Patent Description:
For treating glioblastoma, the TTFields are delivered to patients via four transducer arrays <NUM>-<NUM> that are placed on the patient's skin in close proximity to a tumor (e.g., as depicted in <FIG> for a person with glioblastoma). The transducer arrays <NUM>-<NUM> are arranged in two pairs, and each transducer array is connected via a cable to an AC signal generator. The AC signal generator (a) sends an AC current through one pair of arrays <NUM>, <NUM> during a first period of time, which induces an electric field with a first direction through the tumor; then (b) sends an AC current through the other pair of arrays <NUM>, <NUM> during a second period of time, which induces an electric field with a second direction through the tumor; then repeats steps (a) and (b) for the duration of the treatment.

In the context of glioblastoma, conventional solutions (e.g., NovoTAL software from Novocure) are available for determining where the transducer arrays <NUM>-<NUM> should be placed on a subject's head in order to maximize the field strength within the tumor. But because the prior art solutions are only concerned with the field distribution within the tumor, none of the prior art solutions addressed the uniformity of the electric field in other regions of the brain.

<CIT> discloses systems and methods for determining placement of a transducer array relative to a subject's head, which may be used in treating cancer in the subject.

One aspect of the invention is directed to a method of determining recommended positions for sets of electrode elements on a person's head according to claim <NUM>.

Many types of cancer (e.g., lung, breast, colon, kidney and melanoma) can metastasize to the brain. TTFields can be used to treat and prevent metastases, as described in <CIT>.

Because one never knows in advance the exact location within the brain that a metastasis may appear, a good way to prevent or treat metastases is to treat as much of the brain as possible with TTFields. Keeping the field strength as uniform as possible within the entire brain can maximize the percentage of the brain that receives a field strength large enough to prevent or treat the metastases, while preventing the transducer arrays from getting too hot and also conserving battery power. Consistent with these objectives, this application discloses a variety of configurations for arranging the transducer arrays on a person's head to impose TTFields in the brain at field strengths that are as uniform as possible throughout the entire brain (including the infratentorial regions of the brain).

<FIG> depict the conventional layout for positioning transducer arrays on a person's head for treating glioblastoma using TTFields. With this layout, the AC signal generator first applies an AC voltage across the front/back pair of transducer arrays <NUM>, <NUM>, then applies an AC voltage across the right/left pair of transducer arrays <NUM>, <NUM>, and then repeats that two-step sequence for the duration of the treatment. As tabulated below, the uniformity of field intensity for this conventional layout is relatively low. One of the main reasons for the low uniformity is that the field strengths are quite low in the infratentorial regions of the brain.

<FIG> depict one set of improved layouts for positioning transducer arrays on a person's head for preventing metastases using TTFields. More specifically, <FIG> shows that the first set of electrode elements <NUM> is affixed to a person's head on a right side of the mid-sagittal plane, superior to the external opening of the person's right ear canal; <FIG> shows that the second set of electrode elements <NUM> is affixed to the person's body on a left side of the mid-sagittal plane and behind the mid-coronal plane, with its centroid positioned inferior to an external opening of the person's left ear canal, and superior to the midpoint of the person's C2 vertebra; <FIG> shows that the third set of electrode elements <NUM> is affixed to the person's head on a left side of the mid-sagittal plane, superior to the external opening of the person's left ear canal; and <FIG> shows that the fourth set of electrode elements <NUM> is affixed to the person's body on a right side of the mid-sagittal plane and behind the mid-coronal plane, with its centroid positioned inferior to an external opening of the person's right ear canal, and superior to the midpoint of the person's C2 vertebra. With this layout, the AC signal generator first applies an AC voltage across the first and second sets of electrode elements <NUM>, <NUM>, then applies an AC voltage across the third and fourth sets of electrode elements <NUM>, <NUM>, and then repeats that two-step sequence for the duration of the treatment. As tabulated below, the uniformity of field intensity for this alternative layout is significantly higher than in the conventional <FIG> layout.

