Technical field of the invention

The invention is in the field of dosimetry of charged particles and gamma rays, in particular ultra-high rate radiotherapy (flash-radiotherapy) and industrial sterilization treatments. It is proposed a dosimeter for charged particles and gamma rays, suitable for both continuous and pulsed beams, with linear response between 0.001 MGy/s and 10 MGy/s.

Known art

Oncological radiotherapy has now reached very high levels of accuracy as regards the adjustment of the dose distribution to the shape of the lesion, with the aim of saving healthy tissues as much as possible. The common hospital radiotherapy with high energy electrons and photons (up to about 18 MeV) has come a long way in the last three decades, starting from the three-dimensional conformal radiotherapy (3-D- CRT) (1990s), which evolved into radiotherapy with intensity modulation (IMRT) and in Tomotherapy. The Image-Guided and Adaptive Radiotherapy techniques should be mentioned, wherein the treatment adapts to morphological variations (e.g. reduction in patient weight or gradual reduction in tumor volume) and movements (a typical example is "Respiratory Gating").

Finally, hadrontherapy with protons and carbon ions entails enormous advantages in terms of homogeneous coverage of the tumor volume, with an unprecedented ability to save healthy tissues.

To date, a little explored frontier is that of the time fractionation of the dose: conventional radiotherapy with electrons and photons, even in modern ultra- conformational versions, is based on the paradigm of dose fractionation: that is, it is believed that low dose rates (0.01- 0.05 Gy/s) administered at 2-3 Gy/session for 10- 30 sessions, allow the healthy tissue an adequate recovery.

Radically contradicting this approach, a 2014 study (doi: 10.1126/scitranslmed.3008973) showed in vivo that extreme dose rates (> 40 Gy/s), applied in a single session by fractions of a second, can enormously save healthy tissues compared to the standard fractional approach. Other studies (doi: 10.1016/j.clon.2019.04.001 ) have confirmed these hypotheses in vivo on animals. The scientific community and companies in the oncology sector immediately engaged in the development of this new technique, called "FLASH therapy". Until now, these developments have focused in particular on the use of electrons of less than 15 MeV energy.

The FLASH beams are pulsed with pulses lasting microseconds, repetition frequencies up to tens of Hertz and doses per pulse from Gy to tens of Gy. Within the pulse, the instantaneous dose rate has unprecedented values of the order of MGy/s (Mega Gray per pulse).

These intensities pose enormous challenges for radiobiology but also for dosimetry. The features of a radiotherapy dosimeter are:

1. be "point-like", that is, have the smallest possible size, so that the energy and directional distribution of the radiant field in the medium is the same in the presence or absence of a dosimeter. The dosimeters in use have typical dimensions of a few millimeters;

2. response independent of the dose rate (linearity);

3. response independent of the directional distribution of the beam (isotropy);

4. response independent of the beam energy (energy dependence).

For conventional radiotherapy there are many commercial models of dosimeters, based on the three classic techniques for detecting ionizing radiation: ionization chambers (example: https://www.sunnuclear.com/products), scintillators and semiconductors (examples https: // www.standardimaging.com/products/exradin), all available in sub-centimeter sizes (point 1).

These systems operate linearly (point 2.) at the rates required by conventional radiotherapy (fractions of Gy/s). The energetic response (point 4.) is normally the most crucial point, as dosimetric materials are not "equivalent to tissue". Plastic scintillators are the best from this point of view.

When the dose rate changes from fractions of Gy/s (conventional therapies) to MGy/s (flash radiotherapy), traditional dosimetric techniques fail in the most basic and important of the requirements, linearity. In fact, the enormous rates heavily modify both the mechanisms that produce the signal and the internal structure of the detector. In many cases these structural and crystalline changes are of a permanent nature and lead to irreversible degradation of the dosimeter. Traditional electron dosimetry systems such as Markus ion chambers, diodes, diamonds and scintillators/scintillating fibers stop being linear at doses per pulse of less than 1 Gy/pulse (doi: 10.3389/fphy.2020.570697).

The present invention offers a dosimeter which allows dose measurements with linear performances at dose values per pulse from Gy/pulse fractions up to at least 30 Gy/pulse while maintaining an ease of implementation that does not require expensive processes.

The invention therefore aims to solve the technical problems highlighted by the known art.

If not specifically excluded in the detailed description that follows, what is described in this chapter is to be considered as an integral part of the detailed description of the invention.

