Retrospective comparison of rectal toxicity between carbon-ion radiotherapy and intensity-modulated radiation therapy based on treatment plan, normal tissue complication probability model, and clinical outcomes in prostate cancer.

This retrospective study assessed the treatment planning data and clinical outcomes for 152 prostate cancer patients: 76 consecutive patients treated by carbon-ion radiation therapy and 76 consequtive patients treated by moderate hypo-fractionated intensity-modulated photon radiation therapy. These two modalities were compared using linear quadratic model equivalent doses in 2 Gy per fraction for rectal or rectal wall dose-volume histogram, 3.6 Gy per fraction-converted rectal dose-volume histogram, normal tissue complication probability model, and actual clinical outcomes. Carbon-ion radiation therapy was predicted to have a lower probability of rectal adverse events than intensity-modulated photon radiation therapy based on dose-volume histograms and normal tissue complication probability model. There was no difference in the clinical outcome of rectal adverse events between the two modalities compared in this study.

Calculation of Stopping-Power Ratio from Multiple CT Numbers Using Photon-Counting CT System: Two- and Three-Parameter-Fitting Method.

The two-parameter-fitting method (PFM) is commonly used to calculate the stopping-power ratio (SPR). This study proposes a new formalism: a three-PFM, which can be used in multiple spectral computed tomography (CT). Using a photon-counting CT system, seven rod-shaped samples of aluminium, graphite, and poly(methyl methacrylate) (PMMA), and four types of biological phantom materials were placed in a water-filled sample holder. The X-ray tube voltage and current were set at 150 kV and 40 µA, respectively, and four CT images were obtained at four threshold settings. A semi-empirical correction method that corrects the difference between the CT values from the photon-counting CT images and theoretical values in each spectral region was also introduced. Both the two- and three-PFMs were used to calculate the effective atomic number and electron density from multiple CT numbers. The mean excitation energy was calculated via parameterisation with the effective atomic number, and the SPR was then calculated from the calculated electron density and mean excitation energy. Then, the SPRs from both methods were compared with the theoretical values. To estimate the noise level of the CT numbers obtained from the photon-counting CT, CT numbers, including noise, were simulated to evaluate the robustness of the aforementioned PFMs. For the aluminium and graphite, the maximum relative errors for the SPRs calculated using the two-PFM and three-PFM were 17.1% and 7.1%, respectively. For the PMMA and biological phantom materials, the maximum relative errors for the SPRs calculated using the two-PFM and three-PFM were 5.5% and 2.0%, respectively. It was concluded that the three-PFM, compared with the two-PFM, can yield SPRs that are closer to the theoretical values and is less affected by noise.

Estimations of relative biological effectiveness of secondary fragments in carbon ion irradiation of water using CR-39 plastic detector and microdosimetric kinetic model.

PURPOSE: To estimate relative biological effectiveness (RBE) ascribed to secondary fragments in a lateral distribution of carbon ion irradiation. The RBE was estimated with the microdosimetric kinetic (MK) model and measured linear energy transfer (LET) obtained with CR-39 plastic detectors. METHODS: A water phantom was irradiated by a 12 C pencil beam with energy of 380 MeV/u at the Gunma University Heavy Ion Medical Center (GHMC), and CR-39 detectors were exposed to secondary fragments. Because CR-39 was insensitive to low LET, we conducted Monte Carlo simulations with Geant4 to calculate low LET particles. The spectra of low LET particles were combined with experimental spectra to calculate RBE. To estimate accuracy of RBE, we calculated RBE by changing yield of low LET particles by ± 10% and ± 40%. RESULTS: At a small angle, maximum RBE by secondary fragments was 1.3 for 10% survival fractions. RBE values of fragments gradually decreased as the angle became larger. The shape of the LET spectra in the simulation reproduced the experimental spectra, but there was a discrepancy between the simulation and experiment for the relative yield of fragments. When the yield of low LET particles was changed by ± 40%, the change in RBE was smaller than 10%. CONCLUSIONS: An RBE of 1.3 was expected for secondary fragments emitted at a small angle. Although, we observed a discrepancy in the relative yield of secondary fragments between simulation and experiment, precision of RBE was not so sensitive to the yield of low LET particles.

