Dosimetric comparison of magnetic resonance-guided radiation therapy, intensity-modulated proton therapy and volumetric-modulated arc therapy for distal esophageal cancer.

Advances in radiotherapy (RT) technologies permit significant decreases in the dose delivered to organs at risk (OARs) for patients with esophageal cancer (EC). Novel RT modalities such as proton beam therapy (PBT) and magnetic resonance-guided radiotherapy (MRgRT), as well as motion management techniques including breath hold (BH) are expected to further improve the therapeutic ratio. However, to our knowledge, the dosimetric benefits of PBT vs MRgRT vs volumetric-modulated arc therapy (VMAT) have not been directly compared for EC. We performed a retrospective in silico evaluation using the images and datasets of nine distal EC patients who were treated at our institution with a 0.35-Tesla MR linac to 50.4 Gy in 28 fractions in mid-inspiration BH (BH-MRgRT). Comparison free-breathing (FB) intensity-modulated PBT (FB-IMPT) and FB-VMAT plans were retrospectively created using the same prescription dose, target volume coverage goals, and OAR constraints. A 5 mm setup margin was used for all plans. BH-IMPT and BH-VMAT plans were not evaluated as they would not reflect our institutional practice. Planners were blinded to the results of the treatment plans created using different radiation modalities. The primary objective was to compare plan quality, target volume coverage, and OAR doses. All treatment plans met pre-defined target volume coverage and OAR constraints. The median conformity and homogeneity indices between FB-IMPT, BH-MRgRT and FB-VMAT were 1.13, 1.25, and 1.43 (PITV) and 1.04, 1.15, 1.04 (HI), respectively. For FB-IMPT, BH-MRgRT and FB-VMAT the median heart dose metrics were 52.8, 79.3, 146.8 (V30Gy, cc), 35.5, 43.8, 77.5 (V40Gy, cc), 16.9, 16.9, 32.5 (V50Gy, cc) and 6.5, 14.9, 17.3 (mean, Gy), respectively. Lung dose metrics were 8.6, 7.9, 18.5 (V20Gy, %), and 4.3, 6.3, 11.2 (mean, Gy), respectively. The mean liver dose (Gy) was 6.5, 19.6, 22.2 respectively. Both FB-IMPT and BH-MRgRT achieve substantial reductions in heart, lung, and liver dose compared to FB-VMAT. We plan to evaluate dosimetric outcomes across these RT modalities assuming consistent use of BH.

Monte Carlo evaluation of high-gradient magnetically focused planar proton minibeams in a passive nozzle.

Objective. To investigate the potential of using a single quadrupole magnet with a high magnetic field gradient to create planar minibeams suitable for clinical applications of proton minibeam radiation therapy.Approach. We performed Monte Carlo simulations involving single quadrupole Halbach cylinders in a passively scattered nozzle in clinical use for proton therapy. Pencil beams produced by the nozzle of 10-15 mm initial diameters and particle range of âˆ¼10-20 cm in water were focused by magnets with field gradients of 225-350 T m-1and cylinder lengths of 80-110 mm to produce very narrow elongated (planar) beamlets. The corresponding dose distributions were scored in a water phantom. Composite minibeam dose distributions composed from three beamlets were created by laterally shifting copies of the single beamlet distribution to either side of a central beamlet. Modulated beamlets (with 18-30 mm nominal central SOBP) and corresponding composite dose distributions were created in a similar manner. Collimated minibeams were also compared with beams focused using one magnet/particle range combination.Main results. The focusing magnets produced planar beamlets with minimum lateral FWHM of ∼1.1-1.6 mm. Dose distributions composed from three unmodulated beamlets showed a high degree of proximal spatial fractionation and a homogeneous target dose. Maximal peak-to-valley dose ratios (PVDR) for the unmodulated beams ranged from 32 to 324, and composite modulated beam showed maximal PVDR ranging from 32 to 102 and SOBPs with good target dose coverage.Significance.Advantages of the high-gradient magnets include the ability to focus beams with phase space parameters that reflect beams in operation today, and post-waist particle divergence allowing larger beamlet separations and thus larger PVDR. Our results suggest that high gradient quadrupole magnets could be useful to focus beams of moderate emittance in clinical proton therapy.

Experimental validation of magnetically focused proton beams for radiosurgery.

