Patent Description:
Non-invasive methods of treating cancer are important methods, particularly for cancers such as glioblastoma which are difficult to remove by surgery. There is a desire for new non-invasive methods of treating cancer which effectively reduce or eliminate the cancerous cells from a target site in the body.

Radiotherapy is a type of cancer therapy which uses ionizing radiation to kill malignant cells at a target site. The ionizing radiation is provided to the target site, which causes damage by the direct or indirect action of radiation on DNA and other cell molecules. In the direct action, the radiation hits e.g. the DNA molecule directly, disrupting its molecular structure. Such structural change leads to cell damage or even cell death, and thus provides a mechanism for treatment of malignant cells.

Another form of treatment, known as alternating electric field therapy or tumour treating fields (TT-Fields) applies non-ionizing electric fields to the target site. The mechanism of TT-Fields which renders it useful for cancer treatment is different to that of radiotherapy. In particular, during the formation of mitotic spindles, the microtubule assembly deforms. Mitosis of tumour cells remains in the interdivision stage for a long time. When the cleavage furrow forms in mid to late mitosis, all polar molecules and dipoles in cells undergo di-electrophoresis under the action of TT-Fields, which accumulates in the cleavage furrow and eventually causes the cell membrane to rupture. Mitotic outcomes elicited by TT-Fields application include abnormal chromosome segregation, which triggers different forms of cell death.

Hyperthermia is a known method for treating a cancerous site. However, it can be difficult to target the cancerous site effectively. On the one hand, tissue surrounding the area being treated may also be affected by hyperthermia, particularly when the cancerous site is heated to a high temperature. On the other hand, the cancerous site may not be effectively destroyed if the site is not heated to a sufficiently high temperature. Further, whilst applying heat to a cancerous site may cause cell damage and even cell death at the cancerous site, if the heat is not correctly and accurately applied to the cancerous site in the correct dose, the cancerous site may be resistant to such heating. For example, if the hyperthermia heats up the healthy surrounding tissue in addition to the cancerous growth, blood flow will be enhanced, and nutrients supply to the cancerous growth may be higher. Thus, under some circumstances the high blood flow as a result of heating helps the dissemination of nutrients which could reach the cancerous site and therefore have the opposite intended effect, or at least result in an ineffective treatment. Further, different phases in the cell cycle of cancerous cells have been observed to have different resistances to heating. Yet further, temperature elevations in cells transiently upregulate heat shock genes that encode a class of heat shock proteins (HSPs). The mechanism responsible for the heat shock response is an autoregulatory loop; HSPs normally keep the responsible transcription factor (HSF-<NUM>) inactive but upon heating HSP bind with higher affinity to unfolded proteins, triggering the release of HSF-<NUM> from HSP which initiates HSP gene transcription. Once the protein damage/aggregation is restored after the heat shock by the HSP, substrate-free HSP themselves may be involved in attenuating the response by rebinding HSF-<NUM>. As a result, HSP levels transiently rise after heating but also gradually decline again upon prolonged stress-free periods. The upregulation of HSP is closely associated with a transient resistant state of cells towards a subsequent second heat shock. It is thought that the elevated HSP levels, by their chaperone activity, protect cells against protein damage induced by further heating. Accordingly, there is a need to provide hyperthermia which provides the required heating to the cancerous site more accurately and reliably, in order to avoid any resistance to heating of the cancerous cells as a result of deviation from the required amount of applied heat.

Many methods of hyperthermia require a mediator (such as a nanoparticle fluid) to be administered to the site. The mediator is then heated, for example by an electric field, which then indirectly heats the target site. The mediator may be heated using an electric field which has the same or similar frequency range as TT-fields. This may be seen as advantageous as the cancerous site is attacked both via hyperthermia and via the TT-field mechanism. However, as the mediator is a fluid injected into the patient's body, the location of heating when the electromagnetic radiation is administered is hard to control.

There is a desire to find more effective cancer treatment methods for the above methods of treatment. In this context, document <CIT> providing a combined cancer therapy is mentioned.

The present invention confronts the problem of providing more effective cancer treatment methods by providing an apparatus for treating a cancerous target site, comprising:.

wherein the apparatus is configured to apply the non-ionizing alternating electromagnetic field and the heating independently. In particular, the heat source is configured to provide direct heating at the target site.

It is herein noted that the heat source may be any heat source which heats a specific target site without the use of a mediator (e.g. directly and not indirectly via a mediator).

In a preferred embodiment, the apparatus is configured to provide the non-ionizing alternating electromagnetic field at the target for a first time period, and to provide the direct heating at the target site for a second time period. The second time period may partially or fully overlap with the first time period. For example, the first time period may begin at the same time as the second time period, or may begin a predetermined amount of time after the first time period begins, or may begin when the first time period expires. It is preferred that the first and second time periods completely overlap so that the TT-Fields and heating are applied to the site simultaneously, providing a synergistic effect on the cells in the target site as discussed in further detail below.

It is noted that the sequence of the first and second time periods may be repeated two or more times. For example, the apparatus may be configured to apply the non-ionizing alternating electromagnetic field for a first time period, and apply the heating for a second time period a predetermined time after the first period begins. Subsequently, the apparatus may be configured to, again, apply the non-ionizing alternating electromagnetic field for a first time period, and apply the heating for a second time period the predetermined time after the first period begins. The length of the first and second time periods, and their start times relative to each other, may be configurable by a user or according to one or more schedules saved in a memory of the apparatus.

Preferably, the apparatus is configured to provide the non-ionizing alternating electromagnetic field at the target site for a first time period of between <NUM> minute and <NUM> hours.

In another preferred embodiment, the apparatus is further configured to provide the heating at the target site for a second time period of between <NUM> minute and <NUM> minutes. The heating may be applied simultaneously to the non-ionizing alternating electromagnetic field for a third time period. The third time period may be all or part of the second time period.

The electromagnetic emitter is configured to provide an alternating electromagnetic field having a frequency of between <NUM> and <NUM>, preferably in the range from <NUM> to <NUM>. It is observed that the therapeutic effect of the tumour-treating field is significantly increased when the frequency is below <NUM>.

Furthermore, the electromagnetic emitter is configured to provide an alternating electromagnetic field at the target site having a magnetic flux density of between <NUM> pT and <NUM> mT, or between <NUM> pT and <NUM>µT, or between <NUM>µT and <NUM> mT and preferably an electric field strength of between <NUM> V/cm and <NUM> V/cm.

In another preferred embodiment, electromagnetic emitter is configured to provide an alternating electromagnetic field at the target site having a magnetic flux density of between <NUM>µT and <NUM> mT, and more preferably between <NUM>µT and <NUM> mT.

In another preferred embodiment, the heat source is configured to heat the target site to a temperature of at least <NUM> and preferably between <NUM> and <NUM>. Heating the target site to a temperature of at least <NUM> induces heating effects on the target site which corresponds to extreme hyperpyrexia.

In another preferred embodiment, the heat source comprises an ultrasonic emitter configured to provide ultrasound radiation to the target site, optionally wherein the ultrasound radiation has one or more focal areas in the target site. The one or more focal areas may be provided from a single transducer or a plurality of transducers.

In a further preferred embodiment, the heat source comprises one or more of:.

In a still further preferred embodiment, the apparatus additionally comprises an electronic controller for electronically controlling the electromagnetic emitter and the heat source.

A further aspect of the present invention refers to a method for treating a cancerous target site using an apparatus according to the supra embodiments, wherein the apparatus may take any configuration disclosed therein and wherein the method is preferably implemented by suitably positioning the emitter <NUM> and heat source <NUM> on the patient. For example, the applicators of the electromagnetic emitter <NUM> may be placed at predetermined points on the patient's body and the heat source <NUM> (for example the transducer <NUM> described in relation to <FIG>) may also be suitably positioned. Wherein the method comprises:
In step S1, the non-ionizing alternating electromagnetic field is provided to give a magnetic flux density at the target site using electromagnetic emitter <NUM>.

In step S2, the heat (and more particularly direct heat) is provided to the target site using heat source <NUM>. This may be provided whilst the electromagnetic field is also being provided to the target site <NUM> or within a predetermined time before or after the electromagnetic field is provided. In some embodiments, it may be that only the alternating electromagnetic field is provided to produce the magnetic flux density at the target site without the heating for a first time period, before both are provided simultaneously to the target site.

Optionally, in step S3, an anti-carcinogenic composition is provided to the target site. The anti-carcinogenic composition may be administered by any suitable means, such as orally or intravenously. It is noted that the anti-carcinogenic composition may be provided before or simultaneously to steps S1, S2 and step S4 or a predetermined time after step S1, S2 or S4.

Examples of anti-carcinogenic compositions that may be used to implement the present invention are described in detail throughout the present invention.

Also optionally, in step S4, a Glutathione (GSH) depleting composition is provided to the target site in addition to the anti-carcinogenic compound. The GSH depleting composition may be administered by any suitable means, such as orally or intravenously. It is noted that the GSH depleting composition may be provided before or simultaneously to steps S1, S2 and step S3 or a predetermined time after step S1, S2 or S3, preferably at a predetermined time after step S3. Examples of GSH depleting compositions that may be used to implement the present invention are described in detail throughout the present invention.

In step S5, the direct heating is stopped and in step S6 the non-ionizing alternating electric field is stopped. It is noted that steps S5 and S6 may occur simultaneously or the direct heating may be stopped before the non-ionizing alternating electromagnetic field is stopped, such that only the non-ionizing alternating electromagnetic field is applied for a predetermined time after the direct heating is stopped.