<FIG> depict another set of improved layouts for positioning transducer arrays on a person's head for preventing metastases using TTFields. This layout is similar to the <FIG> layout, except that the second and fourth sets of electrode elements <NUM>, <NUM> are positioned lower down on the person's body. More specifically, <FIG> shows that the first set of electrode elements <NUM> is affixed to a person's head on a right side of the mid-sagittal plane, superior to the external opening of the person's right ear canal; <FIG> shows that the second set of electrode elements <NUM> is affixed to the person's body on a left side of the mid-sagittal plane and behind the mid-coronal plane, with its centroid positioned inferior to the midpoint of the person's C2 vertebra and superior to the person's C7 vertebra; <FIG> shows that the third set of electrode elements <NUM> is affixed to the person's head on a left side of the mid-sagittal plane, superior to the external opening of the person's left ear canal; and <FIG> shows that the fourth set of electrode elements <NUM> is affixed to the person's body on a right side of the mid-sagittal plane and behind the mid-coronal plane, with its centroid positioned inferior to the midpoint of the person's C2 vertebra and superior to the person's C7 vertebra. With this layout, the AC signal generator first applies an AC voltage across the first and second sets of electrode elements <NUM>, <NUM>, then applies an AC voltage across the third and fourth sets of electrode elements <NUM>, <NUM>, and then repeats that two-step sequence for the duration of the treatment. As tabulated below, the uniformity of field intensity for this alternative layout is also significantly higher than in the conventional <FIG> layout.

<FIG> depict yet another set of improved layouts for positioning transducer arrays on a person's head for preventing metastases using TTFields. More specifically, <FIG> shows that the first set of electrode elements <NUM> is affixed to a right side of the person's head. The first set of electrode elements <NUM> has an upper section <NUM> positioned above (i.e., superior to) the external opening of the person's right ear canal with an orientation that is predominantly horizontal, and a rear section 41V positioned behind the external opening of the person's right ear canal with an orientation that is predominantly vertical. <FIG> shows that the second set of electrode elements <NUM> is affixed to a left side of the person's head. The second set of electrode elements has an upper section <NUM> positioned above the external opening of the person's left ear canal with an orientation that is predominantly horizontal, and a rear section 42V positioned behind the external opening of the person's left ear canal with an orientation that is predominantly vertical. <FIG> show that the third set of electrode elements <NUM> is affixed to the person's head with its centroid positioned on top of the person's head; and <FIG> shows that the fourth set of electrode elements <NUM> is affixed to the back of the person's neck with its centroid positioned below the person's C2 vertebra and above the person's C7 vertebra. With this layout, the AC signal generator first applies an AC voltage across the first and second sets of electrode elements <NUM>, <NUM>, then applies an AC voltage across the third and fourth sets of electrode elements <NUM>, <NUM>, and then repeats that two-step sequence for the duration of the treatment. As tabulated below, the uniformity of field intensity for this alternative layout is also significantly higher than in the conventional <FIG> layout.

Optionally, in the <FIG> layout, the upper section <NUM> of the first set of electrode elements includes at least three capacitively coupled electrode elements, the rear section 41V of the first set of electrode elements includes at least three capacitively coupled electrode elements, the upper section <NUM> of the second set of electrode elements includes at least three capacitively coupled electrode elements, and the rear section 42V of the second set of electrode elements includes at least three capacitively coupled electrode elements. In alternative embodiments, each of those sections <NUM>, 41V, <NUM>, 42V can include a different number of electrode elements (e.g., between <NUM> and <NUM>).

Optionally, in the <FIG> layout, the upper section of each of the first and second sets of electrode elements (a) has a length of at least <NUM>, (b) is positioned less than <NUM> above the external opening of the respective ear canal, (c) has a front end positioned at least <NUM> in front of the external opening of the respective ear canal, and (d) has a rear end positioned at least <NUM> behind the external opening of the respective ear canal.

Optionally, in the <FIG> layout, the rear section of each of the first and second sets of electrode elements (a) has a length of at least <NUM>, (b) is positioned less than <NUM> behind the external opening of the respective ear canal, (c) has an upper end positioned at least <NUM> above the external opening of the respective ear canal, and (d) has a rear end positioned at least <NUM> below the external opening of the respective ear canal.

Optionally, in the <FIG> layout, the third set of electrode elements is affixed with its centroid positioned between <NUM> and <NUM> anterior to a vertex of the person's head.

Optionally, in the <FIG> layout, the fourth set of electrode elements is affixed with its centroid positioned below the person's C3 vertebra and above the person's C6 vertebra.

