Evaluation of radiophotoluminescent glass dosimeter response for therapeutic spot scanning proton beam: suggestion of linear energy transfer-based correction.

A radiophotoluminescent glass dosimeter (RGD) is used for a postal audit of a photon beam because of its various excellent characteristics. However, it has not been used for scanning proton beams because its response characteristics have not been verified. In this study, the response of RGD to scanning protons was investigated to develop a dosimetry protocol using the linear energy transfer (LET)-based correction factor. The responses of RGD to four maximum-range-energy-pattern proton beams were verified by comparing it with ionization chamber (IC) dosimetry. The LET at each measurement depth was calculated via Monte Carlo (MC) simulation. The LET correction factor ( k LET RGD ) was the ratio between the uncorrected RGD dose ( D raw RGD ) and the IC dose at each measurement depth. k LET RGD can be represented as a function of LET using the following equation: k LET RGD LET = - 0.035 LET + 1.090 . D raw RGD showed a linear under-response with increasing LET, and the maximum dose difference between the IC dose and D raw RGD was 15.2% at an LET of 6.07 keV/µm. The LET-based correction dose ( D LET RGD ) conformed within 3.6% of the IC dose. The mean dose difference (±SD) of D raw RGD and D LET RGD was -2.5 ± 6.9% and 0.0 ± 1.6%, respectively. To achieve accurate dose verification for scanning proton beams using RGD, we derived a linear regression equation based on LET. The results show that with appropriate LET correction, RGD can be used for dose verification of scanning proton beams.

Biological effects of passive scattering and spot scanning proton beams at the distal end of the spread-out Bragg peak in single cells and multicell spheroids.

PURPOSE: The present study investigated the biological effects of spot scanning and passive scattering proton therapies at the distal end region of the spread-out Bragg peak (SOBP) using single cell and multicell spheroids. MATERIALS AND METHODS: The Geant4 Monte Carlo simulation was used to calculate linear energy transfer (LET) values in passive scattering and spot scanning beams. The biological doses of the two beam options at various points of the distal end region of SOBP were investigated using EMT6 single cells and 0.6-mm V79 spheroids irradiated with 6 and 15 Gy, respectively, by inserting the fractions surviving these doses onto dose-survival curves and reading the corresponding dose. RESULTS: LET values in the entrance region of SOBP were similar between the two beam options and increased at the distal end region of SOBP, where the LET value of spot scanning beams was higher than that of passive scattering beams. Increases in biological effects at the distal end region were similarly observed in single cells and spheroids; biological doses at 2-10 mm behind the distal end were 4.5-57% and 5.7-86% higher than physical doses in passive scattering and spot scanning beams, respectively, with the biological doses of spot scanning beams being higher than those of passive scattering beams (p < .05). CONCLUSIONS: In single cells and spheroids, the effects of proton irradiation were stronger than expected from measured physical doses at the distal end of SOBP and were correlated with LET increases.

Dosimetric response of a glass dosimeter in proton beams: LET-dependence and correction factor.

A radiophotoluminescent glass dosimeter (RGD) is widely used in postal audit system for photon beams in Japan. However, proton dosimetry in RGDs is scarcely used owing to a lack of clarity in their response to beam quality. In this study, we investigated RGD response to beam quality for establishing a suitable linear energy transfer (LET)-corrected dosimetry protocol in a therapeutic proton beam. The RGD response was compared with ionization chamber measurement for a 100-225 MeV passive proton beam. LET of the measurement points was calculated by the Monte Carlo method. An LET-correction factor, defined as a ratio between the non-corrected RGD dose and ionization chamber dose, of 1.226×(LET)-0.171 was derived for the RGD response. The magnitude of the LET-dependence of RGD increased with LET; for an LET of 8.2 keV/µm, the RGD under-response was up to 16%. The coefficient of determination, mean difference ± SD of non-corrected RGD dose, residual range-corrected RGD dose, and LET-corrected RGD dose to the ionization chamber are 0.923, 3.7 ± 4.2%, -2.4 ± 7.5%, and 0.04 ± 2.1%, respectively. The LET-corrected RGD dose was within 5% of the corresponding ionization chamber dose at all energies until 200 MeV, where it was 5.3% lower than the ionization chamber dose. A corrected LET-dependence of RGD using a correction factor based on a power function of LET and precise dosimetric verification close to the maximum LET were realized here. We further confirmed establishment of an accurate postal audit under various irradiation conditions.