A still aspect of the present invention, refers to an anti-carcinogenic composition for use in a method for treating a cancerous target site using an apparatus according to the supra embodiments, wherein the apparatus may take any configuration disclosed therein and wherein the method is preferably implemented by suitably positioning the emitter <NUM> and heat source <NUM> on the patient. For example, the applicators of the electromagnetic emitter <NUM> may be placed at predetermined points on the patient's body and the heat source <NUM> (for example the transducer <NUM>) may also be suitably positioned. Wherein the method comprises:
In step S1, the non-ionizing alternating electromagnetic field is provided to give a magnetic flux density at the target site using electromagnetic emitter <NUM>.

In step S3, an anti-carcinogenic composition is provided to the target site. The anti-carcinogenic composition may be administered by any suitable means, such as orally or intravenously. It is noted that the anti-carcinogenic composition may be provided before or simultaneously to steps S1, S2 and step S4 or a predetermined time after step S1, S2 or S4. Examples of anti-carcinogenic compositions that may be used to implement the present invention are described in detail through out the present invention.

Optionally, in step S4, a Glutathione (GSH) depleting composition is provided to the target site in addition to the anti-carcinogenic compound. The GSH depleting composition may be administered by any suitable means, such as orally or intravenously. It is noted that the GSH depleting composition may be provided before or simultaneously to steps S1, S2 and step S3 or a predetermined time after step S1, S2 or S3, preferably at a predetermined time after step S3. Examples of GSH depleting compositions that may be used to implement the present invention are described in detail through out the present invention.

Embodiments will now be explained in detail, by way of non-limiting example only, with reference to the accompanying figures described below.

The present invention related to an apparatus which is configured to provide both a non-ionizing alternating electromagnetic field and hyperthermia to a target site, wherein the electromagnetic field and hyperthermia can be provided independently. The electromagnetic field may be applied, for example, by means of a magnetic applicator that provides a magnetic flux density in the target site. In hyperthermia treatments involving a mediator, such an alternating electromagnetic field is provided which also may be absorbed by the mediator. However, as the mediator absorbs the electromagnetic energy, the tumour-treating effects of the electromagnetic field may be reduced. The present invention overcomes this problem by providing hyperthermia independently such that both treatments can be provided to the cancerous site without reducing the effectiveness of the other. In the present invention, the tumour-treating effects are due to a combined application of electromagnetic fields with direct hyperthermia. The electromagnetic field may be introduced with a magnetic field applicator. In some further examples of the present disclosure, the treatment may further include the administration of an anti-cancer composition.

As used herein, the term "tumour treating field", "TT-Field" or "TTF" may be understood to mean an oscillating electromagnetic field applied to a target site. In particular, the electromagnetic field is generated by applicators which are electrically isolated from the target site so that electrical current does not flow between the target site and the applicators.

<FIG> shows a schematic diagram of an apparatus <NUM> for treating a cancerous target site <NUM>. The apparatus comprises an electromagnetic emitter <NUM> and a heat source <NUM>. The electromagnetic emitter <NUM> is configured to provide a non-ionizing alternating electromagnetic field <NUM> at the target site <NUM>. The heat source <NUM> is configured to provide direct heating <NUM> at the target site <NUM> to cause hyperthermia at the target site <NUM>. In one configuration, the apparatus <NUM> is configured to provide the non-ionizing alternating electromagnetic field and the direct heating at the target site <NUM> within a predetermined time period. The target site <NUM> may include at least a cancerous growth and may further include some of the tissue surrounding the cancerous growth. In some embodiments, the apparatus <NUM> may be configured to provide a non-ionizing alternating magnetic field <NUM>.

As disclosed herein, hyperthermia may be defined as elevation to a temperature above <NUM>. Accordingly, the apparatuses disclosed herein may be configured to heat a target site to temperatures above <NUM>. It is noted that hyperthermia is defined as a temperature greater than between <NUM> to <NUM> (depending on the reference used), occurring without a change in the body's temperature set point. In contrast, hyperpyrexia is an extreme elevation of body temperature which, depending upon the source, is classified as a core body temperature greater than or equal to <NUM> or <NUM>; the range of hyperpyrexias include cases considered severe (≥ <NUM>) and extreme (≥ <NUM>). It differs from hyperthermia in that one's thermoregulatory system's set point for body temperature is set above normal, then heat is generated by the body to achieve it. In contrast, hyperthermia involves body temperature rising above its set point due to outside factors.

Further, it is noted that thermal ablation is a type of procedure that uses heat, cold, microwave and electrical currents to vaporize (ablate) cancer cells and tumors by heating to above ><NUM>.

In preferred embodiments, the apparatus is configured to heat the target site to a temperature of between <NUM> and <NUM> (heating to above <NUM> may increase the sensitivity of a cancerous growth to other therapies such as TT-fields, chemotherapy and radiotherapy) and preferably at least <NUM> (above which, advantageously, irreversible damage is caused to cells). It is preferred that the heat source is configured to heat the target site to a temperature of at least <NUM> and preferably between <NUM> and <NUM>. Heating the target site to a temperature of at least <NUM> induces heating effects on the target site which corresponds to extreme hyperpyrexia.

The heat source <NUM> may be any suitable heat source for providing direct heating to the target site <NUM>, and may comprise electromagnetic heating, such as capacitive radiofrequency heating, radiative radiofrequency heating, microwave heating, infrared heating and laser heating, heating by ultrasound, heating via a heated fluid, heating by conductive heat emitter, or any other suitable method which heats the target site <NUM> independently of the non-ionizing alternating electromagnetic field <NUM>. The heat source <NUM> may be any heat source which heats the target site without the use of a mediator (e.g. directly and not indirectly via a mediator).

In any of the embodiments disclosed herein, the electromagnetic emitter <NUM> may be configured to provide an electromagnetic field <NUM> having a frequency of between <NUM> to <NUM> and more preferably between <NUM> and <NUM>. The electromagnetic field may have a magnetic flux density of between <NUM>. 1pT and 1mT, or between <NUM>. 1pT and 100µT, or between 100µT and 1mT, and/or the corresponding electric field of between <NUM> V/cm and <NUM> V/cm depending on the tissue impedance (i.e. taking into account possible attenuation of the field as it travels from the electromagnetic emitter <NUM> to the target site <NUM>, which can be determined from the impedance arising from the different types of tissue present between the electromagnetic emitter <NUM> and the target site <NUM>). As noted above, the electromagnetic field <NUM> is non-ionizing, and its mechanism on the cancerous site is different to that of ioinizing radiation as discussed in the background section of the present disclosure. Further, the electromagnetic field <NUM> itself does not provide direct heating to the target site <NUM> due to the relatively low intensity of the oscillating field.

It will be appreciated that in any of the embodiments disclosed herein the electromagnetic emitter <NUM> and heat sources may be powered by any power source, and may be powered by the same or different power sources. Likewise, each of the electromagnetic emitter <NUM> and the heat source <NUM> may comprise a user interface for selecting the operating parameters of each emitter (frequency, field strength, amplitude, etc), or the emitter <NUM> and heat source <NUM> may comprise pre-programmed sequences for emitting electromagnetic radiation and heat according to a predetermined program selectable by the user.

In any of the embodiments disclosed herein, the apparatus may further comprise a thermometry element for measuring the temperature of the target site <NUM>. For example, the apparatus may comprise an implantable thermometry probe configured to be implanted proximal to the target site <NUM> to measure a temperature indicating the temperature of the target site <NUM>. The probe may comprise, for example, thermocouples, thermistors and/or fibreoptic sensors. In other embodiments, non-invasive thermometry such as infrared sensing, CT thermometry, or magnetic resonance thermometry may be used.

<FIG> shows a schematic diagram of an electromagnetic emitter <NUM> and a heat source <NUM> according to one or more embodiments.

The electromagnetic emitter <NUM> may comprise one or more sources <NUM> (such as one or more current or voltage sources) electrically connected to one or more applicators <NUM>. The applicators <NUM> may be configured to be placed on or proximal to the surface of the patient body <NUM> and are electrically insulated from the patient body (i.e. do not form a closed electrical circuit between the source <NUM> and the patient body). In some embodiments, the applicators <NUM> may comprise one or more electrodes with an electrically insulating coating for preventing electrical contact between the electrodes and the surface of the patient and thus the target site. It is noted that even if the applicators are placed on the surface of the patient of the patient body <NUM>, they remain electrically insulated from the body by, for example, the presence of the electrically insulating coatings. The source <NUM> may be configured to provide an alternating electromagnetic field to the applicators <NUM>, which in turn produce a magnetic flux density towards the target site <NUM> to provide the non-ionizing alternating electromagnetic field <NUM> at the target site <NUM>. It will be appreciated that any number of applicators <NUM> may be used depending on the type of target site, and the strength of the resulting magnetic flux density at the target site <NUM> can be readily calculated from the setup by superposition of the electromagnetic fields emitted by each applicator <NUM>. In some embodiments, the applicators <NUM> may comprise a coil with positive and negative terminals. The one or more sources may be configured to provide an alternating current through the coil to generate a magnetic field out of the coil. The coil may comprise any number of turns, for example <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM>, <NUM> or more.

The heat source <NUM> shown in <FIG> may be an ultrasound emitter and may comprise an ultrasonic source <NUM> which emits an ultrasonic signal to one or more transducers <NUM>. The transducer <NUM> is configured to transmit focussed ultrasonic radiation <NUM> to the target site <NUM>. The one or more transducers <NUM> may include, for example, one or more piezoelectric transducers. The one or more transducers <NUM> may comprise one or more plastic and/or ceramic transducers. A coupling medium (not shown) may be provided on the patient body <NUM> between the transducer <NUM> and the patient body <NUM> to improve propagation of the ultrasound waves from the transducer <NUM> to inside the patient body <NUM> (i.e. to reduce reflections of ultrasound waves). A coupling medium is defined herein as any suitable solid or liquid (or combination thereof) for improving propagation of the ultrasound waves from the transducer <NUM> to inside the patient body <NUM>. The shape of transducer <NUM> may be selected in order to select the amount of focussing of the ultrasound, and may be selected to focus the ultrasonic radiation <NUM> to one or more focal area in the target site <NUM>. For example, the one or more transducers <NUM> may be 3D printed or otherwise manufacture to a custom shape which is configured to propagate focussed ultrasonic radiation to one or more focal areas within the target site <NUM>.