<FIG> depicts a block diagram of a system that includes an AC voltage generator <NUM> that may be used to apply the AC voltage across the first and second sets of electrode elements (<NUM>/<NUM>, <NUM>/<NUM>, and <NUM>/<NUM> in <FIG>, <FIG>, and <FIG>, respectively) and across the third and fourth sets of electrode elements (<NUM>/<NUM>, <NUM>/<NUM>, and <NUM>/<NUM> in <FIG>, <FIG>, and <FIG>, respectively) in an alternating sequence as described above in connection with <FIG> above.

For each of the transducer array layouts depicted above, electric fields were simulated using a realistic human head model extending as far as the shoulders. In the simulations, transducer arrays with <NUM> capacitively coupled disc-shaped electrode elements, each having a diameter of <NUM>, were placed on the locations on the body described above in connection with <FIG>, and a constant current of 2A peak-to-peak with a <NUM> frequency was applied to the outer surfaces of the disks. The simulations were performed using Sim4Life version <NUM> platform (ZMT-Zurich). To analyze the uniformity of the electric field, the brain was divided into five compartments as depicted in <FIG>: the infratentorial areas "in" (including the cerebellum and brain stem), and four compartments for the upper brain - front-right α, front-left β, rear-left γ, and rear-right δ. The boundaries between these regions of the brain are depicted in <FIG>. The field intensity was calculated for each voxel in each of the five compartments using finite element simulation. For each compartment the mean and median field intensities of all voxels in the compartment were calculated. Data was taken only for grey and white matter cells.

For each pair of transducer arrays in each of the layouts depicted above, ψ was defined as the standard deviation between the mean of the different compartments divided by the average of the different compartments, as follows.

In these three equations, SD stands for standard deviation; µi is the mean of each compartment; α, β, γ and δ are the cerebral compartments (see <FIG>); and "in" is the cerebellum / brain stem compartment (see <FIG>).

The value of ψ obtained (in percent) for each individual pair of transducer arrays are presented in Table <NUM> below.

Based on the results in Table <NUM>, when only a single pair of transducer arrays is used to impose a field in a person's brain, the two best layouts for positioning the transducer arrays to obtain the highest uniformity throughout the brain are the layouts <NUM>/<NUM> (depicted in <FIG>); and the layouts <NUM>/<NUM> (depicted in <FIG>).

Next, for each set of the transducer array layouts depicted in <FIG>, the uniformity of the field created throughout the brain was evaluated by using finite element simulation to calculate the field strength at each voxel in the brain in the following two situations: (a) when an AC voltage is applied across the first and second sets of electrode elements (<NUM>/<NUM>, <NUM>/<NUM>, <NUM>/<NUM>, and <NUM>/<NUM>, in <FIG>, <FIG>, <FIG>, and <FIG>, respectively), and (b) when an AC voltage is applied across the third and fourth sets of electrode elements (<NUM>/<NUM>, <NUM>/<NUM>, <NUM>/<NUM>, and <NUM>/<NUM>, in <FIG>, <FIG>, <FIG>, and <FIG>, respectively). Then, for each voxel in the brain, the field strength result for situation (a) and the field strength result for situation (b) were averaged.

After obtaining the average field strength at each voxel in the brain, ψ was calculated using the same three equations that were used to calculate ψ described above in connection with Table <NUM>. Except this time, instead of using a single field strength for each voxel in the brain as the input to the equations, an average of two field strengths for each voxel in the brain was used as the input to the equations.

The value of ψ obtained for each set of four transducer arrays (in percent) are presented in Table <NUM> below. These values are based on the assumption that the field is applied between the first and second transducer arrays in any given set half the time, and between the third and fourth transducer arrays in the given set the other half of the time.

Based on the results in Table <NUM>, when two pairs of transducer arrays are used to impose a field in a person's brain, with each pair being energized <NUM>% of the time in an alternating sequence, the two best layouts for positioning the transducer arrays to obtain the highest uniformity throughout the brain are (<NUM>) the layouts <NUM>/<NUM> combined with <NUM>/<NUM> (as depicted in <FIG>); and (<NUM>) the layouts <NUM>/<NUM> combined with <NUM>/<NUM> (as depicted in <FIG>).

