This paper describes BEAM, a general purpose Monte Carlo code to simulate the radiation beams from radiotherapy units including high-energy electron and photon beams, 60Co beams and orthovoltage units. The code handles a variety of elementary geometric entities which the user puts together as needed (jaws, applicators, stacked cones, mirrors, etc.), thus allowing simulation of a wide variety of accelerators. The code is not restricted to cylindrical symmetry. It incorporates a variety of powerful variance reduction techniques such as range rejection, bremsstrahlung splitting and forcing photon interactions. The code allows direct calculation of charge in the monitor ion chamber. It has the capability of keeping track of each particle's history and using this information to score separate dose components (e.g., to determine the dose from electrons scattering off the applicator). The paper presents a variety of calculated results to demonstrate the code's capabilities. The calculated dose distributions in a water phantom irradiated by electron beams from the NRC 35 MeV research accelerator, a Varian Clinac 2100C, a Philips SL75-20, an AECL Therac 20 and a Scanditronix MM50 are all shown to be in good agreement with measurements at the 2 to 3% level. Eighteen electron spectra from four different commercial accelerators are presented and various aspects of the electron beams from a Clinac 2100C are discussed. Timing requirements and selection of parameters for the Monte Carlo calculations are discussed.

Purpose: While Monte Carlo particle transport has proven useful in many areas (treatment head design, dose calculation, shielding design, and imaging studies) and has been particularly important for proton therapy (due to the conformal dose distributions and a finite beam range in the patient), the available general purpose Monte Carlo codes in proton therapy have been overly complex for most clinical medical physicists. The learning process has large costs not only in time but also in reliability. To address this issue, we developed an innovative proton Monte Carlo platform and tested the tool in a variety of proton therapy applications. Methods: Our approach was to take one of the already-established general purpose Monte Carlo codes and wrap and extend it to create a specialized user-friendly tool for proton therapy. The resulting tool, TOol for PArticle Simulation (TOPAS), should make Monte Carlo simulation more readily available for research and clinical physicists. TOPAS can model a passive scattering or scanning beam treatment head, model a patient geometry based on computed tomography (CT) images, score dose, fluence, etc., save and restart a phase space, provides advanced graphics, and is fully four-dimensional (4D) to handle variations in beam delivery and patient geometry during treatment. A custom-designed TOPAS parameter control system was placed at the heart of the code to meet requirements for ease of use, reliability, and repeatability without sacrificing flexibility.Results: We built and tested the TOPAS code. We have shown that the TOPAS parameter system provides easy yet flexible control over all key simulation areas such as geometry setup, particle source setup, scoring setup, etc. Through design consistency, we have insured that user experience gained in configuring one component, scorer or filter applies equally well to configuring any other component, scorer or filter. We have incorporated key lessons from safety management, proactively removing possible sources of user error such as line-ordering mistakes. We have modeled proton therapy treatment examples including the UCSF eye treatment head, the MGH stereotactic alignment in radiosurgery treatment head and the MGH gantry treatment heads in passive scattering and scanning modes, and we have demonstrated dose calculation based on patient-specific CT data. Initial validation results show agreement with measured data and demonstrate the capabilities of TOPAS in simulating beam delivery in 3D and 4D. Conclusions: We have demonstrated TOPAS accuracy and usability in a variety of proton therapy setups. As we are preparing to make this tool freely available for researchers in medical physics, we anticipate widespread use of this tool in the growing proton therapy community.

The Monte Carlo (MC) method has been shown through many research studies to calculate accurate dose distributions for clinical radiotherapy, particularly in heterogeneous patient tissues where the effects of electron transport cannot be accurately handled with conventional, deterministic dose algorithms. Despite its proven accuracy and the potential for improved dose distributions to influence treatment outcomes, the long calculation times previously associated with MC simulation rendered this method impractical for routine clinical treatment planning. However, the development of faster codes optimized for radiotherapy calculations and improvements in computer processor technology have substantially reduced calculation times to, in some instances, within minutes on a single processor. These advances have motivated several major treatment planning system vendors to embark upon the path of MC techniques. Several commercial vendors have already released or are currently in the process of releasing MC algorithms for photon and/or electron beam treatment planning. Consequently, the accessibility and use of MC treatment planning algorithms may well become widespread in the radiotherapy community. With MC simulation, dose is computed stochastically using first principles; this method is therefore quite different from conventional dose algorithms. Issues such as statistical uncertainties, the use of variance reduction techniques, the ability to account for geometric details in the accelerator treatment head simulation, and other features, are all unique components of a MC treatment planning algorithm. Successful implementation by the clinical physicist of such a system will require an understanding of the basic principles of MC techniques. The purpose of this report, while providing education and review on the use of MC simulation in radiotherapy planning, is to set out, for both users and developers, the salient issues associated with clinical implementation and experimental verification of MC dose algorithms. As the MC method is an emerging technology, this report is not meant to be prescriptive. Rather, it is intended as a preliminary report to review the tenets of the MC method and to provide the framework upon which to build a comprehensive program for commissioning and routine quality assurance of MC-based treatment planning systems.

