Technical Field

The invention relates to a method of exploiting the ionizing radiation synergistic action on a tumour cell potentiated by the delivery of another substance to the patient’s body.

Background of the Art

There are methods of action within the BNCT procedures - Boron Neutron Capture Therapy known in the art, taking advantage of thermal neutron energy spectrum having a high effective fusion interaction cross section on the isotope 10B. This isotope is bound to a suitable carrier (together forming a drug), selectively captured in areas with higher metabolic activity, i.e. in the area a tumour.

A known solution according to patent KR101568938 (B1) entitled THE RADIATION THERAPY AND DIAGNOSIS DEVICE USING PROTON BORON FUSION REACTION, which briefly discloses the principle of a method without providing a more precise definition of boron carrier and without implementing it into the planning system. The key moment is not the description of the nuclear interaction per se, the description and course thereof is very well known, and the related information is freely available. The present patent differs from the disclosure mentioned above, in particular, in the description of the clinical application, which will enable the implementation of an increased effect in the tissue. Without the present extension regarding treatment planning, the procedure patented in KR101568938 cannot be clinically implemented.

Another known solution according to patent document US2016074512 (A1) called PROTON INDUCED BORON CAPTURE THERAPY, however, differs in description and the method described therein does not fall within the scope of the newly present patent application. Description of the Invention

The substance that is delivered to the patient’s body may not have any biological effect per se; it functions as a carrier for a specific isotope of the target nucleus (TN) of one of the light elements. This carrier is used to transport the said TN to the area of the tumour lesion and to increase its concentration there. Based on the interaction of the proton beam with the selected TN, there is a nuclear interaction with the emission of secondary particles with high linear energy transfer (LET) and thus high radiobiological effectiveness (RBE), in radiobiological experiments sometimes referred to as the dose enhancement ratio (DER). The invention consists in combining this known and described principle directly in the process of planning radiotherapy in clinical practice. Modified proton beam data are directly introduced into the radiotherapy planning system (TPS), respecting the increase in LET and RBE due to the presence of increased TN concentration. This allows safe prediction of biological dose distribution in the patient’s body with a safe fractionation scheme. The benefit of the present invention is the possibility of using lower doses of radiation while maintaining the same biological effect. This results in an improvement in the radiation therapeutic effect with the possibility of escalating equivalent doses to target volumes defined in radiotherapy at the same radiation exposure to critical organs or using an isoeffective regimen on the tumour while significantly reducing radiation exposure to patient’s healthy tissues, or appropriate combination of both mentioned possibilities.

Primarily, the above-mentioned treatment method was designed within the framework of BNCT procedures - Boron Neutron Capture Therapy, taking advantage of thermal neutron energy spectrum having a high effective fusion interaction cross section on the isotope 10 ^B . This isotope is bound to a suitable carrier (together forming a drug), selectively captured in areas with higher metabolic activity, i.e. in the area of the tumour. A suitable carrier may be an organic or inorganic molecule that specifically binds to the surface membranes of tumour cells or is preferentially absorbed by tumour cells so as to produce a higher concentration of boron on or inside these cells than in the case of non-tumour cells. Examples of such a molecule may include sodium borocaptate (BSH) or borfenylalanine (BPA). The examples given are not an exhaustive list of suitable carriers.

The drug is biologically practically inactive and therefore does not alone usually cause any biological response in the organism. Likewise, thermal neutrons do not substantially interact with normal human tissues, i.e. their effect is not specific within different tissues. However, combining these two modalities lead to the above- mentioned fusion reaction, wherein the original boron atom is split into a lithium nucleus, a helium nucleus, and, at the same time, a high-energy photon is released. In terms of radiobiology, the helium and lithium nuclei represent highly effective radiation, which, however, has a very short range and its effect is always local and occurs at the site of high boron concentration, i.e. at the site of the tumour.

In the case of replacing the thermal neutron beam by a high-energy proton beam and using the isotope ¹¹ B, another type of fusion interaction occurs, in which a triad (also of very short range) of alpha particles is produced. In this case, of course, the same carrier/drug can be used (the selected isotope does not affect the chemical and biological properties of the drug). Unlike neutrons, the proton beam in the tissue has a completely different interacting method, as it is a heavy charged particle.

The proton beam, per se, has very advantageous ballistic properties (final range in the tissue, the depth curve course in the form of a Bragg peak) and is therefore a therapeutic modality in itself. In the case of combining proton radiotherapy with the use of a suitable atomic target bound to a tumour cell, we can thus speak of a physical potentiation of the therapeutic effect at a selected site.