Divided-volume matching technique for volume displacement estimation of patient positioning in radiation therapy.

PURPOSE: We propose the Divided-Volume Matching (DVM) technique to visualize and estimate three-dimensional (3D) displacements of internal structures to enable more accurate patient positioning for radiation therapy. METHODS: A CT volume is divided into a volume of interest (VOI) and a base volume (BV); 2D-3D matching is achieved using digital radiography (DR) images and digitally reconstructed radiographs (DRRs), where the DRRs are iteratively generated by changing the 3D positions and rotation angles of the separate volumes independently to identify the best match with the DR images. We demonstrate this technique with two phantom and two clinical cases. RESULTS: 3D displacements of the VOIs could be estimated independently and simultaneously with those of the BVs, with accuracies comparable to those of the conventional 2D-3D matching. The proposed technique yielded more suitable matching results when internal displacements occurred in the regions of interest (ROIs). The best matches were found when the ROI was confined to the focused structure, initial displacement values were coarsely adjusted, one volume was matched while the other was fixed, or any combination thereof. CONCLUSIONS: The proposed technique can be used effectively for independent displacement estimations of VOIs and BVs for patient positioning in radiation therapy.

Annihilation gamma imaging for carbon ion beam range monitoring using Si/CdTe Compton camera.

In this study, we performed on-beam monitoring of 511 keV annihilation gamma emissions using a Compton camera. Beam monitoring experiments were conducted using carbon ion beams of 290 MeV/u irradiated on a polymethyl methacrylate (PMMA) phantom. The intensity of the beams was 3 × 109 particles per pulse, with 20 pulses per minute. A Compton camera based on a silicon/cadmium telluride (Si/CdTe) detector was used to monitor the annihilation gamma rays emitted from the phantom. We successfully reconstructed the energy events of 511 keV annihilation gamma rays and developed Compton images using a simple back-projection method. The distribution of the annihilation gamma ray generation traced the beam trajectory and the peak intensity position was a few millimeters shorter than the Bragg peak position. Moreover, the effect of the beam range shifter with 30, 60, and 90 mm water equivalent thickness (WET) was clearly visualized in the reconstructed Compton images. The experimentally measured values of the corresponding range shifts in the PMMA phantom (28.70 mm, 52.49 mm, and 76.77 mm, respectively) were consistent with the shifts of the Bragg peak position (25.50 mm, 51.30 mm and 76.70 mm, respectively) evaluated by Monte Carlo simulation. The results show that the Si/CdTe Compton camera has strong potential for on-beam monitoring of annihilation gamma rays in particle therapy in clinical situations.

MRI response of obturator internus muscle to carbon-ion dose in prostate cancer treatment.

It is important to confirm the dose distribution and its biophysiological response in patients subjected to carbon-ion radiotherapy (CIRT) by using medical imaging methods. In this study, the correlation between the signal intensity changes of muscles observed in magnetic resonance imaging (MRI) after CIRT and planned dose distribution was evaluated. Seven patients were arbitrarily selected from among localized prostate cancer patients on whom CIRT was performed in our facilities in 2010. All subjects received the same dose of CIRT, namely, 57.6 Gy relative biological effectiveness (RBE) in 16 fractions. The following two types of images were acquired for each subject: planning computed tomography (CT) images overlaying the dose distribution of CIRT and MRI T2-weighted images (T2WI) taken 1 year after CIRT. The fusion image of the planning CT and MRI images was registered by using a treatment-planning system, and the CIRT dose distribution was compared with changes observed in the MRI of the obturator internus muscles located near the prostate. The signal changes in the axial image passing through the isocenter of the planning target volume were digitized, and a scatter diagram was created showing the relationship between the radiation dose and digitized signal changes. A strong correlation between the radiation dose and the MRI signal intensity changes was observed, and a quadratic function was found to have the best fit. However, estimating the dose distribution from the normalized MRI signal intensity is difficult at this point, owing to the wide variation. Therefore, further investigation is required.

