Patent Description:
Tumor Treating Fields, or TTFields, are low intensity (e.g., <NUM>-<NUM> V/cm) alternating electrical fields within the intermediate frequency range (<NUM>-<NUM>). This non-invasive treatment targets solid tumors and is described in <CIT>. TTFields disrupt cell division through physical interactions with key molecules during mitosis. TTFields therapy is an approved mono-treatment for recurrent glioblastoma, and an approved combination therapy with chemotherapy for newly diagnosed patients. Conventionally, these electrical fields are induced non-invasively by transducer arrays (i.e., arrays of electrodes) placed directly on the patient's scalp. TTFields also appear to be beneficial for treating tumors in other parts of the body.

<CIT> discloses a system for treating tumors comprising an extracorporeal part and an intracorporeal part, where the intracorporeal part comprises a subcutaneous module connected to an implant.

<CIT> discloses medical device systems which include electric field shaping elements for use in treating cancerous tumors within bodily tissue.

In one aspect the present invention provides a system according to claim <NUM>.

Additional advantages of the invention will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

These and other features of the preferred embodiments of the invention will become more apparent in the detailed description in which reference is made to the appended drawings wherein:.

The disclosed system and method may be understood more readily by reference to the following detailed description of particular embodiments and the examples included therein and to the Figures and their previous and following description.

It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

It must be noted that as used herein and in the appended claims, the singular forms "a", "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an electrode" includes one or more of such electrodes, and so forth.

"Optional" or "optionally" means that the subsequently described event, circumstance, or material may or may not occur or be present, and that the description includes instances where the event, circumstance, or material occurs or is present and instances where it does not occur or is not present.

When such a range is expressed, also specifically contemplated and considered disclosed is the range from the one particular value and/or to the other particular value unless the context specifically indicates otherwise. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another, specifically contemplated embodiment that should be considered disclosed unless the context specifically indicates otherwise. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint unless the context specifically indicates otherwise. Finally, it should be understood that all of the individual values and subranges of values contained within an explicitly disclosed range are also specifically contemplated and should be considered disclosed unless the context specifically indicates otherwise. The foregoing applies regardless of whether in particular cases some or all of these embodiments are explicitly disclosed.

Optionally, in some aspects, when values are approximated by use of the antecedents "about," "substantially," "approximately," or "generally," it is contemplated that values within up to <NUM>%, up to <NUM>%, up to <NUM>%, or up to <NUM>% (above or below) of the particularly stated value or characteristic can be included within the scope of those aspects.

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed apparatus, system, and method belong. Although any apparatus, systems, and methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present apparatus, system, and method, the particularly useful methods, devices, systems, and materials are as described.

As used herein, the term "patient" refers to a human or animal subject who is in need of treatment using the disclosed systems and devices.

As used herein, the term "electrode" refers to any structure that permits generation of an electric potential, electric current, or electrical field as further disclosed herein. Optionally, an electrode can comprise a transducer. Optionally, an electrode can comprise a non-insulated portion of a conductive element.

Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising" and "comprises," means "including but not limited to," and is not intended to exclude, for example, other additives, components, integers or steps. In particular, in methods stated as comprising one or more steps or operations it is specifically contemplated that each step comprises what is listed (unless that step includes a limiting term such as "consisting of'), meaning that each step is not intended to exclude, for example, other additives, components, integers or steps that are not listed in the step.

<FIG> shows an example apparatus <NUM> for electrotherapeutic treatment. Generally, the apparatus <NUM> can be a portable, battery or power supply operated device that produces alternating electrical fields within the body by means of transducer arrays or other electrodes. The apparatus <NUM> can comprise an electrical field generator <NUM> and one or more electrode (e.g., transducer) arrays <NUM>, each comprising a plurality of electrodes <NUM>. The apparatus <NUM> can be configured to generate tumor treating fields (TTFields) (e.g., at <NUM>) via the electrical field generator <NUM> and deliver the TTFields to an area of the body through the one or more electrode arrays <NUM>. The electrical field generator <NUM> can be a battery and/or power supply operated device.

