Study on the RBE estimation for carbon beam scanning irradiation using a solid-state microdosimeter.

PURPOSE: The purpose of this study was to study the field size effect on the estimated Relative Biological Effectiveness (RBE) for carbon scanning beam irradiation. METHODS: A silicon-on-insulator (SOI) microdosimeter system developed by the Centre for Medical Radiation Physics, University of Wollongong, Australia, was used for lineal-energy measurements (microdosimetric quantity). The RBE values were derived based on the modified microdosimetric kinetic model (MKM) at different depths in a water phantom in the scanning carbon beam for various scanned areas. RESULTS: Our study shows that the difference in RBE values derived from the SOI microdosimeter measurements with the MKM model and from the Treatment Planning System (TPS). The difference of the RBE values is within 6.5 % at the peak point of the spread-out Bragg Peak (SOBP) region. Compared to the spot-beam, RBE values obtained in the scanned-beam with a larger scanned area of 1.0 × 1.0 cm2 have better agreement with which estimated by the TPS. CONCLUSIONS: This study shows the possibility of using the SOI microdosimeter system as a quality assurance (QA) tool for RBE evaluation in carbon-pencil beam scanning radiotherapy.

Dose response analysis program (DREAP): A user-friendly program for the analyses of radiation-induced biological responses utilizing established deterministic models at cell population and organ scales.

PURPOSE: To develop a user-friendly program for biological modeling to analyze radiation-induced responses at the scales of the cell population and organ. METHODS: The program offers five established cell population surviving fraction (SF) models to estimate the SF and the relative biological effectiveness (RBE) from clonogenic assay data, and two established models to calculate the normal tissue complication probability (NTCP) and tumor control probability (TCP) from radiation treatment plans. Users can also verify the results with multiple types of quantitative analyses and graphical representation tools. RESULTS: Users can verify the estimated SF, model parameters, RBE, and the respective uncertainties in the calculations of the SF and RBE modes. The qualities of the treatment plans can also be compared with at most three rival plans in terms of the NTCP, TCP, uncomplicated TCP (UCP), and user-dependent weight-based UCP (UUCP), in the calculation of the NTCP and TCP modes. Based on the validation study on accuracy and speed, the averaged mean relative errors (MREs) of the estimated parameters for all tested cell lines were not higher than 0.3% in each of the studied SF models, and the averaged MREs of the calculated NTCP and TCP for all tested treatment plans were not higher than 0.1%. The computation times for SF, RBE, NTCP, and TCP were less than 1.5 s. CONCLUSIONS: The dose response analysis program can provide a trustworthy and convenient environment for researchers to analyze radiation-induced biological effects.

Estimation of the medical need for carbon-ion radiotherapy in Korea.

The Korea Heavy Ion Medical Accelerator project focuses on the development of medical accelerator facilities for delivering carbon-ion beams to cancer patients. The purpose of the present study was to estimate the clinical need for carbon-ion therapy in Korea. Seven tumor sites, namely head and neck, liver, lung, colon and rectum, prostate, bone and soft tissue, and pancreas were selected as eligible sites for receiving carbon-ion radiotherapy (RT) by radiation oncologists of the Korea Institute of Radiological and Medical Sciences. Cancer incidence data for the selected tumor sites were obtained from the Korea National Cancer Incidence Database in order to estimate the potential medical need for carbon-ion RT. The carbon-ion RT adaption rate was assessed based on the clinical experience of other carbon-ion therapy facilities. An estimation model was constructed for estimating the medical need for carbon-ion RT, and from this, 25 606 patients were deemed to be potential candidates for carbon-ion RT. This estimated potential need corresponded to 10% of newly diagnosed cancer patients in Korea. The realistic estimation was calculated as ranging between 4000 and 6300 patients, depending on the carbon-ion RT adaptation rate. This estimated medical need corresponded to 2-3% of newly diagnosed cancer patients in Korea. Taken together, our findings suggest that there is a clear medical need for carbon-ion RT in Korea, with at least 4000 potential patients per year.