We performed experiments using a triplet of quadrupole permanent magnets to focus protons and compared their dose distributions with unfocused collimated beams using energies and field sizes typically employed in proton radiosurgery. Experiments were performed in a clinical treatment room wherein small-diameter proton beams were focused by a magnet triplet placed immediately upstream of a water tank. The magnets consisted of segments of Sm2Co17 rare-earth permanent magnetic material adhered into Halbach cylinders with nominal field gradients of 100, 150, 200, and 250 T m-1. Unmodulated beams with initial diameters of 3 mm-20 mm were delivered using a single scattering system with nominal energies of 127 and 157 MeV (respective ranges of ~10 cm and 15 cm in water), commonly used for proton radiosurgery at our institution. For comparison, small-diameter unfocused collimated beams were similarly delivered. Transverse and depth dose distributions were measured using radiochromic film and a diode detector, respectively, and compared between the focused and unfocused beams (UNF). The focused beams produced low-eccentricity beam spots (defined by the 80% dose contour) at Bragg depth, with full width at 80% maximum dose values ranging from 3.8 to 7.6 mm. When initial focused beam diameters were larger than matching unfocused diameters (19 of 29 cases), the focused beams peak-to-entrance dose ratios were 13% to 73% larger than UNF. In addition, in 17 of these cases the efficiency of dose delivery to the target was 1.3× to 3.3× larger. Both peak-to-entrance dose ratios and efficiency tended to increase with initial beam diameter, while efficiency also tended to increase with magnet gradient. These experimental results are consistent with our previous Monte Carlo (MC) studies and suggest that a triplet of quadrupole Halbach cylinders could be clinically useful for irradiating small-field radiosurgical targets with fewer beams, lower entrance dose, and shorter treatment times.

A phase I trial of Proton stereotactic body radiation therapy for liver metastases.

BACKGROUND: A phase I trial to determine the maximum tolerated dose (MTD) of Proton stereotactic body radiation therapy (SBRT) for liver metastases in anticipation of a subsequent phase II study. METHODS: An institutional IRB approved phase I clinical trial was conducted. Eligible patients had 1-3 liver metastases measuring less than 5 cm, and no metastases location within 2 cm of the GI tract. Dose escalation was conducted with three dose cohorts. The low, intermediate, and high dose cohorts were planned to receive 36, 48, and 60 respectively to the internal target volume (ITV) in 3 fractions. At least 700 mL of normal liver had to receive <15. Dose-limiting toxicity (DLT) included acute grade 3 liver, intestinal or spinal cord toxicity or any grade 4 toxicity. The MTD is defined as the dose level below that which results in DLT in 2 or more of the 6 patients in the highest dose level cohort. RESULTS: Nine patients were enrolled (6 male, 3 female): median age 64 years (range, 33-77 years); median gross tumor volume (GTV) 11.1 mL (range, 2.14-89.3 mL); most common primary site, colorectal (5 patients). Four patients had multiple tumors. No patient experienced a DLT and dose was escalated to 60 in 3 fractions without reaching MTD. The only toxicity within 90 days of completion of treatment was one patient with a grade 1 skin hyperpigmentation without tenderness or desquamation. Two patients in the low dose cohort had local recurrence and repeat SBRT was done to previously treated lesions without any toxicities. CONCLUSIONS: Biologically ablative Proton SBRT doses are well tolerated in patients with limited liver metastases with no patients experiencing any grade 2+ acute toxicity. Results from this trial provide the grounds for an ongoing phase II Proton SBRT study of 60 over 3 fractions for liver metastases.

Monte Carlo evaluation of magnetically focused proton beams for radiosurgery.

The purpose of this project is to investigate the advantages in dose distribution and delivery of proton beams focused by a triplet of quadrupole magnets in the context of potential radiosurgery treatments. Monte Carlo simulations were performed using various configurations of three quadrupole magnets located immediately upstream of a water phantom. Magnet parameters were selected to match what can be commercially manufactured as assemblies of rare-earth permanent magnetic materials. Focused unmodulated proton beams with a range of ~10 cm in water were target matched with passive collimated beams (the current beam delivery method for proton radiosurgery) and properties of transverse dose, depth dose and volumetric dose distributions were compared. Magnetically focused beams delivered beam spots of low eccentricity to Bragg peak depth with full widths at the 90% reference dose contour from ~2.5 to 5 mm. When focused initial beam diameters were larger than matching unfocused beams (10 of 11 cases) the focused beams showed 16%-83% larger peak-to-entrance dose ratios and 1.3 to 3.4-fold increases in dose delivery efficiency. Peak-to-entrance and efficiency benefits tended to increase with larger magnet gradients and larger initial diameter focused beams. Finally, it was observed that focusing tended to shift dose in the water phantom volume from the 80%-20% dose range to below 20% of reference dose, compared to unfocused beams. We conclude that focusing proton beams immediately upstream from tissue entry using permanent magnet assemblies can produce beams with larger peak-to-entrance dose ratios and increased dose delivery efficiencies. Such beams could potentially be used in the clinic to irradiate small-field radiosurgical targets with fewer beams, lower entrance dose and shorter treatment times.