Linear energy transfer (LET) spectra and survival fraction distribution based on the CR-39 plastic charged-particle detector in a spread-out Bragg peak irradiation by a 12C beam.

Facilities for heavy ion therapies are steadily increasing in number worldwide. One of the advantages of heavy ions is their high relative biological effect (RBE). In a model used at NIRS (National Institute of Radiological Sciences), linear energy transfer (LET) spectra are required to estimate biological dose (physical dose × RBE). The CR-39 plastic charged-particle detector (CR-39) is suitable for measurement of LET. For the present study, done at the Gunma University Heavy Ion Medical Center (GHMC), we measured LET spectra at 11 depths in spread-out Bragg peak (SOBP) irradiation by a 12C beam of 380 MeV/u. The lower threshold of the CR-39 to measure LET was about 5 keV µm-1 due to poor sensitivity for low LET. Then we calculated biological dose and survival fraction distributions and compared them with treatment planning results at GHMC. We used Monte Carlo simulation (Geant4) to calculate LET spectra. The simulation results were in good agreement with the experimental spectra. Moreover, the biological dose and survival fraction distributions estimated from the CR-39 reproduced the treatment planning. The CR-39 is suitable for estimating biological dose in carbon ion therapy.

Development of stereotactic radiosurgery using carbon beams (carbon-knife).

The aim of this research is to develop a stereotactic-radiosurgery (SRS) technique using carbon beams to treat small intracranial lesions; we call this device the carbon knife. A 2D-scanning method is adapted to broaden a pencil beam to an appropriate size for an irradiation field. A Mitsubishi slow extraction using third order resonance through a rf acceleration system stabilized by a feed-forward scanning beam using steering magnets with a 290 MeV/u initial beam energy was used for this purpose. Ridge filters for spread-out Bragg peaks (SOBPs) with widths of 5 mm, 7.5 mm, and 10 mm were designed to include fluence-attenuation effects. The collimator, which defines field shape, was used to reduce the lateral penumbra. The lateral-penumbra width at the SOBP region was less than 2 mm for the carbon knife. The penumbras behaved almost the same when changing the air gap, but on the other hand, increasing the range-shifter thickness mostly broadened the lateral penumbra. The physical-dose rates were approximate 6 Gy s-1 and 4.5 Gy s-1 for the 10 × 10 mm2 and 5 × 5 mm2 collimators, respectively.

Evaluation of the accuracy and clinical practicality of a calculation system for patient positional displacement in carbon ion radiotherapy at five sites.

PURPOSE: We developed a system for calculating patient positional displacement between digital radiography images (DRs) and digitally reconstructed radiography images (DRRs) to reduce patient radiation exposure, minimize individual differences between radiological technologists in patient positioning, and decrease positioning time. The accuracy of this system at five sites was evaluated with clinical data from cancer patients. The dependence of calculation accuracy on the size of the region of interest (ROI) and initial position was evaluated for clinical use. METHODS: For a preliminary verification, treatment planning and positioning data from eight setup patterns using a head and neck phantom were evaluated. Following this, data from 50 patients with prostate, lung, head and neck, liver, or pancreatic cancer (n = 10 each) were evaluated. Root mean square errors (RMSEs) between the results calculated by our system and the reference positions were assessed. The reference positions were manually determined by two radiological technologists to best-matching positions with orthogonal DRs and DRRs in six axial directions. The ROI size dependence was evaluated by comparing RMSEs for three different ROI sizes. Additionally, dependence on initial position parameters was evaluated by comparing RMSEs for four position patterns. RESULTS: For the phantom study, the average (± standard deviation) translation error was 0.17 ± 0.05, rotation error was 0.17 ± 0.07, and ΔD was 0.14 ± 0.05. Using the optimal ROI size for each patient site, all cases of prostate, lung, and head and neck cancer with initial position parameters of 10 mm or under were acceptable in our tolerance. However, only four liver cancer cases and three pancreatic cancer cases were acceptable, because of low-reproducibility regions in the ROIs. CONCLUSION: Our system has clinical practicality for prostate, lung, and head and neck cancer cases. Additionally, our findings suggest ROI size dependence in some cases.