Analysis of Neutron Production in Passively Scattered Ion-Beam Therapy.

A new treatment facility for heavy ion therapy since 2010 was constructed. In the broad beam, a range shifter, ridge filter and multi leaf collimator (MLC) for the generation of the spread-out Bragg peak is used. In this case, secondary neutrons produced by the interactions of the ion field with beam-modifying devices (e.g. double-scattering system, beam shaping collimators and range compensators) are very important for patient safety. Therefore, these components must be carefully examined in the context of secondary neutron yield and associated secondary cancer risk. In this article, Monte Carlo simulation has been carried out with the FLUktuierende KAskade particle transport code, the fluence and distribution of neutron generation and the neutron dose equivalent from the broad beam components are compared using carbon and proton beams. As a result, it is confirmed that the yield of neutron production using a carbon beam from all components of the broad beam was higher than using a proton beam. The ambient dose by neutrons per heavy ion and proton ion from the MLC surface was 0.12-0.18 and 0.0067-0.0087 pSv, respectively, which shows that heavy ions generate more neutrons than protons. However, ambient dose per treatment 2 Gy, which means physical dose during treatment by ion beam, is higher than carbon beam because proton therapy needs more beam flux to make 2-Gy prescription dose. Therefore, the neutron production from the MLC, which is closed to the patient, is a very important parameter for patient safety.

Metformin enhances the radiosensitivity of human liver cancer cells to γ-rays and carbon ion beams.

The purpose of this study was to investigate the effect of metformin on the responses of hepatocellular carcinoma (HCC) cells to γ-rays (low-linear energy transfer (LET) radiation) and carbon-ion beams (high-LET radiation). HCC cells were pretreated with metformin and exposed to a single dose of γ-rays or carbon ion beams. Metformin treatment increased radiation-induced clonogenic cell death, DNA damage, and apoptosis. Carbon ion beams combined with metformin were more effective than carbon ion beams or γ-rays alone at inducing subG1 and decreasing G2/M arrest, reducing the expression of vimentin, enhancing phospho-AMPK expression, and suppressing phospho-mTOR and phospho-Akt. Thus, metformin effectively enhanced the therapeutic effect of radiation with a wide range of LET, in particular carbon ion beams and it may be useful for increasing the clinical efficacy of carbon ion beams.

Zoledronic acid is an effective radiosensitizer in the treatment of osteosarcoma.

To overcome radioresistance in the treatment of osteosarcoma, a primary malignant tumor of the bone, radiotherapy is generally combined with radiosensitizers. The purpose of this study was to investigate a third-generation bisphosphonate, zoledronic acid (ZOL), as a radiosensitizer for osteosarcoma. We found that exposure of KHOS/NP osteosarcoma cells to 20 µM ZOL decreased the γ-radiation dose needed to kill 90% of cells. This radiosensitizing effect of ZOL was mediated through decreased mitochondrial membrane potential, increased levels of reactive oxygen species, increased DNA damage (as assessed by counting γ-H2AX foci), decreased abundance of proteins involved in DNA repair pathways (ATR, Rad52, and DNA-PKcs), and decreased phosphorylation of PI3K-Akt and MAPK pathway proteins (Raf1, MEK1/2, ERK1/2, and Akt), as compared to γ-irradiation alone. Cells treated with ZOL plus γ-irradiation showed impaired cell migration and invasion and reduced expression of epithelial-mesenchymal transition markers (vimentin, MMP9, and Slug). In Balb/c nude mice, the mean size of orthotopic osteosarcoma tumors 2 weeks post-inoculation was 195 mm3 following γ-irradiation (8 Gy), while it was 150 mm3 after γ-irradiation plus ZOL treatment (0.1 mg/kg twice weekly for 2 weeks). These results provide a rationale for combining ZOL with radiotherapy to treat osteosarcoma.

Mechanisms of SU5416, an inhibitor of vascular endothelial growth factor receptor, as a radiosensitizer for colon cancer cells.