Initial testing of a pixelated silicon detector prototype in proton therapy.

As technology continues to develop, external beam radiation therapy is being employed, with increased conformity, to treat smaller targets. As this occurs, the dosimetry methods and tools employed to quantify these fields for treatment also have to evolve to provide increased spatial resolution. The team at the University of Wollongong has developed a pixelated silicon detector prototype known as the dose magnifying glass (DMG) for real-time small-field metrology. This device has been tested in photon fields and IMRT. The purpose of this work was to conduct the initial performance tests with proton radiation, using beam energies and modulations typically associated with proton radiosurgery. Depth dose and lateral beam profiles were measured and compared with those collected using a PTW parallel-plate ionization chamber, a PTW proton-specific dosimetry diode, EBT3 Gafchromic film, and Monte Carlo simulations. Measurements of the depth dose profile yielded good agreement when compared with Monte Carlo, diode and ionization chamber. Bragg peak location was measured accurately by the DMG by scanning along the depth dose profile, and the relative response of the DMG at the center of modulation was within 2.5% of that for the PTW dosimetry diode for all energy and modulation combinations tested. Real-time beam profile measurements of a 5 mm 127 MeV proton beam also yielded FWHM and FW90 within ±1 channel (0.1 mm) of the Monte Carlo and EBT3 film data across all depths tested. The DMG tested here proved to be a useful device at measuring depth dose profiles in proton therapy with a stable response across the entire proton spread-out Bragg peak. In addition, the linear array of small sensitive volumes allowed for accurate point and high spatial resolution one-dimensional profile measurements of small radiation fields in real time to be completed with minimal impact from partial volume averaging.

Evaluation and Mitigation of Secondary Dose Delivered to Electronic Systems in Proton Therapy.

PURPOSE: To evaluate the scattered and secondary radiation fields present in and around a passive proton treatment nozzle. In addition, based on these initial tests and system reliability analysis, to develop, install, and evaluate a radiation shielding structure to protect sensitive electronics against single-event effects (SEE) and improve system reliability. METHODS AND MATERIALS: Landauer Luxel+ dosimeters were used to evaluate the radiation field around one of the gantry-mounted passive proton delivery nozzles at Loma Linda University Medical Center's James M Slater, MD Proton Treatment and Research Center. These detectors use optically stimulated luminescence technology in conjunction with CR-39 to measure doses from X-ray, gamma, proton, beta, fast neutron, and thermal neutron radiation. The dosimeters were stationed at various positions around the gantry pit and attached to racks on the gantry itself to evaluate the dose to electronics. Wax shielding was also employed on some detectors to evaluate the usefulness of this material as a dose moderator. To create the scattered and secondary radiation field in the gantry enclosure, a polystyrene phantom was placed at isocenter and irradiated with 250 MeV protons to a dose of 1.3 kGy over 16 hours. Using the collected data as a baseline, a composite shielding structure was created and installed to shield electronics associated with the precision patient positioner. The effectiveness of this shielding structure was evaluated with Landauer Luxel+ dosimeters and the results correlated against system uptime. RESULTS: The measured dose equivalent ranged from 1 to 60 mSv, with proton/photon, thermal neutron, fast neutron, and overall dose equivalent evaluated. The position of the detector/electronics relative to both isocenter and also neutron-producing devices, such as the collimators and first and second scatterers, definitely had a bearing on the dose received. The addition of 1-inch-thick wax shielding decreased the fast neutron component by almost 50%, yet this yielded a corresponding average increase in thermal neutron dose of 150% as there was no Boron-10 component to capture thermal neutrons. Using these data as a reference, a shielding structure was designed and installed to minimize radiation to electronics associated with the patient positioner. The installed shielding reduced the total dose experienced by these electronics by a factor of 5 while additionally reducing the fast and thermal neutron doses by a factor of 7 and 14, respectively. The reduction in radiation dose corresponded with a reduction of SEE-related downtime of this equipment from 16.5 hours to 2.5 hours over a 6-month reporting period. CONCLUSIONS: The data obtained in this study provided a baseline for radiation exposures experienced by gantry- and pit-mounted electronic systems. It also demonstrated and evaluated a shielding structure design that can be retrofitted to existing electronic system installations. It is expected that this study will benefit future upgrades and facility designs by identifying mechanisms that may minimize radiation dose to installed electronics, thus improving facility uptime.