Summary of the invention

The invention relates to a dosimeter for charged particles and gamma rays, capable of operating linearly when exposed to both continuous and pulsed beams, at an instantaneous dose intensity from 0.001 MGy/s to 10 MGy/s. The dosimeter is used in the dosimetry of charged particles and gamma rays, in particular in ultra-high rate radiotherapy (flash-radiotherapy) and in industrial sterilization treatments. The invention also relates to a method of using said dosimeter.

Further purposes and advantages will become evident from the detailed description of the invention that follows, furthermore the claims describe preferred variants of the invention, forming an integral part of the present description.

Brief description of the Figures

Further purposes and advantages of the present invention will become clear from the following detailed description of an example of its embodiment (and its variants) and from the annexed drawings, provided merely for explanatory and non-limiting purposes, wherein:

• Figure 1 is a schematic representation of the dosimeter of the invention in its cylindrical embodiment;

• Figure 2 is a schematic representation of the dosimeter of the invention in its spherical embodiment;

• Figure 3 is a graph showing the linearity of the dosimeter response, in terms of dose per pulse, during its operation, when exposed to a pulsed 9 MeV beam of electrons.

Detailed description of the invention

For the purposes of the present invention, the following definitions apply.

By "dosimeter" we mean a transducer capable of providing, when exposed to a beam of ionizing radiation, an electrical signal proportional to the dose absorbed in a specific medium of interest, such as for instance water. The definition of absorbed dose is given in the ICRU Report 85a (2011 ).

By "flash radiotherapy" we mean radiotherapy wherein the beams of ionizing radiation reach the patient with dose rates greater than 40 Gy/s.

By "secondary charged particles" we mean charged particles generated by the interaction of the primary radiation beam with the materials composing the dosimeter. Said secondary charged particles generally have a different directional distribution and lower energy than the primary radiation beam. In particular, when the primary beam is made of electrons, the secondary charged particles are electrons.

By "mass thickness (measured in gem ² )" of a layer of material we mean the product of the thickness (in cm) and density (in gem ^-3 ).

By "range" of ionizing charged particles (such as electrons, protons or carbon ions) we mean the distance that said charged particles can cross in a certain material before being absorbed by the material itself.

The dosimeter according to the present invention comprises a sensor and a reading system.

By "dark current" of a dosimeter we mean the current it produces when not exposed to radiation.

"MeV" or Megaelectronvolt is used in this text to quantify the kinetic energy of elementary particles.

"MeV/u" or Megaelectronvolt per atomic mass unit is used in this text to quantify the kinetic energy of elementary particles divided by their mass measured in atomic mass units. The reading system can be a common nano-ammeter coupled to a digitizer with state- of-art sampling frequencies (at least 1 MSample/sec).

The sensor has the typical shape of Figure 1 or Figure 2.

For a better understanding of the operation, consider that the dosimeter is formed by an anode and a cathode separated by a thin layer of insulating and resistant to radiation material, said layer of insulating material having a thickness of such dimensions as to allow the secondary charged particles to cross it without being absorbed by the material itself and such as to guarantee electrical insulation and limit the dark current to negligible values compared to the expected values in the presence of the radiant field.

Anode 1 is a metal body with a mass greater than that of cathode 3. As shown in Figures 1 and 2, anode 1 has a mass much greater than that of cathode 3, typically at least 10 times greater. Cathode 3 is typically a metal coating placed externally to the layer of insulating material 2 with the purpose of collecting the charge coming from the anode, said layer 2 being interposed between anode 1 , inside the dosimeter, and cathode 3.

Imagine a radiotherapy irradiation with electron beams between 6 and 15 MeV: interacting with the material of the dosimeter, the electron beam will be diffused, i.e. perturbed in the energy distribution and in the direction of propagation. Both the anode and the cathode will act as diffusion centers for the electrons.

There will be on average, per unit of time, a certain number of electrons diffused by anode 1 which cross the insulating material 2 from inside to outside and reach cathode 3, and a certain number of electrons diffused by cathode 3 which pass through the insulator 2 and reach anode 1. The difference between the two secondary electron flows is equivalent to the current produced by the detector (useful signal) and is recorded by the nano-ammeter. If the two flows were identical, the electrical signal would be zero. In the case of the dosimeter of the invention, anode 1 has a mass greater than that of cathode 3, typically at least 10 times greater. Thus, when exposed to an electron field of such energy that the secondary electrons can cross the thickness of insulator 2, the charge imbalance produces an electrical signal. This signal, collected with a coaxial cable 5 as in Fig. 1 , has a positive polarity.

Cathode 3 will be made of a metal material with a high melting temperature, to prevent the heating during irradiation from damaging it.

It is convenient to make the anode in a metal with a high atomic number such as for instance Tungsten, Rhenium and Gold in order to maximize the number of secondary charged particles it produces during operation.