Combined effects of cisplatin and photon or proton irradiation in cultured cells: radiosensitization, patterns of cell death and cell cycle distribution.

The purpose of the current study was to investigate the biological effects of protons and photons in combination with cisplatin in cultured cells and elucidate the mechanisms responsible for their combined effects. To evaluate the sensitizing effects of cisplatin against X-rays and proton beams in HSG, EMT6 and V79 cells, the combination index, a simple measure for quantifying synergism, was estimated from cell survival curves using software capable of performing the Monte Carlo calculation. Cell death and apoptosis were assessed using live cell fluorescence imaging. HeLa and HSG cells expressing the fluorescent ubiquitination-based cell cycle indicator system (Fucci) were irradiated with X-rays and protons with cisplatin. Red and green fluorescence in the G1 and S/G2/M phases, respectively, were evaluated and changes in the cell cycle were assessed. The sensitizing effects of ≥1.5 µM cisplatin were observed for both X-ray and proton irradiation (P < 0.05). In the three cell lines, the average combination index was 0.82-1.00 for X-rays and 0.73-0.89 for protons, indicating stronger effects for protons. In time-lapse imaging, apoptosis markedly increased in the groups receiving ≥1.5 µM cisplatin + protons. The percentage of green S/G2/M phase cells at that time was higher when cisplatin was combined with proton beams than with X-rays (P < 0.05), suggesting more significant G2 arrest. Proton therapy plus ≥1.5 µM cisplatin is considered to be very effective. When combined with cisplatin, proton therapy appeared to induce greater apoptotic cell death and G2 arrest, which may partly account for the difference observed in the combined effects.

Fruit Fly, Drosophila melanogaster, as an In Vivo Tool to Study the Biological Effects of Proton Irradiation.

The clinical superiority of proton therapy over photon therapy has recently gained recognition; however, the biological effects of proton therapy remain poorly understood. The lack of in vivo evidence is especially important. Therefore, the goal of this study was to validate the usefulness of Drosophila melanogaster as an alternative tool in proton radiobiology. To determine whether the comparative biological effects of protons and X rays are detectable in Drosophila, we assessed their influence on survival and mRNA expression. Postirradiation observation revealed that protons inhibited their development and reduced the overall survival rates more effectively than X rays. The relative biological effectiveness of the proton beams compared to the X rays estimated from the 50% lethal doses was 1.31. At 2 or 24 h postirradiation, mRNA expression analysis demonstrated that the expression patterns of several genes (such as DNA-repair-, apoptosis- and angiogenesis-related genes) followed different time courses depending on radiation type. Moreover, our trials suggested that the knockdown of individual genes by the GAL4/UAS system changes the radiosensitivity in a radiation type-specific manner. We confirmed this Drosophila model to be considerably useful to evaluate the findings from in vitro studies in an in vivo system. Furthermore, this model has a potential to elucidate more complex biological mechanisms underlying proton irradiation.

Fruit Fly, Drosophila melanogaster, as an In Vivo Tool to Study the Biological Effects of Proton Irradiation.