Colorectal cancer is one of the most common cancers worldwide. Previous studies suggest that chemoradiotherapy is more effective for the treatment of colorectal cancer than is radiotherapy or chemotherapy alone. To enhance the radiosensitivity of tumor cells, several investigators have used targeted therapeutic agents that act as radiosensitizers. In the present study, we provide a scientific rationale for the clinical application of SU5416, an inhibitor of vascular endothelial growth factor receptor-2, as a radiosensitizer for colorectal cancer. Two human colorectal adenocarcinoma cell lines, HCT116 and HT-29, were treated with SU5416 and radiation alone or radiation followed by SU5416. In vitro tests were performed using colony forming assays, flow cytometric analysis, immunohistochemistry, senescence-associated ß-galactosidase, tumor cell motility and invasion assays. The combination of radiation and SU5416 synergistically inhibited cell survival and induced apoptosis through reactive oxygen species, enhanced IR-induced premature senescence, and inhibited DNA repair activity, cell migration and invasion. Collectively, our results favor the use of SU5416 and radiotherapy as a combination therapy for the treatment of colon cancer and it can be combined successfully with a radiation regimen to potentiate its antitumor and antimetastatic activities for future clinical trials.

Mechanisms for SU5416 as a radiosensitizer of endothelial cells.

Endothelial cells (ECs), that comprise the tumor vasculature, are critical targets for anticancer radiotherapy. The aim of this work was to study the mechanism by which SU5416, a known anti-angiogenesis inhibitor, modifies the radiation responses of human vascular ECs. Two human endothelial cell lines (HUVEC and 2H11) were treated with SU5416 alone, radiation alone, or a combination of both. In vitro tests were performed using colony forming assays, FACS analysis, western blotting, immunohistochemistry, migration assay, invasion assays and endothelial tube formation assays. The combination of radiation and SU5416 significantly inhibited cell survival, the repair of radiation-induced DNA damage, and induced apoptosis. It also caused cell cycle arrest, inhibited cell migration and invasion, and suppressed angiogenesis. In this study, our results first provide a scientific rationale to combine SU5416 with radiotherapy to target ECs and suggest its clinical application in combination cancer treatment with radiotherapy.

The mechanisms responsible for the radiosensitizing effects of sorafenib on colon cancer cells.

Colorectal cancer is one of the most common malignancies in the world, and is generally treated more effectively by chemoradiotherapy rather than radiotherapy or chemotherapy alone. Targeted radiosensitizers are often used in order to enhance the radiosensitivity of tumor cells. The aim of the present study was to identify the mechanism of radiosensitization by sorafenib in colorectal cancer. Three human colorectal adenocarcinoma cell lines (HCT116, HT29 and SW480) were treated with sorafenib alone or radiation followed by sorafenib. In vitro tests were performed using colony forming assays, FACS analysis, immunohistochemistry, tumor cell motility assays, invasion assays and endothelial tube formation assays. Sorafenib enhanced the anti-proliferative effects of radiation, reducing colony formation, increasing G2/M arrest and enhancing radiation-induced apoptosis by reactive oxygen species. Sorafenib also inhibited the repair of radiation-induced DNA damage by blocking the activation of DNA-dependent protein kinase. Combination treatment significantly inhibited tumor cell migration, tumor cell invasion and vascular endothelial growth factor-mediated angiogenesis in vitro. Taken together, our results provide a scientific rationale for the use of sorafenib with radiotherapy in colon cancer and suggest a clinical utility for this approach.

Effective generation of the spread-out-Bragg peak from the laser accelerated proton beams using a carbon-proton mixed target.