The electrical field generator <NUM> can comprise a processor <NUM> in communication with a signal generator <NUM>. The electrical field generator <NUM> can comprise control software <NUM> configured for controlling the performance of the processor <NUM> and the signal generator <NUM>. Although depicted as being within the electrical field generator <NUM>, it is contemplated that the processor <NUM> and/or control software <NUM> can be provided separately from the electrical field generator, provided the processor is communicatively coupled to the signal generator and configured to execute the control software.

The signal generator <NUM> can generate one or more electric signals in the shape of waveforms or trains of pulses. The signal generator <NUM> can be configured to generate an alternating voltage waveform at frequencies in the range from about <NUM> to about <NUM> (preferably from about <NUM> to about <NUM>) (e.g., the TTFields). The voltages are such that the electrical field intensity in tissue to be treated is typically in the range of about <NUM> V/cm to about <NUM> V/cm.

One or more outputs <NUM> of the electrical field generator <NUM> can be coupled to one or more conductive leads <NUM> that are attached at one end thereof to the signal generator <NUM>. The opposite ends of the conductive leads <NUM> are connected to the one or more electrode arrays <NUM> that are activated by the electric signals (e.g., waveforms). The conductive leads <NUM> can comprise standard isolated conductors with a flexible metal shield and can be grounded to prevent the spread of the electrical field generated by the conductive leads <NUM>. The one or more outputs <NUM> can be operated sequentially. Output parameters of the signal generator <NUM> can comprise, for example, an intensity of the field, a frequency of the waves (e.g., treatment frequency), a maximum allowable temperature of the one or more electrode arrays <NUM>, and/or combinations thereof. In some aspects, a temperature sensor <NUM> can be associated with each electrode array <NUM>. Once a temperature sensor measures a temperature above a threshold, current to the electrode array associated with said temperature sensor can be stopped until a second, lower threshold temperature is sensed. The output parameters can be set and/or determined by the control software <NUM> in conjunction with the processor <NUM>. After determining a desired (e.g., optimal) treatment frequency, the control software <NUM> can cause the processor <NUM> to send a control signal to the signal generator <NUM> that causes the signal generator <NUM> to output the desired treatment frequency to the one or more electrode arrays <NUM>.

The one or more electrode arrays <NUM> can be configured in a variety of shapes and positions so as to generate an electrical field of the desired configuration, direction and intensity at a target site (referred to herein also as a "target volume" or a "target region") so as to focus treatment. Optionally, the one or more electrode arrays <NUM> can be configured to deliver two perpendicular field directions through the volume of interest.

Further disclosure directed to use of such electrotherapeutic systems is provided in <CIT>.

Although transducers are conventionally positioned externally on the patient, the present disclosure recognizes that there are benefits to positioning electrodes within the body of the patient to provide localized electric fields at the site of a tumor.

Optionally, it is contemplated that the administration of TTFields as disclosed herein can beneficially be combined with temozolomide chemotherapy. Overall survival now extends to over <NUM> months in some patients when dexamethasone, which was suspected of interfering with tumor-toxic fields effects, is replaced with celecoxib to control tumorassociated inflammation. The transcranial method of delivering tumor-toxic fields has not changed in light of ongoing advances in deep brain stimulation (DBS) and transcranial electric stimulation (TES). The resistivity of the skull is an obstacle to placing therapeutic electric field strength (e.g., at least <NUM> V/cm, at least <NUM> v/cm, or at least <NUM> V/cm), into target tumor sites, and variation in skull thickness can cause a difference in TES efficiency across individuals. Human head finite element modelling (FEM) predicts that surgical craniectomy beneath electrodes that provide tumor-toxic fields can enhance field strength at target tumor sites. For example, using methods disclosed herein, <NUM>-<NUM> V/cm can be reliably delivered to tumor sites using minimally-invasive strip or ribbon electrode arrays in conjunction with a distal transcranial electrode pre- or post-resection. It is contemplated that using frequencies at about <NUM> (e.g., <NUM>-<NUM>), <NUM>-<NUM> orders of magnitude higher than ion channel time constants, can be too high to stimulate axons in situ, thereby avoiding undesirable nervous system side effects. Further, in accordance with embodiments disclosed herein, field strength can be maintained below levels that cause cell damage.

