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TREATMENT PLANNING SYSTEM FOR BORON NEUTRON CAPTURE THERAPY (BNCT), BNCT SYSTEM, AND BNCT NEW

外国特許コード F200010221
整理番号 (S2019-0092-N0)
掲載日 2020年10月28日
出願国 世界知的所有権機関(WIPO)
国際出願番号 2019JP046256
国際公開番号 WO2020111085
国際出願日 令和元年11月26日(2019.11.26)
国際公開日 令和2年6月4日(2020.6.4)
優先権データ
  • 特願2018-220561 (2018.11.26) JP
発明の名称 (英語) TREATMENT PLANNING SYSTEM FOR BORON NEUTRON CAPTURE THERAPY (BNCT), BNCT SYSTEM, AND BNCT NEW
発明の概要(英語) This treatment planning system for BNCT comprises a storage means which stores an ideal patient position that is ideal for treatment, an assumed average boron concentration during treatment, at least one or more assumed patient positions specific to each patient that are assumed to be likely to be used by the patient during treatment, and an applied dose at an assumed patient position calculated by a calculation means which calculates the applied dose at each assumed patient position. During the actual treatment, when a signal of patient position fluctuation is received from a patient position measurement system, the treatment planning system for BNCT selects the assumed patient position closest to the patient position, and transmits along with the assumed patient position, the applied dose at the assumed patient position to a neutron irradiation control system in the BNCT system.
従来技術、競合技術の概要(英語) BACKGROUND ART
The type of radiation is roughly divided into an alpha (α) ray, beta (β) line, the gamma (γ) line, (X) an X-ray, proton ray, charged particle beam such as a heavy ion, and neutron and, after the substances as those listed in the ability of a large (penetration force).
Radiation typical of the effective utilization of an application to the medical field. In particular for the treatment of cancer and these radiation is used, the use of X-ray X beam therapy, proton, such as carbon particles such as "a particle beam therapy system" is used. Cancer treatment using radiation is carried out, not only while concentrating the radiation to cancerous lesions, relative to normal tissue surrounding the radiation as much as possible so as not to hit, and the normal tissue and cancerous lesions are respectively added to the amount of radiation using a difference in treatment is performed. The state of the radiation therapy in order to obtain a therapeutic effect, and the normal tissue and cancerous lesions such as cancer or close to normal tissue such as cancer are infiltrating in the case of cancer, many normal tissues of the applied radiation and hence, a risk that a fault occurs in the late side effects.
In recent years, in order not to cause side effects such a failure to late, cancer radiation is applied to the pin-point method has been studied. As an example, accurate irradiation of the cancer site to the three-dimensional irradiation of high-dose "radiation therapy (IMRT) intensity modulation method", such as the patient's respiration and cardiac motion in accordance with the movement of the body is irradiated with "the moving-object tracking radiotherapy", the therapeutic effect of the high proton or a heavy line and the like is intensively applied to "the particle radiation therapy method" and the like can be cited.
These X-ray treatment, in addition to the particle beam therapy, in recent years, in particular, neutron rays and the attention of a boron compound in combination, at the cellular level to selectively destroy cancer therapy and "boron neutron capture therapy (Boron Neutron Capture Therapy: BNCT) " is in. The highest position among the penetration force of the radiation is neutron large, depending on the level of energy further maintains, for example classified as follows. Various voltages in the parentheses are the energy of the neutron and, the greater the numerical value that indicates that the transmitting power is large.
From the transmission force is small, (-0.005eV) cold neutrons, thermal neutrons (-0.025eV), epithermal neutrons (0.025eV-10KeV), are classified into a fast neutron (10KeV or more). However, because of the classification are available in a variety of neutron rays and, in parentheses is not an exact value of the energy, for example, thermal energy of the neutron area equal to or less than 0.5eV, as the range of energies of epithermal neutrons, 10KeV or less from the 0.5eV, or 40KeV or less may be referred to as described below.
In addition, the neutron has no electric charges, so that the nucleus is easily absorbed during the striking, in this way can be referred to as neutron capture neutrons. 10 Is boron in the boron isotopes in particular, a thermal neutron capture probability with other elements (referred to as a cross-sectional area) is very high as compared with the nature. 10 Thermal neutron capture boron cause nuclear reaction as follows. 10B+n cell killing effect to cause the nuclear reaction 7Li+4He→helium nuclei emit lithium nuclei (α line). Lithium nucleus is further generated α-ray, only a few micrometers of normal tissue in progress to be stopped.
