[Safety Analysis Using Event Tree Analysis for Multi-Ion Therapy].

At the National Institutes for Quantum Science and Technology (QST), a multi-ion therapy using helium, carbon, oxygen, and neon ions has been studied for charged particle therapy with more optimal biological effects. To make multi-ion therapy clinically feasible, a new treatment system was developed to realize the changes of the ion species in each irradiation using the Heavy Ion Medial Accelerator in Chiba (HIMAC). Since radiation therapy is safety-critical, it is necessary to construct a safety system that includes multiple safety barriers in the new treatment system for multi-ion therapy and to perform a safety analysis for the prevention of serious accidents. In this study, we conducted a safety analysis using event tree analysis (ETA) for newly introduced processes in the treatment planning, accelerator, and irradiation system of the multi-ion therapy. ETA is an optimal method to verify multiple safety barriers that are essential for medical safety and to shorten the time for safety analysis by focusing only on the new processes. Through ETA, we clarified the types of malfunctions and human errors that may lead to serious accidents in the new system for multi-ion therapy, and verified whether safety barriers such as interlock systems and human check procedures are sufficient to prevent such malfunctions and human errors. As a result, 6 initial events which may lead to serious accidents were listed in the treatment planning process, 16 initial events were listed in the accelerator system, and 13 initial events were listed in the irradiation system. Among these 35 initial events, 5 cautionary initial events were identified that could lead to serious final events and they had a probability of occurrence higher than 10-4. Meanwhile, the others were all initial events that do not lead to serious accidents, or the initial events that can lead to serious accidents but were considered to have sufficient safety barriers. The safety analysis using ETA successfully identified the system malfunctions and the human errors that can lead to serious accidents, and the multiple safety barriers against them were systematically analyzed. It became clear that the multiple safety barriers were not sufficient for some initial events. We plan to improve the safety barriers for the five cautionary initial events before the start of the clinical trial. Based on these findings, we achieved our objective to conduct a safety analysis for a new treatment system for multi-ion therapy. The safety analysis procedure using ETA proposed by this study will be effective when new systems for radiotherapy are established at QST and other facilities in the future as well.

Technical note: Application of an optical hydrophone to ionoacoustic range detection in a tissue-mimicking agar phantom.

BACKGROUND: Ionoacoustics is a promising approach to reduce the range uncertainty in proton therapy. A miniature-sized optical hydrophone (OH) was used as a measuring device to detect weak ionoacoustic signals with a high signal-to-noise ratio in water. However, further development is necessary to prevent wave distortion because of nearby acoustic impedance discontinuities while detection is conducted on the patient's skin. PURPOSE: A prototype of the probe head attached to an OH was fabricated and the required dimensions were experimentally investigated using a 100-MeV proton beam from a fixed-field alternating gradient accelerator and k-Wave simulations. The beam range of the proton in a tissue-mimicking phantom was estimated by measuring γ-waves and spherical ionoacoustic waves with resonant frequency (SPIRE). METHODS: Four sizes of probe heads were fabricated from agar blocks for the OH. Using the prototype, the Î³-wave was detected at distal and lateral positions to the Bragg peak on the phantom surface for proton beams delivered at seven positions. For SPIRE, independent measurements were performed at distal on- and off-axis positions. The range positions were estimated by solving the linear equation using the sensitive matrix for the γ-wave and linear fitting of the correlation curve for SPIRE; they were compared with those measured using a film. RESULTS: The first peak of the γ-wave was undistorted with the 3 × 3 × 3-cm3 probe head used at the on-axis and 3-cm off-axis positions. The range positions estimated by the γ-wave agreed with the film-based range in the depth direction (the maximum deviation was 0.7 mm), although a 0.6-2.1 mm deviation was observed in the lateral direction. For SPIRE, the deviation was <1 mm for the two measurement positions. CONCLUSIONS: The attachment of a relatively small-sized probe head allowed the OH to measure the beam range on the phantom surface.

Ionoacoustic application of an optical hydrophone to detect proton beam range in water.