Typically, the body of a cancer patient has an anatomically well-defined mass composed of contiguous cancer cells, or a shell of cancer cells surrounding a 'necrotic' region in which the cells have died due to being starved of nutrients. Such a tumor can be surgically removed ("resected"). The volume of the resection can fill with cerebrospinal fluid in the brain or other body fluid in other body regions, which is electrically-conductive and significantly affects an electric field imposed on the region. Typically, a tumor or resection cavity is surrounded by an anatomically undefined or loosely-defined region containing stray cancer cells, since the extent of stray cancer cells in the vicinity of the tumor is dependent on the tumor cell type, and the highly individualized history, anatomy, immune system, etc. of each patient. The region containing stray, non-contiguous cancer cells is referred to herein as a "peritumoral region.

Referring to <FIG>, in some aspects, a method for treating tumor cells can comprise positioning an implantable device <NUM> within a patient proximate to a target site (e.g., less than <NUM> from the target site, less than <NUM> of the target site, or within <NUM>-<NUM> (or about <NUM> to about <NUM>) of the target site). The proximity to the target site can optionally be as close as possible (without inflicting damage to critical tissue) and no further than a spacing at which the field strength is insufficient to kill the tumor cells within the target site (i.e., a maximum effective distance). The maximum effective distance can be controlled by a number of factors. First, the field strength can be a function of the power provided to the electrodes, and a maximum power threshold can be limited by a temperature threshold. Thus, the implantable device <NUM> can be positioned proximate to the target site to provide sufficient field strength without surpassing a temperature threshold. For example, it is contemplated that the temperature threshold can be maintained below a temperature threshold at which the patient feels pain (e.g., <NUM> degrees Celsius) or at a temperature threshold before tissue damage (that can be higher than the latter temperature threshold). It is contemplated that the temperature achieved can be dependent upon the thermal properties of the tissue surrounding the In further aspects, the implantable device <NUM> can desirably generate sufficient heat (surpassing the temperature threshold at which tissue is damaged) to damage surrounding cells (e.g., ablate surrounding cells). Second, the configuration of the electrode array (further disclosed herein) can determine the shape at which the field emanates from the implantable device <NUM>, thereby affecting the maximum effective distance. Third, the frequency with which the TTFields are applied to the target site can affect the maximum effective distance. Fourth, the geometry of the surrounding tissue and the properties of said surrounding tissue can affect the maximum distance. Accordingly, computational modeling can be used to determine the ideal position of the implantable device with respect to the target site.

In some aspects, the implantable device <NUM> can be positioned in a tumor resection cavity <NUM>, within a peritumoral region <NUM>, or adjacent to a tumor or resection cavity, optionally within the peritumoral region <NUM> or adjacent to the peritumoral region <NUM>. Referring to <FIG>, in still further aspects, it is contemplated that at least two implantable devices <NUM> (optionally, three, four, or more implantable devices <NUM>) can be positioned around the target site (e.g., around the resection cavity, or around a tumor <NUM>). For example, optionally, two implantable devices <NUM> can be positioned on opposing sides or generally opposing sides of the target site. In yet further aspects, it is contemplated that one or more implantable devices <NUM> can be inserted directly into the tumor <NUM> or within the peritumoral region <NUM>. For example, optionally, a first implantable device and a second implantable device can be positioned within the peritumoral region <NUM>, and the first and second implantable devices can optionally generate TTFields between each other. According to various aspects, it is contemplated that, with use of TTField treatment, tumor resection can be avoided. Optionally, for generally spherical tumors or cancer cells, a single implantable device <NUM> can be used, whereas for heterogeneous and non-spherical cancer cells, two (or, optionally, more) implantable devices <NUM> can be used to generate electric fields that overlap the tumor.