BNCT is used the physical characteristics. Such as by injection or infusion therapy in a cancer cell prior to the boron-containing compound 10 (hereinafter, referred to as a boron compound) may be incorporated, in this state is irradiated with thermal neutrons to cancerous lesions, the neutron capture reaction is caused in the cancer cells, and a helium nucleus (α line) generated by the nuclear DNA of cancer in the destruction of the lithium. The size of the cancer cells to be on the order of 10, the nuclei in the cancer cells and the line α lithium stops, does not affect the surrounding normal tissue. According to this principle BNCT is, at the cellular level and destroy the cancer, to preserve the normal tissue can be provided with extremely excellent characteristics.
Is a cancer cell, a boron compound has been actively proliferating cells in the course can easily, in BNCT, effectively utilizing this property to destroy the cancer cells as well as the treatment. This principle may be about 80 years ago in the United States proposed by Locher, such as the influence of the patient to the health of the unit, which is extremely excellent in radiation therapy as noted previously, in many countries have been made to research and development. However, a neutron beam generation device, a therapeutically effective neutron in the development of the selection device for selecting one, other than the affected area of the patient of the effects of the health of the portion (that is, a boron compound can be formed only in cancer cells) and the like, there are a significant development in a wide range and, still customary therapy has not been spread.
Medical neutron rays, in particular for BNCT effectively utilized in the selection of one example of a neutron is shown below. Adverse effects on the body of the high-energy neutron radiation (for example, fast neutron line) to the first excluding as much as possible, in the biological-reaching depth to the low energy neutron little (for example, thermal neutrons, neutron cold) by reducing the, among of the reaching depth of the in-vivo to the amount of energy of the neutron (for example, "epithermal neutrons line (0.5eV-10KeV) ") to increase the ratio of.
Thus, an effective utilization of a medical device capable of for BNCT neutron-ray can be obtained. Epithermal neutrons line, to the tissue in a patient of the reaching depth of the relatively high, in these low-energy portion of the speed of the neutron and thermal neutron rays outside, for example when applied to the head, unless the tactile cancer deep without the need for surgical craniotomy, the non-opening of the head of the effective irradiation state of the affected part is possible.
On the other hand, such as a neutron and a cold thermal neutrons of neutron radiation is very low energy, the reaching depth is low, in the case of using the surgical treatment of these neutron, superficial treatment for cancer (for example skin cancer or the like) is used. In addition, the low-energy neutron line is used for the treatment of malignant brain tumor, a lesion in order to reach a neutron in the craniotomy is required, becomes a heavy burden to a patient. In order to increase the therapeutic effect in BNCT, mainly line epithermal neutrons, thermal neutrons and neutron include some important and necessary amount of the affected area is irradiated.
Specifically, the irradiation time is about 1 time necessary in the case where the heat and outside the neutron flux, and the approximate position of the irradiation port 0.5-1.0x109 [n/cm2/sec]. The intensity of the epithermal neutrons in order to generate, in the generation of neutrons emitted from the energy source from the accelerator is the proton, neutron-ray generating target (Be) in the case of using beryllium, approximately 5-30MeV, the average current value is about 1mA - and the number of required mA respectively. In addition, in the case of using lithium (Li) target, the emitted energy of the proton, is used before and after 2.5MeV, the average current value, and should be at least about 10mA-30mA and.
X-ray treatment, the particle radiation therapy, radiation treatment such as BNCT, using the pre-treatment planning system and the irradiation conditions of the dose evaluation determined in advance. Irradiation conditions is important in particular, patient position and, with respect to the beam irradiation (irradiation port) is determined by the relationship between the position of the patient.
Generally in the radiation treatment (including BNCT), determined in accordance with irradiation conditions prior to treatment the patient is fixed at a predetermined position, applying radiation to the patient. Here, except in the case of the current radiation therapy BNCT, within a very short and the irradiation time for 1, the patient does not move (except for breathing) treatment (irradiation) is performed on the assumption, applied to the patient dose is, when a treatment plan of the pre-calculated dose, and it has been assigned.