Conventional laser accelerated proton beam has broad energy spectra. It is not suitable for clinical use directly, so it is necessary for employing energy selection system. However, in the conventional laser accelerated proton system, the intensity of the proton beams in the low energy regime is higher than that in the high energy regime. Thus, to generate spread-out-Bragg peak (SOBP), stronger weighting value to the higher energy proton beams is needed and weaker weighting value to the lower energy proton beams is needed, which results in the wide range of weighting values. The purpose of this research is to investigate a method for efficient generating of the SOBP with varying magnetic field in the energy selection system using a carbon-proton mixture target. Energy spectrum of the laser accelerated proton beams was acquired using Particle-In-Cell simulations. The Geant4 Monte Carlo simulation toolkit was implemented for energy selection, particle transportation, and dosimetric property measurement. The energy selection collimator hole size of the energy selection system was changed from 1 to 5 mm in order to investigate the effect of hole size on the dosimetric properties for Bragg peak and SOBP. To generate SOBP, magnetic field in the energy selection system was changed during beam irradiation with each beam weighting factor. In this study, our results suggest that carbon-proton mixture target based laser accelerated proton beams can generate quasi-monoenergetic energy distribution and result in the efficient generation of SOBP. A further research is needed to optimize SOBP according to each range and modulated width using an optimized weighting algorithm.

Low and high linear energy transfer radiation sensitization of HCC cells by metformin.

The purpose of this study was to investigate the efficacy of metformin as a radiosensitizer for use in combination therapy for human hepatocellular carcinoma (HCC). Three human HCC cell lines (Huh7, HepG2, Hep3B) and a normal human hepatocyte cell line were treated with metformin alone or with radiation followed by metformin. In vitro tests were evaluated by clonogenic survival assay, FACS analysis, western blotting, immunofluorescence and comet assay. Metformin significantly enhanced radiation efficacy under high and low Linear Energy Transfer (LET) radiation conditions in vitro. In combination with radiation, metformin abrogated G2/M arrest and increased the cell population in the sub-G1 phase and the ROS level, ultimately increasing HCC cellular apoptosis. Metformin inhibits the repair of DNA damage caused by radiation. The radiosensitizing effects of metformin are much higher in neutron (high LET)-irradiated cell lines than in γ (low LET)-irradiated cell lines. Metformin only had a moderate effect in normal hepatocytes. Metformin enhances the radiosensitivity of HCC, suggesting it may have clinical utility in combination cancer treatment with high-LET radiation.

Multisource modeling of flattening filter free (FFF) beam and the optimization of model parameters.

PURPOSE: With the introduction of flattening filter free (FFF) linear accelerators to radiation oncology, new analytical source models for a FFF beam applicable to current treatment planning systems is needed. In this work, a multisource model for the FFF beam and the optimization of involved model parameters were designed. METHODS: The model is based on a previous three source model proposed by Yang et al. ["A three-source model for the calculation of head scatter factors," Med. Phys. 29, 2024-2033 (2002)]. An off axis ratio (OAR) of photon fluence was introduced to the primary source term to generate cone shaped profiles. The parameters of the source model were determined from measured head scatter factors using a line search optimization technique. The OAR of the photon fluence was determined from a measured dose profile of a 40 x 40 cm2 field size with the same optimization technique, but a new method to acquire gradient terms for OARs was developed to enhance the speed of the optimization process. The improved model was validated with measured dose profiles from 3 x 3 to 40 x 40 cm2 field sizes at 6 and 10 MV from a TrueBeam STx linear accelerator. Furthermore, planar dose distributions for clinically used radiation fields were also calculated and compared to measurements using a 2D array detector using the gamma index method. RESULTS: All dose values for the calculated profiles agreed with the measured dose profiles within 0.5% at 6 and 10 MV beams, except for some low dose regions for larger field sizes. A slight overestimation was seen in the lower penumbra region near the field edge for the large field sizes by 1%-4%. The planar dose calculations showed comparable passing rates (> 98%) when the criterion of the gamma index method was selected to be 3%/3 mm. CONCLUSIONS: The developed source model showed good agreements between measured and calculated dose distributions. The model is easily applicable to any other linear accelerator using FFF beams as the required data include only the measured PDD, dose profiles, and output factors for various field sizes, which are easily acquired during conventional beam commissioning process.