Evaluation of the dosimetric properties of a diode detector for small field proton radiosurgery.

The small fields and sharp gradients typically encountered in proton radiosurgery require high spatial resolution dosimetric measurements, especially below 1-2 cm diameters. Radiochromic film provides high resolution, but requires postprocessing and special handling. Promising alternatives are diode detectors with small sensitive volumes (SV) that are capable of high resolution and real-time dose acquisition. In this study we evaluated the PTW PR60020 proton dosimetry diode using radiation fields and beam energies relevant to radiosurgery applications. Energies of 127 and 157 MeV (9.7 to 15 cm range) and initial diameters of 8, 10, 12, and 20mm were delivered using single-stage scattering and four modulations (0, 15, 30, and 60mm) to a water tank in our treatment room. Depth dose and beam profile data were compared with PTW Markus N23343 ionization chamber, EBT2 Gafchromic film, and Monte Carlo simulations. Transverse dose profiles were measured using the diode in "edge-on" orientation or EBT2 film. Diode response was linear with respect to dose, uniform with dose rate, and showed an orientation-dependent (i.e., beam parallel to, or perpendicular to, detector axis) response of less than 1%. Diodevs. Markus depth-dose profiles, as well as Markus relative dose ratio vs. simulated dose-weighted average lineal energy plots, suggest that any LET-dependent diode response is negligible from particle entrance up to the very distal portion of the SOBP for the energies tested. Finally, while not possible with the ionization chamber due to partial volume effects, accurate diode depth-dose measurements of 8, 10, and 12 mm diameter beams were obtained compared to Monte Carlo simulations. Because of the small SV that allows measurements without partial volume effects and the capability of submillimeter resolution (in edge-on orientation) that is crucial for small fields and high-dose gradients (e.g., penumbra, distal edge), as well as negligible LET dependence over nearly the full the SOBP, the PTW proton diode proved to be a useful high-resolution, real-time metrology device for small proton field radiation measurements such as would be encountered in radiosurgery applications.

Evaluation of mathematical algorithms for automatic patient alignment in radiosurgery.

Image registration techniques based on anatomical features can serve to automate patient alignment for intracranial radiosurgery procedures in an effort to improve the accuracy and efficiency of the alignment process as well as potentially eliminate the need for implanted fiducial markers. To explore this option, four two-dimensional (2D) image registration algorithms were analyzed: the phase correlation technique, mutual information (MI) maximization, enhanced correlation coefficient (ECC) maximization, and the iterative closest point (ICP) algorithm. Digitally reconstructed radiographs from the treatment planning computed tomography scan of a human skull were used as the reference images, while orthogonal digital x-ray images taken in the treatment room were used as the captured images to be aligned. The accuracy of aligning the skull with each algorithm was compared to the alignment of the currently practiced procedure, which is based on a manual process of selecting common landmarks, including implanted fiducials and anatomical skull features. Of the four algorithms, three (phase correlation, MI maximization, and ECC maximization) demonstrated clinically adequate (ie, comparable to the standard alignment technique) translational accuracy and improvements in speed compared to the interactive, user-guided technique; however, the ICP algorithm failed to give clinically acceptable results. The results of this work suggest that a combination of different algorithms may provide the best registration results. This research serves as the initial groundwork for the translation of automated, anatomy-based 2D algorithms into a real-world system for 2D-to-2D image registration and alignment for intracranial radiosurgery. This may obviate the need for invasive implantation of fiducial markers into the skull and may improve treatment room efficiency and accuracy.

Single-Plane Magnetically Focused Elongated Small Field Proton Beams.