Therefore, the patient during irradiation and also moves and, at the planned radiation is not irradiated, in focus, not sufficient in the treatment dose is given, one or more of normal tissue surrounding the planned dose is given the possibility. Therefore, the change in position of the patient during irradiation, X-ray treatment, in the particle beam therapy, the physician or medical personnel viewing the camera monitor. If the patient during treatment when a large motion is occurring, and the alignment treatment is interrupted again, and re-irradiation. Also, in addition to the unexpected change in position of the patient, the organ due to respiration is always periodically fluctuates in position with respect to the lung or the liver cancer treatment is such as X-ray or proton beam therapy, the beam is turned on/off in accordance with respiration by the irradiation accuracy is ensured and and or. For example, X-ray treatment and, in the particle beam therapy, in the motion of the lesion is irradiated, the interval between the beam irradiation is irradiated with X-ray fluoroscopic and identify the location of the lesion being treated. In this case, the therapeutic beam aimed at containing the lesion "ambush irradiation method" and irradiated, the irradiation range of the beam is moved moving lesion is irradiated with the each of the "dynamic tracking irradiation method" is. In addition, as a method to synchronize the breathing is detected, by the laser distance meter or the like to monitor, indirectly measures the change in the position of the organ. Also, gold markers embedded in the vicinity of the lesion, the lesion before and after irradiation of the beam (due to respiration) to confirm the position of the motion of the technique to practical use.
On the other hand, in the case of BNCT, the treatment time is about 1 times, compared with the other radiation treatment for an extremely long, in a long time, there is a possibility that the patient is moving higher than the other radiation treatment. In order to avoid this, the patient does not move and is fixed to complete, because a large burden on the patient, the rigid fixation is not carried out. That is, in the case of BNCT, the treatment time is longer approximately a time period 1, and firm fixation is not performed, the variation of the position of the patient during irradiation is extremely high. If the position remains deviated irradiation is completed, a large dose of the original at the time of planning will be a difference. BNCT is, the movement of the patient during irradiation of the observation of the monitor camera, for some movement of the patient (due to respiration position is within the allowable range in the case of the fluctuation BNCT) to continue the treatment. In addition, in the case of BNCT, and a boron compound is administered to the patient, the blood concentration of boron for decreased with time, the irradiation time exceeds the time 1 necessary for the treatment and it may be less than the boron concentration. Thus temporarily turned off during exposure to neutron irradiation and the positioning work is carried out by a decrease in boron concentration and making it difficult to continue treatment, the treatment itself is not satisfied with the result that, normally, the neutron output on/off by the neutron beam irradiation control is performed, the irradiation is performed continuously. For this reason, in the case of BNCT, therapy, typically 1 times to complete the continuous irradiation. Therefore, while the irradiation position is shifted to be completed, a large dose of the original at the time of planning will be a difference.
BNCT (BNCT in the treatment procedure) the general treatment procedure shown in Fig. 1. Typically, the patient candidate appears BNCT, first "treatment planning system (Treatment Planning System hereinafter, referred to as TPS) " is used to set the treatment plan. Treatment plan, the optimal irradiation condition to the patient: a beam irradiation position, angle, distance and the irradiation time refers to the determining. This treatment planning operation is performed before the irradiation of 1-2 weeks.
An optimal treatment plan using the TPS and planning, actual treatment reaches the end of the day. To about 1-2 of the actual irradiation time on the day before the administration of the boron compound (BPA). Boron compound has been administered some cancerous lesions in the boron compound at a collection, as the patient goes to the irradiation chamber. In the actual irradiation chamber, the irradiation position accurately fixed to the patient. The irradiation position, irradiation condition defined in a guided TPS and, as the condition is fixed to the patient. BNCT is irradiated, is irradiated to the patient by the location of the lesion or may be laid, also in the case of irradiating in a sitting position.
In a conventional patient alignment method, using a laser beam or a plurality of alignment marks, using a ruler on a visual observation beam holes on the eyes and nose, ears while checking the positional relationship between alignment is carried out (note that, in the particle radiation therapy to treat such as X-ray, X-ray fluoroscopic apparatus which can be mounted in the irradiation room for, in general a fixed irradiation position of the X-ray fluoroscopy and radiography with the patient, to confirm the location of cancerous lesions. However ray fluoroscopic apparatus for use in neutron BNCT X irradiation chamber is installed in the device being destroyed immediately for neutron, X-ray fluoroscopic apparatus cannot be installed, by confirming the position of the lesion by the X-ray fluoroscopy of the conventional alignment is not possible).