In a preferred embodiment, cathode 3 consists of a very thin coating in a conductive metal with a low atomic number, such as aluminum, to minimize the number of secondary charged particles it produces during operation.

While anode 1 preferably takes the form of a compact solid, cathode 3 preferably takes the form of a thin coating which is spatially uniformly distributed around anode 1 , and has a mass smaller than that of the anode, typically at least 10 times lower, the difference between the two masses being such as to allow the production of different quantities of secondary particles.

The greater mass of anode 1 , subjected to irradiation, will produce a greater amount of secondary particles and the smaller mass of cathode 3, subjected to the same irradiation, will produce a smaller amount of secondary particles.

The combination of the features described above in relation to cathode 3 and anode 1 allows to obtain a dosimeter for flash radiotherapy that overcomes the problems encountered with state-of-the-art devices. A non-trivial improvement with respect to the state of the art is the realization, as shown in Fig. 2, of a spherical anode 1 , which gives the dosimeter an intrinsically isotropic response, i.e. independent of the direction of arrival of the primary radiation, as required in the aforementioned "features of a radiotherapy dosimeter" (characteristic number 3).

The diameter of anode 1 ranges from 1 mm to 1 cm, in order to be dimensionally compatible with the aforementioned "features of a radiotherapy dosimeter" (characteristic number 1).

In an embodiment, the shape of anode 1 is cylindrical with a diameter and length between 1 mm and 1 cm, to be dimensionally compatible with the aforementioned "features of a radiotherapy dosimeter" (characteristic number 1).

The spherical version offers the notable advantage of providing an isotropic response, i.e. independent of the incidence direction of the primary radiation.

It is also essential that the dimensions of the dosimeter be less than one centimeter, in order to be dimensionally compatible with the aforementioned "features of a radiotherapy dosimeter" (characteristic number 1).

A dosimeter with a significantly larger size, such as a cylinder with a diameter of 5 mm and a length of 30 mm, would not be suitable for operating as a dosimeter in radiotherapy, as it would disturb the radiant field too much.

Insulator 2 has the following features:

- thickness calculated on the basis of the spectrum of secondary electrons: for electrons from 7-9 MeV mass thicknesses from 0.001 to 0.5 g cnr ² are suitable;

- irradiation resistant up to several hundred kGy, such as, for instance, radiation resistant glasses (www.schott.com), silicon carbide ceramics or radiation resistant plastics such as polyether ether ketone ( PEEK) or polyimide.

Radiotherapy dosimetry is required in the following stages:

- measurement of dose distributions in water filled dummies, during the installation of the apparatus and acceptance tests;

- routine measurements to determine the reference doses, verify the repeatability of the beam and the correctness of the TPS (treatment planning systems);

- "in vivo" tests, where the dosimeter is displayed on a patient to verify the "entry" and "exit" doses and compare them with those simulated by the TPS.

The dosimeter of the present invention therefore comprises:

- An anode 1 consisting of a metal body around which a layer of insulating material 2 is placed, said insulating material 2 capable of electrically insulating while allowing the passage of the secondary charged particles generated in anode 1 upon the passage of incident radiation;

- A cathode 3 in the form of a metal coating of said layer of insulating material 2, said cathode 3 having a smaller mass, typically at least ten times smaller than that of anode 1 , with a thickness between 0.01 and 50 micrometers;

- A coaxial cable 5 comprising an internal central conducting element connected to anode 1 and an external conducting element connected to cathode 3, said coaxial cable being able to carry the current produced by the dosimeter up to a reading system. In a further embodiment the invention also comprises a second layer of insulating material 4 placed externally to cathode 3. The aim of said second layer 4 is to ensure the easy handling of the dosimeter itself and not to contaminate or damage cathode 3.

As mentioned above, anode 1 consists of a metal body whose shape can be any, preferably spherical or cylindrical. In the case of spherical geometry, the diameter of the anode can vary from 1 to 10 mm. In the case of cylindrical geometry, the diameter and length can vary between 1 and 10 mm.

Generally, anode 1 consists of a full solid body, that is a full solid, without internal voids, as it guarantees a more efficient performance than a hollow body which, however, could still meet the pre-established operating requirements.

The thickness of the insulating layer 2 is thick enough to ensure electrical insulation and limit the dark current, but at the same time thin enough to allow the secondary charged particles to cross the layer itself. If we consider for instance 7 MeV electrons, the range of these electrons in glass is about 4 g cnr ² . Therefore, the layer of insulating material 2 could range between 0.001 g cnr ² and 0.5 g cnr ² . Thicknesses less than 0.001 g cm ^-2 would not guarantee good electrical insulation and would increase the dark current too much. Thicknesses greater than 0.5 g cnr ² would degrade the secondary electron field too much, making the dosimeter current too low, therefore not measurable.