We previously performed Monte Carlo simulations of magnetically focused proton beams shaped by a single quadrapole magnet and thereby created narrow elongated beams with superior dose delivery characteristics (compared to collimated beams) suitable for targets of similar geometry. The present study seeks to experimentally validate these simulations using a focusing magnet consisting of 24 segments of samarium cobalt permanent magnetic material adhered into a hollow cylinder. Proton beams with properties relevant to clinical radiosurgery applications were delivered through the magnet to a water tank containing a diode detector or radiochromic film. Dose profiles were analyzed and compared with analogous Monte Carlo simulations. The focused beams produced elongated beam spots with high elliptical symmetry, indicative of magnet quality. Experimental data showed good agreement with simulations, affirming the utility of Monte Carlo simulations as a tool to model the inherent complexity of a magnetic focusing system. Compared to target-matched unfocused simulations, focused beams showed larger peak to entrance ratios (26% to 38%) and focused simulations showed a two-fold increase in beam delivery efficiency. These advantages can be attributed to the magnetic acceleration of protons in the transverse plane that tends to counteract the particle outscatter that leads to degradation of peak to entrance performance in small field proton beams. Our results have important clinical implications and suggest rare earth focusing magnet assemblies are feasible and could reduce skin dose and beam number while delivering enhanced dose to narrow elongated targets (eg, in and around the spinal cord) in less time compared to collimated beams.

Clinical immobilization techniques for proton therapy.

Proton therapy through the use of the Bragg peak affords clinicians a tool with which highly conformal dose can be delivered to the target while minimizing integral dose to surrounding healthy tissue. To gain maximum benefit from proton therapy adequate patient immobilization must be maintained to ensure accurate dose delivery. While immobilization in external beam radiation therapy is designed to minimize inter- and intra-fraction target motion, in proton therapy there are other additional aspects which must be considered, chief of which is accurately determining and maintaining the targets water-equivalent depth along the beam axis. Over the past 23 years of treating with protons, the team at the James M. Slater Proton Treatment and Research Center at Loma Linda University Medical Center have developed and implemented extensive immobilization systems to address the specific needs of protons. In this publication we review the immobilization systems that are used at Loma Linda in the treatment of head and neck, prostate, upper GI, lung and breast disease, along with a description of the intracranial radiosurgery immobilization system used in the treatment of brain metastasis and arteriovenous malformations (AVM's).

Biological effects of passive versus active scanning proton beams on human lung epithelial cells.

The goal was to characterize differences in cell response after exposure to active beam scanning (ABS) protons compared to a passive delivery system. Human lung epithelial (HLE) cells were evaluated at various locations along the proton depth dose profile. The dose delivered at the Bragg peak position was essentially identical (∼4 Gy) with the two techniques, but depth dose data showed that ABS resulted in lower doses at entry and more rapid drop-off after the peak. Average dose rates for the passive and ABS beams were 1.1 Gy/min and 5.1 Gy/min, respectively; instantaneous dose rates were 19.2 Gy/min and 2,300 Gy/min (to a 0.5 × 0.5 mm(2) voxel). Analysis of DNA synthesis was based on (3)H-TdR incorporation. Quantitative real-time polymerase chain reaction (RT-PCR) was done to determine expression of genes related to p53 signaling and DNA damage; a total of 152 genes were assessed. Spectral karyotyping and analyses of the Golgi apparatus and cytokines produced by the HLE cells were also performed. At or near the Bragg peak position, ABS protons resulted in a greater decrease in DNA synthesis compared to passively delivered protons. Genes with >2-fold change (P < 0.05 vs. 0 Gy) after passive proton irradiation at one or more locations within the Bragg curve were BTG2, CDKN1A, IFNB1 and SIAH1. In contrast, many more genes had >2-fold difference with ABS protons: BRCA1, BRCA2, CDC25A, CDC25C, CCNB2, CDK1, DMC1, DNMT1, E2F1, EXO1, FEN1, GADD45A, GTSE1, IL-6, JUN, KRAS, MDM4, PRC1, PTTG1, RAD51, RPA1, TNF, WT1, XRCC2, XRCC3 and XRCC6BP1. Spectral karyotyping revealed numerous differences in chromosomal abnormalities between the two delivery systems, especially at or near the Bragg peak. Percentage of cells staining for the Golgi apparatus was low after exposure to passive and active proton beams. Studies such as this are needed to ensure patient safety and make modifications in ABS delivery, if necessary.