However, the physical interaction principle alone does not guarantee defined dose deposition at a particular site. To fully exploit the potential of this type of Bragg peak enhancement, it is necessary to implement the appropriate treatment model in the planning system as well and to be able to predict dose distribution within the patient’s body with appropriate modification of depth dose curve properties within modelling energy deposition along the beam path. This approach includes a number of possible implementations.

Example of Carrying of the Invention The method of binary proton radiotherapy according to the present invention is realized by administering a pharmaceutical substance containing the isotope ¹¹ B, using the fact that low energy protons (i.e. in the region close to the so-called Bragg peak) have a high effective fusion interaction cross section on the isotope ¹¹ B.

This isotope is selectively captured in areas with higher metabolic activity, i.e. in the tumour area.

The drug alone is biologically inactive and does not cause any biological response in the organism. Likewise, higher energy protons interact less with ordinary human tissues, i.e. their effect is not specific within different tissues.

However, combining these two methods leads to the above-mentioned fusion reaction, where the original boron atom is cleaved into three helium nuclei. In terms of radiobiology, helium nuclei represent highly effective radiation, which, however, has a very short range and its effect is always local and occurs at the site of high boron concentration, i.e. at the site of the tumour.

To determine the above desired concentration of the respective isotope in the target volume, in the tumour tissue, it is possible to use the measurement of secondary photon radiation (prompt gamma) emitted specifically after the interaction of the proton with the given isotope.

Regarding the required concentration, proton beam irradiation is then applied at a dose corrected within the planning system by the value of the expected DER. The synergistic effect of proton beam irradiation as such and by increasing its efficiency by means of a nuclear interaction ensures an increase in the radiation effect on the tumour tissue and, at the same time, a reduction or at least a non-increase in the overall toxicity of the surrounding healthy tissue.

For example, the proton radiotherapy method can be used for refractory aggressive tumours in the CNS, such as glioblastomas, which are rapidly growing and have low sensitivity to radiation.

Furthermore, it is advantageous to plan the irradiation using adapted beam data and possibly also a biological computational model to determine a safe irradiation technique.

While the principle of increasing treatment efficacy has been known for a long time, the benefit of the present invention consists in the direct clinical implementation of this approach by incorporating nuclear interaction properties directly into the beam model in the planning system. An example of such an interaction is the interaction of a proton beam on the boron ¹¹ B nucleus.

Figure 1 shows the course of the effective cross section of the respective interaction p + ¹¹ B ® 3a. If the proton’s energy is between 0.1 and 10 MeV, the probability of interaction is highest. In proton radiotherapy, this energy interval is in the Bragg peak region. The position of the Bragg peak is then given by the energy of the proton beam at the moment of entering the patient’s body and it is possible to choose this energy very precisely. As a result of the foregoing, the site of secondary alpha particles maximum production can be very well defined in clinical practice. However, alpha particles are a type of ionizing radiation with a high LET (Linear Energy Transfer) and therefore a high RBE (Relative Biological Effectiveness). In order to correctly prescribe the dose to the target volume, it is necessary to include the RBE increase factor directly in the Treatment Planning System (TPS) to develop an optimal irradiation plan for a particular patient.

Modification of the beam physical data is performed on the basis of the determined increased effectiveness. The values and the method of increasing this effectiveness are determined on the basis of radiobiological experiments and possibly also within clinical studies. The present invention allows for the implementation of the biological dose escalation mechanism into the existing planning systems without the need for a detailed LET spectrum calculation ora detailed biological model. It is a matter of course to refine the calculation in the future using biological modelling methods and the use of methods such as Monte-Carlo for a more precise determination of the biological dose distribution. Monte-Carlo method is a computational approach, often used to solve so-called transport problems, in which analytical calculation is impossible or too complicated. It consists in creating a model of the environment (geometry and material composition thereof), defining projectile particles that need to be transported through the environment (i.e. type of incident particles, energy and spatial distribution thereof) and taking into account the interaction of incident particles on individual elements within the environment material. The second step is to simulate the passage of many projectile particles through the defined geometry of the environment, including the probability of individual interactions. The result is statistics of physical quantity distribution, allowing to read the parameters of the modelled physical situation. In the case of the patented approach, it would refer to a model of the patient’s body; the material composition would be determined on the basis of imaging methods (CT or MRI); the geometry is also based on these images. The projectile particles are protons in the form of a treatment beam, for which energy and spatial distribution are well known. In this case, the result is a Monte Carlo simulation of equivalent dose spatial distribution in the patient’s body.