The ultrasound emitter <NUM> may be configured to provide acoustic energy at frequencies between <NUM> and <NUM> to provide heating at the target site <NUM>.

In some embodiments, the ultrasound emitter <NUM> may comprise one or more multi-transducer arrays or phased arrays, planar devices or bowl-shaped sources. Further, the ultrasound emitter <NUM> may be configured to emit the ultrasound radiation interstitially. That is, the ultrasound emitter <NUM> may comprise one or more catheter-mounted transducers or other emitting components which are configured to be inserted into the body <NUM> at or near the target site <NUM>, in order to emit ultrasonic radiation towards one or more points at the target site <NUM> to provide the required heating.

Whilst <FIG> shows a specific configuration of an ultrasound emitter, it is noted that any suitable ultrasonic emitter may be used. For example, any high-intensity focused ultrasound (HIFU) machine may be used, such as MRI-guided focused ultrasound.

The ultrasound emitter <NUM> is configured to emit ultrasound radiation <NUM> to the target site <NUM> to cause heating at the target site. In particular, the ultrasound emitter <NUM> is configured to heating the target site to a predetermined temperature, preferably a temperature of <NUM> or less, and maintain the temperature at the predetermined temperature whilst the electromagnetic field is applied. It will be appreciated that the ultrasound emitter <NUM> may be configured to heat the target site <NUM> by providing ultrasound radiation having a predetermined frequency and amplitude which causes the required heating at the target site <NUM>. The ultrasound radiation may be continuous or pulsed wave. For a given frequency, amplitude and type of ultrasonic radiation, the amount of heating at a target site can be determined by routine experimentation.

It will be appreciated for the embodiment of <FIG> that the power output of the source <NUM> as well as the duration of application of the ultrasonic radiation may be selected in order to arrive a predetermined amount of heating at the target site <NUM>. This may be determined by prior empirical measurement or the apparatus may additionally include a thermometer component for measuring the temperature of the target site <NUM>, with heat being applied by the apparatus to achieve and maintain a target temperature at the target site <NUM>.

<FIG> shows a schematic of diagram of an electromagnetic emitter <NUM> and a heat source <NUM> according to one or more embodiments. As in the case of <FIG>, the electromagnetic emitter <NUM> may comprise one or more electromagnetic sources <NUM> (such as one or more current or voltage sources) electrically connected to one or more applicators <NUM>. The applicators <NUM> may be configured to be placed on the surface of the patient body <NUM>. The electromagnetic source <NUM> may be configured to provide an alternating electromagnetic field to the applicators <NUM>, which in turn produce a magnetic flux density towards the target site <NUM> to provide the non-ionizing alternating electromagnetic field <NUM> at the target site <NUM>. It will be appreciated that any number of applicators <NUM> may be used depending on the type of target site, and the strength of the resulting magnetic flux density at the target site <NUM> can be readily calculated from the setup by superposition of the electromagnetic fields emitted by each applicator <NUM>.

The heat source <NUM> comprises one or more antennas or applicators <NUM> configured to provide an electromagnetic field <NUM> for providing direct heating to the target site <NUM>. The heat source <NUM> comprises one or more electromagnetic sources <NUM> for driving one or more antennas or applicators <NUM> to provide the heating electromagnetic field <NUM>. The electromagnetic field <NUM> has a field strength and frequency which causes heating of the target site. The frequency of the electromagnetic field <NUM> is sufficiently different (e.g. at least an order of magnitude difference) such that the electromagnetic fields <NUM> and <NUM> interact with the target site <NUM> independently (i.e. such that the electromagnetic interference between the fields is negligible). The frequency of the electromagnetic field <NUM> may be, for example, above <NUM> to cause dielectric heating of the target site <NUM> by molecular dipole rotation, polarization and/or vibration, or Ohms law.

The number and configuration of antennas or applicators <NUM>, including their positions, relative amplitudes and phases, can be selected in order to create constructive and/or destructive interference and cause heating only over a particular volume including the target site <NUM>. For example, the antennas or applicators <NUM> may comprise a single antenna, a pair of antennas, and a 2D or 3D array or phased array of antennas.

In some embodiments, the electromagnetic source <NUM> is a radiofrequency (RF) source configured to operate at a frequency between <NUM> and <NUM> (for example, <NUM>, <NUM> or <NUM>) to cause capacitive heating. The one or more antennas or applicators <NUM> comprise a pair of metal applicators with the target site <NUM> placed between the applicators. Optionally, the applicators may be coupled to water bolus bags or other media for transferring the field into the body <NUM>. When the RF field is applied to the applicators, power is transferred to the target site <NUM> and heating is caused. This technique may be used for both superficial and deep tumours by selecting different configurations of applicators to concentrate the resulting electric field at the target site <NUM>. Alternatively, the applicators may be provided as coplanar, or one or more applicators may be configured to be placed inside the body <NUM> inside insulating catheters. A single applicator may instead be used, coupled to an external ground plane. In all of these configurations, the RF field generated at the target site causes direct heating.

In some embodiments, the electromagnetic source <NUM> is an RF source configured to operate at frequencies between <NUM> and <NUM>. The one or more antennas or applicators <NUM> comprise one or more antennas placed external to the body. The electromagnetic fields generated at this frequency range penetrate deep into the body and so are suitable for heating of deep target sites <NUM>. Again, the one or more antennas may comprise a pair of antennas with the target site <NUM> placed between. The antennas may be coupled to water bolus bags or other media for transferring the electromagnetic field into the body <NUM>.

In some embodiments, the electromagnetic source <NUM> is a microwave (MW) source configured to operate at frequencies between <NUM> and <NUM> (for example <NUM>, <NUM> or <NUM>). The one or more antennas may comprise a pair of antennas or one or more antenna arrays with the target site <NUM> placed between. The antennas may again be coupled to water bolus bags or other media for transferring the electromagnetic field into the body <NUM>.

It will be appreciated for the embodiment of <FIG> that the power output of the source <NUM> as well as the duration of application may be selected in order to arrive a predetermined amount of heating at the target site <NUM>. This may be determined by prior empirical measurement or the apparatus may additionally include a thermometer component for measuring the temperature of the target site <NUM>, with heat being applied to achieve and maintain a target temperature at the target site <NUM>.

<FIG> shows a schematic of diagram of an electromagnetic emitter <NUM> and a heat source <NUM> according to one or more embodiments. As in the case of <FIG> and <FIG>, the electromagnetic emitter <NUM> may comprise one or more electromagnetic sources <NUM> (such as one or more current or voltage sources) electrically connected to one or more applicators <NUM>. The applicators <NUM> may be configured to be placed on the surface of the patient body <NUM>. The electromagnetic source <NUM> may be configured to provide an alternating electromagnetic field to the applicators <NUM>, which in turn produce a magnetic flux density towards the target site <NUM> to provide the non-ionizing alternating electromagnetic field <NUM> at the target site <NUM>. It will be appreciated that any number of applicators <NUM> may be used depending on the type of target site, and the strength of the resulting magnetic flux density at the target site <NUM> can be readily calculated from the setup by superposition of the electromagnetic fields emitted by each applicator <NUM>.

The heat source <NUM> comprises an electromagnetic source <NUM> and one or more electromagnetic emitters <NUM> configured to penetrate the body <NUM> such that a distal portion of the emitters can be positioned within the target site <NUM>. The one or more emitters <NUM> are electrically connected to the electromagnetic source <NUM> so that an electrical current is applied to the one or more emitters <NUM>. The one or more emitters <NUM> may comprise one or more monopole, dipole, slot or helical coil microwave antennas, resistively-coupled radiofrequency, local current field electrodes or capacitively coupled radiofrequency catheter-based electrodes. Capacitively coupled electrodes may be configured to be contained in low-loss catheters such as a Nylon or Teflon catheter.

In some embodiments, the electromagnetic source <NUM> is configured to provide an alternating electric current to the one or more emitters <NUM> in the frequency range of <NUM> to <NUM>, which induces an electric current in the area of tissue near the needle(s) and as a result heats the tissue. In other embodiments, the electromagnetic source <NUM> is configured to provide an alternating electric current to the one or more emitters <NUM> in the frequency range of <NUM> to <NUM> (for example <NUM> or <NUM>), which causes dielectric heating of the tissue surrounding the needle(s).

In other embodiments, the emitters <NUM> comprise a plurality of electrodes configured to be implanted around the target site <NUM>, and the electromagnetic source <NUM> is configured to provide a series of very short (e.g. about <NUM>) direct-current electrical pulses between the electrodes. The voltage of the pulses and the positioning of the electrodes are configured to provide a high field strength (e.g. between about <NUM> V/cm to <NUM> V/cm). It has been observed that such pulses provide heating to the target site <NUM>.

It will again be appreciated for the embodiment of <FIG> that the power output of the source <NUM> as well as the duration of application may be selected in order to arrive a predetermined amount of heating at the target site <NUM>. This may be determined by prior empirical measurement or the apparatus may additionally include a thermometer component for measuring the temperature of the target site <NUM>, with heat being applied to achieve and maintain a target temperature at the target site <NUM>.

The heat source <NUM> comprises one or more infrared light source <NUM> configured to provide infrared radiation <NUM> to the target site <NUM>, and a power source <NUM> for powering the one or more infrared lamps. The infrared light source <NUM> may emit infrared light of any frequency, and in particular frequencies above <NUM>. The penetration depth of the infrared radiation is typically <NUM> or less, so this apparatus may be suitable for target sites <NUM> which is located superficially in the body <NUM>.