Immobilization considerations for proton radiation therapy.

Proton therapy is rapidly developing as a mainstream modality for external beam radiation therapy. This development is largely due to the ability of protons to deposit much of their energy in a region known as the Bragg peak, minimizing the number of treatment fields and hence integral dose delivered to the patient. Immobilization in radiation therapy is a key component in the treatment process allowing for precise delivery of dose to the target volume and this is certainly true in proton therapy. In proton therapy immobilization needs to not only immobilize the patient, placing them in a stable and reproducible position for each treatment, but its impact on the depth dose distribution and range uncertainty must also be considered. The impact of immobilization on range is not a primary factor in X-ray radiation therapy, but it is a governing factor in proton therapy. This contribution describes the immobilization considerations in proton therapy which have been developed at Loma Linda over twenty plus years of clinical operation as a hospital based proton center.

Mechanism of hypocoagulability in proton-irradiated ferrets.

PURPOSE: To determine the mechanism of proton radiation- induced coagulopathy. MATERIAL AND METHODS: Ferrets were exposed to either solar particle event (SPE)-like proton radiation at a predetermined dose rate of 0.5 Gray (Gy) per hour (h) for a total dose of 0 or 1 Gy. Blood was collected pre- and post-irradiation for a complete blood cell count or a soluble fibrin concentration analysis, to determine whether coagulation activation had occurred. Tissue was stained with an anti-fibrinogen antibody to confirm the presence of fibrin in blood vessels. RESULTS: SPE-like proton radiation exposure resulted in coagulation cascade activation, as determined by increased soluble fibrin concentration in blood from 0.7-2.4 at 3 h, and 9.9 soluble fibrin units (p < 0.05) at 24 h post-irradiation and fibrin clots in blood vessels of livers, lungs and kidneys from irradiated ferrets. In combination with this increase in fibrin clots, ferrets had increased prothrombin time and partial thromboplastin time values post-irradiation, which are representative of the extrinsic/intrinsic coagulation pathways. Platelet counts remained at pre-irradiation values over the course of 7 days, indicating that the observed effects were not platelet-related, but instead likely to be due to radiation-induced effects on secondary hemostasis. White blood cell (WBC) counts were reduced in a statistically significant manner from 24 h through the course of the seven-day experiment. CONCLUSIONS: SPE-like proton radiation results in significant decreases in all WBC counts as well as activates secondary hemostasis; together, these data suggest severe risks to astronaut health from exposure to SPE radiation.

The Effects of Gamma and Proton Radiation Exposure on Hematopoietic Cell Counts in the Ferret Model.

Exposure to total-body radiation induces hematological changes, which can detriment one's immune response to wounds and infection. Here, the decreases in blood cell counts after acute radiation doses of γ-ray or proton radiation exposure, at the doses and dose-rates expected during a solar particle event (SPE), are reported in the ferret model system. Following the exposure to γ-ray or proton radiation, the ferret peripheral total white blood cell (WBC) and lymphocyte counts decreased whereas neutrophil count increased within 3 hours. At 48 hours after irradiation, the WBC, neutrophil, and lymphocyte counts decreased in a dose-dependent manner but were not significantly affected by the radiation type (γ-rays verses protons) or dose rate (0.5 Gy/minute verses 0.5 Gy/hour). The loss of these blood cells could accompany and contribute to the physiological symptoms of the acute radiation syndrome (ARS).

New developments in treatment planning and verification of particle beam therapy.

Charged particle beam therapy has been used for almost 60 years. During the initial 40 years, the medical use of protons and heavy ions was explored at accelerator laboratories in a limited number of patients and for a limited number of cancerous and non-cancerous disease conditions. After the development of computed tomography and 3D treatment planning, it was time to move charged particle therapy into the clinical realm. This happened in October 1991 when an ocular melanoma patient became the first patient to be treated at Loma Linda University Medical Center in California. Due to the increased awareness of the advantages of charged particle therapy and promising results of single-institution experiences, one currently observes a phase of rapid expansion of proton treatment centers throughout the world. A few of these centers are combined proton/carbon ion facilities. It is very important that the technological evolution of charged particle therapy will continue during this phase of clinical expansion to ensure that the increasing number of patients exposed to therapeutic charged particles will benefit most from the advantageous dose distributions that these particles afford. This report will give an overview of translational research activities related to planning and verification of proton therapy in which the authors have been involved for a number of years. While our activities focus on protons, these developments are to a large degree also applicable to carbon ion therapy.