In some aspects, with reference to <FIG>, one or more electrodes <NUM> can be positioned outside of the peritumoral region so that the implantable device and the electrode(s) <NUM> positioned outside of the peritumoral region can generate TTFields therebetween. For example, the implantable device <NUM> and electrodes <NUM> can be positioned so that at least a portion of the tumor or peritumoral region lies therebetween (i.e., so that a line extending between the implantable device <NUM> and the electrodes <NUM> extends through the tumor or peritumoral region). Optionally, the one or more electrodes <NUM> can be positioned outside of a cranium <NUM> (e.g., outside the skin of the patient) or otherwise outside of the body (optionally, outside the skin) of the patient so that at least a portion of the peritumoral region is disposed between the implantable device and the one or more electrodes <NUM> outside of the peritumoral region. For example, an OPTUNE device (NOVOCURE Gmbh), as is known to those skilled in the art, can be used to position the electrodes <NUM> against the head of the patient. Optionally, all of the peritumoral region can be disposed between the implantable device and the one or more electrodes <NUM>. In further aspects, in situations where the tumor has not been removed, the one or more electrodes <NUM> can be positioned so that the tumor is between the implantable device and the one or more electrodes <NUM>. It is contemplated that different patterns of fields can be generated between electrodes based on the arrangement of the electrodes. As disclosed herein, computational modeling can be used to predict the activation patterns of the combined internal and external electrode arrays that are most effective to deliver efficacious field strength to the target region. In general, the target region can be located between the internal and external activated electrodes. However, change of direction of the applied field can be desirable. Accordingly, in some aspects, at least one electrode <NUM> can be positioned so that an imaginary line between the implantable device and the at least one electrode <NUM> extends through the target site, and a second pair of electrodes that are skew or orthogonal to the imaginary line between the internal electrodes through the target region to the at least one electrode <NUM> can be desirable for applying the electric field from a different direction. Thus, modeling can be performed for generic tumor locations, for example, in different quadrants of the tissue. In further aspects, image scans for a given patient can be used to tailor individualized optimal field shaping (e.g., different directional paths of TTFields through the target site) by the various electrodes.

- Optionally, in exemplary aspects, the one or more electrodes <NUM> outside of the peritumoral region can comprise one or more transducer arrays that are configured to apply TTFields through a portion of a brain of a patient. For example, such transducer arrays can be provided as components of an OPTUNE system (NOVOCURE Gmbh) for applying TTFields. In exemplary aspects, it is contemplated that such transducer arrays, when positioned external to the patient (e.g., on the head of the patient), can be used in combination with an implantable device comprising a DBS electrode as further disclosed herein.

Referring also to <FIG>, in some aspects, the implantable device can comprise a strip or ribbon electrode assembly comprising a thin substrate <NUM> with one or more electrodes <NUM> coupled thereto (optionally, arranged in an array <NUM>). Optionally, the thin substrate <NUM> can have a thickness of less than <NUM>, such as for example, a thickness from <NUM> to <NUM>. Exemplary ribbon electrode assemblies that are suitable for use as disclosed herein include subdural grid or strip electrodes manufactured by AD-TECH Medical Instrument Corporation. It is contemplated that the thin substrate <NUM> can be flexible for select positioning of the electrodes <NUM> within the resection cavity <NUM>. For example, optionally, the tumor resection cavity can be lined with an anti-bacterial mesh or other surgical material <NUM>. In some aspects, the anti-bacterial mesh or other surgical material <NUM> can be that which is used in conventional neurosurgery. In some aspects, the anti-bacterial mesh or other surgical material <NUM> can have negligible electrical resistance or be designed to minimally interfere with, or enhance, the applied electric field. The implantable device <NUM> can be positioned within the mesh. Optionally, the shape or profile of the implantable device <NUM> can be bent or otherwise modified to match the contour of the mesh. For example, the implantable device <NUM> can be pressed against inner surfaces of the mesh <NUM>.

In some aspects, the implantable device <NUM> can comprise a single electrode <NUM>. In further aspects, the implantable device <NUM> can comprise a plurality of electrodes <NUM> that can be arranged in various configurations. For example, in some aspects, the plurality of electrodes <NUM> can comprise a single row of electrodes that are arranged along an axis. In further aspects, the plurality of electrodes <NUM> can be arranged on a rectangular grid and can be spaced from each other in equal or unequal spacing. In further aspects, the plurality of electrodes <NUM> can comprise a plurality or rows of electrodes, with the electrodes within each row being arranged along a respective axis.

