Application of lung substitute material as ripple filter for multi-ion therapy with helium-, carbon-, oxygen-, and neon-ion beams.

A development project for hypo-fractionated multi-ion therapy has been initiated at the National Institute of Radiological Sciences in Japan. In the treatment, helium, carbon, oxygen, and neon ions will be used as primary beams with pencil beam scanning. A ripple filter (RiFi), consisting of a thin plastic or aluminum plate with a fine periodic ridge and groove structure, has been used to broaden the Bragg peak of heavy-ion beams in the beam direction. To sufficiently broaden the Bragg peak of helium-, carbon-, oxygen-, and neon-ion beams with suppressed lateral scattering and surface dose inhomogeneity, in this study, we tested a plate made of a lung substitute material, Gammex LN300, as the RiFi. The planar integrated dose distribution of a 183.5 MeV u-1neon-ion beam was measured behind a 3 cm thick LN300 plate in water. The Bragg peak of the pristine beam was broadened following the normal distribution with the standard deviationσvalue of 1.29 mm, while the range of the beam was reduced by 8.8 mm by the plate. To verify the LN300 performance as the RiFi in multi-ion therapy, we measured the pencil beam data of helium-, carbon-, oxygen- and neon-ion beams penetrating the 3 cm thick LN300 plate. The data were then modeled and used in a treatment planning system to achieve a uniform 10% survival of human undifferentiated carcinoma cells within a cuboid target by the beam for each of the different ion species. The measured survival fractions were reasonably reproduced by the planned ones for all the ion species. No surface dose inhomogeneity was observed for any ion species even when the plate was placed close to the phantom surface. The plate made of lung substitute material, Gammex LN300, is applicable as the RiFi in multi-ion therapy with helium-, carbon-, oxygen- and neon-ion beams.

Estimating the biological effects of helium, carbon, oxygen, and neon ion beams using 3D silicon microdosimeters.

In this study, the survival fraction (SF) and relative biological effectiveness (RBE) of pancreatic cancer cells exposed to spread-out Bragg peak helium, carbon, oxygen, and neon ion beams are estimated from the measured microdosimetric spectra using a microdosimeter and the application of the microdosimetric kinetic (MK) model. To measure the microdosimetric spectra, a 3D mushroom silicon-on-insulator microdosimeter connected to low noise readout electronics (MicroPlus probe) was used. The parameters of the MK model were determined for pancreatic cancer cells such that the calculated SFs reproduced previously reported in vitro SF data. For a cuboid target of 10 × 10 × 6 cm3, treatment plans of helium, carbon, oxygen, and neon ion beams were designed using in-house treatment planning software (TPS) to achieve a 10% SF of pancreatic cancer cells throughout the target. The physical doses and microdosimetric spectra of the planned fields were measured at different depths in polymethyl methacrylate phantoms. The biological effects, such as SF, RBE, and RBE-weighted dose at different depths along the fields were predicted from the measurements. The predicted SFs at the target region were generally in good agreement with the planned SF from the TPS in most cases.

Experimental validation of stochastic microdosimetric kinetic model for multi-ion therapy treatment planning with helium-, carbon-, oxygen-, and neon-ion beams.

The National Institute of Radiological Sciences (NIRS) has initiated a development project for hypo-fractionated multi-ion therapy. In the treatment, heavy ions up to neon ions will be used as a primary beam, which is a high linear energy transfer (LET) radiation. The fractionated dose of the treatment will be 10 Gy or more. The microdosimetric kinetic (MK) model overestimates the biological effectiveness of high-LET and high-dose radiations. To address this issue, the stochastic microdosimetric kinetic (SMK) model has been developed as an extension of the MK model. By taking the stochastic nature of domain-specific and cell nucleus-specific energies into account, the SMK model could estimate the biological effectiveness of radiations with wide LET and dose ranges. Previously, the accuracy of the SMK model was examined by comparison of estimated and reported survival fractions of human cells exposed to pristine helium-, carbon-, and neon-ion beams. In this study, we verified the SMK model in treatment planning of scanned helium-, carbon-, oxygen-, and neon-ion beams as well as their combinations through the irradiations of human undifferentiated carcinoma and human pancreatic cancer cells. Treatment plans were made with the ion-species beams to achieve a uniform 10% survival of the cells within a cuboid target. The planned survival fractions were reasonably reproduced by the measured survival fractions in the whole region from the plateau to the fragment tail for all planned irradiations. The SMK model offers the accuracy and simplicity required in hypo-fractionated multi-ion therapy treatment planning.

Nuclear-interaction correction for patient dose calculations in treatment planning of helium-, carbon-, oxygen-, and neon-ion beams.