Comparison of proton and electron radiation effects on biological responses in liver, spleen and blood.

PURPOSE: To determine whether differences exist between proton and electron radiations on biological responses after total-body exposure. MATERIALS AND METHODS: ICR mice (n=45) were irradiated to 2 Gray (Gy) using fully modulated 70 MeV protons (0.5 Gy/min) and 21 MeV electrons (3 Gy/min). At 36 h post-irradiation liver gene expression, white blood cell (WBC), natural killer (NK) cell and other analyses were performed. RESULTS: Oxidative stress-related gene expression patterns were strikingly different for irradiated groups compared to 0 Gy (P<0.05). Proton radiation up-regulated 15 genes (Ctsb, Dnm2, Gpx5, Il19, Il22, Kif9, Lpo, Nox4, Park7, Prdx4, Prdx6, Rag2, Sod3, Srxn1, Xpa) and down-regulated 2 genes (Apoe, Prdx1). After electron irradiation, 20 genes were up-regulated (Aass, Ctsb, Dnm2, Gpx1, Gpx4, Gpx5, Gpx6, Gstk1, Il22, Kif9, Lpo, Nox4, Park7, Prdx3, Prdx4, Prdx5, Rag2, Sod1, Txnrd3, Xpa) and 1 was down-regulated (Mpp4). Of the modified genes, only 11 were common to both forms of radiation. Comparison between the two irradiated groups showed that electrons significantly up-regulated three genes (Gstk1, Prdx3, Scd1). Numbers of WBC and major leukocyte types were low in the irradiated groups (P<0.001 vs. 0 Gy). Hemoglobin and platelet counts were low in the electron-irradiated group (P<0.05 vs. 0 Gy). However, spleens from electron-irradiated mice had higher WBC and lymphocyte counts, as well as enhanced NK cell cytotoxicity, compared to animals exposed to protons (P<0.05). There were no differences between the two irradiated groups in body mass, organ masses, and other assessed parameters, although some differences were noted compared to 0 Gy. CONCLUSION: Collectively, the data demonstrate that at least some biological effects induced by electrons may not be directly extrapolated to protons.

Analysis of white blood cell counts in mice after gamma- or proton-radiation exposure.

In the coming decades human space exploration is expected to move beyond low-Earth orbit. This transition involves increasing mission time and therefore an increased risk of radiation exposure from solar particle event (SPE) radiation. Acute radiation effects after exposure to SPE radiation are of prime importance due to potential mission-threatening consequences. The major objective of this study was to characterize the dose-response relationship for proton and γ radiation delivered at doses up to 2 Gy at high (0.5 Gy/min) and low (0.5 Gy/h) dose rates using white blood cell (WBC) counts as a biological end point. The results demonstrate a dose-dependent decrease in WBC counts in mice exposed to high- and low-dose-rate proton and γ radiation, suggesting that astronauts exposed to SPE-like radiation may experience a significant decrease in circulating leukocytes.

Microdosimetric comparison of scanned and conventional proton beams used in radiation therapy.

Multiple groups have hypothesised that the use of scanning beams in proton therapy will reduce the neutron component of secondary radiation in comparison with conventional methods with a corresponding reduction in risks of radiation-induced cancers. Loma Linda University Medical Center (LLUMC) has had FDA marketing clearance for scanning beams since 1988 and an experimental scanning beam has been available at the LLUMC proton facility since 2001. The facility has a dedicated research room with a scanning beam and fast switching that allows its use during patient treatments. Dosimetric measurements and microdosimetric distributions for a scanned beam are presented and compared with beams produced with the conventional methods presently used in proton therapy.

Proton-beam therapy for tumors of the CNS.

The focus of this review is proton radiotherapy for primary neoplasms of the brain. Although glial cells are among the most radioresistant in the body, the presence of sensitive critical structures and the high doses needed to control CNS tumors present a formidable challenge to the treating radiation oncologist. Treatment with conventional photon radiation at doses required to control disease progression all too often results in unacceptable toxicity. Protons have intrinsic properties that often allow radiation oncologists to deliver a higher dose to the tumor compared with photons, while at the same time offering better sparing of normal tissues. Recognition of these advantages has resulted in development of many new proton treatment facilities worldwide.