First Human Cell Experiments With FLASH Carbon Ions.

BACKGROUND/AIM: This study aimed to establish a setup for ultra-high-dose-rate (FLASH) carbon-ion irradiation, and to conduct the first human cell experiments using FLASH carbon ions. MATERIALS AND METHODS: A system for FLASH carbon-ion irradiation (1-3 Gy at 13 or 50 keV/µm) was developed. The growth and senescence of HFL1 lung fibroblasts were assessed by crystal violet staining assays and senescence-associated ß-galactosidase staining, respectively. Survival of HSGc-C5 cancer cells was assessed by clonogenic assays. RESULTS: The dose rates of carbon ions ranged from 96-195 Gy/s, meeting the definition of FLASH. With both 13 and 50 keV/µm beams, no FLASH sparing effect was observed on the growth suppression and senescence of HFL1 cells, nor on the survival of HSGc-C5 cells. CONCLUSION: We successfully conducted the first human cell experiments with FLASH carbon ions. No FLASH effect was observed under the conditions examined.

External dosimetry audit for quality assurance of carbon-ion radiation therapy clinical trials.

PURPOSE: The QA team of the Japan carbon-ion radiation oncology study group (J-CROS) was organized in 2015 to enhance confidence in the accuracy of clinical dosimetry and ensure that the facility QA procedures are adequate. The team conducted onsite dosimetry audits in all the carbon-ion radiation therapy centers in Japan. MATERIALS AND METHODS: A special phantom was fabricated for the onsite dosimetry audit. Target volumes such as the GTV, CTV, and PTV were contoured to the obtained CT images, and two plans with different isocenter depths were created. The dose at the isocenter was measured by an ionization chamber, in the onsite audit and compared with the calculated dose. RESULTS: For all the centers, the average of the percentage ratio between the measured and calculated doses (measured/calculated) was 0.5% (-2.7% to +2.6%) and the standard deviation, 1.7%. In all the centers, the beams were within the set tolerance level of 3%. CONCLUSIONS: The audit demonstrated that the dose at a single point in the water phantom was within tolerance, but it is a big step to say that all doses are correct. In addition, this external dosimetry audit encouraged centers to improve the quality of their dosimetry systems.

Changes in Rectal Dose Due to Alterations in Beam Angles for Setup Uncertainty and Range Uncertainty in Carbon-Ion Radiotherapy for Prostate Cancer.

BACKGROUND AND PURPOSE: Carbon-ion radiotherapy of prostate cancer is challenging in patients with metal implants in one or both hips. Problems can be circumvented by using fields at oblique angles. To evaluate the influence of setup and range uncertainties accompanying oblique field angles, we calculated rectal dose changes with oblique orthogonal field angles, using a device with fixed fields at 0° and 90° and a rotating patient couch. MATERIAL AND METHODS: Dose distributions were calculated at the standard angles of 0° and 90°, and then at 30° and 60°. Setup uncertainty was simulated with changes from -2 mm to +2 mm for fields in the anterior-posterior, left-right, and cranial-caudal directions, and dose changes from range uncertainty were calculated with a 1 mm water-equivalent path length added to the target isocenter in each angle. The dose distributions regarding the passive irradiation method were calculated using the K2 dose algorithm. RESULTS: The rectal volumes with 0°, 30°, 60°, and 90° field angles at 95% of the prescription dose were 3.4±0.9 cm3, 2.8±1.1 cm3, 2.2±0.8 cm3, and 3.8±1.1 cm3, respectively. As compared with 90° fields, 30° and 60° fields had significant advantages regarding setup uncertainty and significant disadvantages regarding range uncertainty, but were not significantly different from the 90° field setup and range uncertainties. CONCLUSIONS: The setup and range uncertainties calculated at 30° and 60° field angles were not associated with a significant change in rectal dose relative to those at 90°.

Evaluation of an empirical monitor output estimation in carbon ion radiotherapy.