In charged-particle therapy treatment planning, the patient is conventionally modeled as variable-density water, i.e. stopping effective density ρ S, and the planar integrated dose distribution measured in water (PID) is applied for patient dose calculation based on path length scaling with the ρ S. This approximation assures the range accuracy of charged-particle beams. However, it causes dose calculation errors due to water nonequivalence of body tissues in nuclear interactions originating from compositional differences. We had previously proposed and validated a PID correction method for the errors in carbon-ion radiotherapy. In the present study, we verify the PID correction method for helium-, oxygen-, and neon-ion beams. The one-to-one relationships between ρ S and the nuclear effective density ρ N of body tissues were constructed for helium-, carbon-, oxygen-, and neon-ion beams, and were used to correct the PIDs to account for the dose calculation errors in patient. The correction method was tested for non-water materials with un-scanned and scanned ion beams. In un-scanned beams penetrating the materials, the dose calculation errors of up to 5.9% were observed at the Bragg peak region, while they were reduced to ⩽0.9% by the PID correction method. In scanned beams penetrating olive oil, the dose calculation errors of up to 2.7% averaged over the spread-out Bragg peak were observed, while they were reduced to ⩽0.4% by the correction method. To investigate the influence of water nonequivalence of body tissues on tumor dose, we carried out a treatment planning study for prostate and uterine cases. The tumor over-doses of 0.9%, 1.8%, 2.0%, and 2.2% were observed in the uterine case for the helium-, carbon-, oxygen-, and neon-ion beams, respectively. These dose errors could be diminished by the PID correction method. The present results verify that the PID correction method is simple, practical, and accurate for treatment planning of these four ion species.

Effect of External Magnetic Fields on Biological Effectiveness of Proton Beams.

PURPOSE: The purpose is to verify experimentally whether application of magnetic fields longitudinal and perpendicular to a proton beam alters the biological effectiveness of the radiation. METHODS AND MATERIALS: Proton beams with linear energy transfer of 1.1 and 3.3 keV/µm irradiated human cancer and normal cells under a longitudinal (perpendicular) magnetic field of BL (BP) = 0, 0.3, or 0.6 T. Cell survival curves were constructed to evaluate the effects of the magnetic fields on the biological effectiveness. The ratio of dose that would result in a survival fraction of 10% without the magnetic field Dwo to the dose with the magnetic field Dw, R10 = Dwo/Dw, was determined for each cell line and magnetic field. RESULTS: For cancer cells exposed to the 1.1- (3.3-) keV/µm proton beams, R10s were increased to 1.10 ± 0.07 (1.11 ± 0.07) and 1.11 ± 0.07 (1.12 ± 0.07) by the longitudinal magnetic fields of BL = 0.3 and 0.6 T, respectively. For normal cells, R10s were increased to 1.13 ± 0.06 (1.17 ± 0.06) and 1.17 ± 0.06 (1.30 ± 0.06) by the BLs. In contrast, R10s were not changed significantly from 1 by the perpendicular magnetic fields of BP = 0.3 and 0.6 T for both cancer and normal cells exposed to 1.1- and 3.3-keV/µm proton beams. CONCLUSIONS: The biological effectiveness of proton beams was significantly enhanced by longitudinal magnetic fields of BL = 0.3 and 0.6 T, whereas the biological effectiveness was not altered by perpendicular magnetic fields of the same strengths. This enhancement effect should be taken into account in magnetic resonance imaging guided proton therapy with a longitudinal magnetic field.

Effects of Magnetic Field Applied Just Before, During or Immediately after Carbon-Ion Beam Irradiation on its Biological Effectiveness.

Previously reported studies have revealed that the application of a magnetic field longitudinal to a carbon-ion beam enhances its biological effectiveness. Here we investigated how timing of the magnetic field application with respect to beam irradiation influenced this effect. Human cancer cells were exposed to carbon-ion beams with linear energy transfer (LET) of 12 and 50 keV/µm. The longitudinal magnetic field of 0.3 T was applied to the cells just before, during or immediately after the beam irradiation. The effects of the timing on the biological effectiveness were evaluated by cell survival. The biological effectiveness increased only if the magnetic field was applied during beam irradiation for both LETs.

Influence of a perpendicular magnetic field on biological effectiveness of carbon-ion beams.