Several times before the irradiation is started and the boron concentration in the blood in the blood is measured. Based on the measurement of the concentration of boron, the boron concentration is estimated during irradiation. Here the brain and skin, mucous membrane, lesion such as cancer of each organ, and a boron concentration in the tissue, the ratio of the boron concentration in the blood, is known from past studies that the characteristics. For example in the case of a BPA, 1 and the boron concentration in the blood, the concentration ratio of the skin 1.2, 1.0 of the brain, cancer cells are in the 3-5. Therefore, the boron concentration in the blood in the blood by measuring, on each tissue are integrated with the boron concentration can be estimated. Blood and also during the irradiation of each organ, the boron concentration of the tissue is sequentially changed (reduced), because the boron concentration can be measured during the irradiation, the measurement value of the immediately prior, and based on past studies that the pharmacokinetics of a boron concentration on the basis of the attenuation curve, the estimated change in the boron concentration. During irradiation in the irradiation of the actual "mean a boron concentration" is estimated, during irradiation of the calculated "average boron dose" (1ppm of the boron dose is calculated per TPS) method is used. Here the "boron dose", the neutron is absorbed by boron, boron 10 and the neutron ray α generated by the reaction of lithium is applied to the dose of the cell nuclei. The boron dose, hereinafter, also referred to as the dose applied to the boron concentration. The boron concentration of the cancer cells and normal tissue in the boron concentration difference is generated, due to the difference in boron dose, the difference between the boron dose, the therapeutic effect of BNCT (cancer cells and normal cells to the difference of the dose) becomes.
In accordance with the position of the patient (TPS is led to the irradiation position of the "ideal" is fixed) is completed, estimated average boron concentration in the blood collection, to determine the irradiation time, irradiation is started. However, the time change of the boron concentration in the blood may fluctuate for each patient, from the measured value immediately ahead of the estimation of the average during the irradiation of the boron concentration is not sufficiently high precision. After the laser beam is radiated, again measured after the irradiation of the boron concentration in the blood and, during exposure and post-evaluation of the average boron concentration, before the prediction, estimated average and a boron concentration and a large displacement is often possible. This deviation may be as large as 10-20% of the error is also common.
The boron concentration by the dose applied to normal tissue and cancerous transmission rate changes. The boron concentration is high, is applied to the site since the dose rate is also increased, the irradiation time is shortened. On the other hand a low boron concentration and the irradiation time becomes longer. BNCT of the irradiation time, the maximum applied to normal tissue (for example 10Gy) by controlling the neutron dose. For example, the boron concentration in the boron dose rate per 1ppm in the case 1Gy/PPM/hr, when the boron concentration of 10ppm, since the boron dose rate is 10Gy/hr, the maximum boron dose 10Gy in order to provide the necessary time 1, will be called. If the case in which the boron concentration is 20ppm, since 20Gy/hr, one 0.5hr=30 10Gy may be irradiated in order to provide, in the computation.
The boron concentration and the boron dose of the pre-estimated value of the irradiation time by the change, and based on that estimation of the boron concentration in the boron dose is very important to the predictive calculation.
For the alignment of the patient, the patient during irradiation in the conventional method that does not move. Typically, (1) the patient is determined by the position of the TPS are the conditions that can be secured. (2) The patient does not move during exposure. Under the assumption that the irradiation is performed. If it is assured that this assumption, a peripheral lesion of the TPS as a neutron irradiation plan can be applied for an organ, as TPS is led to be irradiated to the irradiation time, radiation dose as calculated can be applied to each site, will be called. However, in practice, (1) alignment of the stage before the TPS can be aligned to planned not. (2) For a relatively long irradiation time, and moves the patient during irradiation, the irradiation conditions can be assured in the TPS is not led, at the different plan begins to neutrons, a situation occurs that the.
