practicing radiation oncologists and current senior residents were identified and invited via e-mail to complete a web-based survey. The survey addressed demographic factors, previous academic accomplishments, and residency program structure. The end point, research productivity, was defined as the number of first-author papers produced or research grants awarded on the basis of work initiated during residency. Results: Ninety-seven of the 232 senior residents and recently graduated radiation oncologists surveyed responded (a 42% response rate). The median number of publications produced on the basis of work during residency was 3 (range, 0-7). Twenty-one respondents indicated that they had received 1 or more grants. Forty-four respondents completed <6 months of research, while 53 completed ≥6 months of research. Univariate analysis revealed that a scientific college major and the amount of designated research time were positively correlated (P <.05) with first-author publications. Entering with a PhD, presenting research at an international meeting before residency, participation in the Holman Research Pathway, female gender, publications before residency, and the amount of designated research time were positively correlated (P <.05) with receiving a research grant. On multivariate regression analysis, the amount of designated research time was the sole determinant of first-author papers (P <.007), while participation in the Holman Pathway was the only surveyed factor that was correlated with research grants awarded (P <.001). Conclusions: The amount of designated research time during residency training is the sole independent predictor of research productivity as measured by publications. Participation in the Holman Pathway is the sole detected item shown to be an independent predictor of achieving a peer-reviewed grant. Residency program structure has a major impact on the productivity of residents. © 2013 American College of Radiology.

Lawrence Y.R.,Thomas Jefferson University | Lawrence Y.R.,Center for Translational Research in Radiation Oncology | Lawrence Y.R.,Tel Aviv University | Whiton M.A.,Thomas Jefferson University | And 8 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: In light of concerns regarding the quality of radiation treatment delivery, we surveyed the practice of quality assurance peer review chart rounds at American academic institutions. Methods and Materials: An anonymous web-based survey was sent to the chief resident of each institution across the United States. Results: The response rate was 80% (57/71). The median amount of time spent per patient was 2.7 minutes (range, 0.6-14.4). The mean attendance by senior physicians and residents was 73% and 93%, respectively. A physicist was consistently present at peer review rounds in 66% of departments. There was a close association between attendance by senior physicians and departmental organization: in departments with protected time policies, good attendance was 81% vs. 31% without protected time (p = 0.001), and in departments that documented attendance, attending presence was 69% vs. 29% in departments without documentation (p < 0.05). More than 80% of institutions peer review all external beam therapy courses; however, rates were much lower for other modalities (radiosurgery 58%, brachytherapy 40%-47%). Patient history, chart documentation, and dose prescription were always peer reviewed in >75% of institutions, whereas dosimetric details (beams, wedges), isodose coverage, intensity-modulated radiation therapy constraints, and dose-volume histograms were always peer reviewed in 63%, 59%, 42%, and 50% of cases, respectively. Chart rounds led to both minor (defined as a small multileaf collimator change/repeated port film) and major (change to dose prescription or replan with dosimetry) treatment changes. Whereas at the majority of institutions changes were rare (<10% of cases), 39% and 11% of institutions reported that minor and major changes, respectively, were made to more than 10% of cases. Conclusion: The implementation of peer review chart rounds seems inconsistent across American academic institutions. Brachytherapy and radiosurgical procedures are rarely reviewed. Attendance by senior physicians is variable, but it improves when scheduling clashes are avoided. The potential effect of a more thorough quality assurance peer review on patient outcomes is not known. © 2012 Elsevier Inc.