Additional data for the transducer array layouts depicted above in <FIG> are provided below. For the positioning of the transducer arrays <NUM>/<NUM> depicted in <FIG>, the data was as shown below in Table <NUM>.

For the positioning of the transducer arrays <NUM>/<NUM> depicted in <FIG> the data was as shown below in Table <NUM>.

For the positioning of the transducer arrays <NUM>/<NUM> depicted in <FIG>, the data was as shown below in Table <NUM>.

In the embodiments depicted in <FIG>, <FIG>, and <FIG>, each set of electrode elements is configured as a <NUM> x <NUM> array of individual electrode element discs. As a result, in these embodiments, the centroid of the respective set will coincide with the center of the center disc. But in alternative embodiments, each set of electrode elements may include a different number of electrode elements. For example, a given set of electrode elements may be configured as a <NUM> x <NUM> array of individual electrode element discs. In this situation, the centroid could be in a region that is located between all four disks. In other alternative embodiments, a given set of electrode elements may include only a single electrode element disc (which may be any suitable shape including but not limited to round and rectangular). In this situation, the centroid would coincide with the center of that single electrode element.

In the embodiments depicted in <FIG>, all four sets of electrode elements are preferably capacitively coupled to the person's body. After affixing the first, second, third, and fourth sets of electrode elements as described above for the respective embodiments, the following steps are repeated in an alternating sequence: (a) applying an alternating voltage between the first set of electrode elements and the second set of electrode elements, and (b) applying an alternating voltage between the third set of electrode elements and the fourth set of electrode elements. In some embodiments, the frequency of these alternating voltages is between <NUM> and <NUM>.

For the embodiments described above in connection with <FIG>, the values provided in Tables <NUM>-<NUM> were obtained by simulating the electric fields that are obtained when each of the four sets of electrode elements was positioned as depicted in <FIG>. Note, however, that the positions of each set of electrode elements may be varied from the exact locations depicted in those figures, as long as the movement is small enough so that the respective anatomic description above remains unchanged. For example, the first set of electrode elements <NUM> depicted in <FIG> can move up, down, or to either side, as long as it remains affixed to a person's head on a right side of the mid-sagittal plane, superior to the external opening of the person's right ear canal. Similarly, the second set of electrode elements <NUM> depicted in <FIG> can move up, down, or to either side, as long as it remains affixed to the person's body on a left side of the mid-sagittal plane and behind the mid-coronal plane, with its centroid positioned inferior to an external opening of the person's left ear canal, and superior to the midpoint of the person's C2 vertebra. Within this limited range of movement, the optimum position of each of the four sets of electrode elements may be determined using simulations (e.g., finite element simulations) for each individual person to calculate the resulting electric field for each combination of positions for the various sets of electrodes, and selecting the combination that provides the best results (e.g., the highest uniformity of the field throughout the brain, or the smallest ψ). An indication of the selected combination is then output to the care provider using, for example, a suitable display or printout. The care provider will then apply the sets of electrode elements to the person at the positions indicated by the output, hook the sets of electrode elements up to the AC signal generator <NUM>, and commence treatment.

<FIG> depicts an apparatus that may be used to implement either the first set of electrode elements <NUM> that is affixed to the right side of the person's head (shown in <FIG>) or the second set of electrode elements <NUM> that is affixed to the left side of the person's head (shown in <FIG>).

This apparatus is used for applying an alternating electric field to a person's brain, and it comprises a flexible backing <NUM> having an outer side <NUM> (hidden in <FIG>) and an inner side <NUM>. The flexible backing <NUM> is configured for affixation to a side of the person's head with the inner side <NUM> facing the person's head. Suitable materials for the flexible backing include cloth, foam, and flexible plastic (e.g., similar to corresponding materials used in bandages). The flexible backing has a first arm <NUM> with a length of at least <NUM> in a first direction d1 and a second arm with a length of at least <NUM> in a second direction d2.

