GB2522240A - Minimally invasive applicator for in-situ radiation dosimetry - Google Patents

Abstract

Measuring a dose of ionizing irradiation received during radiotherapy. An applicator, for example catheter or balloon, is introduced into the neighborhood of the irradiated part of the body. It contains a confined volume of radiation sensitive medium, either gas filled microbubbles or emulsion or gel with superheated droplets. Changes in the droplets or bubbles due to radiation can be noted by ultrasonic or X-ray inspection.

Description

Minimally invasive applicator for in-situ radiation dosimetry

Field of the invention

The invention relates to the field of radiation dosimetry. More specifically it relates to systems and methods for minimally invasive in-situ radiation dosimetry, in particular for in vivo dosimetry within or nearby the irradiated tissue and to a device used in said system and method.

Background of the invention

With an estimated 2,9 million new cases (54% occurring in men, 46% in women) and 1,7 million deaths (56% in men, 44% in women) each year, cancer remains a major public health problem in Europe and the rest of the world. An important modality in any therapeutic cancer strategy is irradiation of the tumor with high energy photons or particles, i.e. radiotherapy.

Developments in radiotherapy treatments have brought solutions that allow a more precise delivery of a higher dose of irradiation to the tumor with fewer side effects to healthy tissues.

Among the new techniques, including tomotherapy and cyberknife, both making use of 6MV photons, charged particle beams, i.e. hadrontherapy, play an increasingly important role, due to their intrinsic high ballistic precision. Hadrontherapy can allow a very high dose to the target volume, while keeping the dose to the surrounding healthy tissues limited.

The advancement of these treatments is thoroughly related to advances in dosimetry, to fully exploit their high tumor conformity. There are several reported cases of accidents in conventional radiotherapy treatments due to malfunctioning of the equipment, or due to human errors, as can be seen for instance in "Overview of the Major Incidents in Radiotherapy" from Dr. H. Porter) published at the British Institute of Radiology annual conference, 2012.

Unfortunately no on-line in-vivo dosimetry system is systematically in use in the clinical routine nowadays.

Prior art approaches to on-line in-vivo dosimetry, e.g. making use of diodes, MOSEET's (Metal Oxide Semiconductor Eield Effect Transistor) , diamond detectors, TLD's (Thermoluminoscent Dosimeter) or scintillators, perform a dose measurement at the level of the skin while a measurement in-situ, e.g. at the level of the tumor, would be preferable.

Certain methods are known in the radiotherapy field which enable an in-situ dose assessment using dosimeters that are implanted or inserted into cavities. For example, US2011/121188 discloses a system which comprises internally positioning single-use MOSFET dosimeters in a patient's body to evaluate the radiation dose delivered during a medical procedure or treatment session. The related patent application U52004/236207 discloses positioning single-use adhesive dosimeter patches just onto the skin of a patient. Therefore, the dosage of energy S that is planned for, often cannot be measured, determined or monitored very accurately, in the tumor itself or in the surrounding tissues. W02013/034709 discloses a system for measuring a radiation dose in and around a tumor, during radiotherapy. The system uses gas-filled microbubbles as radio-sensitive agents which undergo measurable and quantifiable changes under the influence of radiation. The quantitative measurements are performed by means of echography. The radiation sensitive microbubbles are systemically administered to the body by injection and distributed with the bloodstream. In particular embodiments, the gas-filled microbubbles may be adapted to comprise at least a binding site to direct them preferentially to the tumor tissue, e.g. by attaching them to a tumor-specific target, e.g. tumor antigen.

In US2010/0176343A1 there is described a system for in vivo dosimetry, using energy-transfer nanocomposite materials, which upon irradiation with ionizing irradiation scintillate, emitting luminescence in a particular wavelength interval. The emitted light can be captured and its intensity used as a measure of the intensity of the ionizing irradiation. The nanocomposite materials are injected into the tumor or into a blood vessel that supplies the tumor with blood. Occasionally, the nanoparticles can be targeted to the tumor tissue using tumor specific ligands.

Yet another known system for in situ dosimetry is based on the use of alanine, which is filled in capsules and placed within body cavities, e.g. within the vagina. Upon irradiation, free radicals are formed which can be detected with Electron Paramagnetic Resonance (EPR).

The system has a number of disadvantages, such as relatively low sensitivity, the fact that it is suited for measurements at discrete locations only and that EPR is not a commonly available technique. Moreover, in process measurements are impossible as the capsules have to be removed and brought into the lab for performing the EPR analysis.