Again, the power output of the power source <NUM> as well as the duration of application of the radiation may be selected in order to arrive a predetermined amount of heating at the target site <NUM>. This may be determined by prior empirical measurement or the apparatus may additionally include a thermometer component for measuring the temperature of the target site <NUM>, with heat being applied to achieve and maintain a target temperature at the target site <NUM>.

<FIG> shows a schematic of diagram of an electromagnetic emitter <NUM> and a heat source <NUM> according to one or more embodiments. As in the case of <FIG>, the electromagnetic emitter <NUM> may comprise one or more electromagnetic sources <NUM> (such as one or more current or voltage sources) electrically connected to one or more applicators <NUM>. The applicators <NUM> may be configured to be placed on the surface of the patient body <NUM>. The electromagnetic source <NUM> may be configured to provide an alternating electromagnetic field to the applicators <NUM>, which in turn produce a magnetic flux density towards the target site <NUM> to provide the non-ionizing alternating electromagnetic field <NUM> at the target site <NUM>. It will be appreciated that any number of applicators <NUM> may be used depending on the type of target site, and the strength of the resulting magnetic flux density at the target site <NUM> can be readily calculated from the setup by superposition the electromagnetic fields emitted by each applicator <NUM>.

The heat source comprises a laser source <NUM> and a power source <NUM> configured to power the laser source. The laser source <NUM> may be configured to emit laser radiation to the target site <NUM> to cause heating at the target site. The laser radiation may be optically guided, by an optical fiber, directly to the target site to cause local ablation of the target site <NUM>. The laser source <NUM> may be configured to emit laser radiation having a wavelength of between <NUM> and <NUM> at any suitable intensity for causing the required heating at the target site <NUM>. The laser source <NUM> may be configured to operate at between <NUM> W and <NUM> W power (for example <NUM> at <NUM> W or <NUM> at <NUM> W). The laser source <NUM> may be moved rotationally and linearly to target multiple regions in one or more target sites <NUM>.

The power output of the power source <NUM> as well as the duration of application of the laser radiation may be selected in order to arrive a predetermined amount of heating at the target site <NUM>. This may be determined by prior empirical measurement or the apparatus may additionally include a thermometer component for measuring the temperature of the target site <NUM>, with heat being applied to achieve and maintain a target temperature at the target site <NUM>. For example, the apparatus may include an MRI machine to perform magnetic resonance thermometry to monitor the temperature of the target site <NUM> during the heating process.

<FIG> shows a schematic of diagram of an electromagnetic emitter <NUM> and a heat source <NUM> for heating the target site <NUM> according to one or more embodiments. As in the case of <FIG>, the electromagnetic emitter <NUM> may comprise one or more electromagnetic sources <NUM> (such as one or more current or voltage sources) electrically connected to one or more applicators <NUM>. The applicators <NUM> may be configured to be placed on the surface of the patient body <NUM>. The electromagnetic source <NUM> may be configured to provide an alternating electromagnetic field to the applicators <NUM>, which in turn produce a magnetic flux density towards the target site <NUM> to form the non-ionizing alternating electromagnetic field <NUM> at the target site <NUM>. It will be appreciated that any number of applicators <NUM> may be used depending on the type of target site, and the strength of the resulting magnetic flux density at the target site <NUM> can be readily calculated from the setup by superposition of the electromagnetic fields emitted by each applicator <NUM>.

The heat source <NUM> comprises a heater <NUM>, a pump <NUM>, a fluidic output <NUM> and a fluidic input <NUM>. The fluidic output <NUM> is configured to fluidically connect to a part the body <NUM> which is upstream from the target site <NUM>, and the fluidic input <NUM> is configured to fluidically connect to a part of the body <NUM> which is downstream from the target site <NUM>. When connected, a fluidic loop is created from the target site <NUM> to the pump <NUM> and back to the target site <NUM> again. The fluidic loop may be configured to be created in any fluidic system of the body <NUM> (e.g. vascular, renal or similar). The heater <NUM> is configured to heat the fluid to a desired temperature as it passes through the heat source <NUM>, which is then delivered to the target site <NUM> via fluidic output <NUM>. Accordingly, the fluidic loop provides a continuous source of heated fluid to the target site <NUM>. It is noted that the fluid may be the patient's blood or additionally the heat source <NUM> may comprise a reservoir of fluid (not shown) which is configured to be heated and added to the fluidic loop. For example, the fluid may comprise a chemotherapeutic composition, anti-cancer drug or similar or may comprise a biocompatible solution such as saline solution or similar.

The heater <NUM> may be any suitable heater, such as a resistive heater, or an electromagnetic heater configured to heat the fluid by the emission of, for example, microwave radiation. The heater <NUM> may be situated externally to the body <NUM> or may be configured to be implanted in the body <NUM>.

The amount of heat provided by the heat source <NUM> as well as the duration of application of the heat source <NUM> may be selected in order to arrive a predetermined amount of heating at the target site <NUM>. This may be determined by prior empirical measurement or the apparatus may additionally include a thermometer component for measuring the temperature of the target site <NUM>, with heat being applied to achieve and maintain a target temperature at the target site <NUM>.

<FIG> shows a schematic of diagram of an electromagnetic emitter <NUM> and a heat source <NUM> for heating the target site <NUM> according to one or more embodiments. As in the case of <FIG>, the electromagnetic emitter <NUM> may comprise one or more electromagnetic sources <NUM> (such as one or more current or voltage sources) electrically connected to one or more applicators <NUM>. The applicators <NUM> may be configured to be placed on the surface of the patient body <NUM>. The electromagnetic source <NUM> may be configured to provide an alternating electromagnetic field to the applicators <NUM>, which in turn produce a magnetic flux density towards the target site <NUM> to provide the non-ionizing alternating electromagnetic field <NUM> at the target site <NUM>. It will be appreciated that any number of applicators <NUM> may be used depending on the type of target site, and the strength of the resulting magnetic flux density at the target site <NUM> can be readily calculated from the setup by superposition of the electromagnetic fields emitted by each applicator <NUM>.

The heat source <NUM> comprises a heater <NUM>, a reservoir <NUM>, a pump <NUM> and a fluidic output <NUM>. The fluidic output <NUM> is configured to be fluidically connected to the target site <NUM>. In use, the pump <NUM> is configured to pump fluid in the reservoir <NUM> to the target site <NUM> via fluidic output <NUM>. The heater <NUM> is configured to heat the fluid in the reservoir <NUM> to a desired temperature before the fluid is pumped to the target site <NUM>. The fluid may comprise a chemotherapeutic composition, anti-cancer drug or similar or may comprise a biocompatible solution such as saline solution or similar.

The amount of heat provided by the heat source <NUM>, the amount of fluid provided from the reservoir <NUM> and the duration of application of the heat source <NUM> may be selected in order to arrive a predetermined amount of heating at the target site <NUM>. This may be determined by prior empirical measurement or the apparatus may additionally include a thermometer component for measuring the temperature of the target site <NUM>, with heat being applied to achieve and maintain a target temperature at the target site <NUM>.

Heat source <NUM> comprises a heat emitter <NUM> configured to provide conductive heating to the target site <NUM>. The heat source may comprise a power source <NUM> to power the heat emitter <NUM> (such as an electrical power source), or the heat emitter <NUM> may be pre-heated or chemically self-heating (e.g. by exothermic chemical reaction). The heat emitter <NUM> may be provided on the surface of the body <NUM>, or may be configured to be implanted inside the body to provide heat to the target site <NUM> at a location proximal to the target site. For example, the heat emitter <NUM> may be an implantable resistive heater configured to be powered by an electrical power source <NUM>. The heat emitter <NUM> may be configured to heat a local region of the body <NUM> or it may be configured to heat the entire body <NUM>.

The amount of heat provided by the heat source <NUM>, and the duration of application of the heat source <NUM> may be selected in order to arrive a predetermined amount of heating at the target site <NUM>. This may be determined by prior empirical measurement or the apparatus may additionally include a thermometer component for measuring the temperature of the target site <NUM>, with heat being applied to achieve and maintain a target temperature at the target site <NUM>.

<FIG> shows a schematic of an apparatus <NUM> for treating a cancerous target site according to one or more embodiments. As in the case of <FIG>, the apparatus comprises an electromagnetic emitter <NUM> and a heat source <NUM>. The electromagnetic emitter <NUM> is configured to provide a magnetic flux density at the target site. The heat source <NUM> is configured to provide direct heating at the target site to cause hyperthermia at the target site by any of the above mechanisms disclosed herein. In one configuration, the apparatus <NUM> is configured to provide the non-ionizing alternating electromagnetic field and the direct heating at the target site simultaneously. The electromagnetic emitter <NUM> and the heat source <NUM> may take any suitable configuration and may take the configurations shown in <FIG>.

The apparatus <NUM> shown in <FIG> further comprises a controller <NUM> for controlling the emitter <NUM> and heat source <NUM>. The controller comprises a first control interface <NUM> for controlling the operation of the electromagnetic emitter <NUM> and a second control interface <NUM> for controlling the operation of the heat source <NUM>. The controller <NUM> is configured to provide control signals to the emitter <NUM> and heat source <NUM> via the control interfaces <NUM> and <NUM>. The emitter <NUM> and heat source <NUM> may receive the control signals by any suitable form of communication, either wired or wireless, such as optic, fiber-optic, ethernet or similar, or any suitable wireless communication. The controller <NUM> may further be configured to power one or more of the emitter <NUM> and heat source <NUM>, or one or more of the emitter <NUM> and heat source <NUM> may be powered independently of controller <NUM>.