PURPOSE: A conventional broad beam method is applied to carbon ion radiotherapy at Gunma University Heavy Ion Medical Center. According to this method, accelerated carbon ions are scattered by various beam line devices to form 3D dose distribution. The physical dose per monitor unit (d/MU) at the isocenter, therefore, depends on beam line parameters and should be calibrated by a measurement in clinical practice. This study aims to develop a calculation algorithm for d/MU using beam line parameters. METHODS: Two major factors, the range shifter dependence and the field aperture effect, are measured via PinPoint chamber in a water phantom, which is an identical setup as that used for monitor calibration in clinical practice. An empirical monitor calibration method based on measurement results is developed using a simple algorithm utilizing a linear function and a double Gaussian pencil beam distribution to express the range shifter dependence and the field aperture effect. RESULTS: The range shifter dependence and the field aperture effect are evaluated to have errors of 0.2% and 0.5%, respectively. The proposed method has successfully estimated d/MU with a difference of less than 1% with respect to the measurement results. Taking the measurement deviation of about 0.3% into account, this result is sufficiently accurate for clinical applications. CONCLUSIONS: An empirical procedure to estimate d/MU with a simple algorithm is established in this research. This procedure allows them to use the beam time for more treatments, quality assurances, and other research endeavors.

Technical approach to individualized respiratory-gated carbon-ion therapy for mobile organs.

We propose a strategy of individualized image acquisitions and treatment planning for respiratory-gated carbon-ion therapy. We implemented it in clinical treatments for diseases of mobile organs such as lung cancers at the Gunma University Heavy Ion Medical Center in June 2010. Gated computed tomography (CT) scans were used for treatment planning, and four-dimensional (4D) CT scans were used to evaluate motion errors within the gating window to help define the internal margins (IMs) and planning target volume for each patient. The smearing technique or internal gross tumor volume (IGTV = GTV + IM), where the stopping power ratio was replaced with the tumor value, was used for range compensation of moving targets. Dose distributions were obtained using the gated CT images for the treatment plans. The influence of respiratory motion on the dose distribution was verified with the planned beam settings using 4D CT images at some phases within the gating window before the adoption of the plan. A total of 14 lung cancer patients were treated in the first year. The planned margins with the proposed method were verified with clinical X-ray set-up images by deriving setup and internal motion errors. The planned margins were considered to be reasonable compared with the errors, except for large errors observed in some cases.

Carbon Ion Radiotherapy at the Gunma University Heavy Ion Medical Center: New Facility Set-up.

Carbon ion radiotherapy (C-ion RT) offers superior dose conformity in the treatment of deep-seated tumors compared with conventional X-ray therapy. In addition, carbon ion beams have a higher relative biological effectiveness compared with protons or X-ray beams. C-ion RT for the first patient at Gunma University Heavy Ion Medical Center (GHMC) was initiated in March of 2010. The major specifications of the facility were determined based on the experience of clinical treatments at the National Institute of Radiological Sciences (NIRS), with the size and cost being reduced to one-third of those at NIRS. The currently indicated sites of cancer treatment at GHMC are lung, prostate, head and neck, liver, rectum, bone and soft tissue. Between March 2010 and July 2011, a total of 177 patients were treated at GHMC although a total of 100 patients was the design specification during the period in considering the optimal machine performance. In the present article, we introduce the facility set-up of GHMC, including the facility design, treatment planning systems, and clinical preparations.

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.

Three-dimensional velocity mapping of lung motion using vessel bifurcation pattern matching.

We present a new quantification technique for three-dimensional (3D) lung motion by means of tracking the anatomical features inside the lung using a set of sequential 3D-CT images (a 4D-CT image). The method is based on the conservation of topology, such as connections and junctions of vessels, during the motion. Lung CT images are used to do lung volume modeling, lung vessel extracting and thinning, and coordinates of vessel bifurcations are derived as feature points. Such feature points are tracked in a series of 3D-CT images, i.e., the points are individually tracked between two successive 3D-CT images, in which the lung is deformed. Consequently, 3D displacement vectors are obtained. The feature point tracking is carried out using point pattern matching with a probabilistic relaxation method. We examined this technique using a lung 3D-CT image and artificially deformed one, and separately scanned CT images for a rigid bifurcation phantom. The studies estimated that the error of the vectors is within approximately 1 voxel, i.e., 1 mm or less. Therefore, the accuracy is expected to be high enough for radiation therapy. This technique enables us to quantify realistic 3D organ motion without any fiducial markers. It can be applied to the quantification of tumor (target volume) deformation by gridding interpolation into all voxels. We expect it to be useful for dose estimation in mobile organs and for 4D treatment planning in radiation therapy.

Evaluation of a pencil beam algorithm for therapeutic carbon ion beam in presence of bolus.