To determine whether the appropriate concentration of the respective isotope in the target volume has already been reached, it is possible to use the measurement of secondary photon radiation (prompt gamma) emitted specifically after the interaction of the proton with the given isotope. An example of this situation is the impact of an accelerated proton on the target boron ¹¹ B nucleus, which is located in the monitored area. Upon the incidence, a nuclear fusion interaction occurs, causing the target nucleus to be excited from the ground state. In a very short time at the level of 10 ¹⁴ s, the nucleus naturally deexcites with the help of characteristic gamma photon radiation so that it returns to the basic energy state. Since this is entails the characteristic photon energy (719 keV), with a suitable detector, it is possible to determine the place where this prompt gamma photon was emitted. The more relevant target nuclei contained in a given area, the greater the number of characteristic photons that will be generated. By calibrating a sample with a known concentration of boron atoms, the prompt gamma detector can be calibrated, and the boron concentration achieved can be measured with a small error directly at the target volume area. In addition to determining the absolute concentration of boron within the target volume, it is also possible to determine the position thereof using a detection set, enabling to determine the direction from which the gamma photon prompt impacted the detector. This can be achieved, for example, by means of a suitable collimation system on a semiconductor (e.g. HPGe) or scintillation (e.g. Nal) detector. In principle, it is possible to use electronic collimations with a set of pixel semiconductor detectors or by means of a Compton camera.

An alternative way to determine the concentration of the target nucleus is to use nuclear magnetic resonance (MR or MRI) and, by means of signal intensity detection within spectroscopy, determine the concentration of the target nucleus. This method is also advantageous in that, in addition to spectroscopic measurement, it is possible to use the imaging function of a medical device for magnetic resonance imaging and thus determine more precisely the location with the required concentration of the target nucleus. For the purpose of correct localization of the site with the required concentration of the target nucleus, the advantage of using boron is the fact this element occurs in trace amounts in the human body, thereby allowing to obtain sharper information with reduced ambient noise, which would be much higher if the nucleus of another, biogenic element was used for binary therapy. The atomic nucleus of each element has a characteristic spectrum within MR spectroscopy, in principle enabling to determine whether in a given voxel (volume element in the tissue for which the signal for MR spectroscopy is evaluated) the element is located (a characteristic peak appears in the spectrum) and how much is in a given voxel (the height of this peak within the detected signal of a specific frequency). The signal must be calibrated using phantoms with a known boron concentration, i.e. target nucleus. For MR spectroscopy of materials other than ordinary human tissues in a clinical environment, it is usually necessary to use higher magnetic field strength and specific frequency generators and detection coils. Another advantage is that during the diagnosis of the boron concentration, i.e. the target nucleus, it is not necessary to use ionizing radiation, thereby providing more advantage from the point of view of radiation protection of the patient.

The invention therefore consists in the implementation of a binary treatment modality in clinical practice.

The nature of the invention consists in particular in the complex solution of potentiation of proton radiation effect by means of a drug enriched with a suitable isotope, e.g. ¹¹ B and the ability to predict the local effect based on determined radiobiological activity. Implementation into the scheduling system can occur in a simplified form of modifying the Bragg depth dose curve (serving as input data for the dose computational model in the radiotherapy scheduling system) in the energy region where intense fusion interaction occurs, and the deposited equivalent dose is potentiated by nuclear interaction fragments. The Bragg curve characterizes the depth dose deposition of heavy charged particles upon interaction with matter. Its shape is characteristic, as shown in Figure 2.

Figure 2 - Bragg curve. After the beam enters the material, energy begins to be transferred (i.e. a deposited dose), while the kinetic energy of the incident particle (proton) decreases. The lower the kinetic energy of the particle, the more readily it is transferred to the material. Just before a complete stop, it transfers the maximum energy; there is no further energy transfer. The position of Bragg peak is given by the input energy of the proton beam into the material and is easily adjustable. During radiation, the area is chosen based on where the proton beam transmits most of its energy and is thus maximally effective.

Figure 3 shows a modification of the depth Bragg curve in the case when the tissue contains boron and protons are used for radiation. As shown in the figure, the amplification of the radiation effect occurs only at the point with the Bragg peak and thus at the point where the target volume is located.