Summary of the invention

Although the methods and systems disclosed in the prior art provide useful solutions for performing dosimetry under certain conditions, there still exists a need for an improved system and method for efficiently measuring a radiation dose in and around a tumor, during radiotherapy.

It is an object of the present invention to provide efficient systems and methods for minimally invasive in situ radiation dose quantification, whereby measurements can be made in a spatially continuous fashion over one, two or three dimensions, i.e. along a line, over a surface or within a volume.

The above objective is accomplished by the present invention.

In a first aspect, the present invention provides a system for measuring a radiation dose received by a pre-determined part of the body. The system comprises a) an applicator which comprises a confined volume of a radiation sensitive medium, which under the influence of ionizing irradiation undergoes measurable and quantifiable physical and/or chemical changes; b) a detector system which allows the mapping and quantification of the physical and/or chemical changes within the radiation sensitive medium, generating a responsive signal which relates to the dose of ionizing irradiation received in each part of the radiation sensitive medium; and c) a control unit which is adapted for calculating a dose of ionizing radiation previously or simultaneously received by each part of the volume of the radiation sensitive medium on basis said response signal.

Preferably, the applicator containing the radiation sensitive medium is a linear catheter or a flexible balloon which adapts itself to the geometry of a natural or surgically created cavity.

In another embodiment of the invention, concentric inflatable balloons may be used, whereby the radiation sensitive medium is filled into the space between the concentric balloons. In order to keep the thickness of the layer of radiation sensitive medium between the two balloons equal all over their surface) spacing elements may be introduced between the two balloons. These spacing elements may e.g. take the form of a raster or open tissue inserted between the balloons or they may take the form of dots or lines attached to or emanating from the outer surface of the inner balloon or the inner surface of the outer balloon. The balloons may be connected with a tube or catheter, which allows filling the balloon or the space between the concentric balloons with the radiation sensitive medium upon insertion into the cavity.

An applicator in the form of a catheter is inserted in the tissue, in a minimally invasive way. It can be positioned within the tumor to be irradiated or in the surrounding tissue.

Irradiation may be applied from an external source (external radiotherapy) or from radioactive seeds or needles which are placed within the tumor (brachytherapy). Especially with brachytherapy it is important to dispose of means to measure the steep radiation gradients at a relatively small distance from the radioactive seeds or needles. In contrast to existing technologies, e.g. the use of MOSFETS (Metal Oxide Semiconductor Field Effect Transistors), which allow quantification of radiation at single points, the system according to the current invention allows a spatially continuous measurement over a distance along the dosimetric catheter. By positioning one or more catheters in a pre-determineci way, taking into account the position of the radiation source ( external or internal in case of brachytherapy) a reliable picture can be obtained of the distribution of irradiation over the relevant tissues.

The catheters can be introduced directly into the tissue -in which case they must be made of rigid material, or they can be introduced through a hollow needle. In any event, the dimensions should be such that the insertion of the catheter can be done in a minimally invasive way.

Balloons as used in the system according to the invention can be inserted into a cavity created upon surgical removal of a tumor (e.g. in breast tumor surgery) during intraoperative radiotherapy (IORT) or brachytherapy of the breast. They can also be inserted in a natural cavity in the neighborhood of a tumor during radiotherapy, for example in the rectum during radiotherapy of the prostate or in the vagina in case of radiotherapy of the bladder. The balloons can be pre-filled with the radiation sensitive medium before insertion. However, in most instances, it will be preferable to insert the balloon in empty folded form, which requires a smaller opening to reach the target cavity. The radiation sensitive medium is then introduced upon placement of the balloon through a tube or catheter connected with it.

In case concentric balloons are used, they may again be inserted in expanded form or, preferably, in folded form, whereby the radiation sensitive medium is contained within the space between the two balloons. Subsequently, the inner balloon is expanded by filling it under appropriate pressure with a gas or a liquid) e.g. air or water, through a tube or catheter connected to the inner balloon. If desired, also the space between the two balloons can be empty at the time of insertion and subsequently filled with the radiation sensitive medium.

In order to keep the distance between the inner and outer balloon constant over their surface, it may be useful to place a grid or open tissue between the two balloons which keeps them separated at a fixed distance while still allowing sufficient space for introducing the radiation sensitive medium. Alternatively, it may be appropriate to attach dots or linear elements with the required dimensions to the outside of the inner balloon or to the inside of the outer balloon or by providing an array of dots or line as protuberances of the surface of one or both of the balloons.