The clinical superiority of proton therapy over photon therapy has recently gained recognition; however, the biological effects of proton therapy remain poorly understood. The lack of in vivo evidence is especially important. Therefore, the goal of this study was to validate the usefulness of Drosophila melanogaster as an alternative tool in proton radiobiology. To determine whether the comparative biological effects of protons and X rays are detectable in Drosophila, we assessed their influence on survival and mRNA expression. Postirradiation observation revealed that protons inhibited their development and reduced the overall survival rates more effectively than X rays. The relative biological effectiveness of the proton beams compared to the X rays estimated from the 50% lethal doses was 1.31. At 2 or 24 h postirradiation, mRNA expression analysis demonstrated that the expression patterns of several genes (such as DNA-repair-, apoptosis- and angiogenesis-related genes) followed different time courses depending on radiation type. Moreover, our trials suggested that the knockdown of individual genes by the GAL4/UAS system changes the radiosensitivity in a radiation type-specific manner. We confirmed this Drosophila model to be considerably useful to evaluate the findings from in vitro studies in an in vivo system. Furthermore, this model has a potential to elucidate more complex biological mechanisms underlying proton irradiation.

Proton therapy for non-squamous cell carcinoma of the head and neck: planning comparison and toxicity.

To investigate optimal treatment planning using proton beams for non-squamous cell carcinoma of the head and neck (NSCHN), the dose distributions of plans involving pencil beam scanning (PBS) with or without a patient-specific aperture system (PSAS), passive-scattering proton therapy (PSPT) and X-ray intensity-modulated radiotherapy (IMRT) were compared. As clinical results, toxicities of PBS with PSAS, including changes in quality of life, were reported. Between April 2014 and August 2016, a total of 30 patients were treated using PBS with PSAS. In 20 patients selected at random, the dose distributions of PBS with or without the PSAS, PSPT and IMRT plans were compared. Neutron exposure by proton therapy was calculated using a Monte Carlo simulation. Toxicities were scored according to CTCAE ver. 4.0. Patients completed EORTC quality of life survey forms (QLQ-C30 and QLQ-HN35) before and 0-12 months after proton therapy. The 95% conformity number of PBS with the PSAS plan was the best, and significant differences were detected among the four plans (P < 0.05, Bonferroni tests). Neutron generation by PSAS was ~1.1-fold higher, but was within an acceptable level. No grade 3 or higher acute dermatitis was observed. Pain, appetite loss and increased weight loss were more likely at the end of treatment, but recovered by the 3 month follow-up and returned to the pretreatment level at the 12 month follow-up. PBS with PSAS reduced the penumbra and improved dose conformity in the planning target volume. PBS with PSAS was tolerated well for NSCHN.

Dosimetric verification of IMPT using a commercial heterogeneous phantom.

The purpose of this study was to propose a verification method and results of intensity-modulated proton therapy (IMPT), using a commercially available heterogeneous phantom. We used a simple simulated head and neck and prostate phantom. An ionization chamber and radiochromic film were used for measurements of absolute dose and relative dose distribution. The measured doses were compared with calculated doses using a treatment planning system. We defined the uncertainty of the measurement point of the ionization chamber due to the effective point of the chamber and mechanical setup error as 2 mm and estimated the dose variation base on a 2 mm error. We prepared a HU-relative stopping power conversion table and fluence correction factor that were specific to the heterogeneous phantom. The fluence correction factor was determined as a function of depth and was obtained from the ratio of the doses in water and in the phantom at the same effective depths. In the simulated prostate plan, composite doses of measurements and calculations agreed within ±1.3% and the maximum local dose differences of each field were 10.0%. Composite doses in the simulated head and neck plan agreed within 4.0% and the maximum local dose difference for each field was 12.0%. The dose difference for each field came within 2% when taking the measurement uncertainty into consideration. In the composite plan, the maximum dose uncertainty was estimated as 4.0% in the simulated prostate plan and 5.8% in the simulated head and neck plan. Film measurements showed good agreement, with more than 92.5% of points passing a gamma value (3%/3 mm). From these results, the heterogeneous phantom should be useful for verification of IMPT by using a phantom-specific HU-relative stopping power conversion, fluence correction factor, and dose error estimation due to the effective point of the chamber.

Evaluation of dosimetric advantages of using patient-specific aperture system with intensity-modulated proton therapy for the shallow depth tumor.