JP-1 (manufactured by sumitomo heavy industries, of the Prior Application) the contents of, the TPS is led to the irradiation conditions of the "ideal" position, when the patient actually fixed and the shift position (before irradiation), in the pre-predicted, (a number of displacement under the condition in the dose calculations) in a position deviated from the pre-calculation of the calculation result of the employed position closest to the condition, although it is. In accordance with the position deviation is also a slight modification in the irradiation time, although it is.
Fig. 2 (the treatment planning system) to, by using the TPS is applied to the patient under the irradiation condition of the dose calculation flow. In addition, in Fig. 3, a treatment plan using the TPS (the determination of the optimum irradiation conditions) shown in the flow. In the TPS, patient CT(Computed Tomography: computed tomography), MRI(Magnetic Resonance Imaging: magnetic resonance imaging) to capture data, first, the three-dimensional model of the patient 3. In the three-dimensional model 3, it is assumed that the irradiation conditions (position of an incident beam, angle, distance), that is the calculation condition is set. And determines the conditions under which this calculation, the calculation model is created and the TPS, which is input to the Monte Carlo (MC) calculation code to perform the calculation. The calculation of MC, in the case of irradiation conditions, the patient's body in the manner in which the neutron distribution=whether the dose distribution, is calculated (simulation exposure).
Typically 1 times (1 times of the calculation condition) for the calculation of the optimum irradiation conditions can be determined or is not, the irradiation conditions are changed, the change condition in the calculations even further. Before and after changing the condition of the calculation result of the calculation result of the comparison, better conditions are selected. This operation is repeated several times, compares the calculation result, the final (optimum conditions) =(which was calculated in the calculation result of the irradiation conditions but the best) is selected, it is to be used in irradiation and actual irradiation conditions.
(Change of the dose distribution due to a misalignment of a patient) Fig. 4 is, in the reactor BNCT shows how the time of. After fixing the irradiation position immediately before the irradiation of the patient to use a device called a "three-dimensional digitizer 3" the patient's eye, nose, ears to measure the position. In the middle of Fig. 4 in the table above, the eye, nose, ear position (coordinate) is, the irradiation time of the simulation by the TPS in advance (when a treatment plan) to the "ideal" case where the irradiation position can be fixed to each of the coordinates.
However, the three-dimensional digitizer 3 is measured in the coordinates, the deviation from the ideal position can be seen (Fig. 4 in the middle of the table below the lower number indicates a shift amount). Conventionally, this was measured by the digitizer 3 is performed several times, adjusting the alignment, only the irradiation conditions can be close to "ideal" it is confirmed that, with the irradiation is started. Is displaced slightly still. Fig. 4 is, in this situation is shifted a little, this is implemented as OK.
The three-dimensional digitizer 3 and immediately ahead of the actual measured position of the patient state and reproduced by using the TPS 5 in the lower right of the figure. And on the right of the irradiation conditions, (the actual fixed) =(actually applied to the patient position) is compared to the lower right part of FIG., cancerous lesions (beam holes near the center of the black area) of the position, the irradiation condition is set with respect to the center of the, a fixed position of the actual patient cancerous lesions is slightly lower than the displacement of the center of the beam can be seen.
BNCT in this way is, as the irradiation conditions of an ideal the actual irradiation can be easily applied to the situation is difficult. Still "are can be fixed to the position of the ideal" as being irradiated.
In addition, in reactor BNCT, in measuring the position of the three-dimensional digitizer 3, is applied for about 5, for measuring directly comes into contact with the patient, the measurement cannot be implemented during irradiation. In addition, three-dimensional digitizer 3 is measured by the eye, nose, ear of the TPS information of the coordinates of the feedback is not simple, the next treatment (irradiation) after completion of one work is performed after the re-calculation is performed, is a procedure.
Therefore, the three-dimensional digitizer 3 are shifted a little from the ideal irradiation position as it was found that, in situ may not be fed back to the TPS, to the context. In the following Patent Document 1 of the present invention, the irradiation position immediately before and by considering the gap, the position of a great number of dose calculations may be performed under conditions, in that, in fact the closest to the position deviated from the irradiation is carried out employing the conditions, that is in.