Referring to <FIG>, in further aspects, the implantable device <NUM> can comprise an elongate body <NUM> and a plurality of electrodes <NUM> coupled thereto. The elongate body <NUM> can optionally be rigid. As shown in <FIG>, the elongate body <NUM> can optionally define at least one cylindrical surface. In further aspects, as shown in <FIG>, the elongate body can define a cross shape in cross-sections in planes perpendicular to the longitudinal axis. Optionally, in these aspects, the elongate body <NUM> can comprise a first body portion <NUM>, a second body portion <NUM>, a third body portion <NUM>, and a fourth body portion <NUM> that converge at the longitudinal axis <NUM>, with the first and second body portions <NUM>, <NUM> being aligned relative to a first transverse axis <NUM> that is perpendicular to the longitudinal axis <NUM>, and with the third and fourth body portions <NUM>, <NUM> being aligned relative to a second transverse axis <NUM> that is perpendicular to the longitudinal axis and the first transverse axis. Optionally, the first and second body portions can have equal or substantially equal dimensions relative to the first transverse axis, and the third and fourth body portions can have equal or substantially equal dimensions relative to the second transverse axis. Optionally, the dimensions of the first and second body portions relative to the first transverse axis can be equal or substantially equal to the dimensions of the third and fourth body portions relative to the second transverse axis.

The electrodes for an exemplary implantable device <NUM> can optionally have uniform dimensions or non-uniform dimensions and can optionally have uniform or non-uniform spacing relative to the longitudinal axis. Optionally, the electrodes can have surface area dimensions ranging from <NUM> x <NUM> to <NUM> x <NUM>. In further aspects, the electrodes can be larger or smaller, depending on the application. Optionally, the electrodes can be spaced by <NUM> or less, by between <NUM> and <NUM>, by at least <NUM>, by <NUM> to <NUM>, or more than <NUM>. The electrodes <NUM> can optionally be circular, circular profiles projected onto a cylindrical surface, rectangular, rectangular profiles projected onto a cylindrical surface, cylindrical, or any other suitable shape.

In some optional aspects, it is contemplated that the implantable device <NUM> can be a deep brain stimulation (DBS) probe as is known in the art. Exemplary DBS probes in accordance with embodiments disclosed herein can include MEDTRONIC <NUM> DBS probes, MEDTRONIC <NUM> DBS probes, ABBOT INFINITY probes, BOSTON SCIENTIFIC probes, DIRECT STNACUTE probes, MEDTRONIC-SAPIENS probes, micro-DBS probes, AD-TEC depth, strip, or ribbon ('Grid') electrodes, AD-TEC subdural electrodes, WISE cortical strips, or DBS probes as described in <NPL>. It is contemplated that the implantable device <NUM> can have any selected dimensions or any arrangement or distribution of electrodes that is capable of providing electrical stimulation in the manner disclosed herein.

Optionally, it is contemplated that the electrodes <NUM> can comprise platinum-iridium. In further aspects, it is contemplated that the electrodes can comprise a ceramic. For example, ceramics can have a preferable impedance at certain beneficial frequencies (e.g., <NUM>-<NUM> or <NUM>-<NUM>).

It is contemplated that the electrodes <NUM> can be activated with a selectable amplitude. Advantageously, the electrodes disclosed herein can be used to generate TTFields in various combinations so that the direction of the field through the target site can be varied. The TTFields can optionally be current- or voltage-controlled. It is contemplated that currentcontrolled TTFields can achieve more fidelity in a desired waveform (e.g., a rectangular shape) as well as more uniform field string over time as fibrous material (e.g., scar tissue) that is electrically resistive forms around the electrode(s). A current-driven waveform can keep the current and field constant as the electrical resistance changes.