In this study, we evaluate dosimetric advantages of using patient-specific aperture system with intensity-modulated proton therapy (IMPT) for head and neck tumors at the shallow depth. We used four types of patient-specific aperture system (PSAS) to irradiate shallow regions less than 4 g/cm2 with a sharp lateral penumbra. Ten head and neck IMPT plans with or without aperture were optimized separately with the same 95% prescription dose and same dose constraint for organs at risk (OARs). The plans were compared using dose volume histograms (DVHs), dose distributions, and some dose indexes such as volume receiving 50% of the prescribed dose (V50 ), mean or maximum dose (Dmean and Dmax ) to the OARs. All examples verified in this study had decreased V50 and OAR doses. Average, maximum, and minimum relative reductions of V50 were 15.4%, 38.9%, and 1.0%, respectively. Dmax and Dmean of OARs were decreased by 0.3% to 25.7% and by 1.0% to 46.3%, respectively. The plans with the aperture over more than half of the field showed decreased V50 or OAR dose by more than 10%. The dosimetric advantage of patient-specific apertures with IMPT was clarified in many cases. The PSAS has some dosimetric advantages for clinical use, and in some cases, it enables to fulfill dose constraints.

Recovery from sublethal damage and potentially lethal damage : Proton beam irradiation vs. X­ray irradiation.

PURPOSE: In order to clarify the biological response of tumor cells to proton beam irradiation, sublethal damage recovery (SLDR) and potentially lethal damage recovery (PLDR) induced after proton beam irradiation at the center of a 10 cm spread-out Bragg peak (SOBP) were compared with those seen after X­ray irradiation. METHODS: Cell survival was determined by a colony assay using EMT6 and human salivary gland tumor (HSG) cells. First, two doses of 4 Gy/GyE (Gray equivalents, GyE) were given at an interfraction interval of 0-6 h. Second, five fractions of 1.6 Gy/GyE were administered at interfraction intervals of 0-5 min. Third, a delayed-plating assay involving cells in plateau-phase cultures was conducted. The cells were plated in plastic dishes immediately or 2-24 h after being irradiated with 8 Gy/GyE of X­rays or proton beams. Furthermore, we investigated the degree of protection from the effects of X­rays or proton beams afforded by the radical scavenger dimethyl sulfoxide to estimate the contribution of the indirect effect of radiation. RESULTS: In both the first and second experiments, SLDR was more suppressed after proton beam irradiation than after X­ray irradiation. In the third experiment, there was no difference in PLDR between the proton beam and X­ray irradiation conditions. The degree of protection tended to be higher after X­ray irradiation than after proton beam irradiation. CONCLUSION: Compared with that seen after X­ray irradiation, SLDR might take place to a lesser extent after proton beam irradiation at the center of a 10 cm SOBP, while the extent of PLDR does not differ significantly between these two conditions.

Correction of stopping power and LET quenching for radiophotoluminescent glass dosimetry in a therapeutic proton beam.

To measure the absorbed dose to water D w in proton beams using a radiophotoluminescent glass dosimeter (RGD), a method with the correction for the change of the mass stopping power ratio (SPR) and the linear energy transfer (LET) dependence of radiophotoluminescent efficiency [Formula: see text] is proposed. The calibration coefficient in terms of D w for RGDs (GD-302M, Asahi Techno Glass) was obtained using a 60Co γ-ray. The SPR of water to the RGD was calculated by Monte Carlo simulation, and [Formula: see text] was investigated experimentally using a 70 MeV proton beam. For clinical usage, the residual range R res was used as a quality index to determine the correction factor for the beam quality [Formula: see text] and the LET quenching effect of the RGD [Formula: see text]. The proposed method was evaluated by measuring D w at different depths in a 200 MeV proton beam. For both non-modulated and modulated proton beams, [Formula: see text] decreases rapidly where R res is less than 4 cm. The difference in [Formula: see text] between a non-modulated and a modulated proton beam is less than 0.5% for the R res range from 0 cm to 22 cm. [Formula: see text] decreases rapidly at a LET range from 1 to 2 keV µm-1. In the evaluation experiments, D w using RGDs, [Formula: see text] showed good agreement with that obtained using an ionization chamber and the relative difference was within 3% where R res was larger than 1 cm. The uncertainty budget for [Formula: see text] in a proton beam was estimated to investigate the potential of RGD postal dosimetry in proton therapy. These results demonstrate the feasibility of RGD dosimetry in a therapeutic proton beam and the general versatility of the proposed method. In conclusion, the proposed methodology for RGDs in proton dosimetry is applicable where R res > 1 cm and the RGD is feasible as a postal audit dosimeter for proton therapy.