Radiation therapy (RT) and chemotherapy (CTX) following surgery are mainstays of treatment for breast cancer (BC). While multiple studies have recently revealed the significance of immune cells as mediators of CTX response in BC, less is known regarding roles for leukocytes as mediating outcomes following RT. To address this, we utilized a syngeneic orthotopic murine model of mammary carcinogenesis to investigate if response to RT could be improved when select immune cells or immune-based pathways in the mammary microenvironment were inhibited. Treatment of mammary tumor-bearing mice with either a neutralizing monoclonal antibody (mAb) to colony-stimulating factor-1 (CSF-1) or a small molecule inhibitor of the CSF-1 receptor kinase (i.e., PLX3397), resulting in efficient macrophage depletion, significantly delayed tumor regrowth following RT. Delayed tumor growth in this setting was associated with increased presence of CD8+ T cells, and reduced presence of CD4+ T cells, the main source of the Th2 cytokine interleukin (IL)4 in mammary tumors. Selective depletion of CD4+ T cells or neutralization of IL4 in combination with RT, phenocopied results following macrophage depletion, whereas depletion of CD8+ T cells abrogated improved response to RT following these therapies. Analogously, therapeutic neutralization of IL4 or IL13, or IL4 receptor alpha deficiency, in combination with the CTX paclitaxel resulted in slowed primary mammary tumor growth by CD8+ T cell-dependent mechanisms. These findings indicate that clinical responses to cytotoxic therapy in general can be improved by neutralizing dominant Th2-based programs driving protumorigenic and immune suppressive pathways in mammary (breast) tumors to improve outcomes.

The TOPAS Monte Carlo (MC) system is used in radiation therapy and medical imaging research, having played a significant role in making Monte Carlo simulations widely available for proton therapy related research. While TOPAS provides detailed simulations of patient scale properties, the fundamental unit of the biological response to radiation is a cell. Thus, our goal was to develop TOPAS-nBio, an extension of TOPAS dedicated to advance understanding of radiobiological effects at the (sub-)cellular, (i.e., the cellular and sub-cellular) scale. TOPAS-nBio was designed as a set of open source classes that extends TOPAS to model radiobiological experiments. TOPAS-nBio is based on and extends Geant4-DNA, which extends the Geant4 toolkit, the basis of TOPAS, to include very low-energy interactions of particles down to vibrational energies, explicitly simulates every particle interaction (i.e., without using condensed histories) and propagates radiolysis products. To further facilitate the use of TOPAS-nBio, a graphical user interface was developed. TOPAS-nBio offers full track-structure Monte Carlo simulations, integration of chemical reactions within the first millisecond, an extensive catalogue of specialized cell geometries as well as sub-cellular structures such as DNA and mitochondria, and interfaces to mechanistic models of DNA repair kinetics. We compared TOPAS-nBio simulations to measured and published data of energy deposition patterns and chemical reaction rates (G values). Our simulations agreed well within the experimental uncertainties. Additionally, we expanded the chemical reactions and species provided in Geant4-DNA and developed a new method based on independent reaction times (IRT), including a total of 72 reactions classified into 6 types between neutral and charged species. Chemical stage simulations using IRT were a factor of 145 faster than with step-by-step tracking. Finally, we applied the geometric/chemical modeling to obtain initial yields of double-strand breaks (DSBs) in DNA fibers for proton irradiations of 3 and 50 MeV and compared the effect of including chemical reactions on the number and complexity of DSB induction. Over half of the DSBs were found to include chemical reactions with approximately 5% of DSBs caused only by chemical reactions. In conclusion, the TOPAS-nBio extension to the TOPAS MC application offers access to accurate and detailed multiscale simulations, from a macroscopic description of the radiation field to microscopic description of biological outcome for selected cells. TOPAS-nBio offers detailed physics and chemistry simulations of radiobiological experiments on cells simulating the initially induced damage and links to models of DNA repair kinetics.

Monte Carlo studies of dose distributions in patients treated with radiotherapy electron beams would benefit from generalized models of clinical beams if such models introduce little error into the dose calculations. Methodology is presented for the design of beam models, including their evaluation in terms of how well they preserve the character of the clinical beam, and the effect of the beam models on the accuracy of dose distributions calculated with Monte Carlo. This methodology has been used to design beam models for electron beams from two linear accelerators, with either a scanned beam or a scattered beam. Monte Carlo simulations of the accelerator heads are done in which a record is kept of the particle phase-space, including the charge, energy, direction, and position of every particle that emerges from the treatment head, along with a tag regarding the details of the particle history. The character of the simulated beams are studied in detail and used to design various beam models from a simple point source to a sophisticated multiple-source model which treats particles from different parts of a linear accelerator as from different sub-sources. Dose distributions calculated using both the phase-space data and the multiple-source model agree within 2%, demonstrating that the model is adequate for the purpose of Monte Carlo treatment planning for the beams studied. Benefits of the beam models over phase-space data for dose calculation are shown to include shorter computation time in the treatment head simulation and a smaller disk space requirement, both of which impact on the clinical utility of Monte Carlo treatment planning.

PEREGRINE is a three-dimensional Monte Carlo dose calculation system written specifically for radiotherapy. This paper describes the implementation and overall dosimetric accuracy of PEREGRINE physics algorithms, beam model, and beam commissioning procedure. Particle-interaction data, tracking geometries, scoring, variance reduction, and statistical analysis are described. The BEAM code system is used to model the treatment-independent accelerator head, resulting in the identification of primary and scattered photon sources and an electron contaminant source. The magnitude of the electron source is increased to improve agreement with measurements in the buildup region in the largest fields. Published measurements provide an estimate of backscatter on monitor chamber response. Commissioning consists of selecting the electron beam energy, determining the scale factor that defines dose per monitor unit, and describing treatment-dependent beam modifiers. We compare calculations with measurements in a water phantom for open fields, wedges, blocks, and a multileaf collimator for 6 and 18 MV Varian Clinac 2100C photon beams. All calculations are reported as dose per monitor unit. Aside from backscatter estimates, no additional, field-specific normalization is included in comparisons with measurements. Maximum discrepancies were less than either 2% of the maximum dose or 1.2 mm in isodose position for all field sizes and beam modifiers.

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