In some aspects, TTFields can be generated between different electrodes <NUM> of the implantable device <NUM>. In further aspects, TTFields can be generated between electrodes <NUM> of the implantable device <NUM> and the one or more electrodes <NUM>. In further aspects, TTFields can be generated between electrodes <NUM> of two different implantable devices <NUM>.

In some optional aspects, TTFields can be generated at one or more frequencies from <NUM>-<NUM>, optionally, from <NUM>-<NUM>. The field strength through the target areas (e.g., the tumor and/or the peritumoral region) can be at least <NUM> V/cm, at least <NUM> V/cm, at least <NUM> V/cm, or between <NUM> V/cm and <NUM> V/cm.

It is contemplated that certain structures, such as microtubules and organelles that can react differently based on the orientation of the field passing therethrough. Accordingly, it is contemplated that the direction of the TTFields can be periodically changed. For example, the activated cathodic and anodic electrodes in an array can be changed periodically to achieve the goal of delivering the most effective field (optionally, the highest field strength) to a given tumor/peritumoral target. In this way, the pattern of activated cathodic and anodic electrodes in an array can be periodically varied to change the direction of the field to optimally deliver the highest field strength to target structures, such as microtubules or organelles, that have different orientations relative to the imposed field due to random cell axis orientations in the target tissues.

In some aspects, changing the direction of the TTFields can comprise switching the polarities of the electrodes inducing the TTFields. For example, a first polarity can be induced between one or more electrodes of the implantable device <NUM> and the electrode(s) <NUM> outside the peritumoral region <NUM> (optionally outside the cranium <NUM> or otherwise outside of the skin of the patient); and, after a select period, a second polarity, opposite the first polarity, can be induced between the electrode(s) <NUM> of the implantable device and the electrode(s) <NUM> outside of the peritumoral region.

In further aspects, the electrodes between which the field is induced can be changed. For example, in some aspects, the field can be induced between at least two electrodes <NUM> of the implantable device, and, to change direction, the field can be induced between a different combination of electrodes <NUM> of the implantable device <NUM>. In further aspects, the field can be induced between at least two electrodes <NUM> of the implantable device, and, to change direction, the field can be switched to being induced between at least one electrode <NUM> of the implantable device <NUM> and the electrode(s) <NUM> outside the peritumoral region. In still further aspects, the field can be induced between a first combination of at least one electrode <NUM> of the implantable device <NUM> and the electrode(s) <NUM>, and the change in direction of the field can be caused by changing the electrodes of the implantable device <NUM> and/or the electrode(s) <NUM> that are inducing the field. In yet further aspects, the field can be induced between a first combination of at least one electrode <NUM> of a first implantable device <NUM> and at least one electrode <NUM> of a second implantable device <NUM>, and the change in direction of the field can be caused inducing a second combination of at least one electrode <NUM> of a first implantable device <NUM> and at least one electrode <NUM> of a second implantable device <NUM>.

In some aspects, the change in direction of the electric field before and after each direction change can be between <NUM> and <NUM> degrees, or between <NUM> and <NUM> degrees, or about <NUM> degrees. In still further aspects, over the course of a single treatment, electric fields can be generated in directions that are angled at at least <NUM> degrees with respect to each other, at least <NUM> degrees with respect to each other, or at least <NUM> degrees with respect to each other. It is contemplated that a mechanism of action of tumor-killing electric fields (i.e., TTFields) is their effect on polarized cell membrane and/or sub-cellular structures. Further, it is contemplated that TTFields can provide significant tumoricidal (tumor-killing) effects when the field is aligned with the cell axis during mitosis, and secondarily, when orthogonal to it. However, it is further contemplated that the tumoricidal (tumor-killing) effects of TTFields can be diminished (or even negligible) when at <NUM> degrees (or about <NUM> degrees) to the cell axis. In the system, one orthogonal change of direction per second of the applied field is performed and provides a <NUM>% increase in efficacy (in comparison to no change of direction). Since cells are randomly arranged in vivo, to achieve the benefit of applying the field aligned with, or orthogonal to, cell axes, changes of direction of the field can be applied over time. It is contemplated that each change of field direction can reduce the variance of field strength to which polarized cell structures are subjected, thereby increasing the minimum field strength to which they are subjected, leading to desirable results. Further, each change of field direction can reduce the maximum field strength necessary to ensure sufficient field strength is delivered to the target.