Cathode 3 is made of a metal layer distributed in a spatially uniform manner around insulator 2. In an embodiment of the invention, cathode 3 is obtained by a micrometric deposition of gold, silver, a conductive copper spray or a micrometric film of aluminum, thus resulting in a metal coating with a thickness between 0.01 and 50 micrometers. In other words, cathode 3 is made of a metal coating with a thickness between 0.01 and 50 micrometers comprising at least one of the following elements: gold, silver, copper or aluminum.

It is not necessary that anode 1 and cathode 3 are made of the same metal material. However, it is recommended that anode 1 has a much greater mass than cathode and an atomic number higher than that of the cathode, to emphasize the difference between the respective flows of secondary charged particles. A practical example is a tungsten anode and an aluminum cathode, with anode having a greater mass, at least 10 times greater than that of the cathode. Both in the presence of a second layer of insulating material 4 and in its absence, the invention provides for a coaxial cable 5 whose internal central conductor is connected to the anode and whose external conductor is connected to cathode 1 , said coaxial cable being able to carry the current produced by the dosimeter up to the signal reading system 6 wherein said current is measured.

The reading system 6 can be made of commercial systems such as, for instance, a nano-ammeter 7 and a digitizer 8, and it is coupled, with sampling frequencies typical of commercial digital electronics of at least 1 Msample/sec.

The dosimeter can be supplied separately from the reading system, as a separate sensor, or combined with the reading system to form a ready-to-use product.

In any case, in order to be used, the assembly formed by the dosimeter and the reading system will be calibrated at a suitable calibration center, i.e. exposed to beams of charged particles or gamma rays that are very well known a priori in terms of energy, time structure, dose and dose rate, and the dosimeter reading must be related to the dose delivered during this process. The result of the calibration is a calibration coefficient which provides the dose value per dosimeter reading unit, as the energy of the charged particle beam or gamma rays varies (calibration curve).

Typically, the method of using the dosimeter according to the present invention comprises the following main steps: a. Arranging the dosimeter according to the present invention and connecting the coaxial cable 5 with a reading system of the generated signal; b. Submitting the dosimeter to calibration irradiation with a plurality of charged particle beams or gamma rays whose energy, angular distribution, time structure, dose and dose rate are known a priori ; c. Obtaining calibration curves specific to the dosimeter in use on the basis of information and data collected in step b, these curves including the dependence of the calibration coefficient on energy, on the incidence angle of charged particles or gamma rays, and on the dose rate; d. Submitting the dosimeter to irradiation with a beam of charged particles or gamma rays, with a certain energy and recording, by means of the reading system 6, the signal generated by the dosimeter in a certain time interval; e. Obtaining the dose value measured in the time interval referred to in the previous step using the calibration curves obtained in step c.

The operation of the dosimeter according to the present invention allows to carry out dose measurements during irradiation with charged particles or gamma radiation.

Specifically, it is possible to use electrons in the energy range from 0.5 MeV to 50 MeV; gamma rays in the energy range from 0.5 MeV to 50 MeV; carbon ions in the energy range from 10 to 500 MeV/u; protons in the energy range from 10 MeV to 250 MeV.

The following examples are provided to illustrate the invention and are not to be considered limitative of its scope.

Examples

The operation of the dosimeter is shown by the linearity graph of Figure 3, obtained by irradiating a dosimeter according to the present invention with an electron beam of 9 MeV and pulses having a duration of 4 microseconds each. The ordinate shows the dose measured per pulse expressed in Gy/pulse (also known as UCD measured dose per pulse); while the dose received per pulse is shown on the abscissa, (always expressed in Gy/pulse). The reading system used is made of a nano-ammeter sampled with a commercial digitizer of 2 MSamples/s.

The measurements shown in Figure 3 were performed in the 0.8-30 Gy/pulse range and show perfect linearity, clearly superior to the systems mentioned as being part of the state of the art.

Although the invention has been illustrated and described in detail in the drawings and in the foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive; the invention is defined by the appended claims and therefore not limited to the embodiments described. Variations to the embodiments described can be understood and made by those skilled in the art and practicing the claimed invention, from a study of the drawings, description and appended claims. In the claims, the word "comprising" does not exclude other elements or passages, and the indefinite article "a" or "an" does not exclude a plurality and may mean "at least one".