The controller <NUM> further comprises one or more of a user interface <NUM>, memory <NUM> and processor <NUM>. The user interface <NUM> allows a user to control operation of the emitter <NUM> and heat source <NUM> manually, for example by controlling the operating parameters of the emitter <NUM> and heat source <NUM>, and switching on or off their operation. The user interface <NUM> may allow the user to select a sequence of operation of the emitter <NUM> and heat source <NUM> over a time period. The memory <NUM> may contain instructions, which when executed using the processor <NUM>, cause the emitter <NUM> and heat source <NUM> to be operated according to any suitable sequence including the sequences of operation disclosed herein.

The memory <NUM> may comprise one or more volatile or non-volatile memory devices, such as DRAM, SRAM, flash memory, read-only memory, ferroelectric RAM, hard disk drives, floppy disks, magnetic tape, optical discs, or similar. Likewise, the processor <NUM> may comprise one or more processing units, such as a microprocessor, GPU, CPU, multi-core processor or similar. The controller <NUM> may further be implemented in software, hardware, or any combination in order to execute the sequences of operation disclosed herein.

<FIG> shows a schematic of a method for treating a cancerous target site using an apparatus according to the disclosure. The apparatus may take any configuration disclosed herein. Before the method of <FIG> is implemented, the emitter <NUM> and heat source <NUM> may be suitably positioned on the patient. For example, the applicators of the electromagnetic emitter <NUM> may be placed at predetermined points on the patient's body and the heat source <NUM> (for example the transducer <NUM>) may also be suitably positioned.

In step S1, the non-ionizing alternating electromagnetic field is provided to give a magnetic flux density at the target site using electromagnetic emitter <NUM>.

The term "anti-carcinogenic composition", as used herein, refers to a composition that comprises an agent that at least partially inhibits the development or progression of a cancer, including inhibiting in whole or in part symptoms associated with the cancer. The term "cancer", a used herein, refers to a disease characterized by uncontrolled cell division (or by an increase of survival or apoptosis resistance) and by the ability of said cells to invade other neighbouring tissues (invasion) and spread to other areas of the body where the cells are not normally located (metastasis) through the lymphatic and blood vessels, circulate through the bloodstream, and then invade normal tissues elsewhere in the body. Depending on whether or not they can spread by invasion and metastasis, tumours are classified as being either benign or malignant: benign tumours are tumours that cannot spread by invasion or metastasis, i.e., they only grow locally; whereas malignant tumours are tumours that are capable of spreading by invasion and metastasis. The anti-carcinogenic composition may comprise one or more anti-carcinogenic compositions, including one or more of those disclosed in relation to <FIG>.

As used herein, the term cancer, is preferably directed to solid tumours and/or infiltrating tumours.

As used herein, a "solid tumour" is understood as an abnormal mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumours are named for the type of cells that form them. Examples of solid tumours are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumours.

As used herein, an "infiltrating tumour" is understood as tumours that have abnormal structures of tumours that show, at the same time, clear growing nodules and infiltrating growth.

Preferably the invention is directed to cancers including, but not limited to, the following types: breast cancer; biliary tract cancer; bladder cancer; brain cancer including glioblastomas, in particular glioblastoma multiforme, and medulloblastomas; cervical cancer; head and neck carcinoma; choriocarcinoma; colon cancer, colorectal cancer; endometrial cancer; esophageal cancer; gastric cancer; intraepithelial neoplasms including Bowen's disease and Paget's disease; liver cancer, hepatoma; lung cancer, pleural mesothelioma; oral cancer including squamous cell carcinoma; parotid gland cancer; ovarian cancer including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells; pancreatic cancer; prostate cancer; kidney cancer, suprarenal cancer; rectal cancer; sarcomas including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma; skin cancer including melanoma, Merkel cell carcinoma, Kaposi's sarcoma, basal cell carcinoma, and squamous cell cancer; cervix cancer, endometrial cancer; testicular cancer including germinal tumors such as seminoma, non-seminoma (teratomas, choriocarcinomas), stromal tumors, and germ cell tumors; thyroid cancer including thyroid adenocarcinoma and medullar carcinoma; and renal cancer including adenocarcinoma and Wilms tumor.

In a particular embodiment, the cancer is melanoma. The term "melanoma", as used herein, refers to a malignant skin tumour of melanocytes and includes, but is not limited to, melanomas, metastatic melanomas, melanomas derived from either melanocytes or melanocyte related nevus cells, melanocarcinomas, melanoepitheliomas, melanosarcomas, melanoma in situ, superficial spreading melanoma, modular melanoma, lentigo malignant melanoma, acral lentiginous melanoma, invasive melanoma and familial atypical mole and melanoma (FAM-M) syndrome. Moreover, the term "melanoma" refers not only to primary melanomas but also to "melanoma metastasis" which, as used herein, refers to the spread of melanoma cells to regional lymph nodes and/or distant organs. This event is frequent, given that melanomas contain multiple cell populations characterized by diverse growth rates, karyotypes, cell-surface properties, antigenicity, immunogenicity, invasion, metastasis, and sensitivity to cytotoxic drugs or biologic agents. Melanoma shows frequent metastasis to brain, lungs, lymph nodes, and skin. Other cancers will-be known to one of ordinary skill in the art.

<FIG> shows experimental data showing the in vitro effect of TT-Fields ("TTF"), hyperthermia ("HT"), pterostilbene ("PT") and their combinations on U87MG cells. The TT-Field applied was at <NUM> for <NUM> mins (from minute <NUM> to minute <NUM>) for an average magnetic flux density of 8µT. The hyperthermia applied was <NUM> for <NUM> minutes (from minute <NUM> to minute <NUM>). <NUM> of pterostilbene was applied for <NUM> minutes (from minute <NUM> to minute <NUM>). The data shows mean number of viable cells for <NUM> experiments, with P<<NUM> using Student's t test vs the control for those labelled *, vs TTF for those labelled + and vs TTF+ HT for those labelled #. The magnetic field was applied using a solenoid with approximately <NUM>µT magnetic flux density at the central axis of the solenoid. The solenoid was placed at a distance from the cell cultures such that the average field strength on the surface of the culture flasks where the cells were attached was 8µT.

It is noted that, as already indicated previously, and as it can be seen in <FIG>, it has been found hyperthermia potentiates the anti-cancer effect of the non-ionizing alternating electromagnetic field (TT-Field). In particular, the combination permits a much lower temperature (<NUM> or less) for the hyperthermia whilst still reducing cell viability. This also means that a larger volume of tissue heated by the hyperthermia can be targeted. Accordingly, the apparatuses disclosed herein provides an effective method of treating cancerous sites by applying a TT-Field and direct heating of the cancerous site (i.e. not via a mediator). Further, as shown in <FIG> the combination of a TT-Field, hyperthermia and pterostilbene effectively eliminates all cells in vitro. The combined therapy is not expected to have any substantial side effects in vivo as the amount of pterostilbene use is well-tolerated in vivo.

<FIG> shows in vitro experimental data for the effect on cell viability for U87MG (ATCC) cells when exposed to various oscillating magnetic fields. Different cell cultures were exposed to one of the following magnetic fields: <NUM>µT at a frequency of <NUM>; <NUM>µT at a frequency of <NUM>; <NUM>µT at a frequency of <NUM>; or <NUM>µT at a frequency of <NUM>. Cell viability for each frequency after <NUM>, <NUM>, <NUM>, <NUM> and <NUM> hours was measured. Five independent experiments were performed for each frequency and time point. The data for each frequency shows the average cell viability and standard deviation over time (<NUM> to <NUM> hours from left to right) for the <NUM> corresponding experiments. A two-ways analysis of variance (ANOVA) was used to make comparisons among the different groups. It can be seen that cell viability is reduced for all frequencies, and the effect is further increased for frequencies equal to or below <NUM>. Letters "a" to "f" are assigned to the data based on statistical tests applied to the data. Data labelled with the same letter are considered statistically similar, whereas data assigned different letters are considered significantly different with P less than <NUM>.

<FIG> shows in vitro experimental data for the effect on cell viability for U87MG cells when exposed to heat. Different cell cultures were heated to temperatures of <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM>. Five independent experiments were performed for each temperature and time point. The data for each temperature shows the average cell viability and standard deviation of the five corresponding experiments after <NUM> and <NUM> minutes of exposure to the temperature. Hyperthermia equivalent to a very high fever (<NUM> or above) reduced the viability of U87MG cells significantly. The data labelled * indicates a P value (student's t test) less than <NUM> compared to the <NUM> data at the corresponding time, and the data labelled + indicates a P value less than <NUM> for the data at <NUM> minutes compared to the data at <NUM> mins for the same temperature.

<FIG> show microscopic images of in vitro U87MG cell cultures after exposed to different external treatments. <FIG> shows a microscopic image of a control vitro U87MG cell culture which was not exposed to any external treatments and maintained at the physiological internal temperature of <NUM>. <FIG> shows a cell culture after being exposed to an electromagnetic field having a magnetic flux density of about <NUM>µT at <NUM> from <NUM> to <NUM> minutes. <FIG> shows a cell culture after being exposed to heating to <NUM> for <NUM> minutes from minute <NUM> to <NUM>. <FIG> shows a cell culture after being exposed to <NUM> pterostilbene from minute <NUM> to minute <NUM>. <FIG> shows a cell culture after exposure to an electromagnetic field having a magnetic flux density of about <NUM>µT at <NUM> from <NUM> to <NUM> minutes and <NUM> pterostilbene from minute <NUM> to minute <NUM>. <FIG> shows a cell culture after exposure to an electromagnetic field having a magnetic flux density of about <NUM>µT at <NUM> from <NUM> to <NUM> minutes, heating to <NUM> for <NUM> minutes from minute <NUM> to <NUM> and <NUM> pterostilbene (PT) from minute <NUM> to minute <NUM>. It is noted that the combination of TTF+HT+PT completely eliminates all U87MG growing cells. This therapy shows the same effectiveness in other glioblastoma lines such as C6 and GL261.