A carbon CT system: how to obtain accurate stopping power ratio using a Bragg peak reduction technique.

In this study, we investigate the performance of the Gunma University Heavy Ion Medical Center's ion computed tomography (CT) system, which measures the residual range of a carbon-ion beam using a fluoroscopy screen, a charge-coupled-device camera, and a moving wedge absorber and collects CT reconstruction images from each projection angle. Each 2D image was obtained by changing the polymethyl methacrylate (PMMA) thickness, such that all images for one projection could be expressed as the depth distribution in PMMA. The residual range as a function of PMMA depth was related to the range in water through a calibration factor, which was determined by comparing the PMMA-equivalent thickness measured by the ion CT system to the water-equivalent thickness measured by a water column. Aluminium, graphite, PMMA, and five biological phantoms were placed in a sample holder, and the residual range for each was quantified simultaneously. A novel method of CT reconstruction to correct for the angular deflection of incident carbon ions in the heterogeneous region utilising the Bragg peak reduction (BPR) is also introduced in this paper, and its performance is compared with other methods present in the literature such as the decomposition and differential methods. Stopping power ratio values derived with the BPR method from carbon-ion CT images matched closely with the true water-equivalent length values obtained from the validation slab experiment.

Robustness of patient positioning for interfractional error in carbon ion radiotherapy for stage I lung cancer: Bone matching versus tumor matching.

BACKGROUND AND PURPOSE: Patient positioning was compared by tumor matching (TM) and conventional bony structure matching (BM) in carbon ion radiotherapy for stage I non-small cell lung cancer to evaluate the robustness of TM and BM in determining interfractional error. MATERIAL AND METHODS: Sixty irradiation fields were analyzed. Computed tomography (CT) images acquired before treatment initiation for confirmation (Conf-CT) were obtained under the same settings as the treatment planning CT images and used to evaluate both positioning methods. The dose distributions were recalculated for Conf-CT using both BM and TM, and the dose-volume histogram parameters [V95% of clinical target volume, V5Gy(RBE) of normal lung, and acceptance ratio (ratio of cases with V95% > 95%)] were evaluated. The required margin, which in 90% of cases achieved the acceptable condition, was also examined. RESULTS: Using BM and TM, the median V95% was 98.93% and 100% (p < 0.001) and the mean V5Gy(RBE) was 135.9 and 125.8 (p = 0.694), respectively. The estimated required margins were 7.9 and 3.3 mm and increased by 53.9% and 2.5% of V5Gy(RBE), respectively, compared with planning. CONCLUSIONS: TM ensured a better dose distribution than did BM. To enable TM, volumetric imaging is crucial and should replace 2D radiographs for carbon therapy of stage I lung cancer.

Margin estimation and disturbances of irradiation field in layer-stacking carbon-ion beams for respiratory moving targets.

