Dose Evaluation in 2-Phase Method for Advanced Esophageal Cancer by Hybrid Irradiation Techniques.

Purpose: In concurrent chemoradiotherapy for advanced esophageal cancer, a 2-phase method consisting of initial irradiation of a wide elective nodal region and boost irradiation of the primary lesion is commonly employed. Although dose escalation to the primary lesion may be required to achieve higher local control rates, the radiation dose to critical organs must not exceed dose constraints. To achieve an optimum balance of dose prescription and dose reduction to surrounding organs, such as the lungs and heart, we compared hybrid dose distributions and investigated the best combination of the following recent irradiation techniques: volumetric modulation arc therapy (VMAT), proton broad-beam irradiation, and intensity-modulated proton beam therapy (IMPT). Materials and Methods: Forty-five patients with advanced esophageal cancer whose primary lesions were located in the middle- or lower-thoracic region were studied. Radiotherapy plans for the initial and boost irradiation in the 2-phase method were calculated using VMAT, proton broad-beam irradiation, and IMPT calculation codes, and the dose-volume histogram indices of the lungs and heart for the accumulated plans were compared. Results: In plans using boost proton irradiation with a prescribed dose of 60 Gy(RBE), all dose-volume histogram indices were significantly below the tolerance limits. Initial and boost irradiation with VMAT resulted in the median dose of V30 Gy(RBE)(heart) of 27.4% and an achievement rate below the tolerance limit of 57.8% (26 cases). In simulations of dose escalation up to 70 Gy(RBE), initial and boost IMPT resulted in the highest achievement rate, satisfying all dose constraints in 95.6% (43 cases). Conclusion: Applying VMAT to both initial and boost irradiation is not recommended because of the increased risk of the cardiac dose exceeding the tolerance limit. IMPT may allow dose escalation of up to 70 Gy(RBE) without radiation risks to the lungs and heart in the treatment of advanced esophageal cancer.

Effectiveness of CT-image guidance in proton therapy for liver cancer and the importance of daily dose monitoring for tumors and organs at risk.

BACKGROUND: It is important to have precise image guidance throughout proton therapy in order to take advantage of the therapy's physical selectivity. PURPOSE: We evaluated the effectiveness of computed tomography (CT)-image guidance in proton therapy for patients with hepatocellular carcinoma (HCC) by assessing daily proton dose distributions. The importance of daily CT image-guided registration and daily proton dose monitoring for tumors and organs at risk (OARs) was investigated. METHODS: A retrospective analysis was conducted using 570 sets of daily CT (dCT) images throughout whole treatment fractions for 38 HCC patients who underwent passive scattering proton therapy with either a 66 cobalt gray equivalent (GyE)/10 fractions (n = 19) or 76 GyE/20 fractions (n = 19) protocol. The actual daily delivered dose distributions were estimated by forward calculation using the dCT sets, their corresponding treatment plans, and the recorded daily couch correction information. We then evaluated the daily changes of the dose indices D99% , V30GyE , and Dmax for the tumor volumes, non-tumorous liver, and other OARs, that is, stomach, esophagus, duodenum, colon, respectively. Contours were created for all dCT sets. We validated the efficacy of the dCT-based tumor registrations (hereafter, "tumor registration") by comparing them with the bone registration and diaphragm registration as a simulation of the treatment based on the positioning using the conventional kV X-ray imaging. The dose distributions and the indices of three registrations were obtained by simulation using the same dCT sets. RESULTS: In the 66 GyE/10 fractions, the daily D99% value in both the tumor and diaphragm registrations agreed with the planned value with 3%-6% (SD), and the V30GyE value for the liver agreed within ±3%; the indices in the bone registration showed greater deterioration. Nevertheless, tumor-dose deterioration occurred in all registration methods for two cases due to daily changes of body shape and respiratory condition. In the 76 GyE/20 fractions, in particular for such a treatment that the dose constraints for the OARs have to be cared in the original planning, the daily D99% in the tumor registration was superior to that in the other registration (p < 0.001), indicating the effectiveness of the tumor registration. The dose constraints, set in the plan as the maximum dose for OARs (i.e., duodenum, stomach, colon, and esophagus) were maintained for 16 patients including seven treated with re-planning. For three patients, the daily Dmax increased gradually or changed randomly, resulting in an inter-fractional averaged Dmax higher than the constraints. The dose distribution would have been improved if re-planning had been conducted. The results of these retrospective analyses indicate the importance of daily dose monitoring followed by adaptive re-planning when needed. CONCLUSIONS: The tumor registration in proton treatment for HCC was effective to maintain the daily dose to the tumor and the dose constraints of OARs, particularly in the treatment where the maintenance for the dose constraints needs to be considered throughout the treatment. Nevertheless daily proton dose monitoring with daily CT imaging is important for more reliable and safer treatment.