Purpose: Our previous study revealed that the application of a magnetic field longitudinal to a carbon-ion beam of 0.1 ≤ B//≤ 0.6 T enhances the biological effectiveness of the radiation. The purpose of this study is to experimentally verify whether the application of a magnetic field perpendicular to the beam also alters the biological effectiveness. Methods and materials: Most experimental conditions other than the magnetic field direction were the same as those used in the previous study to allow comparison of their results. Human cancer and normal cells were exposed to low (12 keV/µm) and high (50 keV/µm) linear energy transfer (LET) carbon-ion beams under the perpendicular magnetic fields of B⊥ = 0, 0.15, 0.3, or 0.6 T generated by a dipole magnet. The effects of the magnetic fields on the biological effectiveness were evaluated by clonogenic cell survival. Doses that would result in the survival of 10%, D10s, were determined for the exposures and analyzed using Student's t-tests. Results: For both cancer and normal cells treated by low- and high-LET carbon-ion beams, the D10s measured in the presence of the perpendicular magnetic fields of B⊥ ≥ 0.15 T were not statistically different (p ≫ .05) from the D10s measured in the absence of the magnetic fields, B⊥ = 0 T. Conclusions: Exposure of human cancer and normal cells to the perpendicular magnetic fields of B⊥ ≤ 0.6 T did not alter significantly the biological effectiveness of the carbon-ion beams, unlike the exposure to longitudinal magnetic fields of the same strength. Although the mechanisms underlying the observed results still require further exploration, these findings indicate that the influence of the magnetic field on biological effectiveness of the carbon-ion beam depends on the applied field direction with respect to the beam.

Enhancement of biological effectiveness of carbon-ion beams by applying a longitudinal magnetic field.

Purpose: A magnetic field longitudinal to an ion beam will potentially affect the biological effectiveness of the radiation. The purpose of this study is to experimentally verify the significance of such effects. Methods and materials: Human cancer and normal cell lines were exposed to low (12 keV/µm) and high (50 keV/µm) linear energy transfer (LET) carbon-ion beams under the longitudinal magnetic fields of B// = 0, 0.1, 0.2, 0.3, or 0.6 T generated by a solenoid magnet. The effects of the magnetic fields on the biological effectiveness were evaluated by clonogenic cell survival. Doses that would result in a survival fraction of 10% (D10s) were determined for each cell line and magnetic field. Results: For cancer cells exposed to the low (high)-LET beams, D10 decreased from 5.2 (3.1) Gy at 0 T to 4.3 (2.4) Gy at 0.1 T, while no further decrease in D10 was observed for higher magnetic fields. For normal cells, decreases in D10 of comparable magnitudes were observed by applying the magnetic fields. Conclusions: Significant decreases in D10, i.e. significant enhancements of the biological effectiveness, were observed in both cancer and normal cells by applying longitudinal magnetic fields of B// ≥ 0.1 T. These effects were enhanced with LET. Further studies are required to figure out the mechanism underlying the observed results.

Performance of the NIRS fast scanning system for heavy-ion radiotherapy.

PURPOSE: A project to construct a new treatment facility, as an extension of the existing HIMAC facility, has been initiated for the further development of carbon-ion therapy at NIRS. This new treatment facility is equipped with a 3D irradiation system with pencil-beam scanning. The challenge of this project is to realize treatment of a moving target by scanning irradiation. To achieve fast rescanning within an acceptable irradiation time, the authors developed a fast scanning system. METHODS: In order to verify the validity of the design and to demonstrate the performance of the fast scanning prior to use in the new treatment facility, a new scanning-irradiation system was developed and installed into the existing HIMAC physics-experiment course. The authors made strong efforts to develop (1) the fast scanning magnet and its power supply, (2) the high-speed control system, and (3) the beam monitoring. The performance of the system including 3D dose conformation was tested by using the carbon beam from the HIMAC accelerator. RESULTS: The performance of the fast scanning system was verified by beam tests. Precision of the scanned beam position was less than +/-0.5 mm. By cooperating with the planning software, the authors verified the homogeneity of the delivered field within +/-3% for the 3D delivery. This system took only 20 s to deliver the physical dose of 1 Gy to a spherical target having a diameter of 60 mm with eight rescans. In this test, the average of the spot-staying time was considerably reduced to 154 micros, while the minimum staying time was 30 micros. CONCLUSIONS: As a result of this study, the authors verified that the new scanning delivery system can produce an accurate 3D dose distribution for the target volume in combination with the planning software.

Two major factors involved in the reverse dose-rate effect for somatic mutation induction are the cell cycle position and LET value.