Carbon-ion therapy by layer-stacking irradiation for static targets has been practised in clinical treatments. In order to apply this technique to a moving target, disturbances of carbon-ion dose distributions due to respiratory motion have been studied based on the measurement using a respiratory motion phantom, and the margin estimation given by the square root of the summation Internal margin2+Setup margin2 has been assessed. We assessed the volume in which the variation in the ratio of the dose for a target moving due to respiration relative to the dose for a static target was within 5%. The margins were insufficient for use with layer-stacking irradiation of a moving target, and an additional margin was required. The lateral movement of a target converts to the range variation, as the thickness of the range compensator changes with the movement of the target. Although the additional margin changes according to the shape of the ridge filter, dose uniformity of 5% can be achieved for a spherical target 93 mm in diameter when the upward range variation is limited to 5 mm and the additional margin of 2.5 mm is applied in case of our ridge filter. Dose uniformity in a clinical target largely depends on the shape of the mini-peak as well as on the bolus shape. We have shown the relationship between range variation and dose uniformity. In actual therapy, the upper limit of target movement should be considered by assessing the bolus shape.

Estimating Annual Individual Doses for Evacuees Returning Home to Areas Affected by the Fukushima Nuclear Accident.

To contribute to the reconstruction and revitalization of Fukushima Prefecture following the 2011 nuclear power disaster, annual individual doses were estimated for evacuees who will return home to Tamura City, Kawauchi Village, and Iitate Village in Fukushima. Ambient external dose rates and individual doses obtained with personal dosimeters were measured at many residential and occupational sites throughout the study areas to obtain fundamental data needed for the estimation. The measurement results indicated that the ratio of individual dose based on a personal dosimeter to the ambient external dose measurement was 0.7 with 10% uncertainty. Multiplying the ambient external dose by 0.7 may be an appropriate measure of the effective dose to an individual in the investigated area. Annual individual doses were estimated for representative lifestyles and occupations based on the ambient external dose rates at the measurement sites, taking into account the relationship between the ambient external dose and individual dose. The results were as follows: 0.6-2.3 mSv y in Tamura, 1.1-5.5 mSv y in Kawauchi, and 3.8-17 mSv y in Iitate. For all areas investigated, the estimated dose to outdoor workers was higher than that to indoor workers. Identifying ways to reduce the amount of time that an outdoor worker spends outdoors would provide an effective measure to reduce dose.

Measurement of electron density in dual-energy x-ray CT with monochromatic x rays and evaluation of its accuracy.

Information on electron density is important for radiotherapy treatment planning in order to optimize the dose distribution in the target volume of a patient. At present, the electron density is derived from a computed tomography (CT) number measured in x-ray CT scanning; however, there are uncertainties due to the beam hardening effect and the method by which the electron density is converted from the CT number. In order to measure the electron density with an accuracy of +/-1%, the authors have developed dual-energy x ray CT using monochromatic x rays. They experimentally proved that the measured linear attenuation coefficients were only a few percent lower than the theoretical ones, which led to an accuracy within 2% for the electron density. There were three factors causing inaccuracy in the linear attenuation coefficient and the electron density: the influence of scattered radiation, the nonlinearity in the detector response function, and a theoretical process to derive the electron density from the linear attenuation coefficients. The linear attenuation coefficients of water were experimentally proved to differ by 1%-2% from the theoretical one even when the scattering effect was negligible. The nonlinearity of the response function played an important role in correcting the difference in the linear attenuation coefficient. Furthermore, the theoretical process used for deriving the electron density from the linear attenuation coefficients introduces about 0.6% deviation from the theoretical value into the resultant electron density. This deviation occurs systematically so that it can be corrected. The authors measured the electron densities for seven samples equivalent to soft tissue in dual-energy x-ray CT, and finally obtained them with an accuracy of around +/-1%.

Dose distribution of a 125 keV mean energy microplanar x-ray beam for basic studies on microbeam radiotherapy.

A multislit collimator was designed and fabricated for basic studies on microbeam radiation therapy (MRT) with an x-ray energy of about 100 keV. It consists of 30 slits that are 25 microm high, 30 mm wide, and 5 mm thick in the beam direction. The slits were made of 25 microm-thick polyimide sheets that were separated by 175 microm-thick tungsten sheets. The authors measured the dose distribution of a single microbeam with a mean energy of 125 keV by a scanning slit method using a phosphor coupled to a charge coupled device camera and found that the ratios of the dose at the center of a microbeam to that at midpositions to adjacent slits were 1050 and 760 for each side of the microbeam. This dose distribution was well reproduced by the Monte Carlo simulation code PHITS.