In some aspects, the processor(s) <NUM> can be configured to control the polarity induction between electrodes. For example, the processor(s) can alternate induced polarities between two or more electrodes. Accordingly, optionally, in some aspects, the processor(s) <NUM> can be configured to switch the induced polarity between two or more electrodes so that the electrodes operating as electrodes and anodes and cathodes, respectively, can be reversed after a predetermined period. In some aspects, the processor(s) can repeatedly reverse the induced polarity. In further aspects, the processor(s) can be configured to change which electrodes serve as anode(s) and cathode(s). For example, the processor(s) can cause the electrical field generator <NUM> (<FIG>) to induce a field between a first pair of electrodes, and, after certain duration, the processor can cause the electric field generator <NUM> to induce a field between a second pair of electrodes. Optionally, the processor(s) can execute a protocol stored in a memory that causes the processor to effect a sequential change in polarity and/or electrode combinations in accordance with a stored protocol. For example, a stored protocol can comprise a predetermined sequence of electrode polarity induction for predetermined durations. Such a stored protocol can optionally be customized for generic tumor locations and electrode arrays or for a particular patient given knowledge of tumor location and physical geometry of the patient. In some aspects, for a generic patient, a random sequence can be preferable for effectivity, whereas for a particular patient for which a clinician has knowledge of tumor location and physical geometry, a tailored sequence and/or arrangement can provide optimal tumoricidal results.

In some aspects, a single implantable device <NUM> can be inserted into or proximate to a target area (e.g., a tumor or a tumor resection cavity). The single implantable device <NUM> can comprise an elongate rigid body <NUM> and a plurality of electrodes <NUM> spaced longitudinally along the length of the body. Optionally, the single implantable device <NUM> can be a DBS probe. It is contemplated that generating electrical fields between electrodes spaced farthest apart can generate a broad (optionally, the broadest possible) field coverage (e.g., through the resection cavity and peritumoral region).

In some aspects, two implantable devices <NUM> can be inserted into or proximate to (e.g., on opposite sides of) a target area (e.g., a tumor or a tumor resection cavity). In further aspects, it is contemplated that the two implantable device <NUM> can be positioned within the cavity (e.g., on opposing edges within the resection cavity). The two implantable devices <NUM> can each comprise an elongate rigid body and a plurality of electrodes <NUM> spaced longitudinally along the length of the body. Optionally, the two implantable devices <NUM> can be DBS probes. Different electrodes on each probe can be polarized in sequence to induce electrical fields in different directions. In some aspects, each of the implantable devices <NUM> can have inner electrodes 106a and outer electrodes 106b, wherein the inner electrodes are relatively closer to the other implantable device than the outer electrodes. In some aspects, TTFields can be generated between respective inner electrodes of each of the two implantable devices to deliver relatively high strength electric fields. In further aspects, TTFields can be generated between respective outer electrodes of each of the two implantable devices to deliver more broadly reaching TTFields (i.e., TTFields propagating further from the electrodes).

In some aspects, ribbon electrode arrays can be placed around the tumor or resection cavity. In some aspects, ribbon electrode arrays can provide smaller and more closely packed electrode arrays than traditional cylindrical DBS probes to more precisely deliver the strongest fields either to the tumor or resection cavity or to the peritumoral region. The electrodes can be activated sequentially around the tumor resection cavity, for example, to deliver strongest doses to the area orthogonal to the electrode faces while delivering a weaker, but still therapeutic dose from a different direction to the areas adjacent to the electrodes.