(During irradiation of the boron concentration) as described above at the time of irradiation of the boron concentration is in a constantly changing BNCT (decrease) with. (B) 2 (a) Fig. 6 is one of a boron compound, a boron concentration in the blood of BPA and BSH indicates actual data. This actually measured data of the data at the time of the reactor BNCT, drawing blood from a patient at various times before that the boron concentration in the blood were measured data. BPA is, immediately after administration of the drug (=when the start of irradiation) decreases rapidly. The characteristics of this phenomenon, the pharmacokinetic and metabolic characteristics of a living body is attached. Based on this attenuation curve, is irradiated during the radiation before the start of the "average concentration" is estimated.
(A) of Fig. 6 in the case of a BPA, the boron concentration in the blood immediately ahead of and the about 24ppm. (Gray areas) in the irradiated, the pharmacokinetics of BPA was estimated from the attenuation curve (curve line in the drawing) is assumed to be attenuated, is about 8ppm immediately after an end of the irradiation and before the start of the prediction. During irradiation on the basis of the "15ppm" for example "mean a boron concentration" and, prior to determining the physician determines that the irradiation.
The exposure dose assessment that is always at 15ppm during the boron concentration, on the assumption that the dose calculation is performed. For example, certain portions of the dose rate as a calculation result is 1Gy/PPM/hr, it is assumed that the 15ppm, and 15Gy/hr, the laser beam 10Gy is completed, the irradiation time (10/15) =40 min to x60 min is calculated. However in practice, the boron concentration of the prediction accuracy is poor in the current.
The change in concentration of the boron compound in a living body, the following non-patent document 1, published in an article of 2. These papers from experience, it is presumed that the attenuation of the boron concentration.
(The boron concentration due to the difference in the difference of the dose distribution in the living body, change) and boron (boron 10) 10 can be sensitive to neutron has characteristics (BNCT established for the treatment). However boron neutron 10 easily reacts with, and also a high concentration of boron 10 and the lesion portion, due to the neutron is stopped in a deep portion is less likely to reach a neutron, a characteristic that it. Boron 10 concentration is smaller the reverse (or boron does not include the 10) case, while the living body can be smoothly through the neutron, a neutron of the normal distribution. That is, the concentration of boron in the living body 10 changes depending on the neutron distribution, as a result (in the vicinity of the lesion) in vivo dose distribution will change also.
Fig. 7 is, the boron containing cancerous lesions 10 (upper line) is not the cancer lesions in the case where the concentration of boron is 50ppm 10 (underlined) on the beam axis of the neutron flux distribution in the comparison. (B) is (a) in Fig. 8, boron (in the range of the white oval) cancer lesion 10 is not in the two-dimensional distribution of the neutron in the living body (a) and 2, boron 10 concentration was 50ppm in the case of a two-dimensional distribution (b) 2 is shown.
Fig. 7 is, the beam enters the body of the cancer lesion distribution of the neutron does not change therebetween, passes through the cancerous lesions, containing boron is not 10, the distribution (normal distribution) on the line and, on the other hand, in the cancerous lesions that contained 50ppm boron is 10, and the distribution of the underline, boron passes the neutron cancerous lesions by be stopped due to the number of neutrons 10, after passing through the cancerous lesions of the neutron is reduced is indicated.
Fig. 8 is the same, (a) containing boron of a cancerous lesion is not 10, the high range of the neutron (in color display, red lines and yellow lines→→orange line) is spreading to a wider and deeper, the concentration of boron in the case of 10 50ppm, the red region of the high neutron cancer lesions and stopping before the, after passing through the cancerous lesions (a) the intensity of the neutrons is lower than the distribution of is shown.
In the conventional TPS dose assessment and treatment regimens, cancerous lesions in a concentration in the boron concentration of the (assumed in the average density of the irradiation: for example 15ppm) computed assuming a model set and calculates the concentration. In the actual treatment, the concentration of the single dose of neutron distribution calculated based on the evaluation to determine the irradiation time, the dose applied to each region are evaluated (Fig. 9). However, in practice (for example 24ppm) is applied to the boron concentration at the start of irradiation (for example 8ppm) immediately before the end of the concentration is, unlike the distribution of neutrons, on the basis of the dose applied to each region are also changed. BNCT they are present has been ignored. At that time i(...)
  • 出願人(英語)
  • ※2012年7月以前掲載分については米国以外のすべての指定国
  • UNIVERSITY OF TSUKUBA
  • 発明者(英語)
  • KUMADA Hiroaki
国際特許分類(IPC)
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