BACKGROUND: Proton range uncertainty has been the main factor limiting the ability of proton therapy to concentrate doses to tumors to their full potential. Ionoacoustic (IA) range verification is an approach to reducing this uncertainty by detecting thermoacoustic waves emitted from an irradiated volume immediately following a pulsed proton beam delivery; however, the signal weakness has been an obstacle to its clinical application. To increase the signal-to-noise ratio (SNR) with the conventional piezoelectric hydrophone (PH), the detector-sensitive volume needs to be large, but it could narrow the range of available beam angles and disturb real-time images obtained during beam delivery. PURPOSE: To prevent this issue, we investigated a millimeter-sized optical hydrophone (OH) that exploits the laser interferometric principle. For two types of IA waves [γ-wave emitted from the Bragg peak (BP) and a spherical IA wave with resonant frequency (SPIRE) emitted from the gold fiducial marker (GM)], comparisons were made with PH in terms of waveforms, SNR, range detection accuracy, and signal intensity robustness against the small detector misalignment, particularly for SPIRE. METHODS: A 100-MeV proton beam with a 27 ns pulse width and 4 mm beam size was produced using a fixed-field alternating gradient accelerator and was irradiated to the water phantom. The GM was set on the beam's central axis. Acrylic plates of various thicknesses, up to 12 mm, were set in front of the phantoms to shift the proton range. OH was set distal and lateral to the beam, and the range was estimated using the time-of-flight method for γ-wave and by comparing with the calibration data (SPIRE intensity versus the distance between the GM and BP) derived from an IA wave transport simulation for SPIRE. The BP dose per pulse was 0.5-0.6 Gy. To measure the variation in SPIRE amplitude against the hydrophone misalignment, the hydrophone was shifted by ± 2 mm at a maximum in lateral directions. RESULTS: Despite its small size, OH could detect γ-wave with a higher SNR than the conventional PH (diameter, 29 mm), and a single measurement was sufficient to detect the beam range with a submillimeter accuracy in water. In the SPIRE measurement, OH was far more robust against the detector misalignment than the focused PH (FPH) used in our previous study [5%/mm (OH) versus 80%/mm (FPH)], and the correlation between the measured SPIRE intensity and the distance between the GM and BP agreed well with the simulation results. However, the OH sensitivity was lower than the FPH sensitivity, and about 5.6-Gy dose was required to decrease the intensity variation among measurements to less than 10%. CONCLUSION: The miniature OH was found to detect weak IA signals produced by proton beams with a BP dose used in hypofractionated regimens. The OH sensitivity improvement at the MHz regime is worth exploring as the next step.

Hyperfractionated intensity-modulated proton therapy for pharyngeal cancer with variable relative biological effectiveness: A simulation study.

BACKGROUND: The relative biological effectiveness (RBE) of proton is considered to be dependent on biological parameters and fractional dose. While hyperfractionated photon therapy was effective in the treatment of patients with head and neck cancers, its effect in intensity-modulated proton therapy (IMPT) under the variable RBE has not been investigated in detail. PURPOSE: To study the effect of variable RBE on hyperfractionated IMPT for the treatment of pharyngeal cancer. We investigated the biologically effective dose (BED) to determine the theoretical effective hyperfractionated schedule. METHODS: The treatment plans of three pharyngeal cancer patients were used to define the ΔBED for the clinical target volume (CTV) and soft tissue (acute and late reaction) as the difference between the BED for the altered schedule with variable RBE and conventional schedule with constant RBE. The ΔBED with several combinations of parameters (treatment days, number of fractions, and prescribed dose) was comprehensively calculated. Of the candidate schedules, the one that commonly gave a higher ΔBED for CTV was selected as the resultant schedule. The BED volume histogram was used to compare the influence of variable RBE and fractionation. RESULTS: In the conventional schedule, compared with the constant RBE, the variable RBE resulted in a mean 2.6 and 2.7 Gy reduction of BEDmean for the CTV and soft tissue (acute reaction) of the three plans, respectively. Moreover, the BEDmean for soft tissue (late reaction) increased by 7.4 Gy, indicating a potential risk of increased RBE. Comprehensive calculation of the ΔBED resulted in the hyperfractionated schedule of 80.52 Gy (RBE = 1.1)/66 fractions in 6.5 weeks. When variable RBE was used, compared with the conventional schedule, the hyperfractionated schedule increased the BEDmean for CTV by 7.6 Gy; however, this was associated with a 7.8 Gy increase for soft tissue (acute reaction). The BEDmean for soft tissue (late reaction) decreased by 2.4 Gy. CONCLUSION: The results indicated a potential effect of the variable RBE on IMPT for pharyngeal cancer but with the possibility that hyperfractionation could outweigh this effect. Although biological uncertainties require conservative use of the resultant schedule, hyperfractionation is expected to be an effective strategy in IMPT for pharyngeal cancer.