Correlation Between Dosimetric Parameters and Acute Dermatitis of Post-operative Radiotherapy in Breast Cancer Patients.

BACKGROUND/AIM: To examine the correlation between dosimetric parameters and acute radiation dermatitis in early breast cancer patients subjected to post-operative radiotherapy. PATIENTS AND METHODS: The data of 84 patients treated with post-operative radiotherapy were analyzed. The total prescribed dose was 50 Gy in 25 fractions over 5 weeks. Radiation dermatitis was assessed according to Common Terminology Criteria for Adverse Events v4.0. We set organ at risk whole body (from neck to abdomen examined by CT images) also as surrogate skin volume (3 mm thickness). RESULTS: A total of 28 patients showed radiation dermatitis grade equal or higher than 2 at the 50 Gy time point. These 28 patients were compared to 56 matched pair patients with grade 0-1 radiation dermatitis during the same treatment period. The mean of V5-20 and V40 in patient's whole volume and V40-50 in skin volume were significantly higher in patients who presented with acute radiation dermatitis Grades ≥2 than in the other patients who did not. The statistically most significant difference was observed for V40 for skin volume and V5 for patient whole volume. Rate of acute radiation dermatitis grade ≥2 was significantly higher for patients with V5 (whole body) >1,360 cm3 than those with V5 (whole body) <1,360 cm3 (47% vs. 27%, p=0.0353), as well as for patients with V40 (skin volume) >45 cm3 compared with those with V40 (skin volume) <45 cm3 (50% vs. 18%, p=0.0043). CONCLUSION: Dosimetric parameters were useful to predict radiation dermatitis grade ≥2. V5 (whole body) 1,360 cm3 and V40 (skin volume) 45 cm3 may be dose volume constrain for radiation dermatitis grade ≥2.

A novel verification method using a plastic scintillator imagining system for assessment of gantry sag in radiotherapy.

PURPOSE: High accuracy of the beam-irradiated position is required for high-precision radiation therapy such as stereotactic body radiation therapy (SBRT), volumetric modulated arc therapy (VMAT), and intensity modulated radiation therapy (IMRT). Users generally perform the verification of the mechanical and radiation isocenters using the star shot test and the Winston Lutz test that allow evaluation of the displacement at the isocenter. However, these methods are unable to evaluate directly and quantitatively the sagging angle that is caused by the weight of the gantry itself along the gantry rotation axis. In addition, the verification of the central axis of the irradiated beam that is not dependent at the isocenter is needed for the mechanical quality assurance of a nonisocentric irradiation technique. In this study, we have developed a prototype system for the verification of three-dimensional (3D) beam alignment and we have verified the system concept for 3D isocentricity. Our system allows detection of the central axis in 3D coordinates and evaluation of the irradiated oblique angle to the gantry rotation axis, i.e., the sagging angle. MATERIALS & METHODS: In order to measure the central axis of the irradiated beam in 3D coordinates, we constructed the prototype verification system consisting of a column-shaped plastic scintillator (CoPS), a truncated cone-shaped mirror (TCsM), and a cooled charged-coupled device (CCD) camera. This verification system was irradiated with 6-MV photon beams and the scintillation light was measured using the CCD camera. The central axis on the axial plane (two-dimensional (2D) central axis) was acquired from the integration of the scintillation light along the major axis of the CoPS, and the central axis in 3D coordinates (3D central axis) was acquired from two curve-shaped profiles which were reflected by the TCsM. We verified the calculation accuracy of the gantry rotation axis, θz . Additionally, we calculated the 3D central axis and the sagging angle at each gantry angle. RESULTS: We acquired the measurement images composed of the 2D central axis and the two curve-shaped profiles. The relationship between the irradiated and measured angles with respect to the gantry rotation axis had good linearity. The mean and standard deviation of the difference between the irradiated and measured angles were 0.012 and 0.078 degrees, respectively. The size of the 2D and 3D radiation isocenters were 0.470 and 0.652 mm on the axial plane and in 3D coordinates, respectively. The sagging angles were -0.31, 0.39, and 0.38 degrees at the gantry angles of 0, 180, and 180E degrees, respectively. CONCLUSION: We developed a novel verification system, designated as the "kompeito shot test system," to verify the 3D beam alignment. This system concept works for both verification of the 3D isocentricity and the direct evaluation of the sagging angle. Next, we want to improve the aspects of this system, such as the shape and the type of scintillator, to increase the system accuracy and nonisocentric beam alignment performance.

Measurement of nuclear reaction cross sections by using Cherenkov radiation toward high-precision proton therapy.