A first plurality of capacitively coupled electrode elements <NUM> is positioned on the inner side <NUM> of the first arm <NUM> of the flexible backing <NUM>, and each of the first plurality of capacitively coupled electrode elements <NUM> has a conductive plate 81c with a dielectric layer disposed thereon that faces inward. A second plurality of capacitively coupled electrode elements <NUM> is positioned on the inner side <NUM> of the second arm <NUM> of the flexible backing <NUM>, and each of the second plurality of capacitively coupled electrode elements <NUM> has a conductive plate 82c with a dielectric layer disposed thereon that faces inward. The electrode elements <NUM>, <NUM> may be similar to the conventional electrode elements used in the Novocure Optune® system. Optionally, temperature sensors (e.g., thermistors) may be positioned beneath some or all of the electrode elements <NUM>, <NUM> in a manner that is similar to the conventional arrangement used in the Novocure Optune® system.

A first set of conductors <NUM> connects to the conductive plates 81c of each of the first plurality of capacitively coupled electrode elements <NUM> in parallel, and a second set of conductors <NUM> connects to the conductive plates 82c of each of the second plurality of capacitively coupled electrode elements <NUM> in parallel. The conductors <NUM> may be implemented using, for example, discrete wiring or using traces on a flex circuit. A layer of adhesive (indicated by the dotted pattern) is positioned on the inner side <NUM> of the flexible backing <NUM>, and this adhesive is configured to hold portions of the flexible backing <NUM> that are not covered by any of the electrode elements <NUM>, <NUM> against the person's head.

In the embodiment depicted in <FIG>, the first plurality of electrode elements <NUM> has four electrode elements and the second plurality of electrode elements <NUM> has three electrode elements. However, in alternative embodiments, the number of electrode elements in each of the first and second pluralities of electrode elements can vary (e.g., between <NUM> and <NUM>).

In the embodiment depicted in <FIG>, the angle θ between the first direction d1 and the second direction d2 is <NUM>°. However, in alternative embodiments, that angle θ can be between <NUM>° and <NUM>°, or between <NUM>° and <NUM>°.

Note that in the orientation depicted in <FIG>, the apparatus is suited for use as the second set of electrodes <NUM> that is positioned next to the left ear in <FIG>, with the first and second pluralities of electrode elements <NUM>, <NUM> in <FIG> corresponding to the upper/horizontal arm <NUM> and the rear/vertical arm 42V, respectively, in <FIG>. But if the backing <NUM> is rotated clockwise by <NUM>° with respect to the orientation shown in <FIG>, the same apparatus would then be suited for use as the first set of electrodes <NUM> that is positioned next to the right ear in <FIG>. More specifically, after a <NUM>° clockwise rotation, the first plurality of electrode elements <NUM> in <FIG> would correspond to the rear/vertical arm 41V in <FIG>, and the second plurality of electrode elements <NUM> in <FIG> would correspond to the upper/horizontal arm <NUM> in <FIG>.

Claim 1:
A method of determining recommended positions for sets of electrode elements on a person's head, the method comprising:
simulating affixation of a first set of electrode elements (<NUM>) to one, right side of the person's head at a first plurality of positions;
simulating affixation of a second set of electrode elements (<NUM>) to the other, left side of the person's head at a second plurality of positions;
simulating application of an alternating voltage between the first set of electrode elements (<NUM>) and the second set of electrode elements (<NUM>) at each of the first plurality of positions and each of the second plurality of positions, respectively;
determining, based on the step of simulating application of an alternating voltage between the first and second sets of electrode elements (<NUM>,<NUM>), an alternating electric field in the person's brain for each of the first plurality of positions and the second plurality of positions; and
outputting, based on the step of determining results from the first and second pluralities of positions, a recommended position for the first set of electrode elements (<NUM>) and a recommended position for the second set of electrode elements (<NUM>), wherein the recommended positions for the first and second sets of electrode elements (<NUM>, <NUM>) are output as a display or printout;
characterized in that:
the first set of electrode elements (<NUM>) have a first, upper section (<NUM>) for positioning above the external opening of the ear canal in the one side with an orientation that is predominantly horizontal, and a second, rear section (41V) for positioning behind the external opening of the ear canal in the one side with an orientation that is predominantly vertical;
the second set of electrode elements (<NUM>) have a first, upper section (<NUM>) for positioning above the external opening of the ear canal in the other side with an orientation that is predominantly horizontal, and a second, rear section (42V) for positioning behind the external opening of the ear canal in the other side with an orientation that is predominantly vertical; and
the step of determining results from the first and second pluralities of positions determines which of the first and second pluralities of positions results in an alternating electric field in the person's brain with high uniformity.!