If desired, in brachytherapy procedures, the radioactive seeds or needles can be fixated to the applicator before insertion, in order to easily achieve an optimal location with respect to the tissue volume to be irradiated. As a special embodiment of this technology, applicators can be shaped according to the needs of individual patients. For example, 3D printing technology would allow the production of patient specific applicators. This personalized applicator can be casted starting from a 3D segmentation performed on patients CT or MRI images. The 3D segmented volume is then converted into a CAD model that is used as input for the 3D printer. Such CAD model can be complemented with spaces for introducing radioactive sources. Also, all around the 3D model, a coating of radiation sensitive material is foreseen is order to generate, upon insertion of the radioactive sources in the applicator, a full, continuous 2D dose map, all around applicators.

The applicators must be made of materials that are acceptable for being brought in contact with living tissue. At least the outer side of the applicators must be non-irritating and non-toxic, especially when they are brought in contact with living tissue, e.g. upon insertion of a catheter in a tumor or surrounding tissue or of a balloon in a surgical cavity.

Preferably, the radiation sensitive medium is a fluid. The fluid is a liquid or semi-liquid substance (e.g. a saline solution, water or a gel or other liquid) in which a radiation sensitive material is dispersed or dissolved. As radiation sensitive materials for the purpose of this invention may be used materials which undergo quantifiable physical or chemical changes under the influence of ionizing radiation, including gamma radiation, X-rays, alpha particles, neutrons, beta particles and charged particles in general.

As a consequence of exposure to ionizing radiation, the physical and/or chemical properties of the medium are modified in such a way that these changes can be recorded non-invasively is situ, using e.g. a clinical ultrasound system and/or a clinical digital radiography system (or a CT scanner) or an MRI scanner. Alternatively, the catheter and or/or the balloon(s) can be extracted and analyzed ex-vivo, using for instance optical tomography.

As radiation sensitive materials for the purpose of the invention there may be used, for example, superheated emulsions. Such emulsions are composed of supercritical droplets composed of a liquid with a relatively low boiling point, such as a perfluorocarbon. The supercritical droplets evaporate when triggered by an external energy contributing event, such as ionizing radiation (such as X-rays, gamma rays, neutrons, alpha and beta particles etc.) and the change can be measured by means of a CT scanner ("Viability of 2D neutron-sensitive superheated emulsions for active cargo interrogation", F. d'Errico and A. Di Fulvio, EN EA report RdS/2011/173).

The superheated droplets may be suspended as such in a gel medium or they may be encapsulated by a surfactant or polymeric shell, such as e.g. dextran or hyaluronic acid. The droplets may be in a stable or in a metastable state.

In another embodiment of the invention, gas-filled microparticles, as described in PCTJEP2O12/067539, which is incorporated herein by reference) are used. Under the influence of ionizing irradiation, the physical and chemical properties of the microparticles undergo changes which can be detected and quantified by means of ultrasound. Preferably said parameters comprise one or more parameters selected from the group consisting of phase velocity, attenuation and nonlinearity. Measurements are performed by directing an energy wave that comprises emitting an ultrasonic or RE wave and detecting a response signal comprises detecting and quantifying the ultrasonic or RE response signal.

Preferably determining the radiation dose includes determining a spatial distribution, e.g. a linear, planar and/or a volumetric distribution, of the radiation dose.

The control unit may be equipped for calculating a dose of ionizing radiation received throughout the volume of the radiation sensitive medium. The control unit will capture the response signal received or generated by the detection system and transform it in a numerical or graphical dataset which reflects the dose of irradiation received at different locations within the volume of the radiation sensitive medium contained in the applicator. By comparing the dose determined this way and comparing it with the treatment protocol, adaptations can be made which allow optimization of the procedure.

Compared with systems that use systemically injected radiation sensitive materials as described in W020131034709 or US2010/0176343A1, the system according to the invention has the advantage of providing a much more stable localization and concentration of the radiation sensitive material. Indeed, systemically injected particles are subject to, sometimes rapid, elimination or redistribution, necessitating repeated re-calibration. Moreover, unlike with injected materials, which remain in the body and are distributed in the systemic circulation, the applicators according to the invention, i.e. catheters or are removed after the procedure. Hence, safety concerns with respect to the materials used are minimal.