Ohri N.,Thomas Jefferson University | Dicker A.P.,Thomas Jefferson University | Lawrence Y.R.,Thomas Jefferson University | Lawrence Y.R.,Center for Translational Research in Radiation Oncology
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: Hypofractionated radiotherapy (hRT) is being explored for a number of malignancies. The potential benefit of giving concurrent chemotherapy with hRT is not known. We sought to predict the effects of combined modality treatments by using mathematical models derived from laboratory data. Methods and Materials: Data from 26 published clonogenic survival assays for cancer cell lines with and without the use of radiosensitizing chemotherapy were collected. The first three data points of the RT arm of each assay were used to derive parameters for the linear quadratic (LQ) model, the multitarget (MT) model, and the generalized linear quadratic (gLQ) model. For each assay and model, the difference between the predicted and observed surviving fractions at the highest tested RT dose was calculated. The gLQ model was fitted to all the data from each RT cell survival assay, and the biologically equivalent doses in 2-Gy fractions (EQD2s) of clinically relevant hRT regimens were calculated. The increase in cell kill conferred by the addition of chemotherapy was used to estimate the EQD2 of hRT along with a radiosensitizing agent. For comparison, this was repeated using conventionally fractionated RT regimens. Results: At a mean RT dose of 8.0 Gy, the average errors for the LQ, MT, and gLQ models were 1.63, 0.83, and 0.56 log units, respectively, favoring the gLQ model (p < 0.05). Radiosensitizing chemotherapy increased the EQD2 of hRT schedules by an average of 28% to 82%, depending on disease site. This increase was similar to the gains predicted for the addition of chemotherapy to conventionally fractionated RT. Conclusions: Based on published in vitro assays, the gLQ equation is superior to the LQ and MT models in predicting cell kill at high doses of RT. Modeling exercises demonstrate that significant increases in biologically equivalent dose may be achieved with the addition of radiosensitizing agents to hRT. Clinical study of this approach is warranted. © 2012 Elsevier Inc. All rights reserved.

Lawrence Y.R.,Thomas Jefferson University | Lawrence Y.R.,Center for Translational Research in Radiation Oncology | Glass C.,Thomas Jefferson University | Symon Z.,Center for Translational Research in Radiation Oncology | And 2 more authors.
Journal of Medical Imaging and Radiation Oncology | Year: 2013

Introduction Over one third of cancer patients receive radiation therapy (RT) at some point. Our purpose was to quantify the risks to patients associated with enrolment onto RT-based phase I trials. Methods All phase I and phase I/II clinical trials involving RT published in English between 2001 and 2010 were identified via a PubMed search. For pragmatic reasons, we focused on trials from 2001, 2005 and 2009. For each trial we calculated a 'toxicity ratio' equal to the number of grade 3/4/5 toxic events divided by the number of patients in the trial. Linear regression was used to determine which variables were associated with higher toxicity ratios. Results There were a total of 33 treatment-related deaths, and 1812 acute grade 3/4 toxicities among the 2994 subjects in 98 trials. The median toxicity ratio over 98 trials was 0.46 (95% confidence interval (CI) 0.34 to 0.58). Multivariate regression analysis showed that toxicity ratios were significantly higher in trials with chemotherapy (P = 0.002) and in trials for cancers of the head-and-neck (P < 0.001). The median toxicity ratio in chemotherapy trials was 0.60 (95% CI: 0.48 to 0.72) compared with trials without chemotherapy 0.08 (95% CI: 0.03 to 0.13). Conclusions Although the risk of grade 5 toxicity is low, the risk of major toxicity is significant in phase I RT trials. These values are comparable to published risk estimates for phase I non-RT trials. © 2013 The Royal Australian and New Zealand College of Radiologists.

Lawrence Y.R.,Center for Translational Research in Radiation Oncology | Blumenthal D.T.,Tel Aviv Sourasky Medical Center | Matceyevsky D.,Tel Aviv Sourasky Medical Center | Kanner A.A.,Stereotactic Radiosurgery Unit | Bokstein F.,Tel Aviv Sourasky Medical Center
Journal of Neuro-Oncology | Year: 2011