A set of Bragg curves analogous to Figure 2 is taken for different energies into the material of the entering proton beam during the launch the planning system operation (TPS). Current planning systems (TPS) can work with this form of input data as standard. If the modification according to Fig. 3 is performed, these modified curves can be introduced into the planning system directly without the need for software modifications or the development of new software modules.

A more complex implementation can be realized either by a LET simplified model (integral value of LET determined over all types in a point of interacting radiation) or on a dose model based on Monte Carlo computation.

The principle of binary therapy consists in the use of two differently acting agents together to increase the therapeutic effect on cancer and, at the same time, reduce or at least no increase in the overall toxicity of the treatment. The first agent is a proton beam, which is used in radiotherapy for cancer and appears to be an effective and safe treatment method. The second agent is a drug containing the respective target nucleus (the example may include boron isotope ¹¹ B), which alone is biologically inactive. The combination of these two agents increases the effectiveness of the treatment without increasing toxicity thereof.

Overview of Figures in the Drawings

Figure 1 shows the course of the effective cross section of the respective interaction Figure 2 Bragg curve

Figure 3 shows a modification of the depth Bragg curve

Industrial Applicability

Proton radiotherapy is a fast and effective method of killing tumour cells and tissues while providing lower radiation exposure to the surrounding healthy tissue and thus also to the patient. This method can be very effectively and easily implemented into existing procedures using radiation exposure to tumour tissues.

The whole method ca be essentially very quickly implemented in clinical practice in all proton centres worldwide with an availability of a suitable carrier/drug of a suitable isotope, interacting with the incident proton beam. Currently, the most common isotope is ¹¹ B. However, any other element that can be attached to a suitable carrier and which undergoes a nuclear interaction with a proton beam, especially in the low energy region (up to 10 MeV proton projectile), can be used. For prompt gamma imaging, it can then be used either directly with the relevant isotope or a different one that again undergoes the nuclear interaction associated with prompt gamma emission. In addition, this method is relatively easy to implement into the existing treatment workflow of any proton radiotherapy workplace. Furthermore, appropriate target nucleus concentrations and effectiveness increases can be adjusted according to the histological type of tumour tissue based on currently or future available radiobiological data.

Examples of Embodiments of the Invention One example of using this treatment method is the possibility of escalating the therapeutic dose in a defined manner, for example for the treatment of refractory aggressive tumours in the CNS region, for example glioblastomas. In this case, these are fast-growing tumour types with a generally poor prognosis and low sensitivity to radiation. Delivering higher doses of radiation, which could result in gaining control over the tumour, is prevented by high doses that are delivered simultaneously to the surrounding healthy tissues. By potentiating the dose effect with the appropriate supplied isotopes, it is possible to increase the dose effect in the tumour lesion by several tens of percent, while maintaining acceptable doses on healthy tissues (e.g. by using isotope ¹¹ B by 40-50% and the carrier BSH - sodium mercaptododecaborate). This significantly increases the likelihood of gaining control of the tumour and the result is a longer survival of the patient.

The detailed process involves the administration of a suitable carrier for the given isotope (drug) in advance before the beginning of the radiation. The time interval between drug administration and radiation is determined based on the individual parameters of the patient. Prior to the drug administration, radiation treatment is planned to use adapted beam data and possibly a biological computational model to determine a safe radiation technique.

The administered drug does not have to contain only the isotope ¹¹ B; the natural representation of the isotope ¹⁰ B is used. When a proton beam interacts with this isotope, gamma photons with a specific energy are emitted. Before the radiation, it is then possible to determine whether there has already been a sufficient increase in the concentration of the drug in the tumour area, using the prompt gamma activation analysis (PGAA) method as part of the patient’s pre-treatment verification. Prior to radiation, it is always verified that the patient will be radiated safely and accurately. Verification procedures include both control of individual steps of the radiotherapy chain and dosimetric verification of radiation plans by phantom measurement to pretreatment determination of target nucleus concentration (e.g. boron ¹¹ B) by measuring prompt gamma intensity when using verification radiation of a patient with a specific energy and low intensity proton beam. Likewise, an accurate position during radiation by means of, for example, X-ray imaging, the concentration of the drug in the target area is verified by means of a proton treatment beam. With sufficient carrier specificity for a given type of tumour tissue, prompt gamma can also be used to more accurately diagnose the position and size of the tumour in the body. The radiation itself then takes place according to the radiation standard of the workplace; it does not represent any additional demands for the patient.