Dosimetry for a microbeam array generated by synchrotron radiation at SPring-8.

A microbeam array was formed with a multi-slit collimator (MSC) for research on radiation therapy (MRT). Kodak EDR2 film was used to measure the dose distribution of the microbeam array. The calibration curve of optical density of the film with respect to a dose was established using a standard Farmer chamber and (60)Co gamma-ray source. The peak dose of 3.6 Gy/s at the maximum was derived from the film dosimetry using the calibration curve. The uncertainty was estimated to be 5% which was mainly attributed to the uncertainty of the calibration. It was found that the ionization chamber used for monitoring the dose during the MRT experiments gave lower dose by about 30% than the dose derived from the film dosimetry.

Computational modeling of beam-customization devices for heavy-charged-particle radiotherapy.

A model for beam customization with collimators and a range-compensating filter based on the phase-space theory for beam transport is presented for dose distribution calculation in the treatment planning of radiotherapy with protons and heavier ions. Independent handling of pencil beams in conventional pencil-beam algorithms causes unphysical collimator-height dependence in the middle of large fields, which is resolved by the framework comprised of generation, transport, collimation, regeneration, range-compensation and edge-sharpening processes with a matrix of pencil beams. The model was verified to be consistent with measurement and analytic estimation at a submillimeter level in the penumbra of individual collimators with a combinational-collimated carbon-ion beam. The model computation is fast, accurate and readily applicable to pencil-beam algorithms in treatment planning with the capability of combinational collimation to make the best use of the beam-customization devices.

Secondary range shifting with range compensator for reduction of beam data library in heavy-ion radiotherapy.

We report our experience with extended usage of range compensators in heavy-ion radiotherapy with broad beams to lighten the management task of the beam data library, which is a collection of the standard beams to be referenced in treatment planning. Partly due to interference between lateral spreading and range shifting, as many as hundreds of beam entries may be necessary to cover all the possible clinical situations. We have introduced downstream secondary range shifting with a range compensator to reduce the interference and consequently to simplify the library. In our case, 30% reduction in beam entries is achieved without significantly degrading the beam quality nor increasing the material consumption by more than 3%, which is experimentally verified with carbon-ion beams or statistically estimated from the clinical records.

Irradiation System for HIMAC.

Clinical trials of carbon radiotherapy started at HIMAC in 1994 using three treatment rooms and four beam ports, two horizontal and two vertical. The broad beam method was adopted to make a three-dimensionally uniform field at an isocenter. A spot beam extracted from an accelerator was laterally spread out by using a pair of wobbler magnets and a scatterer. A bar ridge filter modulated the beam energy to obtain the spread out Bragg peak (SOBP). The SOBP was designed to be flat in terms of the biological dose based on the consideration that the field consisted of various beams with different LET. Finally, the field of 20 cm in diameter with +/- 2.5% uniformity was formed at the isocenter. The width of the maximum SOBP was 15 cm. When treating the lung or liver, organs that move due to breathing, the beam was irradiated only during the expiration period in a respiration-gated irradiation method. This reduced the treatment margin of the moving target. In order to prevent normal tissues adjacent to the target volume from irradiation by an unwanted dose, a layer-stacking method was developed. In this method, thin SOBP layers which have different ranges were piled up step by step from the distal end to the entrance of the target volume. At the same time, a multi-leaf collimator was used to change the aperture shape to match the shape of each layer to the cross-sectional shape of the target. This method has been applied to rather large volume cancers including bone and soft-tissue cancers. Only a few serious problems in the irradiation systems have been encountered since the beginning of the clinical trials. Overall the systems have been working stably and reliably.

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.