Monitoring the in vivo dose distribution in proton therapy is desirable for the accurate irradiation of a tumor. Although positron emission tomography (PET) is widely used for confirmation, the obtained distribution of positron emitters produced by the protons does not trace the dose distribution due to the different physical processes. To estimate the accurate dose from the PET image, the cross sections of nuclear reactions that produce positron emitters are important yet far from being sufficient. In this study, we measured the cross sections of 16O(p,x)15O, 16O(p,x)13N, and 16O(p,x)11C with a wide-energy range (approximately 5-70 MeV) by observing the temporal evolution of the Cherenkov radiation emitted from positrons generated via ß+ decay along the proton path. Furthermore, we implemented the new cross sectional data into a conventional Monte Carlo (MC) simulation, so that a direct comparison was possible with the PET measurement. We confirmed that our MC results showed good agreement with the experimental data, both in terms of the spatial distributions and temporal evolutions. Although this is the first attempt at using the Cherenkov radiation in the measurements of nuclear cross sections, the obtained results suggest the method is convenient and widely applicable for high precision proton therapy.

Improved proton CT imaging using a bismuth germanium oxide scintillator.

Range uncertainty is among the most formidable challenges associated with the treatment planning of proton therapy. Proton imaging, which includes proton radiography and proton computed tomography (pCT), is a useful verification tool. We have developed a pCT detection system that uses a thick bismuth germanium oxide (BGO) scintillator and a CCD camera. The current method is based on a previous detection system that used a plastic scintillator, and implements improved image processing techniques. In the new system, the scintillation light intensity is integrated along the proton beam path by the BGO scintillator, and acquired as a two-dimensional distribution with the CCD camera. The range of a penetrating proton is derived from the integrated light intensity using a light-to-range conversion table, and a pCT image can be reconstructed. The proton range in the BGO scintillator is shorter than in the plastic scintillator, so errors due to extended proton ranges can be reduced. To demonstrate the feasibility of the pCT system, an experiment was performed using a 70 MeV proton beam created by the AVF930 cyclotron at the National Institute of Radiological Sciences. The accuracy of the light-to-range conversion table, which is susceptible to errors due to its spatial dependence, was investigated, and the errors in the acquired pixel values were less than 0.5 mm. Images of various materials were acquired, and the pixel-value errors were within 3.1%, which represents an improvement over previous results. We also obtained a pCT image of an edible chicken piece, the first of its kind for a biological material, and internal structures approximately one millimeter in size were clearly observed. This pCT imaging system is fast and simple, and based on these findings, we anticipate that we can acquire 200 MeV pCT images using the BGO scintillator system.

Radiosensitization by PARP inhibition to proton beam irradiation in cancer cells.

The poly(ADP-ribose) polymerase (PARP)-1 regulates DNA damage responses and promotes base excision repair. PARP inhibitors have been shown to enhance the cytotoxicity of ionizing radiation in various cancer cells and animal models. We have demonstrated that the PARP inhibitor (PARPi) AZD2281 is also an effective radiosensitizer for carbon-ion radiation; thus, we speculated that the PARPi could be applied to a wide therapeutic range of linear energy transfer (LET) radiation as a radiosensitizer. Institutes for biological experiments using proton beam are limited worldwide. This study was performed as a cooperative research at heavy ion medical accelerator in Chiba (HIMAC) in National Institute of Radiological Sciences. HIMAC can generate various ion beams; this enabled us to compare the radiosensitization effect of the PARPi on cells subjected to proton and carbon-ion beams from the same beam line. After physical optimization of proton beam irradiation, the radiosensitization effect of the PARPi was assessed in the human lung cancer cell line, A549, and the pancreatic cancer cell line, MIA PaCa-2. The effect of the PARPi, AZD2281, on radiosensitization to Bragg peak was more significant than that to entrance region. The PARPi increased the number of phosphorylated H2AX (γ-H2AX) foci and enhanced G2/M arrest after proton beam irradiation. This result supports our hypothesis that a PARPi could be applied to a wide therapeutic range of LET radiation by blocking the DNA repair response.

Development of proton CT imaging system using plastic scintillator and CCD camera.

A proton computed tomography (pCT) imaging system was constructed for evaluation of the error of an x-ray CT (xCT)-to-WEL (water-equivalent length) conversion in treatment planning for proton therapy. In this system, the scintillation light integrated along the beam direction is obtained by photography using the CCD camera, which enables fast and easy data acquisition. The light intensity is converted to the range of the proton beam using a light-to-range conversion table made beforehand, and a pCT image is reconstructed. An experiment for demonstration of the pCT system was performed using a 70 MeV proton beam provided by the AVF930 cyclotron at the National Institute of Radiological Sciences. Three-dimensional pCT images were reconstructed from the experimental data. A thin structure of approximately 1 mm was clearly observed, with spatial resolution of pCT images at the same level as that of xCT images. The pCT images of various substances were reconstructed to evaluate the pixel value of pCT images. The image quality was investigated with regard to deterioration including multiple Coulomb scattering.