<FIG> shows in vitro experimental data for the effect on cell viability for U87MG cells when exposed to an electromagnetic field having a magnetic flux density of about <NUM>µT at <NUM> for about <NUM> minutes (data labelled "TTF"), a temperature of <NUM> for about <NUM> minutes (data labelled HT), <NUM> Temozolomide (data labelled "TMZ"), and combinations thereof. The data show mean values for five independent experiments. Data labelled * indicates a P value (student's t test) less than <NUM> compared to control. Data labelled + indicates a P value (student's t test) less than <NUM> compared to the TTF-only data. Data labelled # indicates a P value (student's t test) less than <NUM> compared to the TTF+HT data.

<FIG> shows in vitro experimental data for the effect on cell viability for U87MG cells when exposed to an electromagnetic field having a magnetic flux density of about <NUM>µT at <NUM> for about <NUM> minutes (data labelled "TTF"), a temperature of <NUM> for about <NUM> minutes (data labelled HT) at minute <NUM> to <NUM>, <NUM> resveratrol at minute <NUM> to <NUM> (data labelled "R"), <NUM> resveratrol triphosphate at minute <NUM> to <NUM>, (data labelled "R-triP"), <NUM> <NUM>' butyrate-<NUM>,<NUM>-dihydroxystilbene at minute <NUM> to <NUM>, (data labelled "B-diOH-s"), <NUM> <NUM>-glucoside-<NUM>,<NUM>'-dihydroxystilbene at minute <NUM> to <NUM>, (data labelled "G-diOH-s"), <NUM> <NUM>-amide-<NUM>,<NUM>'-dihydroxystilbene at minute <NUM> to <NUM>, (data labelled "A-diOH-s"), and combinations thereof. The data are means with standard deviation for four independent experiments. Data labelled * indicates a P value (student's t test) less than <NUM> compared to the control. Data labelled + indicates a P value (student's t test) less than <NUM> compared to the TTF-only data. Data labelled # indicates a P value (student's t test) less than <NUM> compared to the TTF+HT data. It is observed that resveratrol and its derivatives do not eliminate all U87MG cell growing in vitro, although it is observed that a significant reduction in cell viability occurs for TTF + HT + G-diOH-s.

The effectiveness of therapy by heating in combination with tumour treating fields and exposure to PT is also observed in other cell lines in vitro, such as A2058 (melanoma), AsPC-<NUM> (pancreas carcinoma), A549 (lung carcinoma), MCF-<NUM> (mammary gland carcinoma), HT-<NUM> (colorectal carcinoma), PC-<NUM> (prostate carcinoma), SK-OV-<NUM> (ovarian carcinoma and HepG2 (hepatocarcinoma).

<FIG> shows the shows in vitro experimental data for the effect on cell viability for AsPC1 (pancreatic adenocarcinoma, ATCC) cells when exposed to various oscillating magnetic fields. Different cell cultures were exposed to one of the following magnetic fields: <NUM>µT at <NUM>; <NUM>µT at <NUM>; <NUM>µT at <NUM>; or <NUM>µT at <NUM>, Cell viability for each frequency after <NUM>, <NUM>, <NUM>, <NUM> and <NUM> hours was measured for each cell culture. Five independent experiments were performed for each frequency and time point. The data for each frequency shows the average cell viability and standard deviation over time (<NUM> to <NUM> hours from left to right) for the <NUM> corresponding experiments. A two-ways analysis of variance (ANOVA) was used to make comparisons among the different groups. It can be seen that cell viability is reduced for frequencies equal to or below <NUM>. Letters "a" and "b" are assigned to the data based on statistical tests applied to the data. Data labelled with the same letter are considered statistically similar, whereas data assigned different letters are considered significantly different with P less than <NUM>.

<FIG> shows in vitro experimental data for the effect on cell viability for AsPC1 cells when exposed to heat. Different cell cultures were heated to temperatures of <NUM>, <NUM>, <NUM> or <NUM>. Five independent experiments were performed for each temperature and time point. The data for each temperature shows the average cell viability and standard deviation of the five corresponding experiments after <NUM>, <NUM> and <NUM> minutes of exposure to the temperature. Heating to <NUM> or above reduced the viability of AsPC1 cells significantly. The data labelled * indicates a P value (student's t test) less than <NUM> compared to the <NUM> data at the corresponding time, and the data labelled + indicates a P value less than <NUM> for the data at <NUM> and <NUM> minutes compared to the data at <NUM> mins for the same temperature.

<FIG> shows experimental data showing the in vitro effect of TT-Fields ("TTF"), hyperthermia ("HT"), pterostilbene ("PT") and their combinations on AsPC1 cells. For TTF data the TT-Field applied was at <NUM> for <NUM> mins (from minute <NUM> to minute <NUM>) for a field intensity of <NUM>µT. For HT data the hyperthermia applied was <NUM> for <NUM> minutes (from minute <NUM> to minute <NUM>). For PT data <NUM> of pterostilbene was applied from minute <NUM> to minute <NUM>. The data shows mean number of viable cells for <NUM> experiments, with P<<NUM> using Student's t test vs the control for those labelled *, vs TTF for those labelled + and vs TTF+ HT for those labelled #.

<FIG> show microscopic images of in vitro AsPC1 cell cultures after exposed to different external treatments. <FIG> shows a microscopic image of a control vitro AsPC1 cell culture which was not exposed to any external treatments and maintained at an optimum temperature for AsPC1. <FIG> shows a cell culture after being exposed to an electromagnetic field having a magnetic flux density of about <NUM>µT at <NUM> from <NUM> to <NUM> minutes. <FIG> shows a cell culture after being exposed to heating to <NUM> for <NUM> minutes from minute <NUM> to <NUM>. <FIG> shows a cell culture after being exposed to <NUM> pterostilbene from minute <NUM> to minute <NUM>. <FIG> shows a cell culture after exposure to an electromagnetic field having a magnetic flux density of about <NUM>µT at <NUM> from <NUM> to <NUM> minutes and heating to <NUM> for <NUM> minutes from minute <NUM> to <NUM>. <FIG> shows a cell culture after exposure to an electromagnetic field having a magnetic flux density of about <NUM>µT at <NUM> from <NUM> to <NUM> minutes and <NUM> pterostilbene (PT) from minute <NUM> to minute <NUM>. <FIG> shows a cell culture after exposure to an electromagnetic field having a magnetic flux density of about <NUM>µT at <NUM> from <NUM> to <NUM> minutes, heating to <NUM> for <NUM> minutes from minute <NUM> to <NUM> and <NUM> pterostilbene (PT) from minute <NUM> to minute <NUM>. <FIG> shows the cell culture of <FIG> after <NUM> hours where cultured cells were maintained at <NUM> without any treatment. The growing cells do not seem to recover <NUM> hours after the combined treatment of <FIG>.

<FIG> shows experimental data showing the in vitro effect of TT-Fields ("TTF"), hyperthermia ("HT"), gemcitabine ("GEM"), pterostilbene ("PT") and their combinations on AsPC1 cells. For TTF data, the TT-Field applied was at <NUM> for <NUM> mins (from minute <NUM> to minute <NUM>) for a field intensity of <NUM>µT. For HT data the hyperthermia applied was <NUM> for <NUM> minutes (from minute <NUM> to minute <NUM>). For GEM data <NUM> of gemcitabine was applied from minute <NUM> to minute <NUM>. For PT data <NUM> of pterostilbene was applied from minute <NUM> to minute <NUM>. The data shows mean number of viable cells for <NUM> experiments per experimental condition, with P<<NUM> using Student's t test vs the control for those labelled *, vs TTF for those labelled + and vs TTF+HT for those labelled #. The application of all four treatments in combination eliminated the AsPC1 cells.

<FIG> shows the shows in vitro experimental data for the effect on cell viability for A2058 (melanoma, ATCC) cells when exposed to different oscillating magnetic fields Different cell cultures were exposed to one of the following magnetic fields: <NUM>µT at a frequency of <NUM>; <NUM>µT at a frequency of <NUM>; <NUM>µT at a frequency of <NUM>; or <NUM>µT at a frequency of <NUM>. Cell viability for each frequency after <NUM>, <NUM>, <NUM>, <NUM> and <NUM> hours was measured for each cell culture. Five independent experiments were performed for each frequency and time point. The data for each frequency shows the average cell viability and standard deviation over time (<NUM> to <NUM> hours from left to right) for the <NUM> corresponding experiments. A two-ways analysis of variance (ANOVA) was used to make comparisons among the different groups. It can be seen that cell viability is reduced for all frequencies, below <NUM>. Letters "a" and "b" are assigned to the data based on statistical tests applied to the data. Data labelled with the same letter are considered statistically similar, whereas data assigned different letters are considered significantly different with P less than <NUM>.

<FIG> shows in vitro experimental data for the effect on cell viability for A2058 cells when exposed to heat. Different cell cultures were heated to temperatures of <NUM>, <NUM>, <NUM> or <NUM>. Five independent experiments were performed for each temperature and time point. The data for each temperature shows the average cell viability and standard deviation of the five corresponding experiments after <NUM>, <NUM> and <NUM> minutes of exposure to the temperature. Heating to <NUM> reduced the viability of A2058 cells significantly. The data labelled * indicates a P value (student's t test) less than <NUM> compared to the <NUM> data at the corresponding time, and the data labelled + indicates a P value less than <NUM> for the data at <NUM> and <NUM> minutes compared to the data at <NUM> mins for the same temperature.