Impact of a spatially dependent dose delivery time structure on the biological effectiveness of scanning proton therapy.

PURPOSE: In the scanning beam delivery of protons, different portions of the target are irradiated with different linear energy transfer protons with various time intervals and irradiation times. This research aimed to evaluate the spatially dependent biological effectiveness of protracted irradiation in scanning proton therapy. METHODS: One and two parallel opposed fields plans were created in water phantom with the prescribed dose of 2 Gy. Three scenarios (instantaneous, continuous, and layered scans) were used with the corresponding beam delivery models. The biological dose (physical dose × relative biological effectiveness) was calculated using the linear quadratic model and the theory of dual radiation action to quantitatively evaluate the dose delivery time effect. In addition, simulations using clinical plans (postoperative seminoma and prostate tumor cases) were conducted to assess the impact of the effects on the dose volume histogram parameters and homogeneity coefficient (HC) in targets. RESULTS: In a single-field plan of water phantom, when the treatment time was 19 min, the layered-scan scenario showed a decrease of <0.2% (almost 3.3%) in the biological dose from the plan on the distal (proximal) side because of the high (low) dose rate. This is in contrast to the continuous scenario, where the biological dose was almost uniformly decreased over the target by approximately 3.3%. The simulation with clinical geometry showed that the decrease rates in D99% were 0.9% and 1.5% for every 10 min of treatment time prolongation for postoperative seminoma and prostate tumor cases, respectively, whereas the increase rates in HC were 0.7% and 0.2%. CONCLUSIONS: In protracted irradiation in scanning proton therapy, the spatially dependent dose delivery time structure in scanning beam delivery can be an important factor for accurate evaluation of biological effectiveness.

The impact of dose delivery time on biological effectiveness in proton irradiation with various biological parameters.

PURPOSE: The purpose of this study is to evaluate the sublethal damage (SLD) repair effect in prolonged proton irradiation using the biophysical model with various cell-specific parameters of (α/ß)x and T1/2 (repair half time). At present, most of the model-based studies on protons have focused on acute radiation, neglecting the reduction in biological effectiveness due to SLD repair during the delivery of radiation. Nevertheless, the dose-rate dependency of biological effectiveness may become more important as advanced treatment techniques, such as hypofractionation and respiratory gating, come into clinical practice, as these techniques sometimes require long treatment times. Also, while previous research using the biophysical model revealed a large repair effect with a high physical dose, the dependence of the repair effect on cell-specific parameters has not been evaluated systematically. METHODS: Biological dose [relative biological effectiveness (RBE) × physical dose] calculation with repair included was carried out using the linear energy transfer (LET)-dependent linear-quadratic (LQ) model combined with the theory of dual radiation action (TDRA). First, we extended the dose protraction factor in the LQ model for the arbitrary number of different LET proton irradiations delivered sequentially with arbitrary time lags, referring to the TDRA. Using the LQ model, the decrease in biological dose due to SLD repair was systematically evaluated for spread-out Bragg peak (SOBP) irradiation in a water phantom with the possible ranges of both (α/ß)x and repair parameters ((α/ß)x  = 1-15 Gy, T1/2  = 0-90 min). Then, to consider more realistic irradiation conditions, clinical cases of prostate, liver, and lung tumors were examined with the cell-specific parameters for each tumor obtained from the literature. Biological D99% and biological dose homogeneity coefficient (HC) were calculated for the clinical target volumes (CTVs), assuming dose-rate structures with a total irradiation time of 0-60 min. RESULTS: The differences in the cell-specific parameters resulted in considerable variation in the repair effect. The biological dose reduction found at the center of the SOBP with 30 min of continuous irradiation varied from 1.13% to 14.4% with a T1/2 range of 1-90 min when (α/ß)x is fixed as 10 Gy. It varied from 2.3% to 6.8% with an (α/ß)x range of 1-15 Gy for a fixed value of T1/2  = 30 min. The decrease in biological D99% per 10 min was 2.6, 1.2, and 3.0% for the prostate, liver, and lung tumor cases, respectively. The value of the biological D99% reduction was neither in the order of (α/ß)x nor prescribed dose, but both comparably contributed to the repair effect. The variation of HC was within the range of 0.5% for all cases; therefore, the dose distribution was not distorted. CONCLUSION: The reduction in biological dose caused by the SLD repair largely depends on the cell-specific parameters in addition to the physical dose. The parameters should be considered carefully in the evaluation of the repair effect in prolonged proton irradiation.