A proton therapy system in Nagoya Proton Therapy Center.

The purpose of this paper is to describe an outline of a proton therapy system in Nagoya Proton Therapy Center (NPTC). The NPTC has a synchrotron with a linac injector and three treatment rooms: two rooms are equipped with a gantry and the other one is equipped with a fixed horizontal beamline. One gantry treatment room has a pencil beam scanning treatment delivery nozzle. The other two treatment rooms have a passive scattering treatment delivery nozzle. In the scanning treatment delivery nozzle, an energy absorber and an aperture system to treat head and neck cancer have been equipped. In the passive treatment delivery nozzle, a multi-leaf collimator is equipped. We employ respiratory gating to treat lung and liver cancers for passive irradiation. The proton therapy system passed all acceptance tests. The first patient was treated on February 25, 2013, using passive scattering fixed beams. Respiratory gating is commonly used to treat lung and liver cancers in the passive scattering system. The MLCs are our first choice to limit the irradiation field. The use of the aperture for scanning irradiation reduced the lateral fall off by half or less. The energy absorber and aperture system in scanning delivery is beneficial to treat head and neck cancer.

Spot Scanning and Passive Scattering Proton Therapy: Relative Biological Effectiveness and Oxygen Enhancement Ratio in Cultured Cells.

PURPOSE: To determine the relative biological effectiveness (RBE), oxygen enhancement ratio (OER), and contribution of the indirect effect of spot scanning proton beams, passive scattering proton beams, or both in cultured cells in comparison with clinically used photons. METHODS AND MATERIALS: The RBE of passive scattering proton beams at the center of the spread-out Bragg peak (SOBP) was determined from dose-survival curves in 4 cell lines using 6-MV X rays as controls. Survival of 2 cell lines after spot scanning and passive scattering proton irradiation was then compared. Biological effects at the distal end region of the SOBP were also investigated. The OER of passive scattering proton beams and 6 MX X rays were investigated in 2 cell lines. The RBE and OER values were estimated at a 10% cell survival level. The maximum degree of protection of radiation effects by dimethyl sulfoxide was determined to estimate the contribution of the indirect effect against DNA damage. All experiments comparing protons and X rays were made under the same biological conditions. RESULTS: The RBE values of passive scattering proton beams in the 4 cell lines examined were 1.01 to 1.22 (average, 1.14) and were almost identical to those of spot scanning beams. Biological effects increased at the distal end of the SOBP. In the 2 cell lines examined, the OER was 2.74 (95% confidence interval, 2.56-2.80) and 3.08 (2.84-3.11), respectively, for X rays, and 2.39 (2.38-2.43) and 2.72 (2.69-2.75), respectively, for protons (P<.05 for both cells between X rays and protons). The maximum degree of protection was significantly higher for X rays than for proton beams (P<.05). CONCLUSIONS: The RBE values of spot scanning and passive scattering proton beams were almost identical. The OER was lower for protons than for X rays. The lower contribution of the indirect effect may partly account for the lower OER of protons.

Evaluation of the influence of double and triple Gaussian proton kernel models on accuracy of dose calculations for spot scanning technique.