<FIG> shows experimental data showing the in vitro effect of TT-Fields ("TTF"), hyperthermia ("HT"), pterostilbene ("PT") and their combinations on A2058 cells. For TTF data, the TT-Field applied was at <NUM> for <NUM> mins (from minute <NUM> to minute <NUM>) for a field intensity of <NUM>µT. For HT data the hyperthermia applied was <NUM> for <NUM> minutes (from minute <NUM> to minute <NUM>). For PT data <NUM> of pterostilbene was applied from minute <NUM> to minute <NUM>. The data shows mean number of viable cells for <NUM> experiments per experimental condition, with P<<NUM> using Student's t test vs the control for those labelled *, vs TTF for those labelled + and vs TTF+HT for those labelled #. The application of all four treatments significantly reduced the viability of the cells compared to TTF+HT.

Comparing the data of <FIG>, <FIG> and <FIG>, the data show that the use of a higher magnetic flux density (about <NUM>µT or above) allows for heating of the tissue to a lower temperature whilst still maintaining or even improving the effectiveness of the treatment. The combination of such a higher magnetic flux density in combination with heating to temperatures above <NUM> and administration of pterostilbene may be sufficient to eliminate the tumour. This is of special importance to areas of the body to which only limited heating can be applied (for example the brain). The data of, for example, <FIG>, show that even if a lower magnetic field is used, the cancer cells may be reduced or even eliminated if the tumour treating field and heating is used in combination with one or more of pterostilbene and another anti-cancer drug.

<FIG> show microscopic images of in vitro A2058 cell cultures after exposed to different external treatments. <FIG> shows a microscopic image of a control in vitro AsPC1 cell culture which was not exposed to any external treatments and maintained at the physiological internal temperature of <NUM>. <FIG> shows a cell culture after being exposed to an electromagnetic field having a magnetic flux density of about <NUM>µT at <NUM> from <NUM> to <NUM> minutes. <FIG> shows a cell culture after being exposed to heating to <NUM> for <NUM> minutes from minute <NUM> to <NUM>. <FIG> shows a cell culture after being exposed to <NUM> pterostilbene from minute <NUM> to minute <NUM>. <FIG> shows a cell culture after exposure to an electromagnetic field having a magnetic flux density of about <NUM>µT at <NUM> from <NUM> to <NUM> minutes and <NUM> pterostilbene from minute <NUM> to minute <NUM>. <FIG> shows a cell culture after exposure to an electromagnetic field having a magnetic flux density of about <NUM>µT at <NUM> from <NUM> to <NUM> minutes and heating to <NUM> for <NUM> minutes from minute <NUM> to <NUM>. <FIG> shows a cell culture after exposure to an electromagnetic field having a magnetic flux density of about <NUM>µT at <NUM> from <NUM> to <NUM> minutes, heating to <NUM> for <NUM> minutes from minute <NUM> to <NUM> and <NUM> pterostilbene (PT) from minute <NUM> to minute <NUM>. <FIG> shows the cell culture of <FIG> after <NUM> hours where cultured cells were maintained at <NUM> without any treatment. The growing cells do not seem to recover <NUM> hours after the combined treatment of <FIG>.

<FIG> shows experimental data showing the in vitro effect of TT-Fields ("TTF"), hyperthermia ("HT"), paclitaxel ("PAC") and their combinations on A2058 cells. For TTF data, the TT-Field applied was at <NUM> for <NUM> mins (from minute <NUM> to minute <NUM>) for a field intensity of <NUM>µT. For HT data the hyperthermia applied was <NUM> for <NUM> minutes (from minute <NUM> to minute <NUM>). For PAC data <NUM> of paclitaxel was applied from minute <NUM> to minute <NUM>. The data shows mean number of viable cells for <NUM> experiments per experimental condition, with P<<NUM> using Student's t test vs the control for those labelled *, vs TTF for those labelled + and vs TTF+HT for those labelled #. The application of all three treatments eliminated the cells.

Table <NUM> shows data examining the effect of GSH depletion on cell viability for U87MG, AsPC1 and A2058 cells in vitro. For rows including "TTF", a TT-Field was applied at <NUM> for <NUM> mins (from minute <NUM> to minute <NUM>) for a field intensity of <NUM>µT. For rows including "HT", hyperthermia applied was at <NUM> for U87MG and <NUM> for AsPC1 and A2058 for <NUM> minutes (from minute <NUM> to minute <NUM>). For rows including "BSO", <NUM> of buthione sulfoximine, a specific inhibitor of GSH synthesis, was added to the cell culture medium at the time the cells of the culture were seeded. When HT and TTF were applied in combination with BSO, the HT and TTF were applied <NUM> hours after seeding. The data show the means and standard deviations for five independent experiments. Data labelled * has a P-value (student's t test) of less than <NUM> compared with the control data. The data labelled + has a P-value (student's t test) of less than <NUM> compared with the TTF+HT data. The data therefor indicate that GSH depletion potentiates the anticancer effect of the electromagnetic radiation and heat.

Accordingly, the use of the apparatuses disclosed herein in combination with the application of pterostilbene provides a highly effective method of treating a cancerous site, and may even entirely eliminate the cancerous cells altogether. Therefore, in one aspect, said anti-carcinogenic composition comprises (i) pterostilbene, pterostilbene phosphate or a pharmaceutically acceptable salt thereof. Alternatively, the anti-cancer composition may be provided in a cocrystal, a water-soluble prodrug, nanoparticle, nanodot, nanorob, nanospike, nanorod, nanocluster, nanoceramic, liposome or exosome formulation, or may be provided in an implantable device configured to release the anti-cancer composition when implanted in the body. Please note that said anti-carcinogenic composition may comprise any anti-oxidant composition. In this sense, the anti-carcinogenic composition may comprise any stilbenoid, apart from pterostilbene, suitable as an anti-carcinogenic agent, such as resveratrol.

The term "pterostilbene" or "Pter" or "trans-<NUM>,<NUM>-dimethoxy-<NUM>'-hydroxystilbene" as used herein, refers to a compound of formula
<CHM>.

The term "pterostilbene phosphate" refers to a compound of formula
<CHM>.

The term "pharmaceutically acceptable salt" refers to any salt of pterostilbene or pterostilbene phosphate which, upon administration to the recipient is capable of providing (directly or indirectly) a compound as described herein. Preferably, as used herein, the term "pharmaceutically acceptable salt" means approved by a regulatory agency of the Federal or a state government or listed in the U. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The preparation of salts can be carried out by methods known in the art. Illustrative non-limitative examples of pharmaceutically acceptable salts include, but are not limited to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate salts. The pharmaceutically acceptable salts of pterostilbene or pterostilbene phosphate are preferably prepared from a polyphenol compound having an acidic functional group, and an acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, ortri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(<NUM>-hydroxy substituted lower alkylamines), such as mono-; bis-, or tris-(<NUM>-hydroxyethyl)amine, <NUM>-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyi-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(<NUM>-hydroxyethyl)amine or tri-(<NUM>-hydroxyethyl)amine; N-methyl-<NUM>-glucamine; and amino acids such as arginine, lysine, and the like. The term "pharmaceutically acceptable salt" also includes a hydrate of a polyphenol compound. In a particular embodiment, the pharmaceutically acceptable salt is a disodium salt.

Further illustrative non-limitative examples of cancer chemotherapeutic agents which may be in accordance to the present invention include: alkylating agents such as nitrogen mustards/oxazaphosphorines (e.g. cyclophosphamide, ifosfamide), nitrosoureas (e.g. carmustine), triazenes (e.g.temozolamide), and alkyl sulfonates (e.g. busulfan); antimetabolite drugs (for example <NUM>-fluorouracil, capecitabine, <NUM>-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine or pemetrexed); anthracycline antibiotics such as doxorubicin and daunorubicin, taxans such as Taxol™ and docetaxel, vinca alkaloids such as vincristin and vinblastine, <NUM>-fluorouracil (<NUM>-FU), leucovorin, irinotecan, idarubicin, mitomycin C, oxaliplatin, raltitrexed, pemetrexed, tamoxifen, cisplatin, carboplatin, methotrexate, actinomycin D, mitoxantrone, blenoxane, mithramycin, paclitaxel, <NUM>-methoxyestradiol, prinomastat, batimastat, BAY <NUM>-<NUM>, carboxyamidotriazole, CC-<NUM>, dextromethorphan acetic acid, dimethylxanthenone acetic acid, endostatin, IM-<NUM>, marimastat, penicillamine, PTK787/ZK <NUM>, RPI. <NUM>, squalamine lactate, SU5416, thalidomide, combretastatin, COL-<NUM>, neovastat, BMS-<NUM>, SU6668, anti-VEGF antibodies, Medi-<NUM> (Vitaxin II), CAI, Interleukin <NUM>, IM862, amiloride, angiostatin, angiostatin Kl-<NUM>, angiostatin Kl-<NUM>, captopril, DL-alpha-difluoromethylomithine, DL-alpha-difluoromethylornithine HCl, endostatin, fumagillin, herbimycin A, <NUM>-hydroxyphenylretinamide, juglone, laminin, laminin hexapeptide, laminin pentapeptide, lavendustin A, medroxyprogesterone, minocycline, placental ribonuclease inhibitor, suramin, thrombospondin, antibodies targeted against proangiogenic factors (for example, bevacizumab, cetuximab, panitumumab, trastuzumab); topoisomerase inhibitors; antimicrotubule agents; low molecular weight tyrosine kinases inhibitors of proangiogenic growth factors (for example erlotinib, sorafenib, sunitinib, gefitinib); GTPase inhibitors; histone deacetylase inhibitors; AKT kinase or ATPase inhibitors; Wnt signaling inhibitors; inhibitors of the E2F transcription factor; mTOR inhibitors (for example temsirolimus); alpha, beta and gamma interferon, IL-<NUM>, matrix metalloproteinase inhibitors (for example, COL3, Marimastat, Batimastat); ZD6474, SUl1248, vitaxin; PDGFR inhibitors (for example imatinib); NM3 and <NUM>- ME2; cyclic peptides such as cilengitide. Other chemotherapy agents suitable are described in detail in The Merck Index in CD-ROM, 13rd Edition. In a preferred embodiment of the invention, chemotherapeutic agents are selected from the group consisting of docetaxel (Taxotere®), cisplatin, pemetrexed, gemcitabine and irinotecan.