Glioblastoma is a malignant tumor characterized by a rapid proliferation rate. Contemporary multimodality treatment consists of maximal surgical resection followed by radiation therapy (RT) combined with cytotoxic chemotherapy. The optimal timing of these different steps is not known. Four studies from the pre-temozolomide era, encompassing a total of 4,584 subjects, have examined the consequences of a delay between resection and starting RT. Whereas the two small single-institution studies found this delay to be detrimental, two large multiinstitutional studies found delay to be either slightly beneficial or at least not harmful. Here, we critically compare the methodologies and results presented in these studies, and include a novel analysis of the combined datasets. We conclude that moderate wait periods (up to 4-6 weeks post-operatively) are safe and may be modestly beneficial. Conversely, there is no evidence to justify waiting longer than 6 weeks. Underlying radiobiological principles are discussed. © Springer Science+Business Media, LLC. 2011.

Zach L.,Sheba Medical Center | Zach L.,Center for Translational Research in Radiation Oncology | Talianski A.,Sheba Medical Center | Talianski A.,Center for Translational Research in Radiation Oncology | And 2 more authors.
Memo - Magazine of European Medical Oncology | Year: 2015

Brain metastases are the most common malignant adult CNS tumor. The blood brain barrier (BBB) prevents many drugs from achieving therapeutic concentrations in the central nervous system (CNS), leaving the brain as a potential sanctuary site of disease and underscoring the importance of radiotherapy. Neurons, glial cells and vascular endothelium are prone to radiation-induced damage. Efforts have been made to reduce radiation-induced toxicity and increase efficacy (Stereotactic radio-surgery - SRS, advanced radiation-techniques that allow decreasing the dose to the hippocampi, while intensifying the radiation dose to large brain metastases or administering neuroprotective or radiation sensitizing agents during whole brain radiotherapy -WBRT in order to increase the therapeutic ratio). Surgery, radiotherapy and new pharmacological agents may become advantages for specific patient subgroups or in specific disease stages. Choosing how to treat brain metastases, must take into consideration patients and disease parameters (the primary tumor, age and performance status, systemic and brain tumor burden), and the potential risks and benefits of a treatment tool emphasising QOL considerations. Which modality to apply and when, is often a matter of local practice and treatment availability since level I evidence is lacking. The technology behind WBRT, FSR and SRS has substantially advanced over the previous decade, however only formal clinical trials will allow a definite answer to the question - are we getting better? © 2014, Springer-Verlag Wien.

Shavit R.,Thoracic Cancer Research and Detection Center | Ilouze M.,Thoracic Cancer Research and Detection Center | Ilouze M.,Davidoff Cancer Center | Feinberg T.,Thoracic Cancer Research and Detection Center | And 4 more authors.
Cellular Oncology | Year: 2015

Introduction: Lung cancer is the leading cause of cancer death. Radiation therapy plays a key role in its treatment. Ionizing radiation induces cell death through chromosomal aberrations, which trigger mitotic catastrophe and apoptosis. However, many lung cancer patients show resistance to radiation. Dichloroacetate (DCA) is a small molecule that can promote mitochondrial activation by increasing the influx of pyruvate. Here, we tested whether DCA may increase the sensitivity of non-small cell lung cancer (NSCLC) cells to radiation through this mechanism. Methods: Two representative NSCLC cell lines (A549 and H1299) were tested for their sensitivity to radiation with and without pre-exposure to DCA. The treatment efficacy was evaluated using a clonogenic survival assay. An extracellular flux analyzer was used to assess the effect of DCA on cellular oxygen consumption as a surrogate marker for mitochondrial activity. Results: We found that DCA increases the oxygen consumption rate in both A549 and H1299 cells by 60 % (p = 0.0037) and 20 % (p = 0.0039), respectively. Pre-exposure to DCA one hour before radiation increased the cytotoxic death rate 4-fold in A549 cells (55 to 13 %, p = 0.004) and 2-fold in H1299 cells (35 to 17 %, p = 0.28) respectively, compared to radiation alone. Conclusion: Mitochondrial induction by DCA may serve as a radio-sensitizer in non-small cell lung cancer. © 2015, International Society for Cellular Oncology.

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