Optionally, in exemplary aspects, it is contemplated that an implantable device <NUM> as disclosed herein can be configured for removal from within the patient before the skin of the patient grows over a cavity within which the implantable device is received (e.g., within about <NUM> to <NUM> weeks). Optionally, in these aspects, it is contemplated that the cavity within which the implantable device is received can be formed by a craniectomy or other similar procedure. It is further contemplated that after the implantable device is removed, cells from within the patient can be gathered from the implantable device to permit analysis of patient cells that remain on surfaces of the implantable device (e.g., a ribbon or strip electrode as disclosed herein), thereby permitting analysis of tumor cells or cells within the peritumoral region or other target area. Alternatively, in other exemplary aspects, it is contemplated that an implantable device <NUM> as disclosed herein can be configured to be powered by a battery or other power source positioned external to the patient, thereby providing a long-term implant configuration.

One advantage of using in situ TTFields with the external array is the ability to steer the electric field across the tumor/peritumoral region by altering the activated electrodes on the external array. Another advantage of in situ tumor-treating fields is the ability to precisely control the field in the vicinity of the target tumor/peritumoral region, thereby avoiding or minimizing collateral damage to nearby, healthy, rapidly-dividing cells. Still further, another advantage is the ability to optimize <NUM>) the static pattern of electrodes at a given point in time, <NUM>) changing field direction in order to impose alignment or orthogonality with cell axes, and <NUM>) changing field direction to attain the largest region of therapeutic dose while minimizing hot spots, which can optionally be characterized by temperature (e.g. <NUM> degrees Centigrade) to avoid pain and/or by surface current density (such as <NUM> or <NUM> microCoulombs per centimeter square) to avoid undesired biochemical reactions at the electrode-tissue interface.

In some aspects, the temperature increase caused by the interaction of current flow through electrically resistive tissue (e.g., "Joule heating") can be a limitation to the maximum voltage, current, and power supplied to device <NUM>. In other aspects, in which deliberate damage to tumor cells proximate to the device is desirable, the implantable device <NUM> can be used to effect a temperature that kills tissue cells. Accordingly, in some optional aspects, the implantable device <NUM> can be used for the dual purpose of destroying tumor cells via tumor-killing electric fields as well as killing cells with heat (tissue 'ablation'). A metric such as the Arrhenius equation can be used in computer simulations to predict the <NUM>-dimensional extent of tumor cell ablation, given parameters of voltage, current, or power supplied to device <NUM>. Optionally, the implantable device can comprise a temperature sensor (e.g., a thermocouple or thermistor). In further aspects, a temperature sensor can be positioned proximate to the implantable device for measuring the temperature of the implantable device or the tissue proximate to the implantable device.

The devices and non-claimed methods disclosed herein can optionally be used to treat glioblastoma or other cancers in the brain. In further optional aspects, the devices and methods disclosed herein can be used to treat cancers or tumor cells in other parts of the body, such as for example, the torso. In these aspects, it is contemplated that the external arrays disclosed herein can be positioned on the skin of a patient while also being in proximity to a tumor or peritumoral region within the body. In exemplary aspects, it is contemplated that the implantable devices disclosed herein can comprise a DBS electrode (e.g., a DBS probe) that is positioned within the torso of a patient.

Although many of the exemplary embodiments disclosed herein are directed to treating brain tumors such as glioblastoma, it should be understood that these examples are not meant to limit the use of embodiments to treating brain tumors. Rather, applications and embodiments of the present disclosure can be used to treat various types of tumors throughout the body of the patient. For example, although various embodiments disclose positioning electrodes outside the skull for treatment of brain tumors, it is contemplated that electrodes can be positioned on various parts of the body depending on the location of the target site. Exemplary target sites outside the brain include the lungs and other internal organs. In exemplary aspects, it is contemplated that electrodes can be positioned outside portions of the torso for treatment of tumors within the lungs or other internal organs, or any other site within the torso where a tumor is identified.

Claim 1:
A system, comprising:
an electric field generator (<NUM>); and
an implantable device (<NUM>) in electrical communication with the field generator (<NUM>) and configured for positioning proximate to or within a target site of a patient, wherein the field generator (<NUM>) is configured to use the implantable device (<NUM>) to generate electric fields at a frequency of from about <NUM> to about <NUM>;
characterized in that:
the field generator (<NUM>) is configured to periodically change a direction of the electric fields at a frequency of one orthogonal change of direction per second.