In a particular embodiment, the cancer chemotherapeutic agent is a taxane, preferably which comprises or consists on paclitaxel. The term "paclitaxel", as used herein, refers to a compound with chemical name (2α,4α,5β,7β,10β,13α)-<NUM>,<NUM>-Bis(acetyloxy)-<NUM>-{[(2R,<NUM>)-<NUM> (benzoylamino)-<NUM>-hydroxy-<NUM>-phenylpropanoyl]oxy}-<NUM>,<NUM>-dihydroxy-<NUM>-oxo-<NUM>,<NUM>-epoxytax-<NUM>-en-<NUM>-yl benzoate and having the chemical formula
<CHM>.

In a more particular embodiment, the paclitaxel is protein bound paclitaxel. The term "protein-bound paclitaxel" or "nab-paclitaxel" or "nanoparticle albumin-bound paclitaxel", as used herein, refers to a formulation in which paclitaxel is bound to albumin as a delivery vehicle.

The cancer chemotherapeutic agent will vary depending on the type of cancer that is going to be treated with the combination of the invention. The skilled person can easily determine which cancer chemotherapeutic agent is more suitable to treat a particular type of cancer.

Also optionally, in step S4, a Glutathione (GSH) depleting agent is provided to the target site in addition to the anti-carcinogenic compound. The GSH depleting agent may be administered by any suitable means, such as orally or intravenously. It is noted that the GSH depleting agent may be provided before or simultaneously to steps S1, S2 and step S3 or a predetermined time after step S1, S2 or S3, preferably at a predetermined time after step S3. The GSH depleting agent provided may be any GSH depleting agent disclosed herein, including in relation to <FIG> or Table <NUM>.

The term "glutathione depleting agent", as used herein, refers to a substance that reduces or eliminates glutathione from a cell that has been contacted with that substance. The skilled person is able of determining if a particular molecule is a glutathione depleting agent, for example, by comparing the effect of the particular molecule with the effect of buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamyl-cysteinyl ligase, using the methodology described for in vitro and in vivo conditions by <NPL>. In a particular embodiment, a particular molecule is a glutathione depleting agent if said molecule has at least a <NUM>%, at least a <NUM>%, at least a <NUM>%, at least a <NUM>%, at least a <NUM>%, at least a <NUM>%, at least a <NUM>%, at least a <NUM>%, at least a <NUM>%, a <NUM>% or more of the glutathione-depleting effect of buthionine sulfoximine. Illustrative non-limitative examples of glutathione depleting agents are:.

In a particular embodiment, the glutathione depleting agent of the combination of the invention is selected from the group consisting of: a) a Bcl-<NUM> antisense oligodeoxynucleotide; b) an inhibitor of multidrug resistance protein <NUM>; c) an inhibitor of the gamma-glutamyl transpeptidase; d) an inhibitor of cystine uptake; e) disodium glutathione disulfide; f) phenethyl isothiocyanate; g) a glucocorticoid receptor antagonist; h) an anti-IL-<NUM> agent; i) buthionine sulfoximine; j) diethylmaleate; k) NPD926; <NUM>) parthenolide; m) piperlongumine and n) an inhibitor of a protein from the bromodomain and extraterminal domain family, in particular GSK525762A or I-BET762.

In a more particular embodiment the inhibitor of multidrug resistance protein <NUM> is verapamil, which is a compound having the formula
<CHM>.

In a more particular embodiment, the inhibitor of gamma-glutamil transpeptidase is acivicin, which is a compound having the formula
<CHM>.

In a more particular embodiment, the inhibitor of cystine uptake is sulfasalazine, which is a compound having the formula
<CHM>.

In a more particular embodiment, the glucocorticoid receptor antagonist is RU-<NUM> or mifepristone, which is a compound having the formula
<CHM>.

In a more particular embodiment, the anti-IL-<NUM> agent is an inhibitory antibody against IL-<NUM> or an inhibitor of the IL-<NUM> receptor. In an even more particular embodiment, the anti-IL-<NUM> agent is selected from the group consisting of tocilizumab, elsilimomab and siltuximab. The term "tocilizumab" refers to a humanized monoclonal antibody against the IL-<NUM> receptor. The term "elsilimomab" refers to a mouse monoclonal antibody against IL-<NUM>. The term "siltuximab" or "CNTO <NUM>" refers to a chimeric monoclonal antibody against IL-<NUM>.

In a more particular embodiment, the inhibitor of a protein from the bromodomain and extraterminal domain family is selected from the group consisting of JQ1, GSK525762A and OTX-<NUM>. The term "JQ1" refers to a compound of formula
<CHM>.

The term "GSK525762A" refers to a compound of formula
<CHM>.

The term "OTX-<NUM>" refers to a compound of formula
<CHM>.

The term "CPI-<NUM>" refers to the compound of reference CAT#: <NUM> markered by MedKoo Biosciencies Inc.

In a particular embodiment, the glutathione depleting agent is diethylmaleate, GSK525762A (I-BET762) or piperlongumine.

It is noted that the order in which the steps are presented in <FIG> does not require any chronological order on steps S1 to S5. For example, steps S3 and/or S4 (depending on whether either or both are implemented in the method) may be implemented at the same time as the start of step S1, or a predetermined time after step S1 begins but before step S2 begins, or at the same time as the start of step S2, or a predetermined amount of time after the start of step S2. Further, in examples where both S3 and S4 are implemented, they may be implemented at the same or different times. For example, independently of when (or whether) step S4 is implemented, step S3 may be implemented at the same time as the start of step S1, or a predetermined time period after the start of step S1 but before the start of step S2, or at the same time as the start of step S2, or a predetermined time after the start of step S2. Meanwhile, independently of when (or whether) step S3 is implemented, step S4 may be implemented at the same time as the start of step S1, or a predetermined time after the start of step S1 but before the start of step S2, or at the same time as the start of step S2 or a predetermined time after the start of step S2. Further, step S1 may be applied for a first time period and step S2 may be applied for a second time period, and the second time period may partially or completely overlap with the first time period or the second time period may begin when the first time period expires.

For example, the non-ionizing alternating electromagnetic field (e.g. at <NUM>) may be provided at the same time as the anti-cancer composition and the GSH depletor (for example pterostilbene and gemcitabine). The alternating electromagnetic field is applied for two hours, and heating is applied within this two-hour period (for example to heat the target site to a temperature of <NUM> for <NUM> minutes). In another example, non-ionizing alternating electromagnetic field may be provided first (e.g. at <NUM>) for a first time period (e.g. <NUM> hours), and upon expiry of the first time period heating is applied in combination with the anti-cancer composition and/or the GSH depletor (for example pterostilbene with heating to <NUM> for two hours).

In the method, the non-ionizing alternating electromagnetic field may have a frequency of between <NUM> to <NUM>, providing a magnetic flux density between <NUM> pT and <NUM> mT, or between <NUM> pT and <NUM>µT, or between <NUM>µT and <NUM> mT, and/or the corresponding electric field strength amplitude of between <NUM> V/cm and <NUM> V/cm depending on the tissue impedance and may be applied for a time period of between <NUM> minute and <NUM> hours.

The direct heating preferably heats the target site to a temperature of at least <NUM>, and preferably between <NUM> and <NUM>.

The mechanism by which the oscillating magnetic field of the tumour treating field may cause heating of the tissue is through inducing Foucault currents (or "eddy currents") in the tissue. These currents revolve around the magnetic field lines in the tissue and by the Joule effect could heat the tumour cells. This is due to the conductivity, σ, of the living tissue. The conductivity of tumour tissue increases with increasing frequency of the oscillating magnetic field and is approximately <NUM> siemens/metre at <NUM>. This conductivity provides the path for microscopic eddy currents which flow in circular paths. The power per unit mass, P, that heats these cells is given by the following equation: <MAT>.

Where B is the magnetic flux density, d is the depth of tissue over which the magnetic field is provided, f is the field frequency, ρ is the tissue resistivity (inverse to the electrical conductivity) and D is the mass density of the tissue.

The conductivity of tumour tissue can be up to five times higher than the conductivity of healthy tissue and has an approximate value of <NUM> siemens/metre at <NUM>-<NUM>. D for biological tissue is variable (between <NUM>-<NUM>/m<NUM>), but can be approximated by that of water, <NUM>/m<NUM>. The highest magnetic flux density of the tumour treating field is 1mT. The highest frequency is <NUM>. In the in vitro experiments, the thickness of the culture flask was approximately <NUM> which is the value of d. This gives a value for P of <NUM> pW/kg. This is an extremely low value. The mechanism of the TT-field is therefore not due to heating. Cell death may be the consequence of charge disruption in the mitochondria. This effect is stronger in tumour tissues due to its higher conductivity, approximately five times higher than the conductivity of healthy cells. The synergetic effect with hyperthermia could be attributable to an increase of the conductivity associated with an increase in the mobility of the charged molecules.

Claim 1:
An apparatus for treating a cancerous target site, comprising:
an electromagnetic emitter (<NUM>, <NUM>) comprising one or more electrodes with an electrically insulating coating for preventing electrical contact between the electrodes and the target site, the electromagnetic emitter configured to provide a tumour treating field at a target site via the one or more electrodes, the tumour treating field being a non-ionizing alternating electromagnetic field having a frequency of between <NUM> to <NUM>; and further having a magnetic flux density of between <NUM> pT and <NUM> mT;
a heat source (<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>) configured to provide heating at the target site to cause hyperthermia at the target site; and
an electronic controller (<NUM>) for electronically controlling the electromagnetic emitter and the heat source;
wherein the apparatus is configured to apply the non-ionizing alternating electromagnetic field and the heating independently.