To study mechanisms which could be involved in the reverse dose rate effect observed during mutation induction after exposure to high LET radiation, synchronized mouse L5178Y cells were exposed to carbon 290 MeV/n beams with different LET values at the G2/M, G1, G1/S or S phases in the cell cycle. The frequency of Hprt-deficient (6-thioguanine-resistant) mutant induction was subsequently determined. The results showed that after exposure to high LET value radiation (50.8 and 76.5 keV/microm), maximum mutation frequencies were seen at the G2/M phase, but after exposure to lower LET radiation (13.3 keV/microm), the highest mutation frequencies were observed at the G1 phase. The higher LET beam always produced higher mutation frequencies in the G2/M phase than in the G1 phase, regardless of radiation dose. These results suggest that cells in the G2/M phase is hyper-sensitive for mutation induction from high LET radiation, but not to mutation induction from low LET radiation. Molecular analysis of mutation spectra showed that large deletions (which could include almost entire exons) of the mouse Hprt gene were most efficiently induced in G2/M cells irradiated with high LET radiation. These entire exon deletions were not as frequent in cells exposed to lower LET radiation. This suggests that inappropriate recombination repair might have occurred in response to condensed damage in condensed chromatin in the G2/M phase. In addition, by using a hyper-sensitive mutation detection system (GM06318-10 cells), a reverse dose-rate effect was clearly observed after exposure to carbon beams with higher LET values (66 keV/microm), but not after exposure to beams with lower LET values (13.3 keV/microm). Thus, G2/M sensitivity towards mutation induction, and the dependence on radiation LET values could both be major factors involved in the reverse dose rate effect produced by high LET radiation.

New accelerator facility for carbon-ion cancer-therapy.

The first clinical trial with carbon beams generated from HIMAC was conducted in June 1994. The total number of patients treated as of December 2006 was in excess of 3,000. In view of the significant growth in the number of protocols, the Japanese government gave its approval for carbon-ion therapy at NIRS as an advanced medical technology in 2003. The impressive advances of carbon-ion therapy using HIMAC have been supported by high-reliability operation and by advanced developments of beam-delivery and accelerator technologies. Based on our ten years of experience with HIMAC, we recently proposed a new accelerator facility for cancer therapy with carbon ions for widespread use in Japan. The key technologies of the accelerator and beam-delivery systems for this proposed facility have been under development since April 2004, with the main thrust being focused on downsizing the facility for cost reduction. Based on the design and R&D studies for the proposed facility, its construction was begun at Gunma University in April 2006. In addition, our future plans for HIMAC also include the design of a new treatment facility. The design work has already been initiated, and will lead to the further development of therapy using HIMAC. The following descriptions give a summary account of the new accelerator facility for cancer therapy with carbon ions and of the new treatment facility at HIMAC.

The response of a spherical tissue-equivalent proportional counter to different heavy ions having similar velocities.

A tissue-equivalent proportional counter (TEPC) has been used as a dosimeter in mixed radiation fields. Since it does not measure LET directly, the response function must be characterized in order to estimate quality factor and thus equivalent dose for the incident radiation. The objectives of this study were to measure the response of a spherical TEPC for different high-energy heavy ions (HZE) having similar velocity and to determine how quality factors can be determined. Data were obtained at the HIMAC heavy ion accelerator for (4)He and (12)C at 220 +/- 5 MeV/nucleon (beta = 0.59) and (12)C, (16)O, (28)Si and (56)Fe at 376 +/- 15 MeV/nucleon (beta = 0.70). A particle spectrometer recorded the charge and position of each incident beam particle. Events with low energy deposition were observed for particles that passed through the wall of the TEPC but not through the sensitive volume. The frequency averaged lineal energy, y(f), was always less than the LET of the incident particles. The dose averaged lineal energy, y(D), was approximately equal to LET for particles with LET greater than 10 keV/mum, whereas y(D) was larger than LET for the lighter particles with lower LET. Part of this effect is due to detector resolution and energy straggling that increases the variance of the response function. Although the TEPC is not a LET spectrometer, it can provide real time measurements of dose and provide estimates of quality factors for HZE particles using averaged values of lineal energy.

The response of a spherical tissue-equivalent proportional counter to different ions having similar linear energy transfer.

The response of a tissue-equivalent proportional counter (TEPC) to different ions having a similar linear energy transfer (LET) has been studied. Three ions, 14N, 20Ne and 28Si, were investigated using the HIMAC accelerator at the National Institute of Radiological Sciences at Chiba, Japan. The calculated linear energy transfer (LET( infinity )) of all ions was 44 +/- 2 keV/microm at the sensitive volume of the TEPC. A particle spectrometer was used to record the charge and position of each incident beam particle. This enabled reconstruction of the location of the track as it passed though the TEPC and ensured that the particle survived without fragmentation. The spectrum of energy deposition events in the TEPC could be evaluated as a function of trajectory through the TEPC. The data indicated that there are many events from particles that did not pass through the sensitive volume. The fraction of these events increased as the energy of the particle increased due to changes in the maximum energy of the delta rays. Even though the LET of the incident particles was nearly identical, the frequency-averaged lineal energy, y(F), as well as the dose-averaged lineal energy, y(D), varied with the velocity of the incident particle. However, both values were within 15% of LET in all cases.