Biocompatible materials for constructing the catheters or balloons are amply available, such as, for example, polymers like polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC), polyethersulfone (PES), polyurethane (PU), polyvinyl alcohol (PVA), polyethylene glycol (PEG), polyethylene oxide (PEO) etc. At no point in time, the radiation sensitive material itself comes in contact with the living tissue and hence there are much less concerns with respect to their safety.

Compared with inserted single point sensors like MOSFETS, the system according to the invention has the advantage that measurements can be performed in a spatially continuous and uninterrupted fashion in one, two or three dimensions. This allows the identification and quantification of radiation gradients within or near the tumor, along a line, over a given surface or within a three-dimensional volume. This is especially useful in combination with brachytherapy, where radiation gradients near the inserted seeds or needles can be very steep.

When using superheated droplets of gas-filled microbubbles as radiation sensitive materials, the cumulated effect of ionizing irradiation is measured. Compared with systems which measure a radiation intensity at a given point in time only, as is the case with MOSFETs diodes or scintillation luminescence particles, there is no need to perform measurements continuously in order to determine the cumulative dose of radiation received. Hence, the radiation sensitive medium itself acts as a memory that keeps a record of the total dose of irradiation received at any point in time.

Depending on the type of treatment, the device will be kept in place only for a few minutes (as in IORT) or for several days (in brachytherapy). After each fraction of irradiation, dosimetry is performed. This is achieved by acquiring ultrasound images and/or radiography images of the radiation sensitive medium within the device and quantifying the change in attenuation (for example) obtained as a result of exposure of the radiation sensitive medium to ionizing irradiation. Dose measurements can be made along lines (using catheters), over a surface (using concentric balloons), or over sections or within volumes (using balloons).

The spatial resolution of the measurements will depend on the radiation sensitive material used and on the nature of the imaging device used, whereby the resolution of a CT scan is in general higher than that of ultrasound.

Differences between the actual delivered dose, as recorded by the device, and the calculated dose can therefore be detected and corrected in time. More specifically, for patients undergoing single IORT treatment with doses of about 20 Gy, online measurements can be foreseen in order to adapt the treatment where needed. For patients undergoing multiple fractions, receiving typically doses of about 5 Gy per fraction and twice a day, a close check can be performed after each fraction, so that the treatment can be adapted if needed. In this way a fully adaptive treatment can be achieved.

In a second aspect, the invention comprises a method of measuring a dose of ionizing radiation received at a given location within or near tumor tissue, using a system as described hereinabove.

In a third aspect the invention comprises an applicator for use in radiation dosimetry as part of a system as described herein. In a preferred embodiment, the applicator is in the form of a catheter or a balloon filled with a radiation sensitive medium.

In a preferred embodiment, the radiation sensitive medium comprises superheated droplets which underthe influence of ionizing irradiation undergo a phase transition which can be measured by means of CT imaging.

In an alternative embodiment, the radiation sensitive medium comprises gas-filled microbubbles which under the influence of ionizing irradiation undergo physical and/or chemical changes which can be measured by means of ultrasound imaging equipment.

In a specific embodiment, the applicator has the form of a flexible balloon which is inserted into a surgical or natural cavity within or near irradiated tissue and contains a volume of a radiation sensitive medium.

In an alternative embodiment, the applicator has the form of two concentric balloons, whereby the space between the balloons is filled with a volume of a radiation sensitive medium.

In a particular embodiment, the distance between the two concentric balloons is kept uniform by inserting between the concentric balloons a grid or open tissue.

In yet another embodiment, the distance between the concentric balloons is kept constant by attaching arrays of dots or lines to the outside of the inner balloon or to the inside of the outer balloon.

In a more preferred embodiment, the distance between the concentric balloons is kept constant by providing arrays of dots or lines as protuberances of the surface of one or both of the concentric balloons.

The invention is further supported by the following examples which are intended to illustrate and not to limit the scope thereof:

Example 1

A tissue equivalent phantom is used in this example. Such phantom allows dose monitoring at different places/organs, upon external irradiation or insertion of one or more brachytherapy sources in the phantom.

A brachytherapy balloon applicator is inserted in the phantom, at the position of one of the critical organs (rectal wall for instance). The balloon is filled with a viscous emulsion containing superheated droplets, with a radius in the order of 1 xm.

Several lr-192 sources are then inserted in the phantom in order to deliver a dose fraction, according to what planned by the computer based treatment planning system.

Upon exposure to radiation, the superheated droplets evaporate) generating gas bubbles inside the balloon. The bubbles have a mean diameter of several jim. As such they can be imaged using conventional clinical ultrasound scanners. Such bubbles are locally "freezed" by the viscous emulsion.