Hot- and cold-dose spots at a shallow depth in a target are formed by carbon ions passing through the bolus with sharp gradients. These spots are caused by sidescatter disequilibrium due to various multiple scattering effects in the different bolus thicknesses. When the dose calculation method by the broad beam algorithm (BBA) is used for treatment planning, these spots cannot be predicted, because the BBA neglects the multiple scattering effects in materials (rms error of 3.9%). On the other hand, since the dose calculation method by the pencil beam algorithm (PBA) takes into account the scattering effects, the results calculated by the PBA agreed better than the BBA with the measured hot- and cold-dose spots, having a rms error of 1.9%. Thus, dose calculation by the PBA improves the accuracy of dose prediction at the shallow depth. However, since dose distributions at deeper positions are affected by many light fragment particles generated by fragment reactions, the results calculated by the PBA disagree with the experimental ones. It is necessary that even the PBA accurately models behavior of fragment particles.

Experimental evaluation of analytical penumbra calculation model for wobbled beams.

The goal of radiotherapy is not only to apply a high radiation dose to a tumor, but also to avoid side effects in the surrounding healthy tissue. Therefore, it is important for carbon-ion treatment planning to calculate accurately the effects of the lateral penumbra. In this article, for wobbled beams under various irradiation conditions, we focus on the lateral penumbras at several aperture positions of one side leaf of the multileaf collimator. The penumbras predicted by an analytical penumbra calculation model were compared with the measured results. The results calculated by the model for various conditions agreed well with the experimental ones. In conclusion, we found that the analytical penumbra calculation model could predict accurately the measured results for wobbled beams and it was useful for carbon-ion treatment planning to apply the model.

[Wiener spectrum and relative electron density resolution in heavy ion CT based on measurement of residual range distribution].

The relative electron density resolution was discussed by the Wiener spectrum in the heavy ion CT image. The two-dimensional (2D) Wiener spectrum in the CT image was obtained from the one-dimensional (1D) Wiener spectrum of the measured residual range distribution of the water phantom for a single projection angle, and the relative electron density resolution in the CT image was calculated from the 2D Wiener spectrum. To examine the usefulness of this method, the relative electron density resolution was also estimated by other two methods; the calculation using the Wiener spectrum of the reconstructed image of the water phantom, and the estimation by the reconstructed image of the electron density resolution phantom. The result of the first method was similar to those of the other two methods. Therefore, it is useful to estimate the relative electron density resolution by the 1D Wiener spectrum of the measured residual range distribution of the water phantom for a single projection angle.

Reconstruction of biologically equivalent dose distribution on CT-image from measured physical dose distribution of therapeutic beam in water phantom.

From the standpoint of quality assurance in radiotherapy, it is very important to compare the dose distributions realized by an irradiation system with the distribution planned by a treatment planning system. To compare the two dose distributions, it is necessary to convert the dose distributions on CT images to distributions in a water phantom or convert the measured dose distributions to distributions on CT images. Especially in heavy-ion radiotherapy, it is reasonable to show the biologically equivalent dose distribution on the CT images. We developed tools for the visualization and comparison of these distributions in order to check the therapeutic beam for each patient at the National Institute of Radiological Sciences (NIRS). To estimate the distribution in a patient, the dose is derived from the measurement by mapping it on a CT-image. Fitting the depth-dose curve to the calculated SOBP curve also gives biologically equivalent dose distributions in the case of a carbon beam. Once calculated, dose distribution information can be easily handled to make a comparison with the planned distribution and display it on a grey-scale CT-image. Quantitative comparisons of dose distributions can be made with anatomical information, which also gives a verification of the irradiation system in a very straightforward way.

Treatment planning for the layer-stacking irradiation system for three-dimensional conformal heavy-ion radiotherapy.

We have upgraded a heavy-ion radiotherapy treatment-planning system to adapt for the layer-stacking irradiation method, which is to conform a variable spread-out Bragg peak to a target volume by means of dynamic control of the conventional beam-modifying devices. The biophysical model, the beam-setup logic, and the dose-calculation algorithm implemented for the layer-stacking method are described and the expected clinical usability is discussed. The layer-stacking method was integrated in perfect accordance with the ongoing conventional treatments so that the established protocols, which are the clinically optimized dose fractionation schemes, will still be valid. On the other hand, a simulation study indicated a substantial improvement of dose distribution with the layer-stacking method though the significance may depend on the size, shape, and location of the tumor. The completed treatment system will provide an option for improved conformal radiotherapy without interfering with the conventional method and we expect a gradual expansion of the clinical cases applicable to the layer-stacking method.