PURPOSE: The main purpose in this study was to present the results of beam modeling and how the authors systematically investigated the influence of double and triple Gaussian proton kernel models on the accuracy of dose calculations for spot scanning technique. METHODS: The accuracy of calculations was important for treatment planning software (TPS) because the energy, spot position, and absolute dose had to be determined by TPS for the spot scanning technique. The dose distribution was calculated by convolving in-air fluence with the dose kernel. The dose kernel was the in-water 3D dose distribution of an infinitesimal pencil beam and consisted of an integral depth dose (IDD) and a lateral distribution. Accurate modeling of the low-dose region was important for spot scanning technique because the dose distribution was formed by cumulating hundreds or thousands of delivered beams. The authors employed a double Gaussian function as the in-air fluence model of an individual beam. Double and triple Gaussian kernel models were also prepared for comparison. The parameters of the kernel lateral model were derived by fitting a simulated in-water lateral dose profile induced by an infinitesimal proton beam, whose emittance was zero, at various depths using Monte Carlo (MC) simulation. The fitted parameters were interpolated as a function of depth in water and stored as a separate look-up table. These stored parameters for each energy and depth in water were acquired from the look-up table when incorporating them into the TPS. The modeling process for the in-air fluence and IDD was based on the method proposed in the literature. These were derived using MC simulation and measured data. The authors compared the measured and calculated absolute doses at the center of the spread-out Bragg peak (SOBP) under various volumetric irradiation conditions to systematically investigate the influence of the two types of kernel models on the dose calculations. RESULTS: The authors investigated the difference between double and triple Gaussian kernel models. The authors found that the difference between the two studied kernel models appeared at mid-depths and the accuracy of predicting the double Gaussian model deteriorated at the low-dose bump that appeared at mid-depths. When the authors employed the double Gaussian kernel model, the accuracy of calculations for the absolute dose at the center of the SOBP varied with irradiation conditions and the maximum difference was 3.4%. In contrast, the results obtained from calculations with the triple Gaussian kernel model indicated good agreement with the measurements within ±1.1%, regardless of the irradiation conditions. CONCLUSIONS: The difference between the results obtained with the two types of studied kernel models was distinct in the high energy region. The accuracy of calculations with the double Gaussian kernel model varied with the field size and SOBP width because the accuracy of prediction with the double Gaussian model was insufficient at the low-dose bump. The evaluation was only qualitative under limited volumetric irradiation conditions. Further accumulation of measured data would be needed to quantitatively comprehend what influence the double and triple Gaussian kernel models had on the accuracy of dose calculations.

A patient-specific aperture system with an energy absorber for spot scanning proton beams: Verification for clinical application.

PURPOSE: In the authors' proton therapy system, the patient-specific aperture can be attached to the nozzle of spot scanning beams to shape an irradiation field and reduce lateral fall-off. The authors herein verified this system for clinical application. METHODS: The authors prepared four types of patient-specific aperture systems equipped with an energy absorber to irradiate shallow regions less than 4 g/cm(2). The aperture was made of 3-cm-thick brass and the maximum water equivalent penetration to be used with this system was estimated to be 15 g/cm(2). The authors measured in-air lateral profiles at the isocenter plane and integral depth doses with the energy absorber. All input data were obtained by the Monte Carlo calculation, and its parameters were tuned to reproduce measurements. The fluence of single spots in water was modeled as a triple Gaussian function and the dose distribution was calculated using a fluence dose model. The authors compared in-air and in-water lateral profiles and depth doses between calculations and measurements for various apertures of square, half, and U-shaped fields. The absolute doses and dose distributions with the aperture were then validated by patient-specific quality assurance. Measured data were obtained by various chambers and a 2D ion chamber detector array. RESULTS: The patient-specific aperture reduced the penumbra from 30% to 70%, for example, from 34.0 to 23.6 mm and 18.8 to 5.6 mm. The calculated field width for square-shaped apertures agreed with measurements within 1 mm. Regarding patient-specific aperture plans, calculated and measured doses agreed within -0.06% ± 0.63% (mean ± SD) and 97.1% points passed the 2%-dose/2 mm-distance criteria of the γ-index on average. CONCLUSIONS: The patient-specific aperture system improved dose distributions, particularly in shallow-region plans.