After dose exposure, an ultrasound clinical scanner is used to perform imaging of the balloon. The intensity of the backscattered signal, proportional to the bubbles concentration, gives information on the absorbed dose. This way a correct monitoring of the dose to critical organs can be carried out eventually resulting in an optimized treatment.

Example 2

A tissue equivalent phantom is used also in this example. Such phantom allows dose monitoring at different places/organs) upon external irradiation or insertion of one or more brachytherapy sources in the phantom.

We consider a brachytherapy treatment of the breast. Several catheters are placed in the phantom, at the location of the breast, in order to host lr-192 sources. These source catheters are all parallel. This source distribution is associated to a sharp dose decrease when moving further from the catheters (i.e. high dose gradient).

In order to monitor the dose gradients, ideally a continuous measurement along a line transversal to the direction of the sources, must be used. To this end, one or more catheters are inserted, transversally to the sources. The catheters are filled with a viscous gel, containing superheated droplets, with a radius in the order to 50 to 100 pm.

when inserting the lr-192 sources in the catheters, sharp dose gradients are created, in particular orthogonally to the direction of the sources. This will eventually result in the formation of bubbles in the dosimetric catheters. Such bubbles are locally "freezed" by the viscous emulsion hosting the droplets. The bubbles will have a mean diameter in the order to 0.5 to 1 mm.

A CT tomographic image of the phantom is acquired. On such image, bubbles are automatically segmented and then counted, voxel by voxel. The amount of bubbles per voxel gives the locally absorbed dose.

Claims (2)

1. CLAIMS1) A system for measuring a dose of ionizing irradiation received by a pre-determined part of the body during radiotherapy which comprises: a) an applicator to be introduced in or in the neighborhood of the irradiated part of the body containing a confined volume of a radiation sensitive medium, which under the influence of ionizing irradiation undergoes measurable physical and/or chemical changes; b) a detector system which allows measuring the physical and/or chemical changes within the radiation sensitive medium by sending an energy wave to the radiation sensitive medium and capturing the signal emitted therefrom; and c) a control unit which is adapted for processing the signal captured by the detector system and calculating a dose of ionizing radiation previously or simultaneously received by each part of the volume of the radiation sensitive medium on basis said signal.
2. 2) A system according to claim 1) wherein said applicator is a catheter 3) A system according to claim 1) wherein said applicator is a balloon 4) A system according to claim 1) wherein said applicator comprises two concentric balloons.5) A system according to any of the claims 1) to 4) wherein the radiation sensitive medium comprises a suspension of superheated droplets.6) A system according to claim 5) wherein the superheated droplets are encapsulated by a polymeric shell.7) A system according to any of the claims 5) and 6) wherein the superheated droplets are in a stable state.8) A system according to any of the claims 5) and 6) wherein the superheated droplets are in a metastable state.9) A system according to any of the claims 1) to 4) wherein the radiation sensitive medium comprises a suspension of gas-filled microbubbles 10) A system according to claim 9) wherein the detector system is a CT scanner 11) A system according to claim 10) wherein the detector system is an ultrasound scanner 12) A method of measuring a dose of ionizing irradiation received in a pre-determined part of the body during radiotherapy which comprises: a) Introducing an applicator into or in the neighborhood of irradiated tissue, whereby said applicator contains a confined volume of a radiation sensitive medium, which under the influence of ionizing irradiation undergoes measurable physical and/or chemical changes; b) capturing a signal emitted by the radiation sensitive medium elicited by an energy wave sent by the detector system to said radiation sensitive medium whereby said emitted signal has characteristics that reflect the physical and/or chemical changes of the radiation sensitive medium under the influence of ionizing irradiation; and c) Processing the signal captured by the detector system in a control unit and calculating the dose of ionizing irradiation received by any part of the radiation sensitive medium on basis of said signal.13) A device for use in the method according to claim 12) which comprises an applicator aimed at being introduced into or in the neighborhood of irradiated tissue, whereby said applicator contains a volume of a radiation sensitive medium which under the influence of ionizing irradiation undergoes measurable physical and/or chemical changes.14) A device according to claim 13) wherein said applicator is in the form of a catheter 15) A device according to claim 13) wherein said applicator is in the form of a balloon 16) A device according to claim 13) wherein said applicator comprises two concentric balloons 17) A device according to claim 13) wherein said applicator is patient specific i.e. it is produced starting from MRI or